Atlas of Diseases of The Kidney

Diseases of Water
Metabolism
Sumit Kumar
Tomas Berl
he maintenance of the tonicity of body fluids within a very narrow physiologic range is made possible by homeostatic mechanisms that control the intake and excretion of water. Critical to
this process are the osmoreceptors in the hypothalamus that control
the secretion of antidiuretic hormone (ADH) in response to changes in
tonicity. In turn, ADH governs the excretion of water by its end-organ
effect on the various segments of the renal collecting system. The
unique anatomic and physiologic arrangement of the nephrons brings
about either urinary concentration or dilution, depending on prevailing physiologic needs. In the first section of this chapter, the physiology of urine formation and water balance is described.
The kidney plays a pivotal role in the maintenance of normal water
homeostasis, as it conserves water in states of water deprivation, and
excretes water in states of water excess. When water homeostasis is
deranged, alterations in serum sodium ensue. Disorders of urine dilution cause hyponatremia. The pathogenesis, causes, and management
strategies are described in the second part of this chapter.
When any of the components of the urinary concentration mechanism is disrupted, hypernatremia may ensue, which is universally
characterized by a hyperosmolar state. In the third section of this
chapter, the pathogenesis, causes, and clinical settings for hypernatremia and management strategies are described.
CHAPTER
1.2
Disorders of Water, Electrolytes, and Acid-Base
Normal water intake

(1.01.5 L/d)
Water of cellular
metabolism
(350500 mL/d)
Extracellular
compartment
(15 L)
Total body water

42L
(60% body weight
in a 70-kg man)
Variable water excretion
Fixed water excretion
Filtrate/d
180L
Stool
0.1 L/d
Sweat
0.1 L/d
Total insensible losses

~0.5 L/d
Pulmonary
0.3 L/d
Total urine output

1.01.5 L/d
Water excretion
Intracellular
compartment
(27 L)
Water intake and distribution
Physiology of the Renal Diluting

and Concentrating Mechanisms
FIGURE 1-1
Principles of normal water balance. In most
steady-state situations, human water intake
matches water losses through all sources.
Water intake is determined by thirst (see
Fig. 1-12) and by cultural and social behaviors. Water intake is finely balanced by the
need to maintain physiologic serum osmolality between 285 to 290 mOsm/kg. Both
water that is drunk and that is generated
through metabolism are distributed in the
extracellular and intracellular compartments that are in constant equilibrium.
Total body water equals approximately
60% of total body weight in young men,
about 50% in young women, and less in
older persons. Infants total body water is
between 65% and 75%. In a 70-kg man,
in temperate conditions, total body water
equals 42 L, 65% of which (22 L) is in the
intracellular compartment and 35% (19 L)
in the extracellular compartment.
Assuming normal glomerular filtration
rate to be about 125 mL/min, the total
volume of blood filtered by the kidney is
about 180 L/24 hr. Only about 1 to 1.5 L
is excreted as urine, however, on account
of the complex interplay of the urine concentrating and diluting mechanism and the
effect of antidiuretic hormone to different
segments of the nephron, as depicted in the
following figures.
Diseases of Water Metabolism
Generation of medullary hypertonicity

Normal function of the thick
ascending limb of loop of Henle
Urea delivery
Normal medullary blood flow
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NaCl
H 2O
GFR
ADH
H 2O
ADH
NaCl
H 2O
NaCl
Determinants of delivery of
NaCl to distal tubule:
GFR
Proximal tubular fluid and
solute (NaCl) reabsorption
NaCl
NaCl
H 2O
ADH
NaCl
H 2O
NaCl
H 2O
H 2O
H 2O
;;
;;
Water delivery
NaCl movement
Solute concentration
Collecting system water

permeability determined by
Presence of arginine vasopressin
Normal collecting system
FIGURE 1-2
Determinants of the renal concentrating mechanism. Human kidneys have two populations of nephrons, superficial and juxtamedullary. This anatomic arrangement has important bearing on the formation of urine by the countercurrent mechanism. The unique
anatomy of the nephron [1] lays the groundwork for a complex yet logical physiologic
arrangement that facilitates the urine concentration and dilution mechanism, leading to the
formation of either concentrated or dilute urine, as appropriate to the persons needs and
dictated by the plasma osmolality. After two thirds of the filtered load (180 L/d) is isotonically reabsorbed in the proximal convoluted tubule, water is handled by three interrelated
processes: 1) the delivery of fluid to the diluting segments; 2) the separation of solute and
water (H2O) in the diluting segment; and 3) variable reabsorption of water in the collecting duct. These processes participate in the renal concentrating mechanism [2].
1. Delivery of sodium chloride (NaCl) to the diluting segments of the nephron (thick
ascending limb of the loop of Henle and the distal convoluted tubule) is determined by
glomerular filtration rate (GFR) and proximal tubule function.
2. Generation of medullary interstitial hypertonicity, is determined by normal functioning
of the thick ascending limb of the loop of Henle, urea delivery from the medullary collecting duct, and medullary blood flow.
3. Collecting duct permeability is determined by the presence of antidiuretic hormone
(ADH) and normal anatomy of the collecting system, leading to the formation of a
concentrated urine.
1.3
1.4
Normal functioning of
Thick ascending limb of loop of Henle
Cortical diluting segment
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NaCl
H 2O
GFR
H 2O
NaCl
NaCl
Determinants of delivery of H2O

to distal parts of the nephron
GFR
Proximal tubular H2O and
NaCl reabsorption
Impermeable
collecting
duct
FIGURE 1-3
Determinants of the urinary dilution mechanism include 1) delivery of water to the
thick ascending limb of the loop of Henle,
distal convoluted tubule, and collecting system of the nephron; 2) generation of maximally hypotonic fluid in the diluting segments (ie, normal thick ascending limb of
the loop of Henle and cortical diluting segment); 3) maintenance of water impermeability of the collecting system as determined by the absence of antidiuretic
hormone (ADH) or its action and other
antidiuretic substances. GFRglomerular
filtration rate; NaClsodium chloride;
H2Owater.
H 2O
NaCl
H 2O
NaCl
H 2O
H 2O
Collecting duct impermeability depends on

Absence of ADH
Absence of other antidiuretic substances
Distal tubule
Urea
H 2O
Cortex
Na+
K+
2Cl2
NaCl
Outer medulla
Na+
K+
2Cl2
2
H 2O
Na+
1
K+
2Cl2
Urea
Outer medullary
collecting duct
Na+
K+
2Cl2
Urea
H 2O
H 2O
Inner medullary
collecting duct
4
3 H 2O
Urea
NaCl
NaCl
Urea
5
NaCl
Inner medulla
Loop of Henle
Collecting tubule
FIGURE 1-4
Mechanism of urine concentration:
overview of the passive model. Several
models of urine concentration have been
put forth by investigators. The passive
model of urine concentration described by
Kokko and Rector [3] is based on permeability characteristics of different parts of
the nephron to solute and water and on the
fact that the active transport is limited to
the thick ascending limb. 1) Through the
Na+, K+, 2 Cl cotransporter, the thick
ascending limb actively transports sodium
chloride (NaCl), increasing the interstitial
tonicity, resulting in tubular fluid dilution
with no net movement of water and urea
on account of their low permeability. 2)
The hypotonic fluid under antidiuretic hormone action undergoes osmotic equilibration with the interstitium in the late distal
tubule and cortical and outer medullary
collecting duct, resulting in water removal.
Urea concentration in the tubular fluid rises
on account of low urea permeability. 3) At
the inner medullary collecting duct, which
is highly permeable to urea and water, especially in response to antidiuretic hormone,
the urea enters the interstitium down its
concentration gradient, preserving interstitial hypertonicity and generating high urea
concentration in the interstitium.
(Legend continued on next page)

FIGURE 1-4 (continued)
4) The hypertonic interstitium causes abstraction of water from the
descending thin limb of loop of Henle, which is relatively impermeable to NaCl and urea, making the tubular fluid hypertonic with
high NaCl concentration as it arrives at the bend of the loop of
Henle. 5) In the thin ascending limb of the loop of Henle, NaCl

moves passively down its concentration gradient into the interstitium, making tubular fluid less concentrated with little or no movement of water. H2Owater.
FIGURE 1-5
Pathways for urea recycling. Urea plays an important role in the
generation of medullary interstitial hypertonicity. A recycling mechanism operates to minimize urea loss. The urea that is reabsorbed
into the inner medullary stripe from the terminal inner medullary
collecting duct (step 3 in Fig. 1-4) is carried out of this region by
the ascending vasa recta, which deposits urea into the adjacent
descending thin limbs of a short loop of Henle, thus recycling the
urea to the inner medullary collecting tubule (pathway A).
Some of the urea enters the descending limb of the loop of Henle
and the thin ascending limb of the loop of Henle. It is then carried
through to the thick ascending limb of the loop of Henle, the distal
collecting tubule, and the collecting duct, before it reaches the
inner medullary collecting duct (pathway B). This process is facilitated by the close anatomic relationship that the hairpin loop of
Henle and the vasa recta share [4].
Cortex
Urea
Urea
Urea
Urea
Outer
stripe
Outer
medulla
Urea
Inner
stripe
Urea
1.5
Collecting
duct
Urea
Urea
Ascending vasa recta
Pathway B
Pathway A
Inner
medulla
Urea
1500
20 mL
0.3 mL
Osmolality, mOsm/kg H2O
1200
900
600
Maximal ADH
300
100 mL
2.0 mL
30 mL
20 mL
no ADH
16 mL
0
Proximal tubule
Loop of Henle
Distal tubule
and cortical
collecting tubule
Outer and
inner medullary
collecting ducts
FIGURE 1-6
Changes in the volume and osmolality of
tubular fluid along the nephron in diuresis
and antidiuresis. The osmolality of the tubular fluid undergoes several changes as it passes through different segments of the tubules.
Tubular fluid undergoes marked reduction in
its volume in the proximal tubule; however,
this occurs iso-osmotically with the glomerular filtrate. In the loop of Henle, because of
the aforementioned countercurrent mechanism, the osmolality of the tubular fluid
rises sharply but falls again to as low as
100 mOsm/kg as it reaches the thick ascending limb and the distal convoluted tubule.
Thereafter, in the late distal tubule and the
collecting duct, the osmolality depends on
the presence or absence of antidiuretic hormone (ADH). In the absence of ADH, very
little water is reabsorbed and dilute urine
results. On the other hand, in the presence
of ADH, the collecting duct, and in some
species, the distal convoluted tubule, become
highly permeable to water, causing reabsorption of water into the interstitium, resulting
in concentrated urine [5].
1.6

Paraventricular neurons
Osmoreceptors
Pineal
Baroreceptors
Third ventricle
VP,NP
Supraoptic neuron
Tanycyte
SON
Optic chiasm
Superior hypophysial
artery
Portal capillaries
in zona externa of
median eminence
Mammilary body
VP,NP
FIGURE 1-7
Pathways of antidiuretic hormone release. Antidiuretic hormone is
responsible for augmenting the water permeability of the cortical
and medullary collecting tubules, thus promoting water reabsorption via osmotic equilibration with the isotonic and hypertonic
interstitium, respecively. The hormone is formed in the supraoptic
and paraventricular nuclei, under the stimulus of osmoreceptors
and baroreceptors (see Fig. 1-11), transported along their axons
and secreted at three sites: the posterior pituitary gland, the portal
capillaries of the median eminence, and the cerebrospinal fluid of
the third ventricle. It is from the posterior pituitary that the antidiuretic hormone is released into the systemic circulation [6].
SONsupraoptic nucleus; VPvasopressin; NPneurophysin.
Posterior pituitary
Long portal vein
Systemic venous system
Anterior pituitary
Short portal vein
VP,NP
Exon 1
Pre-pro-vasopressin
(164 AA)
AVP
Gly
Exon 3
Exon 2
Lys
Arg
Neurophysin II
Arg
Glycopeptide
Neurophysin II
Arg
Glycopeptide
Neurophysin II
Glycopeptide
(Cleavage site)
Signal
peptide
Pro-vasopressin
AVP
Gly
Products of
pro-vasopressin
AVP
NH2
Lys
Arg
FIGURE 1-8
Structure of the human arginine vasopressin
(AVP/antidiuretic hormone) gene and the
prohormone. Antidiuretic hormone (ADH)
is a cyclic hexapeptide (mol. wt. 1099) with
a tail of three amino acids. The biologically
inactive macromolecule, pre-pro-vasopressin is cleaved into the smaller, biologically active protein. The protein of vasopressin is translated through a series of signal transduction pathways and intracellular
cleaving. Vasopressin, along with its binding protein, neurophysin II, and the glycoprotein, are secreted in the form of neurosecretory granules down the axons and stored
in nerve terminals of the posterior lobe of
the pituitary [7]. ADH has a short half-life
of about 15 to 20 minutes and is rapidly
metabolized in the liver and kidneys.
Glyglycine; Lyslysine; Argarginine.
AQP-3
Recycling vesicle
Endocytic
retrieval
AQP-2
cAMP
ATP
AQP-2
PKA
H 2O
Gs
AQP-2
Gs
Exocytic
insertion
Recycling vesicle
AVP
AQP-4
Basolateral
Luminal
1.7
FIGURE 1-9
Intracellular action of antidiuretic hormone. The multiple actions
of vasopressin can be accounted for by its interaction with the V2
receptor found in the kidney. After stimulation, vasopressin binds
to the V2 receptor on the basolateral membrane of the collecting
duct cell. This interaction of vasopressin with the V2 receptor leads
to increased adenylate cyclase activity via the stimulatory G protein
(Gs), which catalyzes the formation of cyclic adenosine 3, 5monophosphate (cAMP) from adenosine triphosphate (ATP). In
turn, cAMP activates a serine threonine kinase, protein kinase A
(PKA). Cytoplasmic vesicles carrying the water channel proteins
migrate through the cell in response to this phosphorylation
process and fuse with the apical membrane in response to increasing vasopressin binding, thus increasing water permeability of the
collecting duct cells. These water channels are recyled by endocytosis once the vasopressin is removed. The water channel responsible
for the high water permeability of the luminal membrane in
response to vasopressin has recently been cloned and designated as
aquaporin-2 (AQP-2) [8]. The other members of the aquaporin
family, AQP-3 and AQP-4 are located on the basolateral membranes and are probably involved in water exit from the cell. The
molecular biology of these channels and of receptors responsible
for vasopressin action have contributed to the understanding of the
syndromes of genetically transmitted and acquired forms of vasopressin resistance. AVParginine vasopressin.
AQUAPORINS AND THEIR CHARACTERISTICS
Size (amino acids)

Permeability to small solutes
Regulation by antidiurectic hormone
Site
Cellular localization
Mutant phenotype
AQP-1
AQP-2
AQP-3
AQP-4
269
No
No
Proximal tubules;
descending thin limb
Apical and basolateral
membrane
Normal
271
No
Yes
Collecting duct; principal cells
285
Urea glycerol
No
Medullary collecting
duct; colon
Basolateral membrane
301
No
No
Hypothalamicsupraoptic, paraventricular nuclei;
ependymal, granular, and Purkinje cells
Basolateral membrane of the prinicpal cells
Unknown
Unknown
Apical membrane and intracellular vesicles

Nephrogenic diabetes insipidus
FIGURE 1-10
Aquaporins and their characteristics. An ever growing family of
aquaporin (AQP) channels are being described. So far, about seven
different channels have been cloned and characterized; however,

only four have been found to have any definite physiologic role.
1.8
50
Isotonic volume depletion

Isovolemic osmotic increase
45
Plasma AVP, pg/mL
40
35
30
25
20
15
10
5
0
0
10
15
Change, %
20
FIGURE 1-11
Osmotic and nonosmotic regulation of antidiuretic hormone (ADH) secretion. ADH is
secreted in response to changes in osmolality and in circulating arterial volume. The
osmoreceptor cells are located in the anterior hypothalamus close to the supraoptic
nuclei. Aquaporin-4 (AQP-4), a candidate osmoreceptor, is a member of the water channel
family that was recently cloned and characterized and is found in abundance in these neurons. The osmoreceptors are sensitive to changes in plasma osmolality of as little as 1%.
In humans, the osmotic threshold for ADH release is 280 to 290 mOsm/kg. This system is
so efficient that the plasma osmolality usually does not vary by more than 1% to 2%
despite wide fluctuations in water intake [9]. There are several other nonosmotic stimuli
for ADH secretion. In conditions of decreased arterial circulating volume (eg, heart failure,
cirrhosis, vomiting), decrease in inhibitory parasympathetic afferents in the carotid sinus
baroreceptors affects ADH secretion. Other nonosmotic stimuli include nausea, which can
lead to a 500-fold rise in circulating ADH levels, postoperative pain, and pregnancy. Much
higher ADH levels can be achieved with hypovolemia than with hyperosmolarity, although
a large fall in blood volume is required before this response is initiated. In the maintenance
of tonicity the interplay of these homeostatic mechanisms also involves the thirst mechanism, that under normal conditions, causes either intake or exclusion of water in an effort
to restore serum osmolality to normal.
Control of Water Balance and

Serum Sodium Concentration
Increased plasma osmolality
or
decreased arterial circulating volume
Decreased plasma osmolality

or
increased arterial circulating blood volume
Increased thirst
Increased ADH release
Decreased thirst
Decreased ADH release
Increased water
intake
Decreased water
excretion
Decreased water
intake
Decreased water
excretion
Water retention
Water excretion
Decreased plasma osmolality

or
increased arterial circulating volume
Increased plasma osmolality

and
decreased arterial circulating volume
Decreased ADH release and thirst
FIGURE 1-12
Pathways of water balance (conservation, A, and excretion, B). In
humans and other terrestrial animals, the thirst mechanism plays
an important role in water (H2O) balance. Hypertonicity is the
most potent stimulus for thirst: only 2% to 3 % changes in plasma
osmolality produce a strong desire to drink water. This absolute
level of osmolality at which the sensation of thirst arises in healthy
persons, called the osmotic threshold for thirst, usually averages
about 290 to 295 mOsm/kg H2O (approximately 10 mOsm/kg
H2O above that of antidiuretic hormone [ADH] release). The socalled thirst center is located close to the osmoreceptors but is
Increased ADH release and thirst
anatomically distinct. Between the limits imposed by the osmotic

thresholds for thirst and ADH release, plasma osmolality may be
regulated still more precisely by small osmoregulated adjustments
in urine flow and water intake. The exact level at which balance
occurs depends on various factors such as insensible losses through
skin and lungs, and the gains incurred from eating, normal drinking, and fat metabolism. In general, overall intake and output come
into balance at a plasma osmolality of 288 mOsm/kg, roughly
halfway between the thresholds for ADH release and thirst [10].
Plasma osmolality
280 to 290 mOsm/kg H2O
Decrease
Supression
of thirst
Supression
of ADH release
Increase
Stimulation
of thirst
Stimulation
of ADH release
Dilute urine
Concentrated urine
Disorder involving urine

dilution with H2O intake
Disorder involving urine

concentration with inadequate
H2O intake
Hyponatremia
Hypernatremia
1.9
FIGURE 1-13
Pathogenesis of dysnatremias. The countercurrent mechanism of
the kidneys in concert with the hypothalamic osmoreceptors via
antidiuretic hormone (ADH) secretion maintain a very finely tuned
balance of water (H2O). A defect in the urine-diluting capacity
with continued H2O intake results in hyponatremia. Conversely, a
defect in urine concentration with inadequate H2O intake culminates in hypernatremia. Hyponatremia reflects a disturbance in
homeostatic mechanisms characterized by excess total body H2O
relative to total body sodium, and hypernatremia reflects a deficiency of total body H2O relative to total body sodium [11].
(From Halterman and Berl [12]; with permission.)
Approach to the Hyponatremic Patient

EFFECTS OF OSMOTICALLY ACTIVE
SUBSTANCES ON SERUM SODIUM
Substances the increase osmolality

without changing serum sodium
Urea
Ethanol
Ethylene glycol
Isopropyl alcohol
Methanol
Substances that increase osmolality and decrease serum sodium

(translocational hyponatremia)
Glucose
Mannitol
Glycine
Maltose
FIGURE 1-14
Evaluation of a hyponatremic patient: effects of osmotically active
substances on serum sodium. In the evaluation of a hyponatremic
patient, a determination should be made about whether hyponatremia is truly hypo-osmotic and not a consequence of translocational or
pseudohyponatremia, since, in most but not all situations, hyponatremia reflects hypo-osmolality.
The nature of the solute plays an important role in determining
whether or not there is an increase in measured osmolality or an
actual increase in effective osmolality. Solutes that are permeable
across cell membranes (eg, urea, methanol, ethanol, and ethylene
glycol) do not cause water movement and cause hypertonicity
without causing cell dehydration. Typical examples are an uremic
patient with a high blood urea nitrogen value and an ethanolintoxicated person. On the other hand, in a patient with diabetic
ketoacidosis who is insulinopenic the glucose is not permeant
across cell membranes and, by its presence in the extracellular
fluid, causes water to move from the cells to extracellular space,
thus leading to cell dehydration and lowering serum sodium. This
can be viewed as translocational at the cellular level, as the serum
sodium level does not reflect changes in total body water but
rather movement of water from intracellular to extracellular space.
Glycine is used as an irrigant solution during transurethral resection of the prostate and in endometrial surgery. Pseudohyponatremia occurs when the solid phase of plasma (usually 6%
to 8%) is much increased by large increments of either lipids
or proteins (eg, in hypertriglyceridemia or paraproteinemias).
1.10

FIGURE 1-15
Pathogenesis of hyponatremia. The
normal components of the renal diluting
mechanism are depicted in Figure 1-3.
Hyponatremia results from disorders of
this diluting capacity of the kidney in the
following situations:
Reabsorption of sodium chloride

in distal convoluted tubule
Thiazide diuretics
Reabsorption of sodium
chloride in thick ascending
limb of loop of Henle
Loop diuretics
Osmotic diuretics
Interstitial disease
GFR diminished
Age
Renal disease
Congestive heart failure
Cirrhosis
Nephrotic syndrome
Volume depletion
NaCl
ADH release or action

Drugs
Syndrome of inappropriate
antidiuretic hormone
secretion, etc.
1. Intrarenal factors such as a diminished glomerular filtration rate

(GFR), or an increase in proximal
tubule fluid and sodium reabsorption, or both, which decrease distal
delivery to the diluting segments of
the nephron, as in volume depletion,
congestive heart failure, cirrhosis, or
nephrotic syndrome.
2. A defect in sodium chloride transport
out of the water-impermeable segments of the nephrons (ie, in the thick
ascending limb of the loop of Henle).
This may occur in patients with interstitial renal disease and administration of thiazide or loop diuretics.
3. Continued secretion of antidiuretic
hormone (ADH) despite the presence
of serum hypo-osmolality mostly
stimulated by nonosmotic mechanisms [12].
NaClsodium chloride.
Assessment of volume status
Hypovolemia
Total body water
Total body sodium
Hypervolemia
Total body water
Total body sodium
Euvolemia (no edema)

Total body water
Total body sodium
UNa >20
UNa <20
UNa >20
UNa >20
UNa <20
Renal losses
Diuretic excess
Mineralcorticoid deficiency
Salt-losing deficiency
Bicarbonaturia with
renal tubal acidosis and
metabolic alkalosis
Ketonuria
Osmotic diuresis
Extrarenal losses
Vomiting
Diarrhea
Third spacing of fluids
Burns
Pancreatitis
Trauma
Glucocorticoid deficiency
Hypothyroidism
Stress
Drugs
Syndrome of inappropriate
secretion
Acute or chronic
renal failure
Nephrotic syndrome
Cirrhosis
Cardiac failure
FIGURE 1-16
Diagnostic algorithm for hyponatremia. The next step in the evaluation of a hyponatremic patient is to assess volume status and identify
it as hypovolemic, euvolemic or hypervolemic. The patient with
hypovolemic hyponatremia has both total body sodium and water
deficits, with the sodium deficit exceeding the water deficit. This
occurs with large gastrointestinal and renal losses of water and
solute when accompanied by free water or hypotonic fluid intake.
In patients with hypervolemic hyponatremia, total body sodium is
increased but total body water is increased even more than sodium,
causing hyponatremia. These syndromes include congestive heart
failure, nephrotic syndrome, and cirrhosis. They are all associated
with impaired water excretion. Euvolemic hyponatremia is the most
common dysnatremia in hospitalized patients. In these patients, by
definition, no physical signs of increased total body sodium are
detected. They may have a slight excess of volume but no edema
[12]. (Modified from Halterman and Berl [12]; with permission.)
DRUGS ASSOCIATED WITH HYPONATREMIA

Antidiuretic hormone analogues
Deamino-D-arginine vasopressin (DDAVP)
Oxytocin
Drugs that enhance release of antidiuretic hormone
Chlorpropamide
Clofibrate
Carbamazepine-oxycarbazepine
Vincristine
Nicotine
Narcotics
Antipsychotics
Antidepressants
Ifosfamide
Drugs that potentiate renal action of antidiuretic hormone
Chlorpropamide
Cyclophosphamide
Nonsteroidal anti-inflammatory drugs
Acetaminophen
Drugs that cause hyponatremia by unknown mechanisms
Haloperidol
Fluphenazine
Amitriptyline
Thioradazine
Fluoxetine
FIGURE 1-17
Drugs that cause hyponatremia. Drug-induced hyponatremia is
mediated by antidiuretic hormone analogues like deamino-D-arginine-vasopressin (DDAVP), or antidiuretic hormone release, or by
potentiating the action of antidiuretic hormone. Some drugs cause
hyponatremia by unknown mechanisms [13]. (From Veis and Berl
[13]; with permission.)
DIAGNOSTIC CRITERIA FOR THE SYNDROME OF

INAPPROPRIATE ANTIDIURETIC HORMONE
SECRETION
Essential
Decreased extracellular fluid effective osmolality (< 270 mOsm/kg H2O)
Inappropriate urinary concentration (> 100 mOsm/kg H2O)
Clinical euvolemia
Elevated urinary sodium concentration (U[Na]), with normal salt and H2O intake
Absence of adrenal, thyroid, pituitary, or renal insufficiency or diuretic use
Supplemental
Abnormal H2O load test (inability to excrete at least 90% of a 20mL/kg H2O load
in 4 hrs or failure to dilute urinary osmolality to < 100 mOsm/kg)
Plasma antidiuretic hormone level inappropriately elevated relative to plasma osmolality
No significant correction of plasma sodium with volume expansion, but improvement
after fluid restriction
1.11
CAUSES OF THE SYNDROME OF INAPPROPRIATE

DIURETIC HORMONE SECRETION
Carcinomas
Bronchogenic
Duodenal
Pancreatic
Thymoma
Gastric
Lymphoma
Ewings sarcoma
Bladder
Carcinoma of the
ureter
Prostatic
Oropharyngeal
Pulmonary
Disorders
Viral pneumonia
Bacterial pneumonia
Pulmonary abscess
Tuberculosis
Aspergillosis
Positive-pressure
breathing
Asthma
Pneumothorax
Mesothelioma
Cystic fibrosis
Central Nervous System Disorders

Encephalitis (viral or bacterial)
Meningitis (viral, bacterial, tuberculous,
fungal)
Head trauma
Brain abscess
Brain tumor
Guillain-Barr syndrome
Acute intermittent porphyria
Subarachnoid hemorrhage or subdural
hematoma
Cerebellar and cerebral atrophy
Cavernous sinus thrombosis
Neonatal hypoxia
Hydrocephalus
Shy-Drager syndrome
Rocky Mountain spotted fever
Delirium tremens
Cerebrovascular accident (cerebral
thrombosis or hemorrhage)
Acute psychosis
Multiple sclerosis
FIGURE 1-18
Causes of the syndrome of inappropriate antidiuretic hormone
secretion (SIADH). Though SIADH is the commonest cause of
hyponatremia in hospitalized patients, it is a diagnosis of exclusion.
It is characterized by a defect in osmoregulation of ADH in which
plasma ADH levels are not appropriately suppressed for the degree
of hypotonicity, leading to urine concentration by a variety of mechanisms. Most of these fall into one of three categories (ie, malignancies, pulmonary diseases, central nervous system disorders) [14].
FIGURE 1-19
Diagnostic criteria for the syndrome of inappropriate antidiuretic
hormone secretion (SIADH). Clinically, SIADH is characterized by
a decrease in the effective extracellular fluid osmolality, with inappropriately concentrated urine. Patients with SIADH are clinically
euvolemic and are consuming normal amounts of sodium and
water (H2O). They have elevated urinary sodium excretion. In the
evaluation of these patients, it is important to exclude adrenal, thyroid, pituitary, and renal disease and diuretic use. Patients with
clinically suspected SIADH can be tested with a water load. Upon
administration of 20 mL/kg of H2O, patients with SIADH are
unable to excrete 90% of the H2O load and are unable to dilute
their urine to an osmolality less than 100 mOsm/kg [15]. (Modified
from Verbalis [15]; with permission.)
1.12
SIGNS AND SYMPTOMS OF HYPONATREMIA

Central Nervous System
Gastrointestinal System
Mild
Apathy
Headache
Lethargy
Moderate
Agitation
Ataxia
Confusion
Disorientation
Psychosis
Severe
Stupor
Coma
Pseudobulbar palsy
Tentorial herniation
Cheyne-Stokes respiration
Death
Anorexia
Nausea
Vomiting
Musculoskeletal System
Cramps
Diminished deep tendon reflexes
FIGURE 1-20
Signs and symptoms of hyponatremia. In evaluating hyponatremic
patients, it is important to assess whether or not the patient is
symptomatic, because symptoms are a better determinant of therapy than the absolute value itself. Most patients with serum sodium
values above 125 mEq/L are asymptomatic. The rapidity with
which hyponatremia develops is critical in the initial evaluation of
such patients. In the range of 125 to 130 mEq/L, the predominant
symptoms are gastrointestinal ones, including nausea and vomiting.
Neuropsychiatric symptoms dominate the picture once the serum
sodium level drops below 125 mEq/L, mostly because of cerebral
edema secondary to hypotonicity. These include headache, lethargy,
reversible ataxia, psychosis, seizures, and coma. Severe manifestations of cerebral edema include increased intracerebral pressure,
tentorial herniation, respiratory depression and death.
Hyponatremia-induced cerebral edema occurs principally with
rapid development of hyponatremia, typically in patients managed
with hypotonic fluids in the postoperative setting or those receiving
diuretics, as discussed previously. The mortality rate can be as
great as 50%. Fortunately, this rarely occurs. Nevertheless, neurologic symptoms in a hyponatremic patient call for prompt and
immediate attention and treatment [16,17].
FIGURE 1-21
Cerebral
adaptation to hyponatremia.
3
Na+/H2O
Na+/H2O
Na+/H2O
A, Decreases in extracellular osmolality
2
cause movement of water (H2O) into the
cells, increasing intracellular volume and
K+, Na+
K+, Na+
K+, Na+
thus causing tissue edema. This cellular
H 2O
H2O
H 2O
osmolytes
osmolytes
osmolytes
edema within the fixed confines of the cranium causes increased intracranial pressure,
leading to neurologic symptoms. To prevent
this from happening, mechanisms geared
toward volume regulation come into operaNormonatremia
Acute hyponatremia
Chronic hyponatremia
A
tion, to prevent cerebral edema from developing in the vast majority of patients with
hyponatremia.
After induction of extracellular fluid hypo-osmolality, H2O moves into the brain in
response to osmotic gradients, producing cerebral edema (middle panel, 1). However,
within 1 to 3 hours, a decrease in cerebral extracellular volume occurs by movement of
K+
fluid into the cerebrospinal fluid, which is then shunted back into the systemic circulation.
Glutamate
This happens very promptly and is evident by the loss of extracellular and intracellular
solutes (sodium and chloride ions) as early as 30 minutes after the onset of hyponatremia.
Na+
As H2O losses accompany the losses of brain solute (middle panel, 2), the expanded brain
Urea
volume decreases back toward normal (middle panel, 3) [15]. B, Relative decreases in individual osmolytes during adaptation to chronic hyponatremia. Thereafter, if hyponatremia
persists, other organic osmolytes such as phosphocreatine, myoinositol, and amino acids
Inositol
like glutamine, and taurine are lost. The loss of these solutes markedly decreases cerebral
Cl
swelling. Patients who have had a slower onset of hyponatremia (over 72 to 96 hours or
Taurine
longer), the risk for osmotic demyelination rises if hyponatremia is corrected too rapidly
Other
B
[18,19]. Na+sodium; K+potassium; Cl-chloride.
1
HYPONATREMIC PATIENTS AT RISK FOR

NEUROLOGIC COMPLICATIONS
Complication
Persons at Risk
Acute cerebral edema
Postoperative menstruant females

Elderly women taking thiazides
Children
Psychiatric polydipsic patients
Hypoxemic patients
Osmotic demyelination syndrome
Alcoholics
Malnourished patients
Hypokalemic patients
Burn victims
Elderly women taking thiazide diuretics
FIGURE 1-22
Hyponatremic patients at risk for neurologic complications. Those
at risk for cerebral edema include postoperative menstruant
women, elderly women taking thiazide diuretics, children, psychiatric patients with polydipsia, and hypoxic patients. In women,
and, in particular, menstruant ones, the risk for developing neurologic complications is 25 times greater than that for nonmenstruant
women or men. The increased risk was independent of the rate of
development, or the magnitude of the hyponatremia [21]. The
osmotic demyelination syndrome or central pontine myelinolysis
seems to occur when there is rapid correction of low osmolality
(hyponatremia) in a brain already chronically adapted (more than
72 to 96 hours). It is rarely seen in patients with a serum sodium
value greater than 120 mEq/L or in those who have hyponatremia
of less than 48 hours duration [20,21]. (Adapted from Lauriat and
Berl [21]; with permission.)
1.13
SYMPTOMS OF CENTRAL PONTINE MYELINOLYSIS

Initial symptoms
Mutism
Dysarthria
Lethargy and affective changes
Classic symptoms
Spastic quadriparesis
Pseudobulbar palsy
Lesions in the midbrain, medulla oblongata, and pontine tegmentum
Pupillary and oculomotor abnormalities
Altered sensorium
Cranial neuropathies
Extrapontine myelinolysis
Ataxia
Behavioral abnormalities
Parkinsonism
Dystonia
FIGURE 1-23
Symptoms of central pontine myelinolysis. This condition has been
described all over the world, in all age groups, and can follow correction of hyponatremia of any cause. The risk for development of
central pontine myelinolysis is related to the severity and chronicity
of the hyponatremia. Initial symptoms include mutism and
dysarthria. More than 90% of patients exhibit the classic symptoms
of myelinolysis (ie, spastic quadriparesis and pseudobulbar palsy),
reflecting damage to the corticospinal and corticobulbar tracts in
the basis pontis. Other symptoms occur on account of extension of
the lesion to other parts of the midbrain. This syndrome follows a
biphasic course. Initially, a generalized encephalopathy, associated
with a rapid rise in serum sodium, occurs. This is followed by the
classic symptoms 2 to 3 days after correction of hyponatremia,
however, this pattern does not always occur [22]. (Adapted from
Laureno and Karp [22]; with permission.)
FIGURE 1-24
A, Imaging of central pontine myelinolysis. Brain imaging is the
most useful diagnostic technique for central pontine myelinolysis.
Magnetic resonance imaging (MRI) is more sensitive than computed
tomography (CT). On CT, central pontine and extrapontine lesions
appear as symmetric areas of hypodensity (not shown). On T2
images of MRI, the lesions appear as hyperintense and on T1
images, hypointense. These lesions do not enhance with gadolinium.

They may not be apparent on imaging until 2 weeks into the illness.
Other diagnostic tests are brainstem auditory evoked potentials,
electroencephalography, and cerebrospinal fluid protein and myelin
basic proteins [22]. B, Gross appearance of the pons in central pontine myelinolysis. (From Laureno and Karp [22]; with permission.)
1.14
Severe hyponatremia (<125 mmol/L)

Symptomatic
Asymptomatic
Acute
Duration <48 h
Chronic
Duration >48 h
Chronic
Rarely <48 h
Emergency correction needed

Hypertonic saline 12 mL/kg/h
Coadministration of furosemide
Some immediate correction needed

Hypertonic saline 12 mL/kg/h
Coadministration of furosemide
Change to water restriction upon
10% increase of sodium or if
symptoms resolve
Perform frequent measurement
of serum and urine electrolytes
Do not exceed 1.5 mmol/L/hr
or 20 mmol/d
No immediate
correction needed
Long-term management
Identification and treatment of
reversible causes
Water restriction
Demeclocycline, 300600 mg bid
Urea, 1560 g/d
V2 receptor antagonists
A. GENERAL GUIDELINES FOR THE TREATMENT OF

SYMPTOMATIC HYPONATREMIA*
Acute hyponatremia (duration < 48 hrs)
Increase serum sodium rapidly by approximately 2 mmol/L/h until symptoms resolve
Full correction probably safe but not necessary
Chronic hyponatremia (duration > 48 hrs)
Initial increase in serum sodium by 10% or 10 mmol/L
Perform frequent neurologic evaluations; correction rate may be reduced with
improvement in symptoms
At no time should correction exceed rate of 1.5 mmol/L/h, or increments of
15 mmol/d
Measure serum and urine electrolytes every 12 h
*The sum of urinary cations (UNa + UK) should be less than the concentration of
infused sodium, to ensure excretion of electrolyte-free water.
FIGURE 1-26
General guidelines for the treatment of symptomatic hyponatremia,
A. Included herein are general guidelines for treatment of patients
with acute and chronic symptomatic hyponatremia. In the treatment of chronic symptomatic hyponatremia, since cerebral water is
increased by approximately 10%, a prompt increase in serum sodium by 10% or 10 mEq/L is permissible. Thereafter, the patients
fluids should be restricted. The total correction rate should not
FIGURE 1-25
Treatment of severe euvolemic hyponatremia (<125 mmol/L). The evaluation of a
hyponatremic patient involves an assessment
of whether the patient is symptomatic, and
if so, the duration of hyponatremia should
be ascertained. The therapeutic approach
to the hyponatremic patient is determined
more by the presence or absence of symptoms than by the absolute level of serum
sodium. Acutely hyponatremic patients
are at great risk for permanent neurologic
sequelae from cerebral edema if the hyponatremia is not promptly corrected. On the
other hand, chronic hyponatremia carries
the risk of osmotic demyelination syndrome
if corrected too rapidly. The next step
involves a determination of whether the
patient has any risk factors for development
of neurologic complications.
The commonest setting for acute, symptomatic hyponatremia is hospitalized, postoperative patients who are receiving hypotonic
fluids. In these patients, the risk of cerebral
edema outweighs the risk for osmotic
demyelination. In the presence of seizures,
obtundation, and coma, rapid infusion of
3% sodium chloride (4 to 6 mL/kg/h) or
even 50 mL of 29.2% sodium chloride has
been used safely. Ongoing careful neurologic monitoring is imperative [20].
B. TREATMENT OF CHRONIC SYMPTOMATIC

HYPONATREMIA
Calculate the net water loss needed to raise the serum sodium (SNa) from 110 mEq/L
to 120 mEq/L in a 50 kg person.
Example
Current SNa Total body water (TBW) = Desired SNa New TBW
Assume that TBW = 60% of body weight
Therefore TBW of patient = 50 0.6 = 30 L
110 mEq/L 30 L
New TBW =
= 27.5 L
120 mEq/L
Thus the electrolyte-free water loss needed to raise the SNa to
120 mEq/L = Present TBW New TBW = 2.5 L
Calculate the time course in which to achieve the desired correction (1 mEq/h)in
this case, 250 mL/h
Administer furosemide, monitor urine output, and replace sodium, potassium, and
excess free water lost in the urine
Continue to monitor urine output and replace sodium, potassium, and excess free
water lost in the urine
exceed 1.0 to 1.5 mEq/L/h, and the total increment in 24 hours

should not exceed 15 mmol/d [12]. A specific example as to how
to increase a patients serum sodium is illustrated in B.
1.15
MANAGEMENT OPTIONS FOR CHRONIC ASYMPTOMATIC HYPONATREMIA

Treatment
Mechanism of Action
Dose
Advantages
Limitations
Fluid restriction
Decreases availability of free water
Variable
Effective and inexpensive
Noncompliance
Inhibits the kidneys response to

Inhibits the kidneys response to
antidiurectic hormone
Antagonizes vasopressin action
9001200 mg/d
Unrestricted water intake
1200 mg/d initially; then,

300900 mg/d
Effective; unrestricted water

intake
Ongoing trials
Polyuria, narrow therapeutic

range, neurotoxicity
Neurotoxicity, polyuria, photosensitivity, nephrotoxicity
Increases free water clearance
Titrate to optimal dose; coadminister 23 g sodium chloride

3060 g/d
Effective
Ototoxicity, K+ and Mg2+ depletion
Effective; unrestricted water

intake
Polyuria, unpalatable gastrointestinal symptoms
Pharmacologic inhibition of
antidiuretic hormone action
Lithium
Demeclocycline
V2-receptor antagonist
Increased solute intake
Furosemide
Urea
Osmotic diuresis
FIGURE 1-27
Management options for patients with chronic asymptomatic
hyponatremia. If the patient has chronic hyponatremia and is
asymptomatic, treatment need not be intensive or emergent.
Careful scrutiny of likely causes should be followed by treatment.
If the cause is determined to be the syndrome of inappropriate
MANAGEMENT OF NONEUVOLEMIC
HYPONATREMIA
Hypovolemic hyponatremia
Volume restoration with isotonic saline
Identify and correct causes of water and sodium losses
Hypervolemic hyponatremia
Water restriction
Sodium restriction
Substitiute loop diuretics for thiazide diurectics
Treatment of timulus for sodium and water retention
V2-receptor antagonist
antidiuretic hormone (ADH) secretion, it must be treated as a

chronic disorder. As summarized here, the treatment strategies
involve fluid restriction, pharmacologic inhibition of ADH action,
and increased solute intake. Fluid restriction is frequently successful in normalizing serum sodium and preventing symptoms [23].
FIGURE 1-28
Management of noneuvolemic hyponatremia. Hypovolemic
hyponatremia results from the loss of both water and solute, with
relatively greater loss of solute. The nonosmotic release of antidiuretic hormone stimulated by decreased arterial circulating blood
volume causes antidiuresis and perpetuates the hyponatremia.
Most of these patients are asymptomatic. The keystone of therapy
is isotonic saline administration, which corrects the hypovolemia
and removes the stimulus of antidiuretic hormone to retain fluid.
Hypervolemic hyponatremia occurs when both solute and water
are increased, but water more than solute. This occurs with heart
failure, cirrhosis and nephrotic syndrome. The cornerstones of
treatment include fluid restriction, salt restriction, and loop diuretics [20]. (Adapted from Lauriat and Berl [20]; with permission.)
1.16
Approach to the Hypernatremic Patient

ADH release or action
Nephrogenic DI
Central DI
(see Fig. 1-)
Reabsorption of sodium
chloride in thick ascending
limb of loop of Henle
Loop diuretics
Osmotic diuretics
Interstitial disease
GFR diminished
Age
Renal disease
Urea
NaCl
Urea in the medulla

Water diuresis
Decreased dietary
protein intake
FIGURE 1-29
Pathogenesis of hypernatremia. The renal
concentrating mechanism is the first line of
defense against water depletion and hyperosmolality. When renal concentration is
impaired, thirst becomes a very effective
mechanism for preventing further increases
in serum osmolality. The components of the
normal urine concentrating mechanism are
shown in Figure 1-2. Hypernatremia results
from disturbances in the renal concentrating
mechanism. This occurs in interstitial renal
disease, with administration of loop and
osmotic diuretics, and with protein malnutrition, in which less urea is available to
generate the medullary interstitial tonicity.
Hypernatremia usually occurs only when
hypotonic fluid losses occur in combination
with a disturbance in water intake, typically
in elders with altered consciousness, in
infants with inadequate access to water,
and, rarely, with primary disturbances of
thirst [24]. GFRglomerular filtration rate;
ADHantidiuretic hormone; DIdiabetes
insipidus.
Assessment of volume status

Hypovolemia
Total body water
Total body sodium
UNa>20
UNa<20
Renal losses
Osmotic or loop diuretic
Postobstruction
Intrinsic renal disease
Extrarenal losses
Excessive sweating
Burns
Diarrhea
Fistulas
Euvolemia (no edema)

Total body water
Total body sodium
Hypervolemia
Total body water
Total body sodium
UNa variable
UNa>20
Renal losses
Diabetes insipidus
Hypodipsia
FIGURE 1-30
Diagnostic algorithm for hypernatremia. As for hyponatremia, the initial evaluation of the patient with hypernatremia involves assessment of
volume status. Patients with hypovolemic hypernatremia lose both
sodium and water, but relatively more water. On physical examination,
they exhibit signs of hypovolemia. The causes listed reflect principally
hypotonic water losses from the kidneys or the gastrointestinal tract.
Euvolemic hyponatremia reflects water losses accompanied by inadequate water intake. Since such hypodipsia is uncommon, hypernatremia usually supervenes in persons who have no access to water or
who have a neurologic deficit that impairs thirst perceptionthe very
young and the very old. Extrarenal water loss occurs from the skin
Extrarenal losses
Insensible losses
Respiratory
Dermal
Sodium gains
Primary
Hyperaldosteronism
Cushing's sydrome
Hypertonic dialysis
Hypertonic sodium bicarbonate
Sodium chloride tablets
and respiratory tract, in febrile or other hypermetabolic states. Very

high urine osmolality reflects an intact osmoreceptorantidiuretic
hormonerenal response. Thus, the defense against the development
of hyperosmolality requires appropriate stimulation of thirst and the
ability to respond by drinking water. The urine sodium (UNa) value
varies with the sodium intake. The renal water losses that lead to
euvolemic hypernatremia are a consequence of either a defect in
vasopressin production or release (central diabetes insipidus) or
failure of the collecting duct to respond to the hormone (nephrogenic
diabetes insipidus) [23]. (Modified from Halterman and Berl [12];
with permission.)
Urine volume = CH2O + COsm
COsm
Isotonic or hypertonic urine
CH2O
Hypotonic urine
Polyuria due to increased

solute excretion
Sodium chloride
Diuretics
Renal sodium wasting
Excessive salt intake
Bicarbonate
Vomiting/metabolic alkalosis
Alkali administration
Mannitol
Diuretics
Bladder lavage
Treatment of cerebral edema
Polyuria due to increased

free water clearance
Excessive water intake
Psychogenic polydipsia
Defect in thirst
Hyper-reninemia
Potassium depletion
Renal vascular disease
Renal tumors
Renal hypoperfusion
Increased renal water excretion
Impaired renal water concentrating
mechanism
Decreased ADH secretion
Increased ADH degradation
Resistance to ADH action
FIGURE 1-31
Physiologic approach to polyuric disorders. Among euvolemic hypernatremic patients, those affected by polyuric disorders are an important subcategory. Polyuria is arbitrarily defined as urine output of
more than 3 L/d. Urine volume can be conceived of as having two
components: the volume needed to excrete solutes at the concentration
of solutes in plasma (called the osmolar clearance) and the other being
the free water clearance, which is the volume of solute-free water that
has been added to (positive free water clearance [CH2O]) or subtracted (negative CH2O) from the isotonic portion of the urine osmolar
clearance (Cosm) to create either a hypotonic or hypertonic urine.
Consumption of an average American diet requires the kidneys to
excrete 600 to 800 mOsm of solute each day. The urine volume in
which this solute is excreted is determined by fluid intake. If the
urine is maximally diluted to 60 mOsm/kg of water, the 600 mOsm
will need 10 L of urine for effective osmotic clearance. If the concentrating mechanism is maximally stimulated to 1200 mOsm/kg of
water, osmotic clearance will occur in a minimum of 500 mL of
urine. This flexibility is affected when drugs or diseases alter the
renal concentrating mechanism.
Polyuric disorders can be secondary to an increase in solute clearance, free water clearance, or a combination of both. ADHantidiuretic hormone.
WATER DEPRIVATION TEST
Diagnosis
Normal
Complete central
diabetes insipidus
Partial central
diabetes insipidus
Nephrogenic
diabetes insipidus
Primary polydipsia
Urine Osmolality with

Water Deprivation
(mOsm/kg H2O)
CLINICAL FEATURES OF
DIABETES INSIPIDUS
Plasma Arginine
Vasopressin (AVP)
after Dehydration
Increase in Urine
Osmolality with
Exogenous AVP
> 800
< 300
> 2 pg/mL
Indetectable
Little or none
Substantial
300800
< 1.5 pg/mL

> 5 pg/mL
> 10% of urine osmolality

after water deprivation
Little or none
< 5 pg/mL
Little or none
< 300500
> 500
1.17
* Water intake is restricted until the patient loses 3%5% of weight or until three consecutive hourly determinations of
urinary osmolality are within 10% of each other. (Caution must be exercised to ensure that the patient does not
become excessively dehydrated.) Aqueous AVP (5 U subcutaneous) is given, and urine osmolality is measured after
60 minutes. The expected responses are given above.
FIGURE 1-32
Water deprivation test. Along with nephrogenic diabetes insipidus and primary polydipsia,
patients with central diabetes insipius present with polyuria and polydipsia. Differentiating
between these entities can be accomplished by measuring vasopressin levels and determining the response to water deprivation followed by vasopressin administration [25]. (From
Lanese and Teitelbaum [26]; with permission.)
Abrupt onset
Equal frequency in both sexes
Rare in infancy, usual in second decade of life
Predilection for cold water
Polydipsia
Urine output of 3 to 15 L/d
Marked nocturia but no diurnal variation
Sleep deprivation leads to fatigue and irritability
Severe life-threatening hypernatremia can be associated with illness or water deprivation
FIGURE 1-33
Clinical features of diabetes insipidus.
Other clinical features can distinguish compulsive water drinkers from patients with
central diabetes insipidus. The latter usually
has abrupt onset, whereas compulsive water
drinkers may give a vague history of the
onset. Unlike compulsive water drinkers,
patients with central diabetes insipidus have
a constant need for water. Compulsive
water drinkers exhibit large variations in
water intake and urine output. Nocturia
is common with central diabetes insipidus
and unusual in compulsive water drinkers.
Finally, patients with central diabetes
insipidus have a predilection for drinking
cold water. Plasma osmolality above
295 mOsm/kg suggests central diabetes
insipidus and below 270 mOsm/kg suggests
compulsive water drinking [23].
1.18

FIGURE 1-34
Causes of diabetes insipidus. The causes of diabetes insipidus can
be divided into central and nephrogenic. Most (about 50%) of the
central causes are idiopathic; the rest are caused by central nervous
system involvement with infection, tumors, granuloma, or trauma.
The nephrogenic causes can be congenital or acquired [23].
CAUSES OF DIABETES INSIPIDUS

Central diabetes insipidus
Congenital
Autosomal-dominant
Autosomal-recessive
Acquired
Post-traumatic
Iatrogenic
Tumors (metastatic from breast,
craniopharyngioma, pinealoma)
Cysts
Histiocytosis
Granuloma (tuberculosis, sarcoid)
Aneurysms
Meningitis
Encephalitis
Idiopathic
Congenital
X-linked
Autosomal-recessive
Acquired
Renal diseases (medullary cystic disease,
polycystic disease, analgesic nephropathy,
sickle cell nephropathy, obstructive uropathy, chronic pyelonephritis, multiple
myeloma, amyloidosis, sarcoidosis)
Hypercalcemia
Hypokalemia
Drugs (lithium compounds, demeclocycline,
methoxyflurane, amphotericin, foscarnet)
SP
VP
NP
NP
Exon 1
NP
CP
Exon 2
Exon 3
83
19..16
47
79
50
87
14
17
57
20
24
3
1
61
62
67
65
Missense mutation
Stop codon
Deletion
FIGURE 1-35
Congenital central diabetes insipidus (DI),
autosomal-dominant form. This condition
has been described in many families in
Europe and North America. It is an autosomal dominant inherited disease associated
with marked loss of cells in the supraoptic
nuclei. Molecular biology techniques have
revealed multiple point mutations in the
vasopressin-neurophysin II gene. This condition usually presents early in life [25].
A rare autosomal-recessive form of central
DI has been described that is characterized
by DI, diabetes mellitus (DM), optic atrophy (OA), and deafness (DIDMOAD or
Wolframs syndrome). This has been linked
to a defect in chromosome-4 and involves
abnormalities in mitochondrial DNA [27].
SPsignal peptide; VPvasopressin;
NPneurophysin; GPglycoprotein.
FIGURE 1-36
Treatment of central diabetes insipidus (DI). Central DI may be
treated with hormone replacement or drugs. In acute settings when
renal water losses are extensive, aqueous vasopressin (pitressin) is
useful. It has a short duration of action that allows for careful monitoring and avoiding complications like water intoxication. This
drug should be used with caution in patients with underlying coronary artery disease and peripheral vascular disease, as it can cause
vascular spasm and prolonged vasoconstriction. For the patient
with established central DI, desmopressin acetate (dDAVP) is the
agent of choice. It has a long half-life and does not have significant
vasoconstrictive effects like those of aqueous vasopressin. It can be
conveniently administered intranasally every 12 to 24 hours. It is
usually tolerated well. It is safe to use in pregnancy and resists
degradation by circulating vasopressinase. In patients with partial
DI, agents that potentiate release of antidiuretic hormone can be
used. These include chlorpropamide, clofibrate, and carbamazepine.
They work effectively only if combined with hormone therapy,
decreased solute intake, or diuretic administration [23].
TREATMENT OF CENTRAL DIABETES INSIPIDUS

Condition
Drug
Dose
Complete central DI
dDAVP
1020 (g intranasally q 1224 h
Partial central DI
Vasopressin tannate
Aqueous vasopressin
Chlorpropamide
Clofibrate
Carbamazepine
25 U IM q 2448 h
510 U SC q 46 h
250500 mg/d
500 mg tidqid
400600 mg/d
S
N
S
S
S
L
S P
E
R
L P
A
R
R T
P
L
D
A
E
L
* L
A
F S I L
A V A V
L
G
S V
A L V N
A
L L
*
*
A
R
R
G
R R G
Intracellular
V
A
D
L
F
D
T
A
K
W
A
L
Q
L P Q
L F V
L A A
C L H
I G
H V
I
P
A
W
H
*
G
T T S A M
L M
1
Extracellular
NH2
R F
R
G
P
A E P W
F
G
D
C
R
A
S G G
A
R
G
E
W
L
T
V
C
V
C
Y *
D T
N
R
V
R
A
T W
A Q F
V K
I
A L
Y
I
L Q
M V
L F P Q
M
F V
V
L
G M
A
P
S
Y
T L
A
L L
S S
G I
S L A F
Y
A A
M
W
I L
C Q
A
A
V
V L
M T
I F
L
V L
P
D
E R
R
I
H
R
H
R
N
A
A
W
S
I
H
V
L
C
H
A
V
R
A
G
*
P
P
G
S
M
G
L
E
G
P
A
Y R H
G
S
E
R
*
P G
G R R
P E
D
W
A
W A
Q L
L V
F F
A P
C W
V L
V Y
V V
V I
L
M T
R
V
T
K
A
S
A V
A
A P
L
E
G
A
L
L
N
N
V
S
P F
L M
A S
S C
P W
Y A
V
L *
L
T
I
S
F
S
S S
S E L R
L
L
C C
C S E D Q P G L
P S
R G
A
R
G
R
T
P
P
T
T
T
R
1.19
S S
371
L A K
D T S
S COOH
FIGURE 1-37
Congenital nephrogenic diabetes insipidus,
X-linkedrecessive form. This is a rare disease of male patients who do not concentrate their urine after administration of
antidiuretic hormone. The pedigrees of
affected families have been linked to a
group of Ulster Scots who emigrated to
Halifax, Nova Scotia in 1761 aboard the
ship called Hopewell. According to
the Hopewell hypothesis, most North
American patients with this disease are
descendants of a common ancestor with a
single gene defect. Recent studies, however, disproved this hypothesis [28]. The
gene defect has now been traced to 87 different mutations in the gene for the vasopressin receptor (AVP-R2) in 106 presumably unrelated families [29]. (From Bichet,
et al. [29]; with permission.)
1.20
Urinary lumen
L A P A
S 11
V
9,12
R
V
L A V
N
A
D
T
A
G
G
8 P
R
L
K
N
I
S
F
M
D
N
D
S
S
A
D
13 C
P
T
H
G
T
6 T
W
T
I
A
V
Y
E
Q A L P S
G
H
F
H
Q
I
W
L
V
G
I
A
P
V
L
L
L
G
T
W
L
A
P
A
G 4 E V
I Q M A
N
L
G H
L
V
A
L
A L
A
G
A
V
S
F
G
G
F
V
A
A
G
L
L
I
S
L
G L
F
L
L T
L
F F
I G T G
G
G
V
Q
Q
A
I
F
L
S 12 S
L
A
V
L 13 V L
L
L
L
V
Q
T L
Y
C
A
Y
F
A
A
N
P
T
A
I
Y
G
F
A
G L
F L
V
A
P
E
L
R
7
H
S
N
A
F
L
I
T
F
E
P
D
G
V
S
V
P
E R R
S
1 G
A
A
A
V
R
K
S
H
S
H
F
L
I
C
Q
P
S
A
S
S
L
2 N
H
P
G
E
I
11
R
L
R
P
V
G
S
M
L
E
T
W E L R
A
L
K
A
V
C
3 V
A
V
T V A
S
L
Q
R
K
R
G
V E
Principal cell
R E
L
E W D T D P E
-intracellular
FIGURE 1-38
Congenital nephrogenic diabetes insipidus (NDI), autosomalrecessive form. In the autosomal recessive form of NDI, mutations
have been found in the gene for the antiiuretic hormone (ADH)
sensitive water channel, AQP-2. This form of NDI is exceedingly
rare as compared with the X-linked form of NDI [30]. Thus far, a
total of 15 AQP-2 mutations have been described in total of 13
families [31]. The acquired form of NDI occurs in various kidney
diseases and in association with various drugs, such as lithium
and amphotericin B. (From Canfield et al. [31]; with permission.)
ACQUIRED NEPHROGENIC DIABETES INSIPIDUS:

CAUSES AND MECHANISMS
Disease State
PATIENT GROUPS AT
INCREASED RISK FOR
SEVERE HYPERNATREMIA
Defect in Generation
of Medullary
Defect in cAMP Downregulation
Interstitial Tonicity
Generation
of AQP-2
Other
Chronic renal failure
Hypokalemia
Hypercalcemia
Sickle cell disease
Protein malnutrition
Demeclocycline
Lithium
Pregnancy
Downregulation of V2
receptor message
Elders and infants

Hospitalized patients receiving
Hypertonic infusions
Tube feedings
Osmotic diuretics
Lactulose
Mechanical ventilation
Altered mental status
Uncontrolled diabetes mellitus
Underlying polyuria
Placental secretion of
vasopressinase
FIGURE 1-39
Causes and mechanisms of acquired nephrogenic diabetes insidpidus. Acquired nephrogenic
diabetes insipidus occurs in chronic renal failure, electrolyte imbalances, with certain drugs,
in sickle cell disease and pregnancy. The exact mechanism involved has been the subject of
extensive investigation over the past decade and has now been carefully elucidated for most
of the etiologies.
FIGURE 1-40
Patient groups at increased risk for severe
hypernatremia. Hypernatremia always
reflects a hyperosmolar state. It usually
occurs in a hospital setting (reported incidence 0.65% to 2.23% of all hospitalized
patients) with very high morbidity and mortality (estimates of 42% to over 70%) [12].
Hypovolemic
hypernatremia
Euvolemic
hypernatremia
Hypervolemic
hypernatremia
Correction of volume deficit

Administer isotonic saline until
hypovolemia improves
Treat causes of losses (insulin,
relief of urinary tract obstruction,
removal of osmotic diuretics)
Correction of water deficit

Calculate water deficit
Administer 0.45% saline, 5%
dextrose or oral water to replace
the deficit and ongoing losses
In central diabetes insipidus with
severe losses, aqueous vasopressin
(pitressin) 5 U SC q 6 hr
Follow serum sodium
concentration carefully to avoid
water intoxication
Removal of sodium
Discontinue offending agents
Administer furosemide
Provide hemodialysis, as
needed, for renal failure
SIGNS AND SYMPTOMS OF

HYPERNATREMIA
Mild
Restlessness
Lethargy
Altered mental status
Irritability
Moderate
Disorientation
Confusion
Severe
Stupor
Coma
Seizures
Death
Correction of water deficit

Calculate water deficit
Administer 0.45% saline, 5%
dextrose or oral water replacing
deficit and ongoing losses
Long term therapy

Central diabetes insipidus (see
Table 112)
Correct plasma potassium and
calcium concentration
Remove offending drugs
Low-sodium diet
Thiazide diuretics
Amiloride (for lithium-induced
nephrogenic diabetes insipidus)
Respiratory System
Labored respiration
Gastrointestinal System
Intense thirst
Nausea
Vomiting
Musculoskeletal System
Muscle twitching
Spasticity
Hyperreflexia
FIGURE 1-41
Signs and symptoms of hypernatremia.
Hypernatremia always reflects a hyperosmolar state; thus, central nervous system symptoms are prominent in affected patients [12].
1.21
FIGURE 1-42
Management options for patients with hypernatremia. The primary goal in the treatment
of hypernatremia is restoration of serum tonicity. Hypovolemic hypernatremia in the context of low total body sodium and orthostatic blood pressure changes should be managed
with isotonic saline until blood pressure normalizes. Thereafter, fluid management generally involves administration of 0.45% sodium chloride or 5% dextrose solution. The goal
of therapy for hypervolemic hypernatremias is to remove the excess sodium, which is
achieved with diuretics plus 5% dextrose. Patients who have renal impairment may need
dialysis. In euvolemic hypernatremic patients, water losses far exceed solute losses, and the
mainstay of therapy is 5% dextrose. To correct the hypernatremia, the total body water
deficit must be estimated. This is based on the serum sodium concentration and on the
assumption that 60% of the body weight is water [24]. (Modified from Halterman and
Berl [12]; with permission.)
GUIDELINES FOR THE TREATMENT OF

SYMPTOMATIC HYPERNATREMIA*
Correct at a rate of 2 mmol/L/h
Replace half of the calculated water deficit over the first 1224 hrs
Replace the remaining deficit over the next 2436 hrs
Perform serial neurologic examinations (prescribed rate of correction can be
decreased as symptoms improve)
Measure serum and urine electrolytes every 12 hrs
*If UNa + U K is less than the concentration of PNa, then water loss is ongoing and
needs to be replaced.
FIGURE 1-43
Guidelines for the treatment of symptomatic hypernatremia.
Patients with severe symptomatic hypernatremia are at high risk of
dying and should be treated aggressively. An initial step is estimating the total body free water deficit, based on the weight (in kilograms) and the serum sodium. During correction of the water
deficit, it is important to perform serial neurologic examinations.
1.22
References
1. Jacobson HR: Functional segmentation of the mammalian nephron.
Am J Physiol 1981, 241:F203.
2. Goldberg M: Water control and the dysnatremias. In The Sea Within
Us. Edited by Bricker NS. New York: Science and Medicine
Publishing Co., 1975:20.
3. Kokko J, Rector F: Countercurrent multiplication system without
active transport in inner medulla. Kidney Int 1972, 114.
4. Knepper MA, Roch-Ramel F: Pathways of urea transport in the mammalian kidney. Kidney Int 1987, 31:629.
5. Vander A: In Renal Physiology. New York: McGraw Hill, 1980:89.
6. Zimmerman E, Robertson AG: Hypothalamic neurons secreting vasopressin and neurophysin. Kidney Int 1976, 10(1):12.
7. Bichet DG: Nephrogenic and central diabetes insipidus. In Diseases of
the Kidney, edn. 6. Edited by Schrier RW, Gottschalk CW. Boston:
Little, Brown, and Co., 1997:2430
8. Bichet DG : Vasopressin receptors in health and disease. Kidney Int
1996, 49:1706.
9. Dunn FL, Brennan TJ, Nelson AE, Robertson GL: The role of blood
osmolality and volume in regulating vasopressin secretion in the rat.
J Clin Invest 1973, 52:3212.
10. Rose BD: Antidiuretic hormone and water balance. In Clinical
Physiology of Acid Base and Electrolyte Disorders, edn. 4. New York:
McGraw Hill, 1994.
11. Cogan MG: Normal water homeostasis. In Fluid & Electrolytes,
Physiology and Pathophysiology. Edited by Cogan MG. Norwalk:
Appleton & Lange, 1991:98.
12. Halterman R, Berl T: Therapy of dysnatremic disorders. In Therapy in
Nephrology and Hypertension. Edited by Brady H, Wilcox C.
Philadelphia: WB Saunders, 1998, in press.
13. Veis JH, Berl T, Hyponatremia: In The Principles and Practice of
Nephrology, edn. 2. Edited by Jacobson HR, Striker GE, Klahr S.
St.Louis: Mosby, 1995:890.
14. Berl T, Schrier RW: Disorders of water metabolism. In Renal and
Electrolyte Disorders, edn 4. Philadelphia: Lippincott-Raven,
1997:52.
15. Verbalis JG: The syndrome of ianappropriate diuretic hormone secretion and other hypoosmolar disorders. In Diseases of the Kidney, edn.
6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown, and
Co., 1997:2393.
16. Berl T, Schrier RW: Disorders of water metabolism. In Renal and

Electrolyte Disorders, edn. 4. Edited by Schrier RW. Philadelphia:
Lippincott-Raven, 1997:54.
17. Berl T, Anderson RJ, McDonald KM, Schreir RW: Clinical Disorders
of water metabolism. Kidney Int 1976, 10:117.
18. Gullans SR, Verbalis JG: Control of brain volume during hyperosmolar and hypoosmolar conditions. Annu Rev Med 1993, 44:289.
19. Zarinetchi F, Berl T: Evaluation and management of severe hyponatremia. Adv Intern Med 1996, 41:251.
20. Lauriat SM, Berl T: The Hyponatremic Patient: Practical focus on
therapy. J Am Soc Nephrol 1997, 8(11):1599.
21. Ayus JC, Wheeler JM, Arieff AI: Postoperative hyponatremic
encephalopathy in menstruant women. Ann Intern Med
1992,117:891.
22. Laureno R, Karp BI: Myelinolysis after correction of hyponatremia.
Ann Intern Med 1997, 126:57.
23. Kumar S, Berl T: Disorders of serum sodium concentration. Lancet
1998. in press.
24. Cogan MG: Normal water homeostasis. In Fluid & Electrolytes,
Physiology and Pathophysiology. Edited by Cogan MG. Norwalk:
Appleton & Lange, 1991:94.
25. Rittig S, Robertson G, Siggaard C, et al.: Identification of 13 new
mutations in the vasopressin-neurophysin II gene in 17 kindreds with
familial autosomal dominant neurohypophyseal diabetes insipidus.
Am J Hum Genet 1996, 58:107.
26. Lanese D, Teitelbaum I: Hypernatremia. In The Principles and
Practice of Nephrology, edn. 2. Edited by Jacobson HR, Striker GE,
Klahr S. St. Louis: Mosby, 1995:895.
27. Barrett T, Bundey S: Wolfram (DIDMOAD) syndrome. J Med Genet
1997, 29:1237.
28. Holtzman EJ, Ausiello DA: Nephrogenic Diabetes insipidus: Causes
revealed. Hosp Pract 1994, Mar 15:89104.
29. Bichet D, Oksche A, Rosenthal W: Congential Nephrogenic Diabetes
Insipidus. J Am Soc Nephrol 1997, 8:1951.
30. Lieburg van, Verdjik M, Knoers N, et al.: Patients with autosomal
nephrogenic diabetes insipidus homozygous for mutations in the
aquaporin 2 water channel. Am J Hum Genet 1994, 55:648.
31. Canfield MC, Tamarappoo BK, Moses AM, et al.: Identification and
characterization of aquaporin-2 water channel mutations causing
nephrogenic diabetes insipidus with partial vasopressin response.
Hum Mol Genet 1997, 6(11):1865.
Disorders of
Sodium Balance
David H. Ellison
odium is the predominant cation in extracellular fluid (ECF); the

volume of ECF is directly proportional to the content of sodium
in the body. Disorders of sodium balance, therefore, may be
viewed as disorders of ECF volume. The body must maintain ECF volume within acceptable limits to maintain tissue perfusion because
plasma volume is directly proportional to ECF volume. The plasma
volume is a crucial component of the blood volume that determines
rates of organ perfusion. Many authors suggest that ECF volume is
maintained within narrow limits despite wide variations in dietary
sodium intake. However, ECF volume may increase as much as 18%
when dietary sodium intake is increased from very low to moderately
high levels [1,2]. Such variation in ECF volume usually is well tolerated and leads to few short-term consequences. In contrast, the same
change in dietary sodium intake causes only a 1% change in mean
arterial pressure (MAP) in normal persons [3]. The body behaves as if
the MAP, rather than the ECF volume, is tightly regulated. Under
chronic conditions, the effect of MAP on urinary sodium excretion
displays a remarkable gain; an increase in MAP of 1 mm Hg is associated with increases in daily sodium excretion of 200 mmol [4].
Guyton [4] demonstrated the importance of the kidney in control
of arterial pressure. Endogenous regulators of vascular tone, hormonal vasoconstrictors, neural inputs, and other nonrenal mechanisms are
important participants in short-term pressure homeostasis. Over the
long term, blood pressure is controlled by renal volume excretion,
which is adjusted to a set point. Increases in arterial pressure lead to
natriuresis (called pressure natriuresis), which reduces blood volume.
A decrease in blood volume reduces venous return to the heart and
cardiac output. Urinary volume excretion exceeds dietary intake until
the blood volume decreases sufficiently to return the blood pressure to
the set point.
Disorders of sodium balance resulting from primary renal sodium
retention lead only to modest volume expansion without edema
because increases in MAP quickly return sodium excretion to baseline
CHAPTER
2.2
levels. Examples of these disorders include chronic renal failure

and states of mineralocorticoid excess. In this case, the price of
a return to sodium balance is hypertension. Disorders of sodium balance that result from secondary renal sodium retention,
as in congestive heart failure, lead to more profound volume
expansion owing to hypotension. In mild to moderates cases,
volume expansion eventually returns the MAP to its set point;
the price of sodium balance in this case is edema. In more severe
cases, volume expansion never returns blood pressure to normal, and renal sodium retention is unremitting. In still other situations, such as nephrotic syndrome, volume expansion results
from changes in both the renal set point and body volume distribution. In this case, the price of sodium balance may be both
edema and hypertension. In each of these cases, renal sodium
(and chloride) retention results from a discrepancy between the
existing MAP and the renal set point.
The examples listed previously emphasize that disorders of
sodium balance do not necessarily abrogate the ability to
achieve sodium balance. When balance is defined as the equation of sodium intake and output, most patients with ECF
expansion (and edema or hypertension) or ECF volume depletion achieve sodium balance. They do so, however, at the
expense of expanded or contracted ECF volume. The failure to
achieve sodium balance at normal ECF volumes characterizes
these disorders.
Frequently, distinguishing disorders of sodium balance from
disorders of water balance is useful. According to this scheme, disorders of water balance are disorders of body osmolality and usually are manifested by alterations in serum sodium concentration
(see Chapter 1). Disorders of sodium balance are disorders of

ECF volume. This construct has a physiologic basis because
water balance and sodium balance can be controlled separately
and by distinct hormonal systems. It should be emphasized,
however, that disorders of sodium balance frequently lead to or
are associated with disorders of water balance. This is evident
from Figure 2-24 in which hyponatremia is noted to be a sign
of either ECF volume expansion or contraction. Thus, the distinction between disorders of sodium and water balance is useful in constructing differential diagnoses; however, the close
interrelationships between factors that control sodium and
water balance should be kept in mind.
The figures herein describe characteristics of sodium homeostasis in normal persons and also describe several of the regulatory systems that are important participants in controlling
renal sodium excretion. Next, mechanisms of sodium transport
along the nephron are presented, followed by examples of disorders of sodium balance that illuminate current understanding
of their pathophysiology. Recently, rapid progress has been
made in unraveling mechanisms of renal volume homeostasis.
Most of the hormones that regulate sodium balance have been
cloned and sequenced. Intracellular signaling mechanisms
responsible for their effects have been characterized. The renal
transport proteins that mediate sodium reabsorption also have
been cloned and sequenced. The remaining challenges are to
integrate this information into models that describe systemic
volume homeostasis and to determine how alterations in one or
more of the well-characterized systems lead to volume expansion or contraction.
Normal Extracellular Fluid Volume Homeostasis

Adult male
Extravascular
(15%)
Plasma (5%)
Blood volume
(9%)
RBC (4%)
Adult female
ECF volume
(20%)
Extravascular
(11%)
Plasma (4%)
Blood volume
(7%)
RBC (3%)
ICF volume
(40%)
ECF volume
(15%)
ICF volume
(35%)
FIGURE 2-1
Fluid volumes in typical adult men and
women, given as percentages of body
weight. In men (A), total body water typically is 60% of body weight (Total body
water = Extracellular fluid [ECF] volume +
Intracellular fluid [ICF] volume). The ECF
volume comprises the plasma volume and
the extravascular volume. The ICF volume
comprises the water inside erythrocytes
(RBCs) and inside other cells. The blood
volume comprises the plasma volume plus
the RBC volume. Thus, the RBC volume is
a unique component of ICF volume that
contributes directly to cardiac output and
blood pressure. Typically, water comprises a
smaller percentage of the body weight in a
woman (B) than in a man; thus, when
expressed as a percentage of body weight,
fluid volumes are smaller. Note, however,
that the percentage of total body water that
is intracellular is approximately 70% in
both men and women [5].
2.3
Disorders of Sodium Balance
ECF volume, L
10
9
8
7
6
5
4
3
2
1
0
13
12
11
10
0
10 15
Days
20
Dietary sodium intake, g
14
25
FIGURE 2-2
Effects of changes in dietary sodium (Na) intake on extracellular fluid (ECF) volume. The
dietary intake of Na was increased from 2 to 5 g, and then returned to 2 g. The relationship between dietary Na intake (dashed line) and ECF volume (solid line) is derived from
the model of Walser [1]. In this model the rate of Na excretion is assumed to be proportional to the content of Na in the body (At) above a zero point (A0) at which Na excretion
ceases. This relation can be expressed as dAt/dt = I - k(At - A0), where I is the dietary Na
intake and t is time. The ECF volume is approximated as the total body Na content divided by the plasma Na concentration. (This assumption is strictly incorrect because approximately 25% of Na is tightly bound in bone; however, this amount is nearly invariant and
can be ignored in the current analysis.) According to this construct, when dietary Na
intake changes from level 1 to level 2, the ECF volume approaches a new steady state
exponentially with a time constant of k according to the following equation:
I
I I
A2 A1 = 2 + 1 2 ekt
k
k
Urinary sodium excretion, g/d

2
3
4
18
100
17
98
Mean arterial pressure, mmHg
15
14
13
12
18%
Urinary sodium excretion, g/d

2
3
4
94
92
90
88
86
1%
84
11
82
10
80
0
96
16
ECF volume, L
3
4
Sodium intake, g/d
FIGURE 2-3
Relation between dietary sodium (Na), extracellular fluid (ECF) volume, and mean arterial pressure (MAP). A, Relation between the
dietary intake of Na, ECF volume, and urinary Na excretion at
steady state in a normal person. Note that 1 g of Na equals 43 mmol
(43 mEq) of Na. At steady state, urinary Na excretion essentially is
identical to the dietary intake of Na. As discussed in Figure 2-2, ECF
volume increases linearly as the dietary intake of Na increases. At an
ECF volume of under about 12 L, urinary Na excretion ceases. The
gray bar indicates a normal dietary intake of Na when consuming a
typical Western diet. The dark blue bar indicates the range of Na
3
4
Sodium intake, g/d
intake when consuming a no added salt diet. The light blue bar
indicates that a low-salt diet generally contains about 2 g/d of Na.
Note that increasing the dietary intake of Na from very low to normal levels leads to an 18% increase in ECF volume. B, Relation
between the dietary intake of Na and MAP in normal persons. MAP
is linearly dependent on Na intake; however, increasing dietary Na
intake from very low to normal levels increases the MAP by only
1%. Thus, arterial pressure is regulated much more tightly than is
ECF volume. (A, Data from Walser [1]; B, Data from Luft and
coworkers [3].)
2.4
UNaV, X normal
6
5
4
3
2
1
0
Nonrenal
fluid loss
+
0
50 100 150 200

MAP, mm Hg
Arterial
pressure
NaCl and
fluid intake
Net volume
intake
Rate of change
of extracellular
fluid volume
Kidney volume
output
Extracellular
fluid volume
+
Total peripheral
resistance
Blood volume
+
Autoregulation
+
Cardiac output
Mean circulatory
filling pressure
Venous return
FIGURE 2-4
Schema for the kidney blood volume pressure feedback mechanism adapted from the
work of Guyton and colleagues [6]. Positive relations are indicated by a plus sign;
inverse relations are indicated by a minus sign. The block diagram shows that increases
Lumen
Na
Blood
DCT
5-7%
Cl
CD
3-5%
PROX
60%
Na
Lumen
Lumen
Na
HCO3
H2CO3
CA
H 2O
H 2O
H
Blood
Blood
K
H+
OH
Lumen
+
Na
K
Cl
CO2
HCO3
Blood
CO2
Na
LOH
25%
in extracellular fluid (ECF) volume result

from increases in sodium chloride (NaCl)
and fluid intake or decreases in kidney volume output. An increase in ECF volume
increases the blood volume, thereby increasing the venous return to the heart and cardiac output. Increases in cardiac output
increase arterial pressure both directly and
by increasing peripheral vascular resistance
(autoregulation). Increased arterial pressure
is sensed by the kidney, leading to increased
kidney volume output (pressure diuresis
and pressure natriuresis), and thus returning the ECF volume to normal. The inset
shows this relation between mean arterial
pressure (MAP), renal volume, and sodium
excretion [4]. The effects of acute increases
in arterial pressure on urinary excretion are
shown by the solid curve. The chronic
effects are shown by the dotted curve; note
that the dotted line is identical to the curve
in Figure 2-3. Thus, when the MAP increases, urinary output increases, leading to
decreased ECF volume and return to the
original pressure set point. UNaVurinary
sodium excretion volume.
FIGURE 2-5
Sodium (Na) reabsorption along the mammalian nephron. About
25 moles of Na in 180 L of fluid daily is delivered into the
glomerular filtrate of a normal person. About 60% of this load is
reabsorbed along the proximal tubule (PROX), indicated in dark
blue; about 25% along the loop of Henle (LOH), including the
thick ascending limb indicated in light blue; about 5% to 7%
along the distal convoluted tubule (DCT), indicated in dark gray;
and 3% to 5% along the collecting duct (CD) system, indicated in
light gray. All Na transporting cells along the nephron express the
ouabain-inhibitable sodium-potassium adenosine triphosphatase
(Na-K ATPase) pump at their basolateral (blood) cell surface. (The
pump is not shown here for clarity.) Unique pathways are
expressed at the luminal membrane that permit Na to enter cells.
The most quantitatively important of these luminal Na entry pathways are shown here. These pathways are discussed in more detail
in Figures 2-15 to 2-19. CAcarbonic anhydrase; Clchloride;
CO2carbon dioxide; Hhydrogen; H2CO3carbonic acid;
HCO3bicarbonate; Kpotassium; OHhydroxyl ion.
2.5
Mechanisms of Extracellular
Fluid Volume Control
Renal tubular sodium reabsoption
ERSNA
Angiotensin II
Activation of
baroreceptors
Renin
Aldosterone
FF
Arterial pressure
ECFV contraction
Normal ECF volume
FIGURE 2-6
Integrated response of the kidneys to changes in extracellular fluid
(ECF) volume. This composite figure illustrates natriuretic and
antinatriuretic mechanisms. For simplicity, the systems are shown
operating only in one direction and not all pathways are shown.
The major antinatriuretic systems are the renin-angiotensin-aldosterone axis and increased efferent renal sympathetic nerve activity
(ERSNA). The most important natriuretic mechanism is pressure
natriuresis, because the level of renal perfusion pressure (RPP)
determines the magnitude of the response to all other natriuretic
systems. Renal interstitial hydrostatic pressure (RIHP) is a link
between the circulation and renal tubular sodium reabsorption.
Atrial natriuretic peptide (ANP) is the major systemic natriuretic
hormone. Within the kidney, kinins and renomedullary
prostaglandins are important modulators of the natriuretic
response of the kidney. AVParginine vasopressin; FFfiltration
fraction. (Modified from Gonzalez-Campoy and Knox [7].)
ECFV expansion
ANP
Arterial pressure
Kinins
RIHP
Prostaglandins
Renal tubular sodium reabsoption
ACE
SVR
+
Angiotensinogen
DRVYIHPFHL
DRVYIHPF
Angiotensin I
Angiotensin II
+
+
Aldo
Renin
UNaV
FIGURE 2-7
Overview of the renin-angiotensin-aldosterone system [8,9].
Angiotensinogen (or renin substrate) is a 56-kD glycoprotein
produced and secreted by the liver. Renin is produced by the
juxtaglomerular apparatus of the kidney, as shown in Figures 2-8
and 2-9. Renin cleaves the 10 N-terminal amino acids from
angiotensinogen. This decapeptide (angiotensin I) is cleaved by
angiotensin converting enzyme (ACE). The resulting angiotensin II
comprises the 8 N-terminal amino acids of angiotensin I. The primary amino acid structures of angiotensins I and II are shown in
single letter codes. Angiotensin II increases systemic vascular resistance (SVR), stimulates aldosterone secretion from the adrenal
gland (indicated in gray), and increases sodium (Na) absorption by
renal tubules, as shown in Figures 2-15 and 2-17. These effects
decrease urinary Na (and chloride excretion; UNaV).
2.6

FIGURE 2-8
The juxtaglomerular (JG) apparatus. This apparatus brings into close apposition the afferent
(A) and efferent (E) arterioles with the macula densa (MD), a specialized region of the thick
ascending limb (TAL). The extraglomerular mesangium (EM), or lacis Goormaghtigh apparatus (cells), forms at the interface of these components. MD cells express the Na-K-2Cl
(sodium-potassium-chloride) cotransporter (NKCC2) at the apical membrane [10,11]. By
way of the action of this transporter, MD cells sense the sodium chloride concentration of
luminal fluid. By way of mechanisms that are unclear, this message is communicated to JG
cells located in and near the arterioles (especially the afferent arteriole). These JG cells
increase renin secretion when the NaCl concentration in the lumen is low [12]. Cells in the
afferent arteriole also sense vascular pressure directly, by way of the mechanisms discussed in
Figure 2-9. Both the vascular and tubular components are innervated by sympathetic nerves
(N). BBowmans space, Gglomerular capillary; IMintraglomerular mesangium. (From
Barajas [13]; with permission.)
B
N
JG
IM
MD
JG
ANP
Prorenin
Renin
Sympathetic
nerves
AC
Renin
cAMP
AT1
All
NO
Ca
PGE2
PGI2
Ca
+
Membrane
depolarization
Membrane
stretch
+
Arterial
pressure
MD NaCl
FIGURE 2-9
Schematic view of a (granular) juxtaglomerular cell showing secretion mechanisms of renin [8]. Renin is generated from prorenin.
Renin secretion is inhibited by increases in and stimulated by
decreases in intracellular calcium (Ca) concentrations. Voltage-sensitive Ca channels in the plasma membrane are activated by membrane stretch, which correlates with arterial pressure and is
assumed to mediate baroreceptor-sensitive renin secretion. Renin
secretion is also stimulated when the concentration of sodium (Na)
and chloride (Cl) at the macula densa (MD) decreases [12,14]. The
mediators of this effect are less well characterized; however, some
studies suggest that the effect of Na and Cl in the lumen is more
potent than is the baroreceptor mechanism [15]. Many other factors affect rates of renin release and contribute to the physiologic
regulation of renin. Renal nerves, by way of receptors coupled
to adenylyl cyclase (AC), stimulate renin release by increasing the
production of cyclic adenosine monophosphate (cAMP), which
reduces Ca release. Angiotensin II (AII) receptors (AT1 receptors)
inhibit renin release, as least in vitro. Prostaglandins E2 and I2
(PGE2 and PGI2, respectively) strongly stimulate renin release
through mechanisms that remain unclear. Atrial natriuretic peptide
(ANP) strongly inhibits renin secretion. Constitutive nitric oxide
(NO) synthase is expressed by macula densa (MD) cells [16]. NO
appears to stimulate renin secretion, an effect that may counteract
inhibition of the renin gene by AII [17,18].

AME or Licorice
Basolateral
FIGURE 2-10
Mechanism of aldosterone action in the distal nephron [19]. Aldosterone, the predominant
human mineralocorticoid hormone, enters distal nephron cells through the plasma membrane and interacts with its receptor (the mineralocorticoid receptor [MR], or Type I
receptor). Interaction between aldosterone and this receptor initiates induction of new
proteins that, by way of mechanisms that remain unclear, increase the number of sodium
channels (ENaC) and sodium-potassium adenosine triphosphatase (Na-K ATPase) pumps
at the cell surface. This increases transepithelial Na (and potassium) transport. Cortisol,
the predominant human glucocorticoid hormone, also enters cells through the plasma
membrane and interacts with its receptor (the glucocorticoid receptor [GR]). Cortisol,
however, also interacts with mineralocorticoid receptors; the affinity of cortisol and aldosterone for mineralocorticoid receptors is approximately equal. In distal nephron cells, this
interaction also stimulates electrogenic Na transport [20]. Cortisol normally circulates at
concentrations 100 to 1000 times higher than the circulating concentration of aldosterone.
In aldosterone-responsive tissues, such as the distal nephron, expression of the enzyme
11-hydroxysteroid dehydrogenase (11-HSD) permits rapid metabolism of cortisol so
that only aldosterone can stimulate Na transport in these cells. An inherited deficiency of
the enzyme 11-HSD (the syndrome of apparent mineralocorticoid excess, AME), or inhibition of the enzyme by ingestion of licorice, leads to hypertension owing to chronic stimulation of distal Na transport by endogenous glucocorticoids [21].
Apical
Cortisone
11 HSD
Cortisol
Cortisol
GR
ENaC
Na/K ATPase
Cortisone
11 HSD
Cortisol
MR
Aldo
Aldo
MR
Distal nephron cell
Preload
SLRRSSCFGGRLDRIGAQSGLGCNSFRY
Plasma ANP
+
Vagal afferent
activity
Capillary
permeability
Renal NaCl
reabsoption
Fluid shift
into
interstitium
Cardiac
output
+
Renin
secretion
Arteriolar
contraction
+
+
Sympathetic
efferent
activity
+
Angiotensin II
+
Aldosterone
+
Vascular
volume
Peripheral
vascular
resistance
+
Preload
+
Blood
pressure
2.7
FIGURE 2-11
Control of systemic hemodynamics by the atrial natriuretic peptide
(ANP) system. Increases in atrial stretch (PRELOAD) increase ANP
secretion by cardiac atria. The primary amino acid sequence of
ANP is shown in single letter code with its disulfide bond indicated
by the lines. The amino acids highlighted in blue are conserved
between ANP, brain natriuretic peptide, and C-type natriuretic peptide. ANP has diverse functions that include but are not limited to
the following: stimulating vagal afferent activity, increasing capillary
permeability, inhibiting renal sodium (Na) and water reabsorption,
inhibiting renin release, and inhibiting arteriolar contraction. These
effects reduce sympathetic nervous activity, reduce angiotensin II
generation, reduce aldosterone secretion, reduce total peripheral
resistance, and shift fluid out of the vasculature into the interstitium. The net effect of these actions is to decrease cardiac output,
vascular volume, and peripheral resistance, thereby returning preload toward baseline. Many effects of ANP (indicated by solid
arrows) are diminished in patients with edematous disorders (there
is an apparent resistance to ANP). Effects indicated by dashed
arrows may not be diminished in edematous disorders; these effects
contribute to shifting fluid from vascular to extravascular tissue,
leading to edema. This observation may help explain the association
between elevated right-sided filling pressures and the tendency for
Na retention [22]. (Modified from Brenner and coworkers [23].)
2.8

Afferent
20
Knockout
Cerebral cortex
Carotid
sinus
16
Hypothalamus
ANP infusion
14
Medulla
IX
12
Carotid
bodies
10
8
6
Thoracic
UNAV, mmol/min/g body wt
Efferent
Wild type
18
4
2
0
30
45
60
75 90 105 120 135 150 165 180

Time, min
Blood vessel
Lumbar
15
FIGURE 2-12
Mechanism of atrial natriuretic peptide (ANP) action on the kidney. Animals with disruption of the particulate form of guanylyl
cyclase (GC) manifest increased mean arterial pressure that is independent of dietary intake of sodium chloride. To test whether ANP
mediates its renal effects by way of the action of GC, ANP was
infused into wild-type and GC-Adeficient mice. In wild-type animals, ANP led to prompt natriuresis. In GC-Adeficient mice, no
effect was observed. UNaVurinary sodium excretion volume.
(Modified from Kishimoto [24].)
Adrenal
Kidney
Sacral
Other somatic
(eg, muscle, splanchnic
viscera, joint receptors)
Spinal
cord
Splanchnic
viscera
FIGURE 2-13
Schematic diagram of neural connections important in circulatory
control. Although the system is bilaterally symmetric, afferent fibers
are shown to the left and efferent fibers to the right. Sympathetic
fibers are shown as solid lines and parasympathetic fibers as dashed
lines. The heart receives both sympathetic and parasympathetic
innervation. Sympathetic fibers lead to vasoconstriction and renal
sodium chloride retention. X indicates the vagus nerve; IX indicates
glossopharyngeal. (From Korner [25]; with permission.)
Normal effective
arterial volume
Low effective
arterial volume
GFR =Filtration fraction

RPF
GFR =Filtration fraction

RPF
Filtration
Filtration
A
onc
onc
Reabsorption
Reabsorption
Pt
Pt
Pi
Backleak
Pi
Backleak
FIGURE 2-14
Cellular mechanisms of increased solute
and water reabsorption by the proximal
tubule in patients with effective arterial
volume depletion. A, Normal effective arterial volume in normal persons. B, Low
effective arterial volume in patients with
both decreased glomerular filtration rates
(GFR) and renal plasma flow (RPF). In contrast to normal persons, patients with low
effective arterial volume have decreased
GFR and RPF, yet the filtration fraction is
increased because the RPF decreases more
than does the GFR. The increased filtration
fraction concentrates the plasma protein
(indicated by the dots) in the peritubular
capillaries leading to increased plasma
oncotic pressure (onc). Increased plasma
oncotic pressure reduces the amount of
backleak from the peritubular capillaries.
Simultaneously, the increase in filtration
fraction reduces volume delivery to the

FIGURE 2-14 (continued)
peritubular capillary, decreasing its hydrostatic pressure, and thereby reducing the renal interstitial hydrostatic pressure (Pi). Even
though the proximal tubule hydrostatic pressure (Pt) may be
2.9
reduced, owing to diminished GFR, the hydrostatic gradient from

tubule to interstitium is increased, favoring increased volume reabsorption. Aafferent arteriole; Eefferent arteriole.
Mechanisms of Sodium and Chloride

Transport along the Nephron
Lumen
Na+
H+
Renal
nerves
See figure 2-13
+
AT1
All
See figure 2-7
DA1
Dopamine
H 2O
FF
~
3Na+
See figure 2-14
2K+
+
Na+
Cl-
Pi
+
Interstitum
onc
FIGURE 2-15
Cellular mechanisms and regulation of sodium chloride (NaCl) and
volume reabsorption along the proximal tubule. The sodium-potassium adenosine triphosphate (Na-K ATPase) pump (shown as
white circle with light blue outline) at the basolateral cell membrane keeps the intracellular Na concentration low; the K concentration high; and the cell membrane voltage oriented with the cell
interior negative, relative to the exterior. Many pathways participate in Na entry across the luminal membrane. Only the sodiumhydrogen (Na-H) exchanger is shown because its regulation in
states of volume excess and depletion has been characterized extensively. Activity of the Na-H exchanger is increased by stimulation
of renal nerves, acting by way of receptors and by increased levels of circulating angiotensin II (AII), as shown in Figures 2-7 and
2-13 [2528]. Increased levels of dopamine (DA1) act to inhibit
activity of the Na-H exchanger [29,30]. Dopamine also acts to
inhibit activity of the Na-K ATPase pump at the basolateral cell
membrane [30]. As described in Figure 2-14, increases in the filtration fraction (FF) lead to increases in oncotic pressure (onc) in peritubular capillaries and decreases in peritubular and interstitial
hydrostatic pressure (Pi). These changes increase solute and volume
absorption and decrease solute backflux. Water flows through
water channels (Aquaporin-1) Na and Cl also traverse the paracellular pathway.
2.10
Lumen
cAMP
Na
?
V2
2Cl
AVP
PGE2
PR
Cl
20-HETE
20-COOH-AA
c-P450
Arachidonic
acid
~
2K+
3Na+
Na
Interstitum
0.16 mol NaCl
H 2O
kD
199-
FIGURE 2-16
Cellular mechanisms and regulation of sodium (Na) and chloride
(Cl) transport by thick ascending limb (TAL) cells. Na, Cl, and
potassium (K) enter cells by way of the bumetanide-sensitive Na-K2Cl cotransporter (NKCC2) at the apical membrane. K recycles back
through apical membrane K channels (ROMK) to permit continued
operation of the transporter. In this nephron segment, the asymmetric operations of the luminal K channel and the basolateral chloride
channel generate a transepithelial voltage, oriented with the lumen
positive. This voltage drives paracellular Na absorption. Although
arginine vasopressin (AVP) is known to stimulate Na reabsorption by
TAL cells in some species, data from studies in human subjects suggest AVP has minimal or no effect [31,32]. The effect of AVP is
mediated by way of production of cyclic adenosine monophosphate
(cAMP). Prostaglandin E2 (PGE2) and cytochrome P450 (c-P450)
metabolites of arachidonic acid (20-HETE [hydroxy-eicosatetraenoic
acid] and 20-COOH-AA) inhibit transepithelial NaCl transport, at
least in part by inhibiting the Na-K-2Cl cotransporter [3335]. PGE2
also inhibits vasopressin-stimulated Na transport, in part by activating Gi and inhibiting adenylyl cyclase [36]. Increases in medullary
NaCl concentration may activate transepithelial Na transport by
increasing production of PGE2. Inset A, Regulation of NKCC2 by
chronic Na delivery. Animals were treated with 0.16 mol NaCl
or water as drinking fluid for 2 weeks. The Western blot shows
upregulation of NKCC2 in the group treated with saline [37].
Giinhibitory G protein; PRprostaglandin receptor; V2 AVP
receptors. (Modified from Ecelbarger [37].)
1208748-
Lumen
+
Aldo receptor
Aldo
Na
See figure Y
Cl
+
~
2K+
3Na+
AT1
All
See figure 2-7
DCT
Interstitum
FIGURE 2-17
Mechanisms and regulation of sodium (Na) and chloride (Cl)
transport by the distal nephron. As in other nephron segments,
intracellular Na concentration is maintained low by the action of
the Na-K ATPase (sodium-potassium adenosine triphosphatase)
pump at the basolateral cell membrane. Na enters distal convoluted tubule (DCT) cells across the luminal membrane coupled directly to chloride by way of the thiazide-sensitive Na-Cl cotransporter.
Activity of the Na-Cl cotransporter appears to be stimulated by
both aldosterone and angiotensin II (AII) [3840]. Transepithelial
Na transport in this segment is also stimulated by sympathetic
nerves acting by way of receptors [41,42]. The DCT is impermeable to water.
2.11
Lumen
Na
Interstitum
Aldo receptor
Aldo
+
~
K
cAMP
Na Na
Na Na
Na Na
Na
cGMP
AR
ANP
GC
2K+
3Na+
GFR
Gi
PGE2
Lumen
PGE2
~
2K+
3Na+
AC
H 2O
Gs
V2
ATP
CCT
AVP
H 2O
V2
AVP
MCT
+
FIGURE 2-18
Principal cortical collecting tubule (CCT) cells. In these cells, sodium (Na) enters across the luminal membrane through Na channels
(ENaC). The movement of cationic Na from lumen to cell depolarizes the luminal membrane, generating a transepithelial electrical
gradient oriented with the lumen negative with respect to interstitium. This electrical gradient permits cationic potassium (K) to diffuse preferentially from cell to lumen through K channels
(ROMK). Na transport is stimulated when aldosterone interacts
with its intracellular receptor [43]. This effect involves both
increases in the number of Na channels at the luminal membrane
and increases in the number of Na-K ATPase (Sodium-potassium
adenosine triphosphatase) pumps at the basolateral cell membrane.
Arginine vasopressin (AVP) stimulates both Na absorption (by
interacting with V2 receptors and, perhaps, V1 receptors) and
water transport (by interacting with V2 receptors) [4446]. V2
receptor stimulation leads to insertion of water channels (aquaporin 2) into the luminal membrane [47]. V2 receptor stimulation is
modified by PGE2 and 2 agonists that interact with a receptor
that stimulates Gi [48]. ACadenylyl cyclase; ATPadenosine
triphosphate; cAMPcyclic adenosine monophosphate; CCTcortical collecting tubule; Giinhibitory G protein; Gsstimulatory
G protein; RRi receptor.
FIGURE 2-19
Cellular mechanism of the medullary collecting tubule (MCT).
Sodium (Na) and water are reabsorbed along the MCT. Atrial natriuretic peptide (ANP) is the best-characterized hormone that affects
Na absorption along this segment [22]. Data on the effects of arginine vasopressin (AVP) and aldosterone are not as consistent
[46,49]. Prostaglandin E2 (PGE2) inhibits Na transport by inner
medullary collecting duct cells and may be an important intracellular mediator for the actions of endothelin and interleukin-1 [50,51].
ANP inhibits medullary Na transport by interacting with a G-proteincoupled receptor that generates cyclic guanosine monophosphate (cGMP). This second messenger inhibits a luminal Na channel
that is distinct from the Na channel expressed by the principal cells
of the cortical collecting tubule, as shown in Figure 2-18 [52,53].
Under normal circumstances, ANP also increases the glomerular filtration rate (GFR) and inhibits Na transport by way of the effects
on the renin-angiotensin-aldosterone axis, as shown in Figures 2-7
to 2-10. These effects increase Na delivery to the MCT. The combination of increased distal Na delivery and inhibited distal reabsorption leads to natriuresis. In patients with congestive heart failure,
distal Na delivery remains depressed despite high levels of circulating ANP. Thus, inhibition of apical Na entry does not lead to natriuresis, despite high levels of MCT cGMP. ARANP receptor;
GCguanylyl cyclase; Kpotassium; V2receptors.
2.12
Causes, Signs, and Symptoms of Extracellular

Fluid Volume Expansion and Contraction
CAUSES OF VOLUME EXPANSION
Primary renal sodium retention (with hypertension but without edema)
Hyperaldosteronism (Conns syndrome)
Cushings syndrome
Inherited hypertension (Liddles syndrome, glucocorticoid remediable hyperaldosteronism, pseudohypoaldosteronism Type II, others)
Renal failure
Nephrotic syndrome (mixed disorder)
Secondary renal sodium retention
Hypoproteinemia
Nephrotic syndrome
Protein-losing enteropathy
Cirrhosis with ascites
Low cardiac output
Hemodynamically significant pericardial effusion
Constrictive pericarditis
Valvular heart disease with congestive heart failure
Severe pulmonary disease
Cardiomyopathies
Peripheral vasodilation
Pregnancy
Gram-negative sepsis
Anaphylaxis
Arteriovenous fistula
Trauma
Cirrhosis
Idiopathic edema (?)
Drugs: minoxidil, diazoxide, calcium channel blockers (?)
Increased capillary permeability
Idiopathic edema (?)
Burns
Allergic reactions, including certain forms of angioedema
Adult respiratory distress syndrome
Interleukin-2 therapy
Malignant ascites
Sequestration of fluid (3rd spacing, urine sodium concentration low)
Peritonitis
Pancreatitis
Small bowel obstruction
Rhabdomyolysis, crush injury
Bleeding into tissues
Venous occlusion
FIGURE 2-20
In volume expansion, total body sodium (Na) content is increased.
In primary renal Na retention, volume expansion is modest and
edema does not develop because blood pressure increases until Na
excretion matches intake. In secondary Na retention, blood pressure may not increase sufficiently to increase urinary Na excretion
until edema develops.
CAUSES OF VOLUME DEPLETION

Extrarenal losses (urine sodium concentration low)
Gastrointestinal salt losses
Vomiting
Diarrhea
Nasogastric or small bowel aspiration
Intestinal fistulae or ostomies
Gastrointestinal bleeding
Skin and respiratory tract losses
Burns
Heat exposure
Adrenal insufficiency
Extensive dermatologic lesions
Cystic fibrosis
Pulmonary bronchorrhea
Drainage of large pleural effusion
Renal losses (urine sodium concentration normal or elevated)
Extrinsic
Solute diuresis (glucose, bicarbonate, urea, mannitol, dextran, contrast dye)
Diuretic agents
Adrenal insufficiency
Selective aldosterone deficiency
Intrinsic
Diuretic phase of oliguric acute renal failure
Postobstructive diuresis
Nonoliguric acute renal failure
Salt-wasting nephropathy
Medullary cystic disease
Tubulointerstitial disease
Nephrocalcinosis
FIGURE 2-21
In volume depletion, total body sodium is decreased.
CLINICAL SIGNS OF VOLUME

EXPANSION
CLINICAL SIGNS OF VOLUME

DEPLETION
Edema
Pulmonary crackles
Ascites
Jugular venous distention
Hepatojugular reflux
Hypertension
Orthostatic decrease in blood pressure and increase

in pulse rate
Decreased pulse volume
Decreased venous pressure
Loss of axillary sweating
Decreased skin turgor
Dry mucous membranes
FIGURE 2-22
Clinical signs of volume expansion.
FIGURE 2-23
Clinical signs of volume depletion.
2.13
LABORATORY SIGNS OF VOLUME

DEPLETION OR EXPANSION
Hypernatremia
Hyponatremia
Acid-base disturbances
Abnormal plasma potassium
Decrease in glomerular filtration rate
Elevated blood urea nitrogencreatinine ratio
Low functional excretion of sodium (FENa)
FIGURE 2-24
Note that laboratory test results for volume
expansion and contraction are similar.
Serum sodium (Na) concentration may be
increased or decreased in either volume
expansion or contraction, depending on the
cause and intake of free water (see Chapter
1). Acid-base disturbances, such as metabolic alkalosis, and hypokalemia are common
in both conditions. The similarity of the laboratory test results of volume depletion and
expansion results from the fact that the
effective arterial volume is depleted in
both states despite dramatic expansion of
the extracellular fluid volume in one.
Unifying Hypothesis of
Renal Sodium Excretion
Myocardial
dysfunction
Extracellular
fluid volume
AV fistula
Cardiac output
High output
failure
Cirrhosis
Pregnancy
Systemic vascular resistance
Mean arterial pressure

+
Sodium excretion
(pressure natriuresis)
FIGURE 2-25
Summary of mechanisms of sodium (Na) retention in volume contraction and in depletion
of the effective arterial volume. In secondary Na retention, Na retention results primarily
from a reduction in mean arterial pressure

(MAP). Some disorders decrease cardiac
output, such as congestive heart failure
owing to myocardial dysfunction; others
decrease systemic vascular resistance, such
as high-output cardiac failure, atriovenous
fistulas, and cirrhosis. Because MAP is the
product of systemic vascular resistance and
cardiac output, all causes lead to the same
result. As shown in Figures 2-3 and 2-4,
small changes in MAP lead to large changes
in urinary Na excretion. Although edematous disorders usually are characterized as
resulting from contraction of the effective
arterial volume, the MAP, as a determinant
of renal perfusion pressure, may be the crucial variable (Figs. 2-26 and 2-28 provide
supportive data). The mechanisms of edema
in nephrotic syndrome are more complex
and are discussed in Figures 2-36 to 2-39.
2.14
Mechanisms of Extracellular Fluid Volume

Expansion in Congestive Heart Failure
130
130
MI
120
115
110
105
100
95
Am J Physiol 1977
120
115
110
105
100
95
90
90
Control
Small MI
Large MI
AVF
Control
FIGURE 2-26
Role of renal perfusion pressure in sodium (Na) retention. A, Results
from studies in rats that had undergone myocardial infarction (MI) or
placement of an arteriovenous fistula (AVF) [54]. Rats with small and
large MIs were identified. Both small and large MIs induced significant Na retention when challenged with Na loads. Renal Na retention
occurred in the setting of mild hypotension. AVF also induced significant Na retention, which was associated with a decrease in mean arterial pressure (MAP) [55,56]. Figure 2-3 has shown that Na excretion
decreases greatly for each mm Hg decrease in MAP. B, Results of two
groups of experiments performed by Levy and Allotey [57,58] in
600
10
UNaV
ANP
MAP
PRA
500
400
6
300
4
200
2
100
0
-5
10
15
20
Days
25
30
35
40
PRA, ng ANG I mL-1h-1
UNaV, mmol/d or plasma ANP, pg/mL or MAP, mmHg;
J Lab Clin Med 1978
125
AVF
125
Balance
Na Ret.
Cirrhosis
Ascites
which experimental cirrhosis was induced in dogs by sporadic feeding

with dimethylnitrosamine. Three cirrhotic stages were identified based
on the pattern of Na retention. In the first, dietary Na intake was balanced by Na excretion. In the second, renal Na retention began, but
still without evidence of ascites or edema. In the last, ascites were
detected. Because Na was retained before the appearance of ascites,
primary renal Na retention was inferred. An alternative interpretation of these data suggests that the modest decrease in MAP is responsible for Na retention in this model. Note that in both heart failure
and cirrhosis, Na retention correlates with a decline in MAP.
FIGURE 2-27
Mechanism of sodium (Na) retention in high-output cardiac failure.
Effects of high-output heart failure induced in dogs by arteriovenous
(AV) fistula [59]. After induction of an AV fistula (day 0), plasma
renin activity (PRA; thick solid line) increased greatly, correlating
temporally with a reduction in urinary Na excretion (UNaV; thin
solid line). During this period, mean arterial pressure (MAP; dotted
line) declined modestly. After day 5, the plasma atrial natriuretic
peptide concentration (ANP; dashed line) increased because of volume expansion, returning urinary Na excretion to baseline levels.
Thus, Na retention, mediated in part by the renin-angiotensin-aldosterone system, led to volume expansion. The volume expansion suppressed the renin-angiotensin-aldosterone system and stimulated
ANP secretion, thereby returning Na excretion to normal. These
experiments suggest that ANP secretion plays an important role in
maintaining Na excretion in compensated congestive heart failure.
This effect of ANP has been confirmed directly in experiments using
anti-ANP antibodies [60]. AIangiotensin I.
UNaV, mol/min
400
FIGURE 2-28
Mechanism of renal resistance to atrial natriuretic peptide (ANP) in experimental low-output heart failure. Low-output heart failure was induced in dogs by thoracic inferior vena
caval constriction (TIVCC), which also led to a significant decrease in renal perfusion
pressure (RPP) (from 127 to 120 mm Hg). ANP infusion into dogs with TIVCC did not
increase urinary sodium (Na) excretion (UNaV, ANP group). In contrast, when the RPP
was returned to baseline by infusing angiotensin II (AII), urinary Na excretion increased
greatly (ANP + AII). To exclude a direct effect of AII on urinary Na excretion, intrarenal
saralasin (SAR) was infused to block renal AII receptors. SAR did not significantly affect
the natriuresis induced by ANP plus AII. An independent effect of SAR on urinary Na
excretion was excluded by infusing ANP plus SAR and AII plus SAR. These treatments
were without effect. These results were interpreted as indicating that the predominant
cause of resistance to ANP in dogs with low-output congestive heart failure is a reduction
in RPP. (Data from Redfield and coworkers [61].)
ANP
300
ANP & SAR

ANP & AII
200
ANP & AII & SAR

AII & SAR
100
0
Baseline
TIVCC
Infusion
Net volume
intake
Nonrenal
fluid loss
Blood volume, L
30
20
20
10
10
0
0
Arterial
pressure
Kidney volume
output
Rate of change
of extracellular
fluid volume
10
20
ECF volume, L
Extracellular
fluid volume
+
Total peripheral
resistance
Autoregulation
+
Cardiac output
Blood volume
+
+
Venous return
Mean circulatory
filling pressure
30
Intersititial volume, L
30
Fluid intake
2.15
FIGURE 2-29
Mechanism of extracellular fluid (ECF) volume expansion in congestive heart failure.
A primary decrease in cardiac output (indicated by dark blue arrow) leads to a
decrease in arterial pressure, which decreases pressure natriuresis and volume excretion. These decreases expand the ECF volume. The inset graph shows that the ratio
of interstitial volume (solid line) to plasma
volume (dotted line) increases as the ECF
volume expands because the interstitial
compliance increases [62]. Thus, although
expansion of the ECF volume increases
blood volume and venous return, thereby
restoring cardiac output toward normal,
this occurs at the expense of a disproportionate expansion of interstitial volume,
often manifested as edema.
2.16
Mechanisms of Extracellular Fluid

Volume Expansion in Cirrhosis
Vasodilation theory
Underfill theory
Hepatic venous
outflow obstruction
Overflow theory
SVR
Hepatic venous
outflow obstruction
Transudation
Transudation
?
+
Renin
ECF volume
Blood volume
?
FIGURE 2-30
Three theories of ascites formation in hepatic cirrhosis. Hepatic
venous outflow obstruction leads to portal hypertension.
According to the underfill theory, transudation from the liver leads
to reduction of the blood volume, thereby stimulating sodium (Na)
retention by the kidney. As indicated by the question mark near the
term blood volume, a low blood volume is rarely detected in clinical or experimental cirrhosis. Furthermore, this theory predicts that
ascites would develop before renal Na retention, when the reverse
generally occurs. According to the overflow theory, increased portal pressure stimulates renal Na retention through incompletely
defined mechanisms. As indicated by the question mark near the
arrow from hepatic venous outflow obstruction to UNaV, the
nature of the portal hypertensioninduced signals for renal Na
retention remains unclear. The vasodilation theory suggests that
portal hypertension leads to vasodilation and relative arterial
hypotension. Evidence for vasodilation in cirrhosis that precedes
renal Na retention is now convincing, as shown in Figures 2-31
and 2-33 [63].
UNaV
Vasodilators
Nitric oxide
Glucagon
CGRP
ANP
VIP
Substance P
Prostaglandin E2
Encephalins
TNF
Andrenomedullin
Vasoconstrictors
SNS
RAAS
Vasopressin
ET-1
C.O.=5.22 L/min
C.O.=6.41 L/min
3.64 L
4.34 L
1.81 L
1.31 L
Central blood
volume
Central blood
volume
Noncentral
blood volume
Noncentral
blood volume
Control subjects, n=16 Cirrhotic patients, n=60
FIGURE 2-31
Alterations in cardiovascular hemodynamics in hepatic cirrhosis. Hepatic dysfunction and
portal hypertension increase the production and impair the metabolism of several vasoactive substances. The overall balance of vasoconstriction and vasodilation shifts in favor of
dilation. Vasodilation may also shift blood away from the central circulation toward the
periphery and away from the kidneys. Some of the vasoactive substances postulated to
participate in the hemodynamic disturbances of cirrhosis include those shown here.
ANPatrial natrivretic peptide; ET-1endothelin-1; CGRPcalcitonin gene related
peptide; RAASrenin/angiotensin/aldosterone system; TNFtumor necrosis factor;
VIP vasoactive intestinal peptide. (Data from Mller and Henriksen [64].)
FIGURE 2-32
Effects of cirrhosis on central and noncentral blood volumes. The central blood volume is
defined as the blood volume in the heart, lungs, and central arterial tree. Compared with
control subjects (A), patients with cirrhosis (B) have decreased central and increased noncentral blood volumes. The higher cardiac output (CO) results from peripheral vasodilation. Perfusion of the kidney is reduced significantly in patients with cirrhosis. (Data from
Hillarp and coworkers [65].)
FIGURE 2-33
Contribution of nitric oxide to vasodilation and sodium (Na)
retention in cirrhosis. Compared with control rats, rats having cirrhosis induced by carbon tetrachloride and phenobarbital exhibited
increased plasma renin activity (PRA) and plasma arginine vasopressin (AVP) concentrations. At steady state, the urinary Na excretion (UNaV) was similar in both groups. After treatment with LNAME for 7 days, plasma renin activity decreased to normal levels, AVP concentrations decreased toward normal levels, and
urinary Na excretion increased by threefold. These changes were
associated with a normalization of mean arterial pressure and cardiac output. (Data compiled from Niederberger and coworkers
[66,67] and Martin and Schrier [68].)
15
Control
Cirrhosis
Cirrhosis & L-name
10
10
UNaV, mmol/d
PRA, ng/min/h or AVP, pg/mL
15
2.17
0
PRA
AVP
UNaV
Blood volume, L
Fluid intake
Net volume
intake
Nonrenal
fluid loss
30
20
20
10
10
0
0
Arterial
pressure
Kidney volume
output
Rate of change
of extracellular
fluid volume
Total peripheral
resistance
30
Extracellular
fluid volume
+
Central
blood volume
Peripheral
blood volume
+
+
Cardiac output
10
20
ECF volume, L
(with low albumin)
30
+
Venous return
Mean circulatory
filling pressure
FIGURE 2-34
Mechanisms of sodium (Na) retention in
cirrhosis. A primary decrease in systemic
vascular resistance (indicated by dark blue
arrow), induced by mediators shown in
Figure 2-31, leads to a decrease in arterial
pressure. The reduction in systemic vascular
resistance, however, is not uniform and
favors movement of blood from the central
(effective) circulation into the peripheral
circulation, as shown in Figure 2-32.
Hypoalbuminemia shifts the interstitial to
blood volume ratio upward (compare the
interstitial volume with normal [dashed
line], and low [solid line], protein levels in
the inset graph). Because cardiac output
increases and venous return must equal cardiac output, dramatic expansion of the
extracellular fluid (ECF) volume occurs.
Mechanisms of Extracellular Fluid Volume

Expansion in Nephrotic Syndrome
FIGURE 2-35
Changes in plasma protein concentration affect the net oncotic pressure difference across
capillaries (c - i) in humans. Note that moderate reductions in plasma protein concentration have little effect on differences in transcapillary oncotic pressure. Only when plasma protein concentration decreases below 5 g/dL do changes become significant. (Data
from Fadnes and coworkers [69].)
14
C - i, mmHg
12
10
8
6
4
2
0
2
4
6
8
Plasma protein concentration, g/dL
2.18
300
20
35
30
30
15
10
150
100
ANP
25
25
20
20
15
15
10
10
50
5
0
0
-6
-5
-4 -3
-2
-1 0
Days
20 mEq
300 mEq
Controls
100
100
Control
PAN
80
60
60
40
40
20
20
0
Proximal
Loop
Distal
CD (*)
Fractional absorption, %
80
GFR
FIGURE 2-36
Time course of recovery from minimal change nephrotic syndrome
in five children. Note that urinary Na excretion (squares) increases
before serum albumin concentration increases. The data suggest
that the natriuresis reflects a change in intrinsic renal Na retention.
The data also emphasize that factors other than hypoalbuminemia
must contribute to the Na retention that occurs in nephrosis.
UNaVurinary Na excretion volume. (Data from Oliver and
Owings [70].)
GFR, % of control
ANP, fmol/mL
200
PRA, ng/L sec
250
Albumin, g/L ( )
UNaV, mmol/24 hrs ( )
PRA
AGN
NS
FIGURE 2-37
Plasma renin activity (PRA) and atrial natriuretic peptide (ANP)
concentration in the nephrotic syndrome. Shown are PRA and
ANP concentration (standard error) in normal persons ingesting
diets high (300 mEq/d) and low (20 mEq/d) in sodium (Na) and in
patients with acute glomerulonephritis (AGN), predominantly poststreptococcal, or nephrotic syndrome (NS). Note that PRA is suppressed in patients with AGN to levels below those in normal persons on diets high in Na. PRA suppression suggests that primary
renal NaCl retention plays an important role in the pathogenesis of
volume expansion in AGN. Although plasma renin activity in
patients with nephrotic syndrome is not suppressed to the same
degree, the absence of PRA elevation in these patients suggests that
primary renal Na retention plays a significant role in the pathogenesis of Na retention in NS as well. (Data from Rodrgeuez-Iturbe
and coworkers [71].)
FIGURE 2-38
Sites of sodium (Na) reabsorption along the nephron in control
and nephrotic rats (induced by puromycin aminonucleoside
[PAN]). The glomerular filtration rates (GFR) in normal and
nephrotic rats are shown by the hatched bars. Note the modest
reduction in GFR in the nephrotic group, a finding that is common
in human nephrosis. Fractional reabsorption rates along the proximal tubule, the loop of Henle, and the superficial distal tubule are
indicated. The fractional reabsorption along the collecting duct
(CD) is estimated from the difference between the end distal and
urine deliveries. The data suggest that the predominant site of
increased reabsorption is the collecting duct. Because superficial
and deep nephrons may differ in reabsorptive rates, these data
would also be consistent with enhanced reabsorption by deep
nephrons. Asteriskdata inferred from the difference between distal and urine samples. (Data from Ichikawa and coworkers [72].)
Blood volume, L
Fluid intake
Net volume
intake
Nonrenal
fluid loss
30
20
20
10
10
0
0
Arterial
pressure
Kidney volume
output
Rate of change
of extracellular
fluid volume
10
20
ECF volume, L
Extracellular
fluid volume
+
Total peripheral
resistance
Blood volume
+
+
Cardiac output
+
Venous return
Mean circulatory
filling pressure
30
30
2.19
FIGURE 2-39
Mechanisms of extracellular fluid (ECF) volume expansion in nephrotic syndrome.
Nephrotic syndrome is characterized by
hypoalbuminemia, which shifts the relation
between blood and interstitial volume
upward (dashed to solid lines in inset). As
discussed in Figure 2-35, these effects of
hypoalbuminemia are evident when serum
albumin concentrations decrease by more
than half. In addition, however, hypoalbuminemia may induce vasodilation and arterial hypotension that lead to sodium (Na)
retention, independent of transudation of
fluid into the interstitium [73,74]. Unlike
other states of hypoproteinemia and vasodilation, however, nephrotic syndrome usually
is associated with normotension or hypertension. Coupled with the observation made in
Figure 2-36 that natriuresis may take place
before increases in serum albumin concentration in patients with nephrotic syndrome,
these data implicate an important role for
primary renal Na retention in this disorder
(dark blue arrow). As suggested by Figure 237, the decrease in urinary Na excretion may
play a larger role in patients with acute
glomerulonephritis than in patients with
minimal change nephropathy [71].
Extracellular Fluid Volume

Homeostasis in Chronic Renal Failure
FIGURE 2-40
Relation between glomerular filtration rate (GFR) and fractional sodium (Na) excretion
(FENa). The normal FENa is less than 1%. Adaptations in chronic renal failure maintain
urinary Na excretion equal to dietary intake until end-stage renal disease is reached. To
achieve this, the FENa must increase as the GFR decreases.
35
30
FENA, %
25
20
15
10
5
0
0
20
40
60
80
GFR, mL/min
100 120
2.20
18
15
Normal
14
Mild CRF
Severe CRF
17
13
12
11
10
15
9
8
14
7
13
Dietary sodium intake, g
ECF volume, L
16
12
FIGURE 2-41
Effects of dietary sodium (Na) intake on extracellular fluid (ECF)
volume in chronic renal failure (CRF) [75]. Compared with normal
persons, patients with CRF have expanded ECF volume at normal
Na intake. Furthermore, the time necessary to return to neutral
balance on shifting from one to another level of Na intake is
increased. Thus, whereas urinary Na excretion equals dietary
intake of Na within 3 to 5 days in normal persons, this process
may take up to 2 weeks in patients with CRF. This time delay
means that not only are these patients susceptible to volume overload, but also to volume depletion. This phenomenon can be modeled simply by reducing the time constant (k) given in the equation
in Figure 2-2, and leaving the set point (A0) unchanged. The curves
here represent time constants of 0.79 0.05 day-1 (normal), 0.5
day-1 (mild CRF), and 0.25 day-1 (severe CRF).
3
2
11
10
0
10
15
20
25
Days
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Disorders of Potassium
Metabolism
Fredrick V. Osorio
Stuart L. Linas
otassium, the most abundant cation in the human body, regulates intracellular enzyme function and neuromuscular tissue
excitability. Serum potassium is normally maintained within the
narrow range of 3.5 to 5.5 mEq/L. The intracellular-extracellular
potassium ratio (Ki/Ke) largely determines neuromuscular tissue
excitability [1]. Because only a small portion of potassium is extracellular, neuromuscular tissue excitability is markedly affected by small
changes in extracellular potassium. Thus, the body has developed
elaborate regulatory mechanisms to maintain potassium homeostasis.
Because dietary potassium intake is sporadic and it cannot be rapidly
excreted renally, short-term potassium homeostasis occurs via transcellular potassium shifts [2]. Ultimately, long-term maintenance of
potassium balance depends on renal excretion of ingested potassium.
The illustrations in this chapter review normal transcellular potassium
homeostasis as well as mechanisms of renal potassium excretion.
With an understanding of normal potassium balance, disorders of
potassium metabolism can be grouped into those that are due to
altered intake, altered excretion, and abnormal transcellular distribution. The diagnostic algorithms that follow allow the reader to limit
the potential causes of hyperkalemia and hypokalemia and to reach a
diagnosis as efficiently as possible. Finally, clinical manifestations of
disorders of potassium metabolism are reviewed, and treatment algorithms for hypokalemia and hyperkalemia are offered.
Recently, the molecular defects responsible for a variety of diseases
associated with disordered potassium metabolism have been discovered [38]. Hypokalemia and Liddles syndrome [3] and hyperkalemia and pseudohypoaldosteronism type I [4] result from mutations at different sites on the epithelial sodium channel in the distal
tubules. The hypokalemia of Bartters syndrome can be accounted for
by two separate ion transporter defects in the thick ascending limb of
Henles loop [5]. Gitelmans syndrome, a clinical variant of Bartters
CHAPTER
3.2
syndrome, is caused by a mutation in an ion cotransporter in a

completely different segment of the renal tubule [6]. The genetic mutations responsible for hypokalemia in the syndrome of
apparent mineralocorticoid excess [7] and glucocorticoidremediable aldosteronism [8] have recently been elucidated
and are illustrated below.
Overview of Potassium Physiology

PHYSIOLOGY OF POTASSIUM BALANCE:
DISTRIBUTION OF POTASSIUM
ECF 350 mEq (10%)
ICF 3150 mEq (90%)
Plasma 15 mEq (0.4%)

Interstitial fluid 35 mEq (1%)
Bone 300 mEq (8.6%)
[K+] = 3.55.0 mEq/L
Urine 9095 mEq/d
Stool 510mEq/d
Sweat < 5 mEq/d
Muscle 2650 mEq (76%)

Liver 250 mEq (7%)
Erythrocytes 250 mEq (7%)
[K+] = 140150 mEq/L
Urine 9095 mEq/d
Stool 510mEq/d
Sweat < 5 mEq/d
FIGURE 3-2
Factors that cause transcellular potassium shifts.
FACTORS CAUSING TRANSCELLULAR

POTASSIUM SHIFTS
Factor
Acid-base status
Metabolic acidosis
Hyperchloremic acidosis
Organic acidosis
Respiratory acidosis
Metabolic alkalosis
Respiratory alkalosis
Pancreatic hormones
Insulin
Glucagon
Catecholamines
-Adrenergic
-Adrenergic
Hyperosmolarity
Aldosterone
Exercise
FIGURE 3-1
External balance and distribution of potassium. The usual Western
diet contains approximately 100 mEq of potassium per day. Under
normal circumstances, renal excretion accounts for approximately
90% of daily potassium elimination, the remainder being excreted
in stool and (a negligible amount) in sweat. About 90% of total
body potassium is located in the intracellular fluid (ICF), the
majority in muscle. Although the extracellular fluid (ECF) contains
about 10% of total body potassium, less than 1% is located in the
plasma [9]. Thus, disorders of potassium metabolism can be classified as those that are due 1) to altered intake, 2) to altered elimination, or 3) to deranged transcellular potassium shifts.
Plasma K+
Diseases of Potassium Metabolism
3.3
FIGURE 3-3
Extrarenal potassium homeostasis: insulin and catecholamines.
Schematic representation of the cellular mechanisms by which insulin
and -adrenergic stimulation promote potassium uptake by
extrarenal tissues. Insulin binding to its receptor results in hyperpolarization of cell membranes (1), which facilitates potassium uptake.
After binding to its receptor, insulin also activates Na+-K+-ATPase
pumps, resulting in cellular uptake of potassium (2). The second
messenger that mediates this effect has not yet been identified.
Catecholamines stimulate cellular potassium uptake via the 2 adrenergic receptor (2R). The generation of cyclic adenosine monophosphate (3, 5 cAMP) activates Na+-K+-ATPase pumps (3), causing an
influx of potassium in exchange for sodium [10]. By inhibiting the
degradation of cyclic AMP, theophylline potentiates catecholaminestimulated potassium uptake, resulting in hypokalemia (4).
FIGURE 3-4
Renal potassium handling. More than half of filtered potassium is
passively reabsorbed by the end of the proximal convolted tubule
(PCT). Potassium is then added to tubular fluid in the descending
limb of Henles loop (see below). The major site of active potassium reabsorption is the thick ascending limb of the loop of Henle
(TAL), so that, by the end of the distal convoluted tubule (DCT),
only 10% to 15% of filtered potassium remains in the tubule
lumen. Potassium is secreted mainly by the principal cells of the
cortical collecting duct (CCD) and outer medullary collecting duct
(OMCD). Potassium reabsorption occurs via the intercalated cells
of the medullary collecting duct (MCD). Urinary potassium represents the difference between potassium secreted and potassium
reabsorbed [11]. During states of total body potassium depletion,
potassium reabsorption is enhanced. Reabsorbed potassium initially enters the medullary interstitium, but then it is secreted into the
pars recta (PR) and descending limb of the loop of Henle (TDL).
The physiologic role of medullary potassium recycling may be to
minimize potassium backleak out of the collecting tubule lumen
or to enhance renal potassium secretion during states of excess
total body potassium [12]. The percentage of filtered potassium
remaining in the tubule lumen is indicated in the corresponding
nephron segment.
3.4
FIGURE 3-5
Cellular mechanisms of renal potassium transport: proximal tubule
and thick ascending limb. A, Proximal tubule potassium reabsorption is closely coupled to proximal sodium and water transport.
Potassium is reabsorbed through both paracellular and cellular
pathways. Proximal apical potassium channels are normally
almost completely closed. The lumen of the proximal tubule is negative in the early proximal tubule and positive in late proximal
tubule segments. Potassium transport is not specifically regulated in
this portion of the nephron, but net potassium reabsorption is
closely coupled to sodium and water reabsorption. B, In the thick
ascending limb of Henles loop, potassium reabsorption proceeds
by electroneutral Na+-K+-2Cl- cotransport in the thick ascending
limb, the low intracellular sodium and chloride concentrations providing the driving force for transport. In addition, the positive
lumen potential allows some portion of luminal potassium to be
reabsorbed via paracellular pathways [11]. The apical potassium
channel allows potassium recycling and provides substrate to the
apical Na+-K+-2Cl- cotransporter [12]. Loop diuretics act by competing for the Cl- site on this carrier.
FIGURE 3-6
Cellular mechanisms of renal potassium transport: cortical collecting tubule. A, Principal cells of the cortical collecting duct: apical
sodium channels play a key role in potassium secretion by increasing the intracellular sodium available to Na+-K+-ATPase pumps and
by creating a favorable electrical potential for potassium secretion.
Basolateral Na+-K+-ATPase creates a favorable concentration gradient for passive diffusion of potassium from cell to lumen through
potassium-selective channels. B, Intercalated cells. Under conditions
of potassium depletion, the cortical collecting duct becomes a site
for net potassium reabsorption. The H+-K+-ATPase pump is regulated by potassium intake. Decreases in total body potassium
increase pump activity, resulting in enhanced potassium reabsorption. This pump may be partly responsible for the maintenance of
metabolic alkalosis in conditions of potassium depletion [11].
3.5
Hypokalemia: Diagnostic Approach
FIGURE 3-7
Overview of diagnostic approach to hypokalemia: hypokalemia without total body
potassium depletion. Hypokalemia can result from transcellular shifts of potassium into
cells without total body potassium depletion or from decreases in total body potassium.
Perhaps the most dramatic examples occur in catecholamine excess states, as after administration of 2adreneric receptor (2AR) agonists or during stress. It is important to note
that, during some conditions (eg, ketoacidosis), transcellular shifts and potassium
depletion exist simultaneously. Spurious
hypokalemia results when blood specimens from leukemia patients are allowed
to stand at room temperature; this results
in leukocyte uptake of potassium from
serum and artifactual hypokalemia.
Patients with spurious hypokalemia do
not have clinical manifestations of hypokalemia, as their in vivo serum potassium
values are normal. Theophylline poisoning prevents cAMP breakdown (see Fig.
3-3). Barium poisoning from the ingestion of soluble barium salts results in
severe hypokalemia by blocking channels
for exit of potassium from cells. Episodes
of hypokalemic periodic paralysis can
be precipitated by rest after exercise,
carbohydrate meal, stress, or administration of insulin. Hypokalemic periodic
paralysis can be inherited as an autosomal-dominant disease or acquired by
patients with thyrotoxicosis, especially
Chinese males. Therapy of megaloblastic
anemia is associated with potassium
uptake by newly formed cells, which is
occasionally of sufficient magnitude to
cause hypokalemia [13].
FIGURE 3-8
Diagnostic approach to hypokalemia: hypokalemia with total body potassium depletion secondary to extrarenal losses. In the absence of redistribution, measurement of urinary potassium
is helpful in determining whether hypokalemia is due to renal or to extrarenal potassium losses. The normal kidney responds to several (3 to 5) days of potassium depletion with appropriate renal potassium conservation. In the absence of severe polyuria, a spot urinary potassium
concentration of less than 20 mEq/L

indicates renal potassium conservation. In
certain circumstances (eg, diuretics abuse),
renal potassium losses may not be evident
once the stimulus for renal potassium
wasting is removed. In this circumstance,
urinary potassium concentrations may be
deceptively low despite renal potassium
losses. Hypokalemia due to colonic villous
adenoma or laxative abuse may be associated with metabolic acidosis, alkalosis, or
no acid-base disturbance. Stool has a relatively high potassium content, and fecal
potassium losses could exceed 100 mEq
per day with severe diarrhea. Habitual
ingestion of clay (pica), encountered in
some parts of the rural southeastern
United States, can result in potassium
depletion by binding potassium in the gut,
much as a cation exchange resin does.
Inadequate dietary intake of potassium,
like that associated ith anorexia or a tea
and toast diet, can lead to hypokalemia,
owing to delayed renal conservation of
potassium; however, progressive potassium
depletion does not occur unless intake is
well below 15 mEq of potassium per day.
3.6
FIGURE 3-9
Diagnostic approach to hypokalemia: hypokalemia due to renal losses with normal acidbase status or metabolic acidosis. Hypokalemia is occasionally observed during the diuretic recovery phase of acute tubular necrosis (ATN) or after relief of acute obstructive
uropathy, presumably secondary to

increased delivery of sodium and water to
the distal nephrons. Patients with acute
monocytic and myelomonocytic leukemias
occasionally excrete large amounts of
lysozyme in their urine. Lysozyme appears
to have a direct kaliuretic effect on the
kidneys (by an undefined mechanism).
Penicillin in large doses acts as a poorly
reabsorbable anion, resulting in obligate
renal potassium wasting. Mechanisms for
renal potassium wasting associated with
aminoglycosides and cisplatin are illdefined. Hypokalemia in type I renal
tubular acidosis is due in part to secondary
hyperaldosteronism, whereas type II renal
tubular acidosis can result in a defect in
potassium reabsorption in the proximal
nephrons. Carbonic anhydrase inhibitors
result in an acquired form of renal tubular
acidosis. Ureterosigmoidostomy results in
hypokalemia in 10% to 35% of patients,
owing to the sigmoid colons capacity for
net potassium secretion. The osmotic diuresis associated with diabetic ketoacidosis
results in potassium depletion, although
patients may initially present with a normal
serum potassium value, owing to altered
transcellular potassium distribution.
FIGURE 3-10
Hypokalemia and magnesium depletion. Hypokalemia and magnesium depletion can occur concurrently in a variety of clinical
settings, including diuretic therapy, ketoacidosis, aminoglycoside
therapy, and prolonged osmotic diuresis (as with poorly controlled diabetes mellitus). Hypokalemia is also a common finding
in patients with congenital magnesium-losing kidney disease. The
patient depicted was treated with cisplatin 2 months before presentation. Attempts at oral and intravenous potassium replacement of up to 80 mEq/day were unsuccessful in correcting the
hypokalemia. Once serum magnesium was corrected, however,
serum potassium quickly normalized [14].
3.7
FIGURE 3-11
Diagnostic approach to hypokalemia:
hypokalemia due to renal losses with metabolic alkalosis. The urine chloride value is
helpful in distinguishing the causes of
hypokalemia. Diuretics are a common
cause of hypokalemia; however, after discontinuing diuretics, urinary potassium and
chloride may be appropriately low. Urine
diuretic screens are warranted for patients
suspected of surreptious diuretic abuse.
Vomiting results in chloride and sodium
depletion, hyperaldosteronism, and renal
potassium wasting. Posthypercapnic states
are often associated with chloride depletion
(from diuretics) and sodium avidity. If
hypercapnia is corrected without replacing
chloride, patients develop chloride-depletion alkalosis and hypokalemia.
FIGURE 3-12
Mechanisms of hypokalemia in Bartters syndrome and Gitelmans syndrome. A, A defective Na+-K+-2Cl- cotransporter in the thick ascending limb (TAL) of Henles loop can
account for virtually all features of Bartters syndrome. Since approximately 30% of filtered sodium is reabsorbed by this segment of the nephron, defective sodium reabsorption
results in salt wasting and elevated renin

and aldosterone levels. The hyperaldosteronism and increased distal sodium delivery
account for the characteristic hypokalemic
metabolic alkalosis. Moreover, impaired
sodium reabsorption in the TAL results in
the hypercalciuria seen in these patients, as
approximately 25% of filtered calcium is
reabsorbed in this segment in a process
coupled to sodium reabsorption. Since
potassium levels in the TAL are much lower
than levels of sodium or chloride, luminal
potassium concentrations are rate limiting
for Na+-K+-2Cl- co-transporter activity.
Defects in ATP-sensitive potassium channels
would be predicted to alter potassium recycling and diminish Na+-K+-2Cl- cotransporter activity. Recently, mutations in the
gene that encodes for the Na+-K+-2Clcotransporter and the ATP-sensitive potassium channel have been described in kindreds
with Bartters syndrome. Because loop
diuretics interfere with the Na+-K+-2Clcotransporter, surrepititious diuretic abusers
have a clinical presentation that is virtually
indistinguishable from that of Bartters
syndrome. B, Gitelmans syndrome, which
typically presents later in life and is associated with hypomagnesemia and hypocalciuria, is due to a defect in the gene encoding
for the thiazide-sensitive Na+-Cl- cotransporter. The mild volume depletion results in
more avid sodium and calcium reabsorption
by the proximal nephrons.
3.8
FIGURE 3-13
Diagnostic approach to hypokalemia: hypokalemia due to renal losses with hypertension and metabolic alkalosis.
FIGURE 3-14
Distinguishing characteristics of
hypokalemia associated with hypertension
and metabolic alkalosis.
CHARACTERISTICS OF HYPOKALEMIA WITH

HYPERTENSION AND METABOLIC ALKALOSIS
Primary aldosteronism
11 -hydroxysteroid
dehydrogenase deficiency
Glucocorticoid remediable
aldosteronism
Liddles syndrome
Aldosterone
Renin
Response to
Dexamethasone
3.9
FIGURE 3-15
Mechanism of hypokalemia in Liddles syndrome. The amiloridesensitive sodium channel on the apical membrane of the distal
tubule consists of homologous , , and subunits. Each subunit
is composed of two transmembrane-spanning domains, an extracellular loop, and intracellular amino and carboxyl terminals.
Truncation mutations of either the or subunit carboxyl terminal result in greatly increased sodium conductance, which creates
a favorable electrochemical gradient for potassium secretion.
Although patients with Liddles syndrome are not universally
hypokalemic, they may exhibit severe potassium wasting with
thiazide diuretics. The hypokalemia, hypertension, and metabolic
alkalosis that typify Liddles syndrome can be corrected with
amiloride or triamterene or restriction of sodium.
FIGURE 3-16
Mechanism of hypokalemia in the syndrome of apparent mineralocorticoid excess (AME). Cortisol and aldosterone have equal affinity for the intracellular mineralocorticoid receptor (MR);
however, in aldosterone-sensitive tissues such as the kidney, the
enzyme 11 -hydroxysteroid dehydrogenase (11 -HSD) converts
cortisol to cortisone. Since cortisone has a low affinity for the MR,
the enzyme 11 -HSD serves to protect the kidney from the effects
of glucocorticoids. In hereditary or acquired AME, 11 -HSD is
defective or is inactiveted (by licorice or carbenoxalone). Cortisol,
which is present at concentrations approximately 1000-fold that
of aldosterone, becomes a mineralocorticoid. The hypermineralocorticoid state results in increased transcription of subunits of the
sodium channel and the Na+-K+-ATPase pump. The favorable electrochemical gradient then favors potassium secretion [7,15].
3.10
FIGURE 3-17
Genetics of glucocorticoid-remediable aldosteronism (GRA): schematic representation of
unequal crossover in GRA. The genes for aldosterone synthase (Aldo S) and 11 -hydroxylase
(11 -OHase) are normally expressed in separate zones of the adrenal cortex. Aldosterone is
produced in the zona glomerulosa and cortisol, in the zona fasciculata. These enzymes
have identical intron-extron structures and are
closely linked on chromosome 8. If unequal
crossover occurs, a new hybrid gene is produced that includes the 5 segment of the 11
-OHase gene (ACTH-response element and
the 11 -OHase segment) plus the 3 segment
of the Aldo S gene (aldosterone synthase segment). The chimeric gene is now under the
contol of ACTH, and aldosterone secretion is
enhanced, thus causing hypokalemia and
hypertension. By inhibiting pituitary release of
ACTH, glucocorticoid administration leads to
a fall in aldosterone levels and correction of
the clinical and biochemical abnormalities of
GRA. The presence of Aldo S activity in the
zona fasciculata gives rise to characteristic elevations in 18-oxidation products of cortisol
(18-hydroxycortisol and 18-oxocortisol),
which are diagnostic for GRA [8].
Hypokalemia: Clinical Manifestations

CLINICAL MANIFESTATIONS OF HYPOKALEMIA
Cardiovascular
Abnormal electrocardiogram
Predisposition for digitalis toxicity
Atrial ventricular arrhythmias
Hypertension
Neuromuscular
Smooth muscle
Constipation/ileus
Bladder dysfunction
Skeletal muscle
Weakness/cramps
Tetany
Paralysis
Myalgias/rhabdomyolysis
Renal/electrolyte
Functional alterations
Decreased glomerular filtration rate
Decreased renal blood flow
Renal concentrating defect
Increased renal ammonia production
Chloride wasting
Metabolic alkalosis
Hypercalciuria
Phosphaturia
Structural alterations
Dilation and vacuolization of
proximal tubules
Medullary cyst formation
Interstitial nephritis
Endocrine/metabolic
Decreased insulin secretion
Carbohydrate intolerance
Increased renin
Decreased aldosterone
Altered prostaglandin synthesis
Growth retardation
FIGURE 3-18
Clinical manifestations of hypokalemia.
FIGURE 3-19
Electrocardiographic changes associated with hypokalemia. A, The
U wave may be a normal finding and is not specific for hypokalemia.
B, When the amplitude of the U wave exceeds that of the T wave,
hypokalemia may be present. The QT interval may appear to be
prolonged; however, this is often due to mistaking the QU interval
for the QT interval, as the latter does not change in duration with
hypokalemia. C, Sagging of the ST segment, flattening of the T wave,
and a prominent U wave are seen with progressive hypokalemia.
D, The QRS complex may widen slightly, and the PR interval is
often prolonged with severe hypokalemia. Hypokalemia promotes
the appearance of supraventricular and ventricular ectopic rhythms,
especially in patients taking digitalis [16].
3.11
FIGURE 3-20
Renal lesions associated with hypokalemia. The predominant pathologic finding accompanying potassium depletion in humans is vacuolization of the epithelium of the proximal
convoluted tubules. The vacoules are large and coarse, and staining for lipids is usually
negative. The tubular vacuolation is reversible with sustained correction of the
hypokalemia; however, in patients with long-standing hypokalemia, lymphocytic infiltration, interstitial scarring, and tubule atrophy have been described. Increased renal ammonia production may promote complement activation via the alternate pathway and can
contribute to the interstitial nephritis [17,18].
Hypokalemia: Treatment
FIGURE 3-21
Treatment of hypokalemia: estimation of potassium deficit. In the
absence of stimuli that alter intracellular-extracellular potassium distribution, a decrease in the serum potassium concentration from 3.5
to 3.0 mEq/L corresponds to a 5% reduction (~175 mEq) in total
body potassium stores. A decline from 3.0 to 2.0 mEq/L signifies an
additional 200 to 400-mEq deficit. Factors such as the rapidity of
the fall in serum potassium and the presence or absence of symptoms
dictate the aggressiveness of replacement therapy. In general,
hypokalemia due to intracellular shifts can be managed by treating
the underlying condition (hyperinsulinemia, theophylline intoxication). Hypokalemic periodic paralysis and hypokalemia associated
with myocardial infarction (secondary to endogenous -adrenergic
agonist release) are best managed by potassium supplementation [19].
3.12

FIGURE 3-22
Treatment of hypokalemia.
Hyperkalemia: Diagnostic Approach
FIGURE 3-23
Approach to hyperkalemia: hyperkalemia without total body potassium excess. Spurious
hyperkalemia is suggested by the absence of electrocardiographic (ECG) findings in patients
with elevated serum potassium. The most common cause of spurious hyperkalemia is
hemolysis, which may be apparent on visual inspection of serum. For patients with extreme
leukocytosis or thrombocytosis, potassium levels should be measured in plasma samples
that have been promptly separated from the cellular components since extreme elevations in
either leukocytes or platelets results in leakage of potassium from these cells. Familial
pseudohyperkalemia is a rare condition of
increased potassium efflux from red blood
cells in vitro. Ischemia due to tight or
prolonged tourniquet application or fist
clenching increases serum potassium concentrations by as much as 1.0 to 1.6 mEq/L.
Hyperkalemia can also result from decreases
in K movement into cells or increases in
potassium movement from cells. Hyperchloremic metabolic acidosis (in contrast to
organic acid, anion-gap metabolic acidosis)
causes potassium ions to flow out of cells.
Hypertonic states induced by mannitol,
hypertonic saline, or poor blood sugar control promote movement of water and potassium out of cells. Depolarizing muscle relaxants such as succinylcholine increase permeability of muscle cells and should be avoided
by hyperkalemic patients. The mechanism
of hyperkalemia with -adrenergic blockade
is illustrated in Figure 3-3. Digitalis impairs
function of the Na+-K+-ATPase pumps and
blocks entry of potassium into cells. Acute
fluoride intoxication can be treated with
cation-exchange resins or dialysis, as
attempts at shifting potassium back into
cells may not be successful.
3.13
FIGURE 3-24
Approach to hyperkalemia: hyperkalemia
with reduced glomerular filtration rate
(GFR). Normokalemia can be maintained
in patients who consume normal quantities
of potassium until GFR decreases to less
than 10 mL/min; however, diminished GFR
predisposes patients to hyperkalemia from
excessive exogenous or endogenous potassium loads. Hidden sources of endogenous and
exogenous potassiumand drugs that predispose to hyperkalemiaare listed.
FIGURE 3-25
Approach to hyperkalemia: hyporeninemic
hypoaldosteronism. Hyporeninemic hypoaldosteronism accounts for the majority of
cases of unexplained hyperkalemia in patients
with reduced glomerular filtration rate (GFR)
whose level of renal insufficiency is not what
would be expected to cause hyperkalemia.
Interstitial renal disease is a feature of most
of the diseases listed. The transtubular
potassium gradient (see Fig. 3-26) can be
used to distinguish between primary tubule
defects and hyporeninemic hypoaldosteronism. Although the transtubular potassium
gradient should be low in both disorders,
exogenous mineralocorticoid would normalize transtubular potassium gradient in
hyporeninemic hypoaldosteronism.
3.14

FIGURE 3-26
Physiologic basis of the transtubular potassium concentration
gradient (TTKG). Secretion of potassium in the cortical collecting
duct and outer medullary collecting duct accounts for the vast
majority of potassium excreted in the urine. Potassium secretion in
these segments is influenced mainly by aldosterone, plasma potassium concentrations, and the anion composition of the fluid in the
lumen. Use of the TTKG assumes that negligible amounts of potassium are secreted or reabsorbed distal to these sites. The final urinary
potassium concentration then depends on water reabsorption in the
medullary collecting ducts, which results in a rise in the final urinary
potassium concentration without addition of significant amounts of
potassium to the urine. The TTKG is calculated as follows:
TTKG = ([K+]urine/(U/P)osm)/[K+]plasma
The ratio of (U/P)osm allows for correction of the final urinary
potassium concentration for the amount of water reabsorbed in
the medullary collecting duct. In effect, the TTKG is an index of the
gradient of potassium achieved at potassium secretory sites, independent of urine flow rate. The urine must at least be iso-osmolal with
respect to serum if the TTKG is to be meaningful [20].
CAUSES FOR HYPERKALEMIA WITH AN

INAPPROPRIATELY LOW TTKG THAT IS UNRESPONSIVE
TO MINERALOCORTICOID CHALLENGE
Potassium-sparing diuretics
Amiloride
Triamterene
Spironolactone
Tubular resistance to aldosterone
Sickle cell disease
Urinary tract obstruction
Pseudohypoaldosteronism type I
Drugs
Trimethoprim
Pentamidine
Increased distal nephron potassium

reabsorption
Pseudohypoaldosteronism type II
FIGURE 3-27
Clinical application of the transtubular potassium gradient (TTKG).
The TTKG in normal persons varies much but is genarally within
the the range of 6 to 12. Hypokalemia from extrarenal causes results
in renal potassium conservation and a TTKG less than 2. A higher
value suggests renal potassium losses, as through hyperaldosteronism. The expected TTKG during hyperkalemia is greater than 10.
An inappropriately low TTKG in a hyperkalemic patient suggests
hypoaldosteronism or a renal tubule defect. Administration of the
mineralocorticoid 9 -fludrocortisone (0.05 mg) should cause TTKG
to rise above 7 in cases of hypoaldosteronism. Circumstances are
listed in which the TTKG would not increase after mineralocorticoid
challenge, because of tubular resistance to aldosterone [21].
3.15
FIGURE 3-28
Approach to hyperkalemia: low aldosterone
with normal to increased plasma renin.
Heparin impairs aldosterone synthesis by
inhibiting the enzyme 18-hydroxylase.
Despite its frequent use, heparin is rarely
associated with overt hyperkalemia; this
suggests that other mechanisms (eg, reduced
renal potassium secretion) must be present
simultaneously for hyperkalemia to manifest itself. Both angiotensin-converting
enzyme inhibitors and the angiotensin type
1 receptor blockers (AT1) receptor blockers
interfere with adrenal aldosterone synthesis.
Generalized impairment of adrenal cortical
function manifested by combined glucocorticoid and mineralocorticoid deficiencies are
seen in Addisons disease and in defects of
aldosterone biosynthesis.
FIGURE 3-29
Approach to hyperkalemia: pseudohypoaldosteronism. The mechanism of decreased potassium excretion is caused either by failure
to secrete potassium in the cortical collecting tubule or enhanced
reabsorption of potassium in the medullary or papillary collecting
tubules. Decreased secretion of potassium in the cortical and
medullary collecting duct results from decreases in either apical
sodium or potassium channel function or diminished basolateral
Na+-K+-ATPase activity. Alternatively, potassium may be secreted
normally but hyperkalemia can develop because potassium reabsorption is enhanced in the intercalated cells of the medullary collecting duct (see Fig. 3-4). The transtubule potassium gradient
(TTKG) in both situations is inappropriately low and fails to normalize in response to mineralocorticoid replacement.
3.16

FIGURE 3-30
Mechanism of hyperkalemia in pseudohypoaldosteronism type I
(PHA I). This rare autosomally transmitted disease is characterized
by neonatal dehydration, failure to thrive, hyponatremia, hyperkalemia, and metabolic acidosis. Kidney and adrenal function are
normal, and patients do not respond to exogenous mineralocorticoids. Genetic mutations responsible for PHA I occur in the and
subunits of the amiloride-sensitive sodium channel of the collecting
tubule. Frameshift or premature stop codon mutations in the cytoplasmic amino terminal or extracellular loop of either subunit disrupt the integrity of the sodium channel and result in loss of channel activity. Failure to reabsorb sodium results in volume depletion
and activation of the renin-aldosterone axis. Furthermore, since
sodium reabsorption is indirectly coupled to potassium and hydrogen ion secretion, hyperkalemia and metabolic acidosis ensue.
Interestingly, when mutations are introduced into the cytoplasmic
carboxyl terminal, sodium channel activity is increased and Liddles
syndrome is observed [4].
Hyperkalemia: Clinical Manifestations

CLINICAL MANIFESTATIONS OF HYPERKALEMIA
Cardiac
Abnormal electrocardiogram
Atrial/ventricular arrhythmias
Pacemaker dysfunction
Neuromuscular
Paresthesias
Weakness
Paralysis
Renal electrolyte
Decreased renal NH4+ production
Natriuresis
Endocrine
Increased aldosterone secretion
Increased insulin secretion
FIGURE 3-31
Clinical manifestations of hyperkalemia.
3.17
FIGURE 3-32
Electrocardiographic (ECG) changes associated with hyperkalemia.
A, Normal ECG pattern. B, Peaked, narrow-based T waves are
the earliest sign of hyperkalemia. C, The P wave broadens and the
QRS complex widens when the plamsa potassium level is above
7 mEq/L. D, With higher elevations in potassium, the P wave
becomes difficult to identify. E, Eventually, an undulating sinusoidal pattern is evident. Although the ECG changes are depicted
here as correlating to the severity of hyperkalemia, patients with
even mild ECG changes may abruptly progress to terminal rhythm
disturbances. Thus, hyperkalemia with any ECG changes should be
treated as an emergency.
Hyperkalemia: Treatment
FIGURE 3-33
Treatment of hyperkalemia.
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2.
3.
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Chang SS, Grunder S, Hanukoglu A, et al.: Mutations in subunits of

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Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogeneity of Bartters syndrome revealed by mutations in the K+ channel,
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Nora NA, Berns AS: Hypokalemic, hypophosphatemic thyrotoxic
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14. Whang R, Flink EB, Dyckner T, et al.: Magnesium depletion as a

cause of refractory potassium repletion. Arch Int Med 1985,
145:16861689.
15. Funder JW: Corticosteroid receptors and renal 11 -hydroxysteroid
dehydrogenase activity. Semin Nephrol 1990, 10:311319.
16. Marriott HJL: Miscellaneous conditions: Hypokalemia. In Practical
Electrocardiography, edn 8. Baltimore: Williams and Wilkins; 1988.
17. Riemanschneider TH, Bohle A: Morphologic aspects of low-potassium and low-sodium nephropathy. Clin Nephrol 1983, 19:271279.
18. Tolins JP, Hostetter MK, Hostetter TH: Hypokalemic nephropathy in
the rat: Role of ammonia in chronic tubular injury. J Clin Invest
1987, 79:14471458.
19. Sterns RH, Cox M, Fieg PU, et al.: Internal potassium balance and
the control of the plasma potassium concentration. Medicine 1981,
60:339344.
20. Kamel KS, Quaggin S, Scheich A, Halperin ML: Disorders of potassium homeostasis: an approach based on pathophysiology. Am J Kidney
Dis 1994, 24:597613.
21. Ethier JH, Kamel SK, Magner PO, et al.: The transtubular potassium
concentration gradient in patients with hypokalemia and hyperkalemia. Am J Kidney Dis 1990, 15:309315.
Divalent Cation
Metabolism: Magnesium
James T. McCarthy
Rajiv Kumar
agnesium is an essential intracellular cation. Nearly 99% of the

total body magnesium is located in bone or the intracellular
space. Magnesium is a critical cation and cofactor in numerous
intracellular processes. It is a cofactor for adenosine triphosphate; an
important membrane stabilizing agent; required for the structural integrity
of numerous intracellular proteins and nucleic acids; a substrate or cofactor for important enzymes such as adenosine triphosphatase, guanosine
triphosphatase, phospholipase C, adenylate cyclase, and guanylate
cyclase; a required cofactor for the activity of over 300 other enzymes; a
regulator of ion channels; an important intracellular signaling molecule;
and a modulator of oxidative phosphorylation. Finally, magnesium is
intimately involved in nerve conduction, muscle contraction, potassium
transport, and calcium channels. Because turnover of magnesium in bone
is so low, the short-term body requirements are met by a balance of
gastrointestinal absorption and renal excretion. Therefore, the kidney
occupies a central role in magnesium balance. Factors that modulate and
affect renal magnesium excretion can have profound effects on magnesium balance. In turn, magnesium balance affects numerous intracellular
and systemic processes [112].
In the presence of normal renal function, magnesium retention and
hypermagnesemia are relatively uncommon. Hypermagnesemia inhibits
magnesium reabsorption in both the proximal tubule and the loop of
Henle. This inhibition of reabsorption leads to an increase in magnesium
excretion and prevents the development of dangerous levels of serum
magnesium, even in the presence of above-normal intake. However, in
familial hypocalciuric hypercalcemia, there appears to be an abnormality of the thick ascending limb of the loop of Henle that prevents excretion of calcium. This abnormality may also extend to Mg. In familial
hypocalciuric hypercalcemia, mild hypermagnesemia does not increase
the renal excretion of magnesium. A similar abnormality may be caused
by lithium [1,2,6,10]. The renal excretion of magnesium also is below
normal in states of hypomagnesemia, decreased dietary magnesium,
dehydration and volume depletion, hypocalcemia, hypothyroidism, and
hyperparathyroidism [1,2,6,10].
CHAPTER
4.2
Magnesium Distribution
TOTAL BODY MAGNESIUM (MG) DISTRIBUTION
Location
Percent of Total
Mg Content, mmol*
Bone
Muscle
Soft tissue
Erythrocyte
Serum
53
27
19.2
0.5
0.3
530
270
192
5
3
12720
6480
4608
120
72
1000
24000
Total
Mg Content, mg*
FIGURE 4-1
Total distribution of magnesium (Mg) in
the body. Mg (molecular weight, 24.305 D)
is predominantly distributed in bone, muscle, and soft tissue. Total body Mg content
is about 24 g (1 mol) per 70 kg. Mg in
bone is adsorbed to the surface of hydroxyapatite crystals, and only about one third is
readily available as an exchangeable pool.
Only about 1% of the total body Mg is in
the serum and interstitial fluid
[1,2,8,9,11,12].
*data typical for a 70 kg adult
Intracellular magnesium (Mg)
Proteins, enzymes,
citrate,
ATP, ADP
Endoplasmic
reticulum
Membrane
proteins
Mg2+
DNA
Mg2+
Ca Mg
ATPase
RNA
Mitochondria
FIGURE 4-2
Intracellular distribution of magnesium (Mg). Only 1% to 3% of
the total intracellular Mg exists as the free ionized form of Mg,
which has a closely regulated concentration of 0.5 to 1.0 mmol.
Total cellular Mg concentration can vary from 5 to 20 mmol,
depending on the type of tissue studied, with the highest Mg concentrations being found in skeletal and cardiac muscle cells. Our
understanding of the concentration and distribution of intracellular
Mg has been facilitated by the development of electron microprobe
analysis techniques and fluorescent dyes using microfluorescence
spectrometry. Intracellular Mg is predominantly complexed to
organic molecules (eg, adenosine triphosphatase [ATPase], cell and
nuclear membrane-associated proteins, DNA and RNA, enzymes,
proteins, and citrates) or sequestered within subcellular organelles
(mitochondria and endoplasmic reticulum). A heterogeneous distribution of Mg occurs within cells, with the highest concentrations
being found in the perinuclear areas, which is the predominant site
of endoplasmic reticulum. The concentration of intracellular free
ionized Mg is tightly regulated by intracellular sequestration and
complexation. Very little change occurs in the concentration of
intracellular free Mg, even with large variations in the concentrations of total intracellular or extracellular Mg [1,3,11]. ADP
adenosine diphosphate; ATPadenosine triphosphate; Ca+ionized calcium.
Divalent Cation Metabolism: Magnesium
4.3
Intracellular Magnesium Metabolism

Extracellular
Mg2+
-Adrenergic receptor
[Mg2+] = 0.7-1.2mmol
Na+ (Ca2+?)
Plasma membrane
?
+?
Cellular
+
Mg
Adenylyl cyclase
2+
ATP+Mg2+
Mitochondrion
Nucleus
Mg2+
cAMP
ADP
Plasma membrane
Mg2+?
E.R. or
S.R.
[Mg2+] = 0.5mmol
Ca2+
Mg2+?
Ca2+
Mg2+
+?
?
Ca2+
Pi +
+
ATPMg
?
Mg2+?
+?
pK C
D.G. + IP3
Muscarinic receptor or
vasopressin receptor
Na+ (Ca2+?)
Extracellular
FIGURE 4-3
Regulation of intracellular magnesium (Mg2+) in the mammalian cell. Shown is an example of Mg2+ movement between intracellular and extracellular spaces and within intracellular compartments. The stimulation of adenylate cyclase activity (eg, through stimulation
of -adrenergic receptors) increases cyclic adenosine monophosphate (cAMP). The
increase in cAMP induces extrusion of Mg from mitochondria by way of mitochondrial
adenine nucleotide translocase, which exchanges 1 Mg2+-adenosine triphosphate (ATP)
for adenosine diphosphate (ADP). This slight increase in cytosolic Mg2+ can then be
extruded through the plasma membrane by way of a Mg-cation exchange mechanism,
which may be activated by either cAMP or Mg. Activation of other cell receptors (eg,
muscarinic receptor or vasopressin receptor) may alter cAMP levels or produce diacyl-
glycerol (DAG). DAG activates Mg influx

by way of protein kinase C (pK C) activity.
Mitochondria may accumulate Mg by the
exchange of a cytosolic Mg2+-ATP for a
mitochondrial matrix Pi molecule. This
exchange mechanism is Ca2+-activated and
bidirectional, depending on the concentrations of Mg2+-ATP and Pi in the cytosol
and mitochondria. Inositol 1,4,5-trisphosphate (IP3) may also increase the release of
Mg from endoplasmic reticulum or sarcoplasmic reticulum (ER or SR, respectively), which also has a positive effect on this
Mg2+-ATP-Pi exchanger. Other potential
mechanisms affecting cytosolic Mg include
a hypothetical Ca2+-Mg2+ exchanger located in the ER and transport proteins that
can allow the accumulation of Mg within
the nucleus or ER. A balance must exist
between passive entry of Mg into the cell
and an active efflux mechanism because
the concentration gradient favors the
movement of extracellular Mg (0.71.2
mmol) into the cell (free Mg, 0.5 mmol).
This Mg extrusion process may be energyrequiring or may be coupled to the movement of other cations. The cellular movement of Mg generally is not involved in the
transepithelial transport of Mg, which is
primarily passive and occurs between cells
[13,7]. (From Romani and coworkers [3];
with permission.)
4.4

Mg2+
Extracellular
Outer membrane
Mg
Mg2+
2+
Periplasm
Mg2+
Mg2+
CorA
ATP
MgtB
MgtA
1 2
Periplasm
Cytosol
6 7
8 9 10
Cytoplasm
ATP
Mg2+
Periplasm
12
Cytoplasm
C
ADP
Mg2+
Mg2+
ADP
37 kDa?
FIGURE 4-4
A, Transport systems of magnesium (Mg). Specific membraneassociated Mg transport proteins only have been described in bacteria such as Salmonella. Although similar transport proteins are
believed to be present in mammalian cells based on nucleotide
sequence analysis, they have not yet been demonstrated. Both
MgtA and MgtB (molecular weight, 91 and 101 kDa, respectively) are members of the adenosine triphosphatase (ATPase) family
of transport proteins. B, Both of these transport proteins have six
C-terminal and four N-terminal membrane-spanning segments,
with both the N- and C-terminals within the cytoplasm. Both
proteins transport Mg with its electrochemical gradient, in contrast to other known ATPase proteins that usually transport ions
MgtA and MgtB
CorA
against their chemical gradient. Low levels of extracellular Mg

are capable of increasing transcription of these transport proteins,
which increases transport of Mg into Salmonella. The CorA system has three membrane-spanning segments. This system mediates
Mg influx; however, at extremely high extracellular Mg concentrations, this protein can also mediate Mg efflux. Another cell
membrane Mg transport protein exists in erythrocytes (RBCs).
This RBC Na+-Mg2+ antiporter (not shown here) facilitates the
outward movement of Mg from erythrocytes in the presence of
extracellular Na+ and intracellular adenosine triphosphate (ATP)
[4,5]. ADPadenosine diphosphate; Ccarbon; Nnitrogen.
(From Smith and Maguire [4]).
Gastrointestinal Absorption of Magnesium
Gastrointestinal
absorption of
dietary magnesium (Mg)
Site
Mg absorption
% of intake
mmol/day mg/day absorption
Stomach
Duodenum
Jejunum
Proximal
Ileum
Distal
Ileum
Colon
0
0.63
1.25
1.88
0
15
30
45
0
5
10
15
1.25
30
10
0.63
15
Total*
5.6
135
45
*Normal dietary Mg intake = 300 mg (12.5 mmol) per day
FIGURE 4-5
Gastrointestinal absorption of dietary intake of magnesium (Mg).
The normal adult dietary intake of Mg is 300 to 360 mg/d (12.515
mmol/d). A Mg intake of about 3.6 mg/kg/d is necessary to maintain
Mg balance. Foods high in Mg content include green leafy vegetables
(rich in Mg-containing chlorophyll), legumes, nuts, seafoods, and
meats. Hard water contains about 30 mg/L of Mg. Dietary intake is
the only source by which the body can replete Mg stores. Net intestinal Mg absorption is affected by the fractional Mg absorption within
a specific segment of intestine, the length of that intestinal segment,
and transit time of the food bolus. Approximately 40% to 50% of
dietary Mg is absorbed. Both the duodenum and jejunum have a
high fractional absorption of Mg. These segments of intestine are relatively short, however, and the transit time is rapid. Therefore, their
relative contribution to total Mg absorption is less than that of the
ileum. In the intact animal, most of the Mg absorption occurs in the
ileum and colon. 1,25-dihydroxy-vitamin D3 may mildly increase the
intestinal absorption of Mg; however, this effect may be an indirect
result of increased calcium absorption induced by the vitamin.
Secretions of the upper intestinal tract contain approximately 1
mEq/L of Mg, whereas secretions from the lower intestinal tract contain 15 mEq/L of Mg. In states of nausea, vomiting, or nasogastric
suction, mild to moderate losses of Mg occur. In diarrheal states, Mg
depletion can occur rapidly owing to both high intestinal secretion
and lack of Mg absorption [2,6,813].
4.5

10
Physiological
Mg-intake,
mmol/d
Mg transported, Eq/h
7
6
3
5
4
3
22
2
1
13
Magnesium absorbed M Mg , mmol
5
4
3
2
1
12
0
0
12
15
18
21
24
[Mg] in bicarbonate saline, mEq/L
10
20
30
40
Oral magnesium dose m, mmol
FIGURE 4-6
Intestinal magnesium (Mg) absorption. In rats, the intestinal Mg
absorption is related to the luminal Mg concentration in a curvilinear fashion (A). This same phenomenon has been observed in
humans (B and C). The hyperbolic curve (dotted line in B and C)
seen at low doses and concentrations may reflect a saturable transcellular process; whereas the linear function (dashed line in B and
C) at higher Mg intake may be a concentration-dependent passive
intercellular Mg absorption. Alternatively, an intercellular process
that can vary its permeability to Mg, depending on the luminal Mg
concentration, could explain these findings (see Fig. 4-7) [1315]. (A,
From Kayne and Lee [13]; B, from Roth and Wermer [14]; C, from
Fine and coworkers [15]; with permission.)
10
Net Mg absorption, mEq/10 hrs
8
6
4
2
0
0
20
40
Mg intake, mEq/meal
Mechanism of
intestinal magnesium absorption
Nucleus
Lumen
Mg2+
A
Mg2+
B
Mg2+
Mg2+
K+
Na+
ATPase
60
80
FIGURE 4-7
Proposed pathways for movement of magnesium (Mg) across the intestinal epithelium. Two
possible routes exist for the absorption of Mg across intestinal epithelial cells: the transcellular route and the intercellular pathway. Although a transcellular route has not yet been
demonstrated, its existence is inferred from several observations. No large chemical gradient
exists for Mg movement across the cell membrane; however, a significant uphill electrical
gradient exists for the exit of Mg from cells. This finding suggests the existence and participation of an energy-dependent mechanism for extrusion of Mg from intestinal cells. If such
a system exists, it is believed it would consist of two stages. 1) Mg would enter the apical
membrane of intestinal cells by way of a passive carrier or facilitated diffusion. 2) An active
Mg pump in the basolateral section of the cell would extrude Mg. The intercellular movement of Mg has been demonstrated to occur by both gradient-driven and solvent-drag
mechanisms. This intercellular path may be the only means by which Mg moves across the
intestinal epithelium. The change in transport rates at low Mg concentrations would reflect
changes in the openness of this pathway. High concentrations of luminal Mg (eg, after a
meal) are capable of altering the morphology of the tight junction complex. High local Mg
concentrations near the intercellular junction also can affect the activities of local membrane-associated proteins (eg, sodium-potassium adenosine triphosphate [Na-K ATPase])
near the tight junction and affect its permeability (see Fig. 4-6) [1315].
4.6
Renal Handling of Magnesium

Afferent
arteriole
Efferent
arteriole
Glomerular
capillary
Bowman's
space
Mg2+-protein
Mg2+ionized
FIGURE 4-8
The glomerular filtration of magnesium (Mg). Total serum Mg
consists of ionized, complexed, and protein bound fractions, 60%,
7%, and 33% of total, respectively. The complexed Mg is bound
to molecules such as citrate, oxalate, and phosphate. The ultrafilterable Mg is the total of the ionized and complexed fractions.
Normal total serum Mg is approximately 1.7 to 2.1 mg/dL (about
0.700.90 mmol/L) [1,2,79,11,12].
Mg2+complexed
Mg2+-ultrafilterable
% of total
serum Mg2+
Mg2+
Ionized Mg
60%
Protein-bound Mg 33%
Complexed Mg
7%
Proximal
tubule
*Normal total serum Mg =

1.72.1 mg/dL (0.700.9 mmol/L)
Juxtamedullary
nephron
Superficial cortical
nephron
510%
05%
Filtered
Mg2+
(100%)
Filtered
Mg2+
(100%)
20%
65%
65%
20%
Excreted
(5%)
FIGURE 4-9
The renal handling of magnesium (Mg2+). Mg is filtered at the
glomerulus, with the ultrafilterable fraction of plasma Mg entering
the proximal convoluted tubule (PCT). At the end of the PCT, the
Mg concentration is approximately 1.7 times the initial concentra-
tion of Mg and about 20% of the filtered Mg has been reabsorbed. Mg reabsorption occurs passively through paracellular
pathways. Hydrated Mg has a very large radius that decreases its
intercellular permeability in the PCT when compared with sodium. The smaller hydrated radius of sodium is 50% to 60% reabsorbed in the PCT. No clear evidence exists of transcellular reabsorption or secretion of Mg within the mammalian PCT. In the
pars recta of the proximal straight tubule (PST), Mg reabsorption
can continue to occur by way of passive forces in the concentrating kidney. In states of normal hydration, however, very little Mg
reabsorption occurs in the PST. Within the thin descending limb of
the loop of Henle, juxtamedullary nephrons are capable of a small
amount of Mg reabsorption in a state of antidiuresis or Mg depletion. This reabsorption does not occur in superficial cortical
nephrons. No data exist regarding Mg reabsorption in the thin
ascending limb of the loop of Henle. No Mg reabsorption occurs
in the medullary portion of the thick ascending limb of the loop of
Henle; whereas nearly 65% of the filtered load is absorbed in the
cortical thick ascending limb of the loop of Henle in both juxtamedullary and superficial cortical nephrons. A small amount of
Mg is absorbed in the distal convoluted tubule. Mg transport in
the connecting tubule has not been well quantified. Little reabsorption occurs and no evidence exists of Mg secretion within the
collecting duct. Normally, 95% of the filtered Mg is reabsorbed
by the nephron. In states of Mg depletion the fractional excretion
of Mg can decrease to less than 1%; whereas Mg excretion can
increase in states of above-normal Mg intake, provided no evidence of renal failure exists [1,2,69,11,12].
FIGURE 4-10
Magnesium (Mg) reabsorption in the cortical thick ascending limb (cTAL) of the loop of
Henle. Most Mg reabsorption within the nephron occurs in the cTAL owing primarily to
voltage-dependent Mg flux through the intercellular tight junction. Transcellular Mg
movement occurs only in response to cellular metabolic needs. The sequence of events necessary to generate the lumen-positive electrochemical gradient that drives Mg reabsorption
is as follows: 1) A basolateral sodium-potassium-adenosine triphosphatase (Na+-K+ATPase) decreases intracellular sodium, generating an inside-negative electrical potential
difference; 2) Intracellular K is extruded by an electroneutral K-Cl (chloride) cotransporter; 3) Cl is extruded by way of conductive pathways in the basolateral membrane; 4)
The apical-luminal Na-2Cl-K (furosemide-sensitive) cotransport mechanism is driven by
the inside-negative potential difference and decrease in intracellular Na; 5) Potassium is
recycled back into the lumen by way of an apical K conductive channel; 6) Passage of
approximately 2 Na molecules for every Cl molecule is allowed by the paracellular pathway (intercellular tight junction), which is cation permselective; 7) Mg reabsorption occurs
passively, by way of intercellular channels, as it moves down its electrical gradient
[1,2,6,7]. (Adapted from de Rouffignac and Quamme [1].)
Mg absorption in cTAL
78mV
+8mV
0mV
2Na+
1Cl
4
3Na+
6Cl
3K+
2K+
3Na+
2K+
2Cl
4Cl
3K+
4.7
5
Mg
Mg
~1.0mmol
Mg
~1.0mmol
A
Mg 0.5mmol
FIGURE 4-11
Voltage-dependent net magnesium (Mg) flux in the cortical thick
ascending limb (cTAL). Within the isolated mouse cTAL, Mg flux
(JMg) occurs in response to voltage-dependent mechanisms. With
a relative lumen-positive transepithelial potential difference (Vt),
Mg reabsorption increases (positive JMg). Mg reabsorption equals
zero when no voltage-dependent difference exists, and Mg is
capable of moving into the tubular lumen (negative JMg) when a
lumen-negative voltage difference exists [1,16]. (From di Stefano
and coworkers [16]).
JMg, pmol.min1.mm1
0.8
0.6
0.4
(7)
0.2
Vt, mV
18 15 12 9 6 3
0.2
0.4
(8)
0.6
0.8
3 6
(15)
12
15 18
4.8
Net fluxes, pmol min1 mm1
JMg2+
1.0
AVP
GLU
HCT
PTH
ISO
INS
0.8
*
0.6
0.4
0.2
0
FIGURE 4-12
Effect of hormones on magnesium (Mg)
transport in the cortical thick ascending
limb (cTAL). In the presence of arginine
vasopressin (AVP), glucagon (GLU), human
calcitonin (HCT), parathyroid hormone
(PTH), 1,4,5-isoproteronol (ISO), and
insulin (INS), increases occur in Mg reabsorption from isolated segments of mouse
cTALs. These hormones have no effect on
medullary TAL segments. As already has
been shown in Figure 4-3, these hormones
affect intracellular second messengers
and cellular Mg movement. These hormone-induced alterations can affect the
paracellular permeability of the intercellular
tight junction. These changes may also
affect the transepithelial voltage across the
cTAL. Both of these forces favor net Mg
reabsorption in the cTAL [1,2,7,8].
Asterisksignificant change from preceding
period; JMgMg flux; Ccontrol, absence
of hormone. (Adapted from de Rouffignac
and Quamme [1].)
Magnesium Depletion
CAUSES OF MAGNESIUM (Mg) DEPLETION
Poor Mg intake
Starvation
Anorexia
Protein calorie malnutrition
No Mg in intravenous fluids
Renal losses
see Fig. 4-14
Increased gastrointestinal Mg losses
Nasogastric suction
Vomiting
Intestinal bypass for obesity
Short-bowel syndrome
Inflammatory bowel disease
Pancreatitis
Diarrhea
Laxative abuse
Villous adenoma
Other
Lactation
Extensive burns
Exchange transfusions
FIGURE 4-13
The causes of magnesium (Mg) depletion. Depletion of Mg can
develop as a result of low intake or increased losses by way of the
gastrointestinal tract, the kidneys, or other routes [1,2,813].

Renal magnesium (Mg) wasting
Thiazides(?)
Volume
expansion
Osmotic diuresis
Glucose
Mannitol
Urea
Diuretic phase
acute renal failure*
Post obstructive diuresis*
Hypercalcemia*
Phosphate depletion*
Chronic renal disease*
? Aminoglycosides*
Renal transplant*
Interstitial nephritis*
Tubular defects
Bartter's syndrome
Gitelman's syndrome
Renal tubular acidosis
Medullary calcinosis
Drugs/toxins
Cis-platinum
Amphotericin B
Cyclosporine
Pentamidine
? Aminoglycosides*
Foscarnet (?ATN)
Ticarcillin/carbenicillin
? Digoxin
Electrolyte imbalances
Hypercalcemia*
Phosphate depletion*
Metabolic acidosis
Starvation
Ketoacidosis
Alcoholism
4.9
FIGURE 4-14
Renal magnesium (Mg) wasting. Mg is normally reabsorbed in the
proximal tubule (PT), cortical thick ascending limb (cTAL), and distal convoluted tubule (DCT) (see Fig. 4-9). Volume expansion and
osmotic diuretics inhibit PT reabsorption of Mg. Several renal diseases and electrolyte disturbances (asterisks) inhibit Mg reabsorption
in both the PT and cTAL owing to damage to the epithelial cells and
the intercellular tight junctions, plus disruption of the electrochemical forces that normally favor Mg reabsorption. Many drugs and
toxins directly damage the cTAL. Thiazides have little direct effect
on Mg reabsorption; however, the secondary hyperaldosteronism
and hypercalcemia effect Mg reabsorption in CD and/or cTAL.
Aminoglycosides accumulate in the PT, which affects sodium reabsorption, also leading to an increase in aldosterone. Aldosterone leads
to volume expansion, decreasing Mg reabsorption. Parathyroid
hormone has the direct effect of increasing Mg reabsorption in
cTAL; however, hypercalcemia offsets this tendency. Thyroid hormone increases Mg loss. Diabetes mellitus increases Mg loss by way
of both hyperglycemic osmotic diuresis and insulin abnormalities
(deficiency and resistance), which decrease Mg reabsorption in the
proximal convoluted tubule and cTAL, respectively. Cisplatin causes a
Gitelman-like syndrome, which often can be permanent [1,2,812].
Hormonal changes
Hyperaldosteronism
Primary
hyperparathyroidism
Hyperthyroidism
Uncontrolled diabetes
mellitus
SIGNS AND SYMPTOMS OF HYPOMAGNESEMIA
Cardiovascular
Electrocardiographic results
Prolonged P-R and Q-T intervals,
U waves
Angina pectoris
?Congestive heart failure
Atrial and ventricular arrhythmias
?Hypertension
Digoxin toxicity
Atherogenesis
Neuromuscular
Central nervous system
Seizures
Obtundation
Depression
Psychosis
Coma
Ataxia
Nystagmus
Choreiform and athetoid movements
Muscular
Cramps
Weakness
Carpopedal spasm
Chvosteks sign
Trousseaus sign
Fasciculations
Tremulous
Hyperactive reflexes
Myoclonus
Dysphagia
Skeletal
Osteoporosis
Osteomalacia
FIGURE 4-15
Signs and symptoms of hypomagnesemia. Symptoms of hypomagnesemia can develop when the serum magnesium (Mg) level falls
below 1.2 mg/dL. Mg is a critical cation in nerves and muscles and
is intimately involved with potassium and calcium. Therefore, neuromuscular symptoms predominate and are similar to those seen in
hypocalcemia and hypokalemia. Electrocardiographic changes of
hypomagnesemia include an increased P-R interval, increased Q-T
duration, and development of U waves. Mg deficiency increases the
mortality of patients with acute myocardial infarction and congestive heart failure. Mg depletion hastens atherogenesis by increasing
total cholesterol and triglyceride levels and by decreasing high-density lipoprotein cholesterol levels. Hypomagnesemia also increases
hypertensive tendencies and impairs insulin release, which favor
atherogenesis. Low levels of Mg impair parathyroid hormone
(PTH) release, block PTH action on bone, and decrease the activity
of renal 1--hydroxylase, which converts 25-hydroxy-vitamin D3
into 1,25-dihydroxy-vitamin D3, all of which contribute to
hypocalcemia. Mg is an integral cofactor in cellular sodium-potassium-adenosine triphosphatase activity, and a deficiency of Mg
impairs the intracellular transport of K and contributes to renal
wasting of K, causing hypokalemia [6,812].
4.10
Total serum Mg
(On normal diet of
250350 mg/d of Mg)
Magnesium deficiency
Insulin
resistance
Altered synthesis
of eicosanoids
Enhanced AII
action
(PGI2 , : TXA2 , and 12-HETE)

Platelet
aggregation
Aldosterone
Increased vasomotor tone
Na+ reabsorption
Normal
(1.72.1 mg/dL)
Low
(<1.7 mg/dL)
24 hour urine Mg
24 hour urine Mg
Normal
(> 24 mg/24 hrs)
Low
(< 24 mg/24 hrs)
No Mg
deficiency
Tolerance Mg test
(see Figure 418)
MAGNESIUM (Mg) TOLERANCE TEST FOR PATIENTS

WITH NORMAL SERUM MAGNESIUM
Time
Action
0 (baseline)
04 h
Urine (spot or timed) for molar Mg:Cr ratio

IV infusion of 2.4 mg (0.1 mmol) of Mg/kg lean body
wt in 50 mL of 50% dextrose
Collect urine (staring with Mg infusion) for Mg and Cr
Calculate % Mg retained (%M)
024 h
End
%M=1
(24-h urine Mg) ([Preinfusion urine Mg:Cr] [24-h urine Cr])

100
Total Mg infused
Mg retained, %
Mg deficiency
>50
2050
<20
Definite
Probable
None
Crcreatinine; IVintravenous; Mgmagnesium.
High
(> 24 mg/24 hrs)
Mg deficiency
present
Hypertension
FIGURE 4-16
Mechanism whereby magnesium (Mg) deficiency could lead
to hypertension. Mg deficiency does the following: increases
angiotensin II (AII) action, decreases levels of vasodilatory
prostaglandins (PGs), increases levels of vasoconstrictive PGs
and growth factors, increases vascular smooth muscle cytosolic
calcium, impairs insulin release, produces insulin resistance, and
alters lipid profile. All of these results of Mg deficiency favor the
development of hypertension and atherosclerosis [10,11].
Na+ionized sodium; 12-HETEhydroxy-eicosatetraenoic [acid];
TXA2thromboxane A2. (From Nadler and coworkers [17].)
Low
(< 24 mg/24 hrs)
Check for
nonrenal causes
Mg deficiency
present
Renal Mg wasting
Normal
Mg retention
Mg
retention
No Mg
deficiency
Normal
Mg deficiency
present
Check for
nonrenal causes
FIGURE 4-17
Evaluation in suspected magnesium (Mg) deficiency. Serum Mg levels may
not always indicate total body stores. More refined tools used to assess the
status of Mg in erythrocytes, muscle, lymphocytes, bone, isotope studies,
and indicators of intracellular Mg, are not routinely available. Screening
for Mg deficiency relies on the fact that urinary Mg decreases rapidly in
the face of Mg depletion in the presence of normal renal function
[2,6,815,18]. (Adapted from Al-Ghamdi and coworkers [11].)
FIGURE 4-18
The magnesium (Mg) tolerance test, in various forms [2,6,812,18],
has been advocated to diagnose Mg depletion in patients with normal
or near-normal serum Mg levels. All such tests are predicated on the
fact that patients with normal Mg status rapidly excrete over 50% of
an acute Mg load; whereas patients with depleted Mg retain Mg in an
effort to replenish Mg stores. (From Ryzen and coworkers [18].)
4.11
MAGNESIUM SALTS USED IN MAGNESIUM REPLACEMENT THERAPY

Magnesium salt
Chemical formula
Mg content, mg/g
Examples*
Mg content
Diarrhea
27-mg tablet
54 mg/5 mL
Gluconate
Cl2H22MgO14
58
Magonate
Chloride
MgCl2 . (H2O)6
120
Mag-L-100
100-mg capsule
Lactate
C6H10MgO6
120
MagTab SR*
84-mg caplet
Citrate
C12H10Mg3O14
Multiple
4756 mg/5 mL
++
Hydroxide
Mg(OH)2
410
Maalox, Mylanta, Gelusil

Riopan
83 mg/ 5 mL and 63-mg tablet

96 mg/5 mL
++
Oxide
MgO
600
Mag-Ox 400
Uro-Mag
Beelith
241-mg tablet
84.5-mg tablet
362-mg tablet
++
Sulfate
MgSO4 . (H2O)7
100
IV
IV
Oral epsom salt
10%9.9 mg/mL
50%49.3 mg/mL
97 mg/g
++
Phillips Milk of Magnesia
168 mg/ 5 mL
++
53
Milk of Magnesia
++
Data from McLean [9], Al-Ghamdi and coworkers [11], Oster and Epstein [19], and Physicians Desk Reference [20].
*Magonate, Fleming & Co, Fenton, MD; MagTab Sr, Niche Pharmaceuticals, Roanoke, TX; Maalox, Rhone-Poulenc Rorer Pharmaceutical, Collegeville, PA; Mylanta,
J & J-Merck Consumer Pharm, Ft Washinton, PA; Riopan, Whitehall Robbins Laboratories, Madison, NJ; Mag-Ox 400 and Uro-Mag, Blaine, Erlanger, KY; Beelith,
Beach Pharmaceuticals, Conestee, SC; Phillips Milk of Magnesia, Bayer Corp, Parsippany, NJ.
FIGURE 4-19
Magnesium (Mg) salts that may be used in Mg replacement therapy.
GUIDELINES FOR MAGNESIUM (Mg) REPLACEMENT

Life-threatening event, eg, seizures and cardiac arrhythmia
I. 24 g MgSO4 IV or IM stat
(24 vials [2 mL each] of 50% MgSO4)
Provides 200400 mg of Mg (8.316.7 mmol Mg)
Closely monitor:
Deep tendon reflexes
Heart rate
Blood pressure
Respiratory rate
Serum Mg (<2.5 mmol/L [6.0 mg/dL])
Serum K
Subacute and chronic Mg replacement

I. 400600 mg (16.725 mmol Mg daily for 25 d)
IV: continuous infusion
IM: painful
Oral: use divided doses to minimize diarrhea
II. IV drip over first 24 h

to provide no more
than 1200 mg (50
mmol) Mg/24 h
FIGURE 4-20
Acute Mg replacement for life-threatening events such as seizures or
potentially lethal cardiac arrhythmias has been described [812,19].
Acute increases in the level of serum Mg can cause nausea, vomiting, cutaneous flushing, muscular weakness, and hyporeflexia. As
Mg levels increase above 6 mg/dL (2.5 mmol/L), electrocardiographic changes are followed, in sequence, by hyporeflexia, respiratory paralysis, and cardiac arrest. Mg should be administered with
caution in patients with renal failure. In the event of an emergency
the acute Mg load should be followed by an intravenous (IV) infusion, providing no more than 1200 mg (50 mmol) of Mg on the
first day. This treatment can be followed by another 2 to 5 days of
Mg repletion in the same dosage, which is used in less urgent situations. Continuous IV infusion of Mg is preferred to both intramuscular (which is painful) and oral (which causes diarrhea) administration. A continuous infusion avoids the higher urinary fractional
excretion of Mg seen with intermittent administration of Mg.
Patients with mild Mg deficiency may be treated with oral Mg salts
rather than parenteral Mg and may be equally efficacious [8].
Administration of Mg sulfate may cause kaliuresis owing to excretion of the nonreabsorbable sulfate anion; Mg oxide administration
has been reported to cause significant acidosis and hyperkalemia
[19]. Parenteral Mg also is administered (often in a manner different
from that shown here) to patients with preeclampsia, asthma, acute
myocardial infarction, and congestive heart failure.
4.12
References
1. de Rouffignac C, Quamme G: Renal magnesium handling and its
hormonal control. Physiol Rev 1994, 74:305322.
2. Quamme GA: Magnesium homeostasis and renal magnesium handling. Miner Electrolyte Metab 1993, 19:218225.
3. Romani A, Marfella C, Scarpa A: Cell magnesium transport and
homeostasis: role of intracellular compartments. Miner Electrolyte
Metab 1993, 19:282289.
4. Smith DL, Maguire ME: Molecular aspects of Mg2+ transport systems.
Miner Electrolyte Metab 1993, 19:266276.
5. Roof SK, Maguire ME: Magnesium transport systems: genetics and
protein structure (a review). J Am Coll Nutr 1994, 13:424428.
6. Sutton RAL, Domrongkitchaiporn S: Abnormal renal magnesium handling. Miner Electrolyte Metab 1993, 19:232240.
7. de Rouffignac C, Mandon B, Wittner M, di Stefano A: Hormonal control of magnesium handling. Miner Electrolyte Metab 1993, 19:226231.
8. Whang R, Hampton EM, Whang DD: Magnesium homeostasis and
clinical disorders of magnesium deficiency. Ann Pharmacother 1994,
28:220226.
9. McLean RM: Magnesium and its therapeutic uses: a review. Am J Med
1994, 96:6376.
10. Abbott LG, Rude RK: Clinical manifestations of magnesium deficiency. Miner Electrolyte Metab 1993, 19:314322.
11. Al-Ghamdi SMG, Cameron EC, Sutton RAL: Magnesium deficiency:
pathophysiologic and clinical overview. Am J Kid Dis 1994, 24:737752.
12. Nadler JL, Rude RK: Disorders of magnesium metabolism.

Endocrinol Metab Clin North Am 1995, 24:623641.
13. Kayne LH, Lee DBN: Intestinal magnesium absorption. Miner
Electrolyte Metab 1993, 19:210217.
14. Roth P, Werner E: Intestinal absorption of magnesium in man. Int J
Appl Radiat Isotopes 1979, 30:523526.
15. Fine KD, Santa Ana CA, Porter JL, Fordtran JS: Intestinal absorption
of magnesium from food and supplements. J Clin Invest 1991,
88:396402.
16. di Stefano A, Roinel N, de Rouffignac C, Wittner M: Transepithelial
Ca+ and Mg+ transport in the cortical thick ascending limb of Henles
loop of the mouse is a voltage-dependent process. Renal Physiol
Biochem 1993, 16:157166.
17. Nadler JL, Buchanan T, Natarajan R, et al.: Magnesium deficiency
produces insulin resistance and increased thromboxane synthesis.
Hypertension 1993, 21:10241029.
18. Ryzen E, Elbaum N, Singer FR, Rude RK: Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium
1985, 4:137147.
19. Oster JR, Epstein M: Management of magnesium depletion. Am J
Nephrol 1988, 8:349354.
20. Physicians Desk Reference (PDR). Montvale, NJ: Medical Economics
Company; 1996.
Divalent Cation
Metabolism: Calcium
James T. McCarthy
Rajiv Kumar
alcium is an essential element in the human body. Although over

99% of the total body calcium is located in bone, calcium is a
critical cation in both the extracellular and intracellular spaces.
Its concentration is held in a very narrow range in both spaces. In addition to its important role in the bone mineral matrix, calcium serves a
vital role in nerve impulse transmission, muscular contraction, blood
coagulation, hormone secretion, and intercellular adhesion. Calcium
also is an important intracellular second messenger for processes such
as exocytosis, chemotaxis, hormone secretion, enzymatic activity, and
fertilization. Calcium balance is tightly regulated by the interplay
between gastrointestinal absorption, renal excretion, bone resorption,
and the vitamin Dparathyroid hormone (PTH) system [17].
CHAPTER
5.2
Calcium Distribution
TOTAL DISTRIBUTION OF CALCIUM IN THE BODY
Ca Content*
Location
Concentration
mmol
mg
99%
2.4 mmol
0.1 mol
~31.4 103
35
<1
~1255 103
~1400
<40
~31.5 103
~1260 103
Bone
Extracellular fluid
Intracellular fluid
Total
FIGURE 5-1
Total distribution of calcium (Ca) in the body. Ca (molecular weight,
40.08 D) is predominantly incorporated into bone. Total body Ca
content is about 1250 g (31 mol) in a person weighing 70 kg. Bone
Ca is incorporated into the hydroxyapatite crystals of bone, and
about 1% of bone Ca is available as an exchangeable pool. Only
1% of the total body calcium exists outside of the skeleton.
*data for a 70 kg person
Intracellular Calcium Metabolism

[Ca2+]o1-3mM
Ca2+o
+8-0mV
-50mV
Ca2+-binding proteins;
phosphate, citrate, etc. complexes
VOC
ROC
SOC
Ca2+i
[Ca2+]i<10-3mM
Mitochondria
Nucleus
~
2+
SRCa Ca s
ATPase
InsP3 receptor
Ca2+
Plasma
membrane
ATPase
Sarcoplasmic or
endoplasmic
reticulum
Na+
3Na+: Ca2+exchanger
~
Ca2+
Ca2+
FIGURE 5-2
General scheme of the distribution and movement of intracellular calcium (Ca). In contrast to magnesium, Ca has a particularly
adaptable coordination sphere that facilitates its binding to

the irregular geometry of proteins, a binding that is readily
reversible. Low intracellular Ca concentrations can function as
either a first or second messenger. The extremely low concentrations of intracellular Ca are necessary to avoid Ca-phosphate
microprecipitation and make Ca an extremely sensitive cellular
messenger. Less than 1% of the total intracellular Ca exists in
the free ionized form, with a concentration of approximately
0.1 mol/L. Technical methods available to investigate intracellular free Ca concentration include Ca-selective microelectrodes,
bioluminescent indicators, metallochromic dyes, Ca-sensitive
fluorescent indicators, electron-probe radiographic microanalysis, and fluorine-19 nuclear magnetic resonance imaging.
Intracellular Ca is predominantly sequestered within the endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR). Some
sequestration of Ca occurs within mitochondria and the nucleus.
Ca can be bound to proteins such as calmodulin and calbindin,
and Ca can be complexed to phosphate, citrate, and other
anions. Intracellular Ca is closely regulated by balancing Ca
entry by way of voltage-operated channels (VOC), receptoroperated channels (ROC), and store-operated channels (SOC),
with active Ca efflux by way of plasma membraneassociated
Ca-adenosine triphosphatase (ATPase) and a Na-Ca exchanger.
Intracellular Ca also is closely regulated by balancing Ca movement into the SR (SR Ca-ATPase) and efflux from the SR by an
inositol 1,4,5-trisphosphate (InsP3) receptor [17].
The highest concentration of intracellular Ca is found in the
brush border of epithelial cells, where there is also the highest
concentration of Ca-binding proteins such as actin-myosin and
calbindin. Intracellular Ca messages are closely modulated by
the phospholipase C-InsP3 pathway and also the phospholipase
A2arachidonic acid pathway, along with intracellular Ca, which
itself modulates the InsP3 receptor.
Divalent Cation Metabolism: Calcium
5.3
Vitamin D and Parathyroid Hormone Actions
7-dehydrocholesterol
HO
UV light
Skin
Vitamin D3
Liver 25-hydroxylase
HO
OH
+
PTH
PTHrP
Hypophosphatemia
Hypocalcemia
24R, 25(OH)2D3
IGF-1
25-hydroxyvitamin D3
Hypercalcemia
Hyperphosphatemia
1, 25(OH)2D3
Acidosis
HO
Kidney
1-alphahydroxylase
24-hydroxylase
+
1, 25(OH)2D3
Hypercalcemia
Hyperphosphatemia
Kidney, intestine,
other tissue
OH
OH
OH
24, 25-hydroxyvitamin D3
1, 25-hydroxyvitamin D3
HO
HO
OH
Various tissue enzymes
Hydroxylated and conjugated polar metabolites
FIGURE 5-4
Calcium (Ca) flux between body compartments. Ca balance is a
complex process involving bone, intestinal absorption of dietary
Ca, and renal excretion of Ca. The parathyroid glands, by their
production of parathyroid hormone, and the liver, through its participation in vitamin D metabolism, also are integral organs in the
maintenance of Ca balance. (From Kumar [1]; with permission.)
Soft tissue and

intracellular
calcium
Oral calcium intake

~1000 mg/d
Intestine
400 mg
200 mg
Extracellular
fluid and
plasma
10,000 mg
500 mg
500 mg
9800 mg
Bone
Feces
800 mg
Kidney
Urine
200 mg
FIGURE 5-3
Metabolism of vitamin D. The compound 7dehydrocholesterol, through the effects of heat
(37C) and (UV) light (wavelength 280305
nm), is converted into vitamin D3 in the skin.
Vitamin D3 is then transported on vitamin D
binding proteins (VDBP) to the liver. In the
liver, vitamin D3 is converted to 25-hydroxyvitamin D3 by the hepatic microsomal and
mitochondrial cytochrome P450containing
vitamin D3 25-hydroxylase enzyme. The 25hydroxy-vitamin D3 is transported on VDBP
to the proximal tubular cells of the kidney,
where it is converted to 1,25-dihydroxy-vitamin D3 by a 1--hydroxylase enzyme, which
also is a cytochrome P450containing enzyme.
The genetic information for this enzyme is
encoded on the 12q14 chromosome.
Alternatively, 25-hydroxy-vitamin D3 can be
converted to 24R,25-dihydroxy-vitamin D3, a
relatively inactive vitamin D metabolite. 1,25dihydroxy-vitamin D3 can then be transported
by VDBP to its most important target tissues
in the distal tubular cells of the kidney, intestinal epithelial cells, parathyroid cells, and bone
cells. VDBP is a 58 kD -globulin that is a
member of the albumin and -fetoprotein gene
family. The DNA sequence that encodes for
this protein is on chromosome 4q11-13. 1,25dihydroxy-vitamin D3 is eventually metabolized to hydroxylated and conjugated polar
metabolites in the enterohepatic circulation.
Occasionally, 1,25-dihydroxy-vitamin D3 also
may be produced in extrarenal sites, such as
monocyte-derived cells, and may have an
antiproliferative effect in certain lymphocytes
and keratinocytes [1,79]. (Adapted from
Kumar [1].)
5.4

FIGURE 5-5
Effects of 1,25-dihydroxy-vitamin D3 (calcitriol) on bone. In
addition to the effects on parathyroid cells, the kidney, and intestinal epithelium, calcitriol has direct effects on bone metabolism.
Calcitriol can promote osteoclast differentiation and activity from
monocyte precursor cells. Calcitriol also promotes osteoblast differentiation into mature cells. (From Holick [8]; with permission.)
1,25(OH)2D3
???
Osteoblast
precusor
T-lymphocyte
Monoblast
Osteoclast
Osteoblast
Cytokines
Osteocalcin
Osteopontin
Alkaline
Phosphatase
Bone
DNA binding
glyasp
30
hisgln
32
Hinge region
arggln
70
arggln
42
NH2
18
Calcitiriol binding
cystrp
187
arggln
77
42
44
lysglu pheile
149
glnstop
tyrstop
292
271
argleu
424
COOH
ZN
Mutant amino acid
FIGURE 5-6
The vitamin D receptor (VDR). Within its target tissues, calcitriol binds to the VDR.
The VDR is a 424 amino acid polypeptide. Its genomic information is encoded on the
VDBP
VDR-D3 complex
1,25 (OH)2D3
VDRE
VDR
RAF
Pi
Regulation
mRNA
transcription
Nucleus
CaBP
24-OHase
PTH
Osteocalcin
Osteopontin
Alkaline phosphatase
12q12-14 chromosome, near the gene

for the 1--hydroxylase enzyme. The
VDR is found in the intestinal epithelium,
parathyroid cells, kidney cells, osteoblasts,
and thyroid cells. VDR also can be detected in keratinocytes, monocyte precursor
cells, muscle cells, and numerous other
tissues. The allele variations for the vitamin D receptor. Two allele variations
exist for the vitamin D receptor (VDR):
the b allele and the B allele. In general,
normal persons with the b allele seem to
have a higher bone mineral density [9].
Among patients on dialysis, those with
the b allele may have higher levels of
circulating parathyroid hormone (PTH)
[7,9,10,11]. COOHcarboxy terminal;
NH2amino terminal. (From Root [7];
with permission.)
FIGURE 5-7
Mechanism of action of 1-25-dihydroxy-vitamin D3 (1,25(OH)2D3).
1,25(OH)2D3 is transported to the target cell bound to the vitamin
Dbinding protein (VDBP). The free form of 1,25(OH)2D3 enters the target cell and interacts with the vitamin D receptor (VDR) at the nucleus.
This complex is phosphorylated and combined with the nuclear accessory
factor (RAF). This forms a heterodimer, which then interacts with the vitamin D responsive element (VDRE). The VDRE then either promotes or
inhibits the transcription of messenger RNA (mRNA) for proteins regulated by 1,25(OH)2D3, such as Ca-binding proteins, the 25-hydroxy-vitamin D3 24-hydroxylase enzyme, and parathyroid hormone. Piinorganic
phosphate. (Adapted from Holick [8].)
Parathyroid cell
Cell membrane
Ca2+ Sensing
receptor
DNA
Ca2+
G-protein
VDRE
VDR
Nucleus
OH
HO
PTH mRNA
PTH mRNA
OH
Degradation
1,25 (OH)2D3
or Calcitriol
PTH
PTH
proPTH
Secretory
granules
preproPTH
Rough endoplasmic
reticulum
Golgi apparatus
1
PTH (mw 9600)
PTH-like peptide
(mw 16,000)
34
84
C
-2
-1
141
C
PTH LYS ARG SER VAL SER GLU ILE
10
11
12
13
GLN LEU MET HIS ASN LEU GLY LYS
PTH-like peptide LYS ARG ALA VAL SER GLU HIS GLN LEU LEU HIS ASP LYS GLY LYS
5.5
FIGURE 5-8
Metabolism of parathyroid hormone (PTH).
The PTH gene is located on chromosome
11p15. PTH messenger RNA (mRNA) is
transcribed from the DNA fragment and
then translated into a 115 amino acid
containing molecule of prepro-PTH. In the
rough endoplasmic reticulum, this undergoes hydrolysis to a 90 amino acidcontaining molecule, pro-PTH, which undergoes
further hydrolysis to the 84 amino
acidcontaining PTH molecule. PTH is then
stored within secretory granules in the cytoplasm for release. PTH is metabolized by
hepatic Kupffer cells and renal tubular cells.
Transcription of the PTH gene is inhibited
by 1,25-dihydroxy-vitamin D3, calcitonin,
and hypercalcemia. PTH gene transcription
is increased by hypocalcemia, glucocorticoids, and estrogen. Hypercalcemia also can
increase the intracellular degradation of
PTH. PTH release is increased by hypocalcemia, -adrenergic agonists, dopamine,
and prostaglandin E2. Hypomagnesemia
blocks the secretion of PTH [7,12]. VDR
vitamin D receptor; VDREvitamin D
responsive element. (Adapted from Tanaka
FIGURE 5-9
Parathyroid-hormonerelated protein
(PTHrP). PTHrP was initially described as
the causative circulating factor in the
humoral hypercalcemia of malignancy, particularly in breast cancer, squamous cell
cancers of the lung, renal cell cancer, and
other tumors. It is now clear that PTHrP
can be expressed not only in cancer but
also in many normal tissues. It may play an
important role in the regulation of smooth
muscle tone, transepithelial Ca transport
(eg, in the mammary gland), and the differentiation of tissue and organ development
[7,13]. Note the high degree of homology
between PTHrP and PTH at the amino end
of the polypeptides. MWmolecular
weight; Namino terminal; Ccarboxy
terminal. (From Root [7]; with permission.)
5.6

50
SP
100
NH2
HS
Inactivating
Arg186Gln
Asp216Glu
Tyr219Glu
Glu298Lys
Ser608Stop
Ser658Tyr
Gly670Arg
Pro749Arg
Arg796Trp
Val818Ile
Stop
Activating
Glu128Ala
500
600
550
450
350
400
250
300
200
S
*
S
X
614
671
684
746
771
829
829
Cell
membrane
636
651
701
726
793
808
863
P
P
P
Cysteline
Conserved
Acidic
P PKC phosphorylation site
N-glycosylation
HOOC
FIGURE 5-10
The calcium-ion sensing receptor (CaSR). The CaSR is a guanosine
triphosphate (GTP) or G-proteincoupled polypeptide receptor.
The human CaSR has approximately 1084 amino acid residues.
The CaSR mediates the effects of Ca on parathyroid and renal tissues. CaSR also can be found in thyroidal C cells, brain cells, and
in the gastrointestinal tract. The CaSR allows Ca to act as a first
messenger on target tissues and then act by way of other secondmessenger systems (eg, phospholipase enzymes and cyclic adenosine monophosphate). Within parathyroid cells, hypercalcemia
increases CaSR-Ca binding, which activates the G-protein. The Gprotein then activates the phospholipase C--1phosphatidylinositol-4,5-biphosphate pathway to increase intracellular Ca, which
then decreases translation of parathyroid hormone (PTH), decreases PTH secretion, and increases PTH degradation. The CaSR also
is an integral part of Ca homeostasis within the kidney. The gene
for CaSR is located on human chromosome 3q13 [3,4,7,1416].
PKCprotein kinase C; HShydrophobic segment; NH2amino
terminal. (From Hebert and Brown [4]; with permission.)
5.7
Gastrointestinal Absorption of Calcium
Gastrointestinal
absorption of
dietary calcium (Ca)
Net Ca absorption
mmol/d
mg/d
Site
Stomach
% of intake
absorbed
Duodenum
0.75
30
Jejunum
1.0
40
Ileum
3.25
130
13
Colon
Total*
200
20
*Normal dietary Ca intake =1000 mg (25 mmol) per day
Lumen
Ca2+
Microvilli
Ca2+
2
Ca2+
3
Ca2+
4
Actin
Myosin-I
Calmodulin
Ca2+
Calbindin-Ca2+
complex
Ca2+
Free
Ca2+
Micro- diffusion
vesicular
transport
Calbindinsynthesis
Calcitriol
Nucleus
Ca2+
Exocytosis
Na
Na/Ca
exchange
Ca2+
~
Ca2+
Ca2+-ATPase
Ca2+
Lamina propria
FIGURE 5-11
Gastrointestinal absorption of dietary calcium (Ca). The normal
recommended dietary intake of Ca for an adult is 800 to 1200
mg/d (2030 mmol/d). Foods high in Ca content include milk,
dairy products, meat, fish with bones, oysters, and many leafy
green vegetables (eg, spinach and collard greens). Although serum
Ca levels can be maintained in the normal range by bone resorption, dietary intake is the only source by which the body can
replenish stores of Ca in bone. Ca is absorbed almost exclusively
within the duodenum, jejunum, and ileum. Each of these intestinal segments has a high absorptive capacity for Ca, with their
relative Ca absorption being dependent on the length of each
respective intestinal segment and the transit time of the food
bolus. Approximately 400 mg of the usual 1000 mg dietary Ca
intake is absorbed by the intestine, and Ca loss by way of intestinal secretions is approximately 200 mg/d. Therefore, a net
absorption of Ca is approximately 200 mg/d (20%). Biliary and
pancreatic secretions are extremely rich in Ca. 1,25-dihydroxyvitamin D3 is an extremely important regulatory hormone for
intestinal absorption of Ca [1,2,17,18].
FIGURE 5-12
Proposed pathways for calcium (Ca) absorption across the intestinal
epithelium. Two routes exist for the absorption of Ca across the
intestinal epithelium: the paracellular pathway and the transcellular
route. The paracellular pathway is passive, and it is the predominant
means of Ca absorption when the luminal concentration of Ca is
high. This is a nonsaturable pathway and can account for one half to
two thirds of total intestinal Ca absorption. The paracellular absorptive route may be indirectly influenced by 1,25-dihydroxy-vitamin D3
(1,25(OH)2D3) because it may be capable of altering the structure of
intercellular tight junctions by way of activation of protein kinase C,
making the tight junction more permeable to the movement of Ca.
However, 1,25(OH)2D3 primarily controls the active absorption of
Ca. (1) Ca moves down its concentration gradient through a Ca
channel or Ca transporter into the apical section of the microvillae.
Because the intestinal concentration of Ca usually is 10-3 mol and the
intracellular Ca concentration is 10-6 mol, a large concentration gradient favors the passive movement of Ca. Ca is rapidly and reversibly
bound to the calmodulin-actin-myosin I complex. Ca may then move
to the basolateral area of the cell by way of microvesicular transport,
or ionized Ca may diffuse to this area of the cell. (2) As the calmodulin complex becomes saturated with Ca, the concentration gradient
for the movement of Ca into the microvillae is not as favorable,
which slows Ca absorption. (3) Under the influence of calcitriol,
intestinal epithelial cells increase their synthesis of calbindin. (4) Ca
binds to calbindin, thereby unloading the Ca-calmodulin complexes,
which then remove Ca from the microvillae region. This decrease in
Ca concentration again favors the movement of Ca into the microvillae. As the calbindin-Ca complex dissociates, the free intracellular Ca
is actively extruded from the cell by either the Ca-adenosine triphosphatase (ATPase) or Na-Ca exchanger. Calcitriol may also increase
the synthesis of the plasma membrane Ca-ATPase, thereby aiding in
the active extrusion of Ca into the lamina propria [2,7,9,17,18].
5.8
Renal Handling of Calcium

Afferent
arteriole
Efferent
arteriole
Glomerular
capillary
Bowman's
space
Ca2+-Protein
Ca2+
ionized
Ca2+
complexed
FIGURE 5-13
Glomerular filtration of calcium (Ca). Total serum Ca consists of
ionized, protein bound, and complexed fractions (47.5%, 46.0%,
and 6.5%, respectively). The complexed Ca is bound to molecules
such as phosphate and citrate. The ultrafilterable Ca equals the
total of the ionized and complexed fractions. Normal total serum
Ca is approximately 8.9 to 10.1 mg/dL (about 2.22.5 mmol/L).
Ca can be bound to albumin and globulins. For each 1.0 gm/dL
decrease in serum albumin, total serum Ca decreases by 0.8 mg/dL;
for each 1.0 gm/dL decrease in serum globulin fraction, total serum
Ca decreases by 0.12 mg/dL. Ionized Ca is also affected by pH. For
every 0.1 change in pH, ionized Ca changes by 0.12 mg/dL.
Alkalosis decreases the ionized Ca [1,6,7].
Ca2+-ultrafilterable
Proximal
tubule
Ca2+ ATPase, VDR,

CaBP-D, Na+/Ca2+ exchanger
colocalized here
Parathyroid hormone
and 1,25(OH)2D3
Calcitonin
Thiazides
CNT
DCT
PCT
Cortex
CTAL
Medulla
MAL
Papilla
PT
Ca remaining in tubular fluid, %
100
DT
Urine
100
80
60
40
20
0
(40)
(20)
(10)
(2)
FIGURE 5-14
Renal handling of calcium (Ca). Ca is filtered at the glomerulus,
with the ultrafilterable fraction (UFCa) of plasma Ca entering the
proximal tubule (PT). Within the proximal convoluted tubule
(PCT) and the proximal straight tubule (PST), isosmotic reabsorption of Ca occurs such that at the end of the PST the UFCa to TFCa
ratio is about 1.1 and 60% to 70% of the filtered Ca has been
reabsorbed. Passive paracellular pathways account for about 80%
of Ca reabsorption in this segment of the nephron, with the
remaining 20% dependent on active transcellular Ca movement.
No reabsorption of Ca occurs within the thin segment of the loop
of Henle. Ca is reabsorbed in small amounts within the medullary
segment of the thick ascending limb (MAL) of the loop of Henle
and calcitonin (CT) stimulates Ca reabsorption here. However, the
cortical segments (cTAL) reabsorb about 20% of the initially filtered load of Ca. Under normal conditions, most of the Ca reabsorption in the cTAL is passive and paracellular, owing to the
favorable electrochemical gradient. Active transcellular Ca transport can be stimulated by both parathyroid hormone (PTH) and
1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) in the cTAL. In the
early distal convoluted tubule (DCT), thiazide-activated Ca transport occurs. The DCT is the primary site in the nephron at which
Ca reabsorption is regulated by PTH and 1,25(OH)2D3. Active
transcellular Ca transport must account for Ca reabsorption in the
DCT, because the transepithelial voltage becomes negative, which
would not favor passive movement of Ca out of the tubular lumen.
About 10% of the filtered Ca is reabsorbed in the DCT, with
another 3% to 10% of filtered Ca reabsorbed in the connecting
tubule (CNT) by way of mechanisms similar to those in the DCT
[1,2,6, 7,18]. ATPaseadenosine triphosphatase; CaBP-DCabinding protein D; DTdistal tubule; VDRvitamin D receptor.
(Adapted from Kumar [1].)

Cortical thick ascending limb
5
Ca2+,
Mg2+
Na
2Cl
Ca2+
2
PK-C
PLA2
3
AA
P-450
system
4
20-HETE
Urinary
space
K+
Ca2+
G-protein
IP3
cAMP
1
CaSR
ATP Hormone
recptor
5
Ca2+, Mg2+
Hormone
DHP sensitive
channel
Ca2+
Thiazide sensitive
channel Ca2+
Ca2+
Tubular lumen
Distal
convoluted
tubule cell
Ca2+
CaBP28
CaBP9
Ca2+
cAMP
ATP
PTH
Nucleus
+
?+
VDR
Na+
~ PMCA
Ca2+ Ca2+
Calcitriol
5.9
FIGURE 5-15
Effects of hypercalcemia on calcium (Ca) reabsorption in the
cortical thick ascending limb (cTAL) of the loop of Henle and
urinary concentration. (1) Hypercalcemia stimulates the Ca-sensing
receptor (CaSR) of cells in the cTAL. (2) Activation of the G-protein increases intracellular free ionized Ca (Ca2+) by way of the
inositol 1,4,5-trisphosphate (IP3) pathway, which increases the
activity of the P450 enzyme system. The G-protein also increases
activity of phospholipase A2 (PLAA), which increases the concentration of arachidonic acid (AA). (3) The P450 enzyme system
increases production of 20-hydroxy-eicosatetraenoic acid (20HETE) from AA. (4) 20-HETE inhibits hormone-stimulated production of cyclic adenosine monophosphate (cAMP), blocks sodium reabsorption by the sodium-potassium-chloride (Na-K-2Cl)
cotransporter, and inhibits movement of K out of K-channels. (5)
These changes alter the electrochemical forces that would normally
favor the paracellular movement of Ca (and Mg) such that Ca (and
Mg) is not passively reabsorbed. Both the lack of movement of Na
into the renal interstitium and inhibition of hormonal (eg, vasopressin) effects impair the ability of the nephron to generate maximally concentrated urine [3,4,14]. ATPadenosine triphosphate;
PK-Cprotein kinase C.
FIGURE 5-16
Postulated mechanism of the Ca transport pathway shared by PTH
and 1,25(OH)2D3. Cyclic adenosine monophosphate (cAMP) generated by PTH stimulation leads to increased influx of Ca into the
apical dihydropyridine-sensitive Ca channel. There also is increased
activity of the basolateral Na-Ca exchanger and, perhaps, of the
plasma membraneassociated Ca-adenosine triphosphatase
(PMCA), which can rapidly extrude the increased intracellular free
Ca (Ca2+). Calcitriol (1,25(OH)2D3), by way of the vitamin D
receptor (VDR), stimulates transcription of calbindin D28k
(CaBP28) and calbindin D9k (CaBP9). CaBP28 increases apical
uptake of Ca by both the dihydropyridine- and thiazide-sensitive Ca
channels by decreasing the concentration of unbound free Ca2+ and
facilitates Ca movement to the basolateral membrane. CaBP9 stimulates PMCA activity, which increases extrusion of Ca by the cell.
Similar hormonally induced mechanisms of Ca transport are
believed to exist throughout the cortical thick ascending limb, the
DCT, and the connecting tubule (CNT) [6]. ATPadenosine
triphosphate; Na+ionized sodium.
5.10
Disturbances of Serum Calcium

Hypocalcemia
Parathyroid glands
Kidney
+
+
PTH
Gastrointestinal
tract
+
PT
DCT
+
PTH
Parathyroid cell
Nucleus
FIGURE 5-17
Physiologic response to hypocalcemia.
Hypocalcemia stimulates both parathyroid
hormone (PTH) release and PTH synthesis.
Both hypocalcemia and PTH increase the
activity of the 1--hydroxylase enzyme in the
proximal tubular (PT) cells of the nephron,
which increases the synthesis of 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3). PTH
increases bone resorption by osteoclasts.
PTH and 1,25(OH)2D3 stimulate Ca reabsorption in the distal convoluted tubule
(DCT). 1,25(OH)2D3 increases the fractional
absorption of dietary Ca by the gastrointestinal (GI) tract. All these mechanisms aid in
returning the serum Ca to normal levels [1].
Bone
+
1,25(OH)2D3
Intestinal Ca2+ absorption
Renal Ca2+ excretion
Bone resorption
Normocalcemia
FIGURE 5-18
Causes of hypocalcemia (decrease in ionized plasma calcium).
CAUSES OF HYPOCALCEMIA
Lack of parathyroid hormone (PTH)
Increased calcium complexation
After thyroidectomy or parathyroidectomy

Hereditary (congenital) hypoparathyroidism
Pseudohypoparathyroidism (lack of
effective PTH)
Hypomagnesemia (blocks PTH secretion)
Bone hunger after parathyroidectomy

Rhabdomyolysis
Acute pancreatitis
Tumor lysis syndrome
(hyperphosphatemia)
Malignancy (increased
osteoblastic activity)
Lack of Vitamin D
Dietary deficiency or
malabsorption (osteomalacia)
Inadequate sunlight
Defective metabolism
Anticonvulsant therapy
Liver disease
Renal disease
Vitamin Dresistant rickets
Hypercalcemia
Thyroid and
parathyroid glands
Kidney
C-cells
CT
PTH
Gastrointestinal
tract
PT
DCT
PTH
Parathyroid cell
Nucleus
Bone
1,25(OH)2D3
Intestinal Ca2+ absorption
Renal Ca2+ excretion
FIGURE 5-19
Physiologic response to hypercalcemia.
Hypercalcemia directly inhibits both
parathyroid hormone (PTH) release
and synthesis. The decrease in PTH and
hypercalcemia decrease the activity of the
1--hydroxylase enzyme located in the
proximal tubular (PT) cells of the nephron,
which in turn, decreases the synthesis of
1,25-dihydroxy-vitamin D3 (1,25(OH)2D3).
Hypercalcemia stimulates the C cells in the
thyroid gland to increase synthesis of calcitonin (CT). Bone resorption by osteoclasts
is blocked by the increased CT and
decreased PTH. Decreased levels of PTH
and 1,25(OH)2D3 inhibit Ca reabsorption
in the distal convoluted tubules (DCT) of
the nephrons and overwhelm the effects of
CT, which augment Ca reabsorption in the
medullary thick ascending limb leading to
an increase in renal Ca excretion. The
decrease in 1,25(OH)2D3 decreases gastrointestinal (GI) tract absorption of dietary
Ca. All of these effects tend to return serum
Ca to normal levels [1].
Bone resorption
Normocalcemia
FIGURE 5-20
Causes of hypercalcemia (increase in
ionized plasma calcium).
CAUSES OF HYPERCALCEMIA
Excess parathyroid hormone (PTH) production
Increased intestinal absorption of calcium
Primary hyperparathyroidism
Tertiary hyperparathyroidism*
Vitamin D intoxication
Milk-alkali syndrome*
Excess 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3)
Decreased renal excretion of calcium
Sarcoidosis and granulomatous diseases
Severe hypophosphatemia
Neoplastic production of 1,25(OH)2D3 (lymphoma)
Familial hypocalciuric hypercalcemia

Thiazides
Increased bone resorption
Aluminum intoxication*
Adynamic (low-turnover) bone disease*
Corticosteroids
Metastatic (osteolytic) tumors (eg, breast, colon, prostate)

Humoral hypercalcemia
PTH-related protein (eg, squamous cell lung, renal
cell cancer)
Osteoclastic activating factor (myeloma)
1,25 (OH)2D3 (lymphoma)
Prostaglandins
Hyperthyroidism
Immobilization
Paget disease
Vitamin A intoxication
*Occurs in renal failure.
Impaired bone formation and incorporation of

calcium
5.11
5.12

FIGURE 5-21
Therapy available for the treatment of hypercalcemia.
AVAILABLE THERAPY FOR HYPERCALCEMIA*

Agent
Mechanism of action
Saline and loop diuretics

Corticosteroids
Increase renal excretion of calcium

Block 1,25-dihydroxy-vitamin D3
synthesis and bone resorption
Blocks P450 system, decreases
1, 25-dihydroxy-vitamin D3
Complexes calcium
Inhibits bone resorption
Inhibits bone resorption
Inhibit bone resorption
Ketoconazole
Oral or intravenous phosphate
Calcitonin
Mithramycin
Bisphosphonates
*Always identify and treat the primary cause of hypercalcemia.
Secondary Hyperparathyroidism
Renal failure
Number of nephrons
PT
H+ excretion
P excretion
1,25(OH)2D3
Hyperphosphatemia
Ca
absorption
Gastrointestinal
tract
Hypocalcemia
Activity
Activity
VDR
Degradation
of PTH
PTH
CaSR
Increased
transcription
Release PTH
Hyperparathyroidism
ProPTH
Pre-proPTH
Parathyroid cell
Proliferation
Nucleus
FIGURE 5-22
Pathogenesis of secondary hyperparathyroidism (HPT) in chronic
renal failure (CRF). Decreased numbers of proximal tubular (PT)
cells, owing to loss of renal mass, cause a quantitative decrease in
synthesis of 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3). Loss of
renal mass also impairs renal phosphate (P) and acid (H+) excretion.
These impairments further decrease the activity of the 1--hydroxylase enzyme in the remaining PT cells, further contributing to the
decrease in levels of 1,25(OH)2D3. 1,25(OH)2D3 deficiency decreases intestinal absorption of calcium (Ca), leading to hypocalcemia,
which is augmented by the direct effect of hyperphosphatemia.
Hypocalcemia and hyperphosphatemia stimulate PTH release and
synthesis and can recruit inactive parathyroid cells into activity and
PTH production. Hypocalcemia also may decrease intracellular
degradation of PTH. The lack of 1,25(OH)2D3, which would ordinarily feed back to inhibit the transcription of prepro-PTH and
exert an antiproliferative effect on parathyroid cells, allows the
increased PTH production to continue. In CRF there may be
decreased expression of the Ca-sensing receptor (CaSR) in parathyroid cells, making them less sensitive to levels of plasma Ca.
Patients with the b allele or the bb genotype vitamin D receptor
(VDR) may be more susceptible to HPT, because the VDR1,25(OH)2D3 complex is less effective at suppressing PTH production and cell proliferation. The deficiency of 1,25(OH)2D3 may also
decrease VDR synthesis, making parathyroid cells less sensitive to
1,25(OH)2D3. Although the PTH receptor in bone cells is downregulated in CRF (ie, for any level of PTH, bone cell activity is lower in
CRF patients than in normal persons), the increased plasma levels
of PTH may have harmful effects on other systems (eg, cardiovascular system, nervous system, and integument) by way of alterations
of intracellular Ca. Current therapeutic methods used to decrease
PTH release in CRF include correction of hyperphosphatemia,
maintenance of normal to high-normal levels of plasma Ca, administration of 1,25(OH)2D3 orally or intravenously, and administration of a Ca-ion sensing receptor (CaSR) agonist [1416,1922].
5.13
Calcium and Vitamin D Preparations

FIGURE 5-23
Calcium (Ca) content of oral Ca preparations.
CALCIUM CONTENT OF ORAL

CALCIUM PREPARATIONS
Calcium (Ca) salt

Carbonate
Acetate
Citrate
Lactate
Gluconate
Tablet size, mg
Elemental Ca, mg, %
1250
667
950
325
500
500 (40)
169 (25)
200 (21)
42 (13)
4.5 (9)
Fractional intestinal absorption of Ca may differ between Ca salts.

Data from McCarthy and Kumar [19] and Physicians Desk Reference [23].
VITAMIN D PREPARATIONS AVAILABLE IN THE UNITED STATES
Ergocalciferol
(Vitamin D2)
Calcifediol
(25-hydroxy-vitamin D3)
Dihydrotachysterol
Commercial name
Calciferol
Calderol (Organon, Inc,

West Orange, NJ)
DHT Intensol (Roxane

Laboratories, Columbus, OH)
Oral preparations
50,000 IU tablets
20- and 50-g capsules
0.125-, 0.2-, 0.4-mg tablets
Rocaltrol (Roche Laboratories,

Nutley, NJ)
Calcijex (Abbott Laboratories,
Abbott Park, NJ)
0.25- and 0.50-g capsules
50,000500,000 IU
Not used
48 wk
20200 g
2040 g*
24 wk
0.21.0 mg
0.2-0.4 mg*
12 wk
0.255.0 g
0.250.50 g
47 d
1760 d
730 d
314 d
210 d
Usual daily dose

Hypoparathyroidism
Renal failure
Time until increase in
serum calcium
Time for reversal of
toxic effects
*Not currently advised in patients with chronic renal failure.

In patients with hypoparathyroidism who have normal renal function.
Data from McCarthy and Kumar [19] and Physicians Desk Reference [23].
FIGURE 5-24
Vitamin D preparations.
Calcitriol
(1,25-dihydroxy-vitamin D3)
5.14
References
1. Kumar R: Calcium metabolism. In The Principles and Practice of
Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis:
Mosby-Year Book; 1995, 964971.
2. Johnson JA, Kumar R: Renal and intestinal calcium transport: roles of
vitamin D and vitamin D-dependent calcium binding proteins. Semin
Nephrol 1994, 14:119128.
3. Hebert SC, Brown EM, Harris HW: Role of the Ca2+-sensing receptor
in divalent mineral ion homeostasis. J Exp Biol 1997, 200:295302.
4. Hebert SC, Brown EM: The scent of an ion: calcium-sensing and its roles
in health and disease. Curr Opinion Nephrol Hypertens 1996, 5:4553.
5. Berridge MJ: Elementary and global aspects of calcium signalling.
J Exp Biol 1997, 200:315319.
6. Friedman PA, Gesek FA: Cellular calcium transport in renal epithelia:
measurement, mechanisms, and regulation. Physiol Rev 1995,
75:429471.
7. Root AW: Recent advances in the genetics of disorders of calcium
homeostasis. Adv Pediatr 1996, 43:77125.
8. Holick MF: Defects in the synthesis and metabolism of vitamin D.
Exp Clin Endocrinol 1995, 103:219227.
9. Kumar R: Calcium transport in epithelial cells of the intestine and
kidney. J Cell Biochem 1995, 57:392398.
10. White CP, Morrison NA, Gardiner EM, Eisman JA: Vitamin D receptor alleles and bone physiology. J Cell Biochem 1994, 56:307314.
11. Fernandez E, Fibla J, Betriu A, et al.: Association between vitamin D
receptor gene polymorphism and relative hypoparathyroidism in
patients with chronic renal failure. J Am Soc Nephrol 1997,
8:15461552.
12. Tanaka Y, Funahashi J, Imai T, et al.: Parathyroid function and bone
metabolic markers in primary and secondary hyperparathyroidism.
Sem Surg Oncol 1997, 13:125133.
13. Philbrick WM, Wysolmerski JJ, Galbraith S, et al.: Defining the roles
of parathyroid hormone-related protein in normal physiology. Physiol
Rev 1996, 76:127173.
14. Goodman WG, Belin TR, Salusky IB: In vivo> assessments of
calcium-regulated parathyroid hormone release in secondary
hyperparathyroidism [editorial review]. Kidney Int 1996,
50:18341844.
15. Chattopadhyay N, Mithal A, Brown EM: The calcium-sensing
receptor: a window into the physiology and pathophysiology of
mineral ion metabolism. Endocrine Rev 1996, 17:289307.
16. Nemeth EF, Steffey ME, Fox J: The parathyroid calcium receptor:
a novel therapeutic target for treating hyperparathyroidism. Pediatr
Nephrol 1996, 10:275279.
17. Wasserman RH, Fullmer CS: Vitamin D and intestinal calcium transport:
facts, speculations and hypotheses. J Nutr 1995, 125:1971S1979S.
18. Johnson JA, Kumar R: Vitamin D and renal calcium transport. Curr
Opinion Nephrol Hypertens 1994, 3:424429.
19. McCarthy JT, Kumar R: Renal osteodystrophy. In The Principles and
Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S.
St. Louis: Mosby-Year Book; 1995, 10321045.
20. Felsenfeld AJ: Considerations for the treatment of secondary hyperparathyroidism in renal failure. J Am Soc Nephrol 1997, 8:9931004.
21. Parfitt AM. The hyperparathyroidism of chronic renal failure: a
disorder of growth. Kidney Int 1997, 52:39.
22. Salusky IB, Goodman WG: Parathyroid gland function in secondary
hyperparathyroidism. Pediatr Nephrol 1996, 10:359363.
23. Physicians Desk Reference (PDR). Montvale NJ: Medical Economics
Company; 1996.
Disorders of
Acid-Base Balance
Horacio J. Adrogu
Nicolaos E. Madias
aintenance of acid-base homeostasis is a vital function of the

living organism. Deviations of systemic acidity in either
direction can impose adverse consequences and when severe
can threaten life itself. Acid-base disorders frequently are encountered
in the outpatient and especially in the inpatient setting. Effective management of acid-base disturbances, commonly a challenging task, rests
with accurate diagnosis, sound understanding of the underlying
pathophysiology and impact on organ function, and familiarity with
treatment and attendant complications [1].
Clinical acid-base disorders are conventionally defined from the
vantage point of their impact on the carbonic acid-bicarbonate buffer
system. This approach is justified by the abundance of this buffer pair
in body fluids; its physiologic preeminence; and the validity of the isohydric principle in the living organism, which specifies that all the
other buffer systems are in equilibrium with the carbonic acid-bicarbonate buffer pair. Thus, as indicated by the Henderson equation,
[H+] = 24 PaCO2/[HCO3] (the equilibrium relationship of the carbonic acid-bicarbonate system), the hydrogen ion concentration of
blood ([H+], expressed in nEq/L) at any moment is a function of the
prevailing ratio of the arterial carbon dioxide tension (PaCO2,
expressed in mm Hg) and the plasma bicarbonate concentration
([HCO3], expressed in mEq/L). As a corollary, changes in systemic
acidity can occur only through changes in the values of its two determinants, PaCO2 and the plasma bicarbonate concentration. Those
acid-base disorders initiated by a change in PaCO2 are referred to as
respiratory disorders; those initiated by a change in plasma bicarbonate concentration are known as metabolic disorders. There are four
cardinal acid-base disturbances: respiratory acidosis, respiratory alkalosis, metabolic acidosis, and metabolic alkalosis. Each can be
encountered alone, as a simple disorder, or can be a part of a mixeddisorder, defined as the simultaneous presence of two or more simple
CHAPTER
6.2
acid-base disturbances. Mixed acid-base disorders are frequently observed in hospitalized patients, especially in the critically ill.
The clinical aspects of the four cardinal acid-base
disorders are depicted. For each disorder the following are
illustrated: the underlying pathophysiology, secondary

adjustments in acid-base equilibrium in response to the initiating disturbance, clinical manifestations, causes, and therapeutic principles.
Respiratory Acidosis
Arterial blood [H+], nEq/L
150 125
100
80 70 60
PaCO2
mm Hg
50
40
30
120 100 90 80 70
20
60
50
40
iratory
ic resp
Chron acidosis
Arterial plasma [HCO3], mEq/L
50
40
30
30
Acute respira
tory
acidosis
Normal
20
20
10
10
6.8
6.9
7.0
7.1
7.2
7.3
7.4
7.5
7.6
7.7
Arterial blood pH
Steady-state relationships in respiratory acidosis:
average increase per mm Hg rise in PaCO2
[HCO3] mEq/L
[H+] nEq/L
Acute adaptation
0.1
0.75
Chronic adaptation
0.3
0.3
FIGURE 6-1
Quantitative aspects of adaptation to respiratory acidosis.
Respiratory acidosis, or primary hypercapnia, is the acid-base disturbance initiated by an increase in arterial carbon dioxide tension
(PaCO2) and entails acidification of body fluids. Hypercapnia elicits adaptive increments in plasma bicarbonate concentration that
should be viewed as an integral part of respiratory acidosis. An
immediate increment in plasma bicarbonate occurs in response to
hypercapnia. This acute adaptation is complete within 5 to 10 minutes from the onset of hypercapnia and originates exclusively from
acidic titration of the nonbicarbonate buffers of the body (hemoglobin, intracellular proteins and phosphates, and to a lesser extent
plasma proteins). When hypercapnia is sustained, renal adjustments markedly amplify the secondary increase in plasma bicarbonate, further ameliorating the resulting acidemia. This chronic
adaptation requires 3 to 5 days for completion and reflects generation of new bicarbonate by the kidneys as a result of upregulation
of renal acidification [2]. Average increases in plasma bicarbonate
and hydrogen ion concentrations per mm Hg increase in PaCO2
after completion of the acute or chronic adaptation to respiratory
acidosis are shown. Empiric observations on these adaptations
have been used for construction of 95% confidence intervals for
graded degrees of acute or chronic respiratory acidosis represented
by the areas in color in the acid-base template. The black ellipse
near the center of the figure indicates the normal range for the
acid-base parameters [3]. Note that for the same level of PaCO2,
the degree of acidemia is considerably lower in chronic respiratory
acidosis than it is in acute respiratory acidosis. Assuming a steady
state is present, values falling within the areas in color are consistent with but not diagnostic of the corresponding simple disorders.
Acid-base values falling outside the areas in color denote the presence of a mixed acid-base disturbance [4].
Eucapnia
Stable Hypercapnia
Bicarbonate reabsorption
Chloride excretion
Net acid excretion
Disorders of Acid-Base Balance
2
Days
FIGURE 6-2
Renal acidification response to chronic hypercapnia. Sustained hypercapnia entails a persistent increase in the secretory rate of the renal
tubule for hydrogen ions (H+) and a persistent decrease in the reabsorption rate of chloride ions (Cl-). Consequently, net acid excretion
(largely in the form of ammonium) transiently exceeds endogenous
6.3
acid production, leading to generation of new bicarbonate ions

(HCO3) for the body fluids. Conservation of these new bicarbonate
ions is ensured by the gradual augmentation in the rate of renal bicarbonate reabsorption, itself a reflection of the hypercapnia-induced
increase in the hydrogen ion secretory rate. A new steady state
emerges when two things occur: the augmented filtered load of bicarbonate is precisely balanced by the accelerated rate of bicarbonate
reabsorption and net acid excretion returns to the level required to
offset daily endogenous acid production. The transient increase in
net acid excretion is accompanied by a transient increase in chloride
excretion. Thus, the resultant ammonium chloride (NH4Cl) loss generates the hypochloremic hyperbicarbonatemia characteristic of
chronic respiratory acidosis. Hypochloremia is sustained by the
persistently depressed chloride reabsorption rate. The specific cellular
mechanisms mediating the renal acidification response to chronic
hypercapnia are under active investigation. Available evidence supports a parallel increase in the rates of the luminal sodium ion
hydrogen ion (Na+-H+) exchanger and the basolateral Na+-3HCO3
cotransporter in the proximal tubule. However, the nature of these
adaptations remains unknown [5]. The quantity of the H+-adenosine
triphosphatase (ATPase) pumps does not change in either cortex or
medulla. However, hypercapnia induces exocytotic insertion of H+ATPasecontaining subapical vesicles to the luminal membrane of
proximal tubule cells as well as type A intercalated cells of the cortical
and medullary collecting ducts. New H+-ATPase pumps thereby are
recruited to the luminal membrane for augmented acidification [6,7].
Furthermore, chronic hypercapnia increases the steady-state abundance of mRNA coding for the basolateral ClHCO3 exchanger
(band 3 protein) of type A intercalated cells in rat renal cortex and
medulla, likely indicating increased band 3 protein levels and therefore augmented basolateral anion exchanger activity [8].
SIGNS AND SYMPTOMS OF RESPIRATORY ACIDOSIS
Respiratory System
Cardiovascular System
Mild to moderate hypercapnia

Cerebral vasodilation
Increased intracranial pressure
Headache
Confusion
Combativeness
Hallucinations
Transient psychosis
Myoclonic jerks
Flapping tremor
Severe hypercapnia
Manifestations of pseudotumor cerebri
Stupor
Coma
Constricted pupils
Depressed tendon reflexes
Extensor plantar response
Seizures
Papilledema
Breathlessness
Central and peripheral cyanosis
(especially when breathing
room air)
Pulmonary hypertension
Mild to moderate hypercapnia

Warm and flushed skin
Bounding pulse
Well maintained cardiac
output and blood pressure
Diaphoresis
Severe hypercapnia
Cor pulmonale
Decreased cardiac output
Systemic hypotension
Cardiac arrhythmias
Prerenal azotemia
Peripheral edema
FIGURE 6-3
Signs and symptoms of respiratory acidosis. The effects of respiratory acidosis on the central
nervous system are collectively known as hypercapnic encephalopathy. Factors responsible for
its development include the magnitude and

time course of the hypercapnia, severity of
the acidemia, and degree of attendant
hypoxemia. Progressive narcosis and coma
may occur in patients receiving uncontrolled oxygen therapy in whom levels of
arterial carbon dioxide tension (PaCO2)
may reach or exceed 100 mm Hg. The
hemodynamic consequences of carbon
dioxide retention reflect several mechanisms, including direct impairment of
myocardial contractility, systemic vasodilation caused by direct relaxation of vascular
smooth muscle, sympathetic stimulation,
and acidosis-induced blunting of receptor
responsiveness to catecholamines. The net
effect is dilation of systemic vessels, including the cerebral circulation; whereas vasoconstriction might develop in the pulmonary and renal circulations. Salt and
water retention commonly occur in chronic
hypercapnia, especially in the presence of
cor pulmonale. Mechanisms at play include
hypercapnia-induced stimulation of the
renin-angiotensin-aldosterone axis and the
sympathetic nervous system, elevated levels
of cortisol and antidiuretic hormone, and
increased renal vascular resistance. Of
course, coexisting heart failure amplifies
most of these mechanisms [1,2].
6.4
Load
Pump
Cerebrum
Voluntary control
Controller
Ventilatory requirement
(CO2 production, O2 consumption)
Brain stem
Automatic control
Spinal cord
Airway resistance
Phrenic and
intercostal nerves
Lung elastic recoil
Effectors
Muscles
of respiration
V
Ppl
Pabd
Chest wall elastic recoil

Diaphragm
Abdominal
cavity
FIGURE 6-4
Main components of the ventilatory system. The ventilatory system is responsible for maintaining
the arterial carbon dioxide tension (PaCO2) within normal limits by adjusting minute ventilation
(V) to match the rate of carbon dioxide production. The main elements of ventilation are the respiratory pump, which generates a pressure gradient responsible for air flow, and the loads that
oppose such action. The machinery of the respiratory pump includes the cerebrum, brain stem,
spinal cord, phrenic and intercostal nerves, and the muscles of respiration. Inspiratory muscle contraction lowers pleural pressure (Ppl) thereby inflating the lungs (V). The diaphragm, the most
important inspiratory muscle, moves downward as a piston at the floor of the thorax, raising
abdominal pressure (Pabd). The inspiratory decrease in Ppl by the respiratory pump must be sufficient to counterbalance the opposing effect of the combined loads, including the airway flow resistance, and the elastic recoil of the lungs and chest wall. The ventilatory requirement influences the
load by altering the frequency and depth of the ventilatory cycle. The strength of the respiratory
pump is evaluated by the pressure generated (P = Ppl - Pabd).
6.5
DETERMINANTS AND CAUSES OF CARBON DIOXIDE RETENTION

Respiratory Pump
Depressed Central Drive
Acute
General anesthesia
Sedative overdose
Head trauma
Cerebrovascular accident
Central sleep apnea
Cerebral edema
Brain tumor
Encephalitis
Brainstem lesion
Chronic
Sedative overdose
Methadone or heroin addiction
Sleep disordered breathing
Brain tumor
Bulbar poliomyelitis
Hypothyroidism
Abnormal Neuromuscular Transmission

Acute
High spinal cord injury
Status epilepticus
Botulism
Tetanus
Crisis in myasthenia gravis
Hypokalemic myopathy
Familial periodic paralysis
Drugs or toxic agents eg, curare,
succinylcholine, aminoglycosides,
organophosphorus
Chronic
Poliomyelitis
Multiple sclerosis
Muscular dystrophy
Amyotrophic lateral sclerosis
Diaphragmatic paralysis
Myopathic disease eg, polymyositis
Muscle Dysfunction
Acute
Fatigue
Hyperkalemia
Hypokalemia
Hypoperfusion state
Hypoxemia
Malnutrition
Chronic
Myopathic disease eg, polymyositis
FIGURE 6-5
Determinants and causes of carbon dioxide retention. When the respiratory pump is unable to balance the opposing load, respiratory
acidosis develops. Decreases in respiratory pump strength, increases
in load, or a combination of the two, can result in carbon dioxide
retention. Respiratory pump failure can occur because of depressed
central drive, abnormal neuromuscular transmission, or respiratory
Load
Increased Ventilatory Demand
High carbohydrate diet
Sorbent-regenerative hemodialysis
Pulmonary thromboembolism
Fat, air pulmonary embolism
Sepsis
Hypovolemia
Augmented Airway Flow Resistance
Acute
Upper airway obstruction
Coma-induced hypopharyngeal obstruction
Aspiration of foreign body or vomitus
Laryngospasm
Angioedema
Obstructive sleep apnea
Inadequate laryngeal intubation
Laryngeal obstruction after intubation
Lower airway obstruction
Generalized bronchospasm
Airway edema and secretions
Severe episode of spasmodic asthma
Bronchiolitis of infants and adults
Chronic
Upper airway obstruction
Tonsillar and peritonsillar hypertrophy
Paralysis of vocal cords
Tumor of the cords or larynx
Airway stenosis after prolonged intubation
Thymoma, aortic aneurysm
Lower airway obstruction
Airway scarring
Chronic obstructive lung disease eg, bronchitis,
bronchiolitis, bronchiectasis, emphysema
Lung Stiffness
Acute
Severe bilateral pneumonia
or bronchopneumonia
Acute respiratory
distress syndrome
Severe pulmonary edema
Atelectasis
Chronic
Severe chronic pneumonitis
Diffuse infiltrative disease eg,
alveolar proteinosis
Interstitial fibrosis
Chest Wall Stiffness
Acute
Rib fractures with flail chest
Pneumothorax
Hemothorax
Abdominal distention
Ascites
Peritoneal dialysis
Chronic
Kyphoscoliosis, spinal arthritis
Obesity
Fibrothorax
Hydrothorax
Chest wall tumor
muscle dysfunction. A higher load can be caused by increased ventilatory demand, augmented airway flow resistance, and stiffness of
the lungs or chest wall. In most cases, causes of the various determinants of carbon dioxide retention, and thus respiratory acidosis, are
categorized into acute and chronic subgroups, taking into consideration their usual mode of onset and duration [2].
6.6

Spontaneous
breathing
FIGURE 6-6
Posthypercapnic metabolic alkalosis. Development of posthypercapnic metabolic alkalosis is shown after abrupt normalization of the
arterial carbon dioxide tension (PaCO2) by way of mechanical ventilation in a 70-year-old man with respiratory decompensation who
has chronic obstructive pulmonary disease and chronic hypercapnia.
The acute decrease in plasma bicarbonate concentration ([HCO3])
over the first few minutes after the decrease in PaCO2 originates
from alkaline titration of the nonbicarbonate buffers of the body.
When a diet rich in chloride (Cl-) is provided, the excess bicarbonate is excreted by the kidneys over the next 2 to 3 days, and acidbase equilibrium is normalized. In contrast, a low-chloride diet sustains the hyperbicarbonatemia and perpetuates the posthypercapnic
metabolic alkalosis. Abrupt correction of severe hypercapnia by
way of mechanical ventilation generally is not recommended.
Rather, gradual return toward the patients baseline PaCO2 level
should be pursued [1,2]. [H+]hydrogen ion concentration.
Mechanical ventilation
PaCO2, mm Hg
80
60
40
[HCO3], mEq/L
40
Low-Cl diet
Cl - rich diet
30
Cl- rich diet
20
pH
7.50
30
7.40
40
7.30
50
7.20
60
0
[H+], nEq/L
7.60
Days
Airway patency
secured?
No
Remove dentures, foreign bodies, or food particles; Heimlich maneuver

(subdiaphragmatic abdominal thrust); tracheal intubation; tracheotomy
ent
pat
y
a
w
Air
Yes
Oxygen-rich mixture
delivered
Mental status and

blood gases evaluated
Alert, blood pH > 7.10,

or PaCO2 <60 mm Hg
Obtunded, blood pH < 7.10,

or PaCO2 > 60 mm Hg
Administer O2 via nasal mask or prongs to maintain

PaO2 > 60 mm Hg.
Correct reversible causes of pulmonary dysfunction
with antibiotics, bronchodilators, and
corticosteroids as needed.
Monitor patient with arterial blood gases initially at
intervals of 20 to 30 minutes and less frequently
thereafter.
If PaO2 does not increase to > 60 mm Hg or PaCO2
rises to > 60 mm Hg proceed to steps described in
the box below.
Consider intubation and initiation of mechanical
ventilation.
If blood pH is below 7.10 during mechanical
ventilation, consider administration of sodium
bicarbonate, to maintain blood pH between 7.10
and 7.20, while monitoring arterial blood gases closely.
Correct reversible causes of pulmonary dysfunction
as in box above.
FIGURE 6-7
Acute respiratory acidosis management.
Securing airway patency and delivering an
oxygen-rich mixture are critical initial steps
in management. Subsequent measures must
be directed at identifying and correcting the
underlying cause, whenever possible [1,9].
PaCO2arterial carbon dioxide tension.
Yes
PaO2 > 60 mm Hg
on room air
PaO2 < 55 mm Hg
PaO2 55 mm Hg, patient stable
Consider intubation and use of

standard ventilator support.
Correct reversible causes of
pulmonary dysfunction with
antibiotics, bronchodilators,
and corticosteroids as needed.
Mental status deteriorates
Administer O2 via nasal cannula or Venti mask

Correct reversible causes of pulmonary
dysfuntion with antibiotics, bronchodilators,
and corticosteroids as needed.
No
Yes
Observation, routine care.
Hemodynamic instability
No
CO2 retention worsens
Severe
hypercapnic
encephalopathy
or hemodynamic
instability
Consider use of noninvasive nasal mask ventilation

(NMV) or intubation and standard ventilator support.
6.7
FIGURE 6-8
Chronic respiratory acidosis management.
Therapeutic measures are guided by the
presence or absence of severe hypercapnic
encephalopathy or hemodynamic instability.
An aggressive approach that favors the
early use of ventilator assistance is most
appropriate for patients with acute respiratory acidosis. In contrast, a more conservative approach is advisable in patients with
chronic hypercapnia because of the great
difficulty often encountered in weaning
these patients from ventilators. As a rule,
the lowest possible inspired fraction of
oxygen that achieves adequate oxygenation
(PaO2 on the order of 60 mm Hg) is used.
Contrary to acute respiratory acidosis, the
underlying cause of chronic respiratory acidosis only rarely can be resolved [1,9].
Continue same measures.
Respiratory Alkalosis
150 125
100
80 70 60
PaCO2
mm Hg
50
40
30
120 100 90 80 70
20
60
50
40
40
30
30
Normal
20
Acut
e resp
alkalo iratory
sis
ato
pir
res osis
nic al
ro alk
Ch
50
20
10
ry
10
6.8
6.9
7.0
7.1
7.2
7.3
7.4
7.5
7.6
7.7
Arterial blood pH
Steady-state relationships in respiratory alkalosis:
average decrease per mm Hg fall in PaCO2
Acute adaptation
Chronic adaptation
[HCO3] mEq/L
0.2
[H+] nEq/L
0.75
0.4
0.4
FIGURE 6-9
Adaptation to respiratory alkalosis. Respiratory alkalosis, or
primary hypocapnia, is the acid-base disturbance initiated by a
decrease in arterial carbon dioxide tension (PaCO2) and entails
alkalinization of body fluids. Hypocapnia elicits adaptive decrements in plasma bicarbonate concentration that should be viewed
as an integral part of respiratory alkalosis. An immediate decrement in plasma bicarbonate occurs in response to hypocapnia. This
acute adaptation is complete within 5 to 10 minutes from the onset
of hypocapnia and is accounted for principally by alkaline titration
of the nonbicarbonate buffers of the body. To a lesser extent, this
acute adaptation reflects increased production of organic acids,
notably lactic acid. When hypocapnia is sustained, renal adjustments cause an additional decrease in plasma bicarbonate, further
ameliorating the resulting alkalemia. This chronic adaptation
requires 2 to 3 days for completion and reflects retention of hydrogen ions by the kidneys as a result of downregulation of renal acidification [2,10]. Shown are the average decreases in plasma bicarbonate and hydrogen ion concentrations per mm Hg decrease in
PaCO2after completion of the acute or chronic adaptation to respiratory alkalosis. Empiric observations on these adaptations have
been used for constructing 95% confidence intervals for graded
degrees of acute or chronic respiratory alkalosis, which are represented by the areas in color in the acid-base template. The black
ellipse near the center of the figure indicates the normal range for
the acid-base parameters. Note that for the same level of PaCO2,
the degree of alkalemia is considerably lower in chronic than it is
in acute respiratory alkalosis. Assuming that a steady state is present, values falling within the areas in color are consistent with but
not diagnostic of the corresponding simple disorders. Acid-base
values falling outside the areas in color denote the presence of a
mixed acid-base disturbance [4].
6.8
Stable Hypocapnia
Bicarbonate reabsorption
Sodium excretion
Net acid excretion
Eucapnia
Days
Km
Vmax
NS
P<0.01
1000
nmol/mg protein min
mmol/L
10
Control
Chronic
hypocapnia
(9% O2)
500
Control
Chronic
hypocapnia
(9% O2)
FIGURE 6-10
Renal acidification response to chronic hypocapnia. A, Sustained
hypocapnia entails a persistent decrease in the renal tubular secretory
rate of hydrogen ions and a persistent increase in the chloride reabsorption rate. As a result, transient suppression of net acid excretion
occurs. This suppression is largely manifested by a decrease in
ammonium excretion and, early on, by an increase in bicarbonate
excretion. The transient discrepancy between net acid excretion and
endogenous acid production, in turn, leads to positive hydrogen ion
balance and a reduction in the bicarbonate stores of the body.
Maintenance of the resulting hypobicarbonatemia is ensured by the
gradual suppression in the rate of renal bicarbonate reabsorption.
This suppression itself is a reflection of the hypocapnia-induced
decrease in the hydrogen ion secretory rate. A new steady state
emerges when two things occur: the reduced filtered load of bicarbonate is precisely balanced by the dampened rate of bicarbonate
reabsorption and net acid excretion returns to the level required to
offset daily endogenous acid production. The transient retention of
acid during sustained hypocapnia is normally accompanied by a loss
of sodium in the urine (and not by a retention of chloride as analogy
with chronic respiratory acidosis would dictate). The resulting extracellular fluid loss is responsible for the hyperchloremia that typically
accompanies chronic respiratory alkalosis. Hyperchloremia is sustained by the persistently enhanced chloride reabsorption rate. If
dietary sodium is restricted, acid retention is achieved in the company of increased potassium excretion. The specific cellular mechanisms mediating the renal acidification response to chronic hypocapnia are under investigation. Available evidence indicates a parallel
decrease in the rates of the luminal sodium ionhydrogen ion
(Na+-H+) exchanger and the basolateral sodium ion3 bicarbonate
ion (Na+-3HCO3) cotransporter in the proximal tubule. This parallel
decrease reflects a decrease in the maximum velocity (Vmax) of each
transporter but no change in the substrate concentration at halfmaximal velocity (Km) for sodium (as shown in B for the Na+-H+
exchanger in rabbit renal cortical brush-border membrane vesicles)
[11]. Moreover, hypocapnia induces endocytotic retrieval of H+adenosine triphosphatase (ATPase) pumps from the luminal membrane of the proximal tubule cells as well as type A intercalated cells
of the cortical and medullary collecting ducts. It remains unknown
whether chronic hypocapnia alters the quantity of the H+-ATPase
pumps as well as the kinetics or quantity of other acidification transporters in the renal cortex or medulla [6]. NSnot significant. (B,
From Hilden and coworkers [11]; with permission.)
SIGNS AND SYMPTOMS OF RESPIRATORY ALKALOSIS

Neuromuscular System
Cerebral vasoconstriction
Reduction in intracranial pressure
Light-headedness
Confusion
Increased deep tendon reflexes
Generalized seizures
Chest oppression
Angina pectoris
Ischemic electrocardiographic changes
Normal or decreased blood pressure
Cardiac arrhythmias
Peripheral vasoconstriction
Numbness and paresthesias

of the extremities
Circumoral numbness
Laryngeal spasm
Manifestations of tetany
Muscle cramps
Carpopedal spasm
Trousseaus sign
Chvosteks sign
FIGURE 6-11
Signs and symptoms of respiratory alkalosis. The manifestations of primary hypocapnia frequently occur in the acute phase, but
seldom are evident in chronic respiratory
alkalosis. Several mechanisms mediate these
clinical manifestations, including cerebral
hypoperfusion, alkalemia, hypocalcemia,
hypokalemia, and decreased release of oxygen to the tissues by hemoglobin. The cardiovascular effects of respiratory alkalosis
are more prominent in patients undergoing
mechanical ventilation and those with
ischemic heart disease [2].
6.9
CAUSES OF RESPIRATORY ALKALOSIS
Hypoxemia or Tissue Hypoxia

Decreased inspired oxygen tension
High altitude
Bacterial or viral pneumonia
Aspiration of food, foreign object,
or vomitus
Laryngospasm
Drowning
Cyanotic heart disease
Severe anemia
Left shift deviation of
oxyhemoglobin curve
Hypotension
Severe circulatory failure
Pulmonary edema
Central Nervous
System Stimulation
Drugs or Hormones
Stimulation of Chest Receptors
Miscellaneous
Voluntary
Pain
Anxiety syndromehyperventilation syndrome
Psychosis
Fever
Subarachnoid hemorrhage
Cerebrovascular accident
Meningoencephalitis
Tumor
Trauma
Nikethamide, ethamivan
Doxapram
Xanthines
Salicylates
Catecholamines
Angiotensin II
Vasopressor agents
Progesterone
Medroxyprogesterone
Dinitrophenol
Nicotine
Pneumonia
Asthma
Pneumothorax
Hemothorax
Flail chest
Acute respiratory distress syndrome
Cardiogenic and noncardiogenic
pulmonary edema
Pulmonary embolism
Pulmonary fibrosis
Pregnancy
Gram-positive septicemia
Gram-negative septicemia
Hepatic failure
Mechanical hyperventilation
Heat exposure
Recovery from metabolic acidosis
FIGURE 6-12
Respiratory alkalosis is the most frequent acid-base disorder
encountered because it occurs in normal pregnancy and highaltitude residence. Pathologic causes of respiratory alkalosis
include various hypoxemic conditions, pulmonary disorders, central nervous system diseases, pharmacologic or hormonal stimulation of ventilation, hepatic failure, sepsis, the anxiety-hyperventilation syndrome, and other entities. Most of these causes
are associated with the abrupt occurrence of hypocapnia; however, in many instances, the process might be sufficiently prolonged
Acute
Blood pH 7.55
Chronic
No
Manage underlying disorder.

No specific measures indicated.
Yes
Hemodynamic instability,
altered mental status,
or cardiac arrhythmias
No
Consider having patient rebreathe

into a closed system.
Manage underlying disorder.
Yes
Consider measures to correct blood pH 7.50 by:
Reducing [HCO3]:
acetazolamide, ultrafiltration and normal saline
replacement, hemodialysis using a low bicarbonate bath.
Increasing PaCO2:
rebreathing into a closed system, controlled hypoventilation
by ventilator with or without skeletal muscle paralysis.
to permit full chronic adaptation to occur. Consequently, no

attempt has been made to separate these conditions into acute
and chronic categories. Some of the major causes of respiratory
alkalosis are benign, whereas others are life-threatening. Primary
hypocapnia is particularly common among the critically ill,
occurring either as the simple disorder or as a component of
mixed disturbances. Its presence constitutes an ominous prognostic sign, with mortality increasing in direct proportion to the
severity of the hypocapnia [2].
FIGURE 6-13
Respiratory alkalosis management. Because chronic respiratory alkalosis poses a low risk to health and produces few or no symptoms,
measures for treating the acid-base disorder itself are not required. In
contrast, severe alkalemia caused by acute primary hypocapnia
requires corrective measures that depend on whether serious clinical
manifestations are present. Such measures can be directed at reducing
plasma bicarbonate concentration ([HCO3]), increasing the arterial
carbon dioxide tension (PaCO2), or both. Even if the baseline plasma
bicarbonate is moderately decreased, reducing it further can be particularly rewarding in this setting. In addition, this maneuver combines
effectiveness with relatively little risk [1,2].
6.10
Lungs
Normal
pH
7.40
PCO2
40
24
[HCO3 ]
95
PO2
0.21
FiO2
LV
Peripheral tissues
Arterial
compartment
Venous
compartment
Circulatory
Failure
7.42
pH
35
PCO2
22
[HCO3 ]
80
PO2
0.35
FiO2
LV
7.29
pH
60
PCO2
28
[HCO3 ]
30
PO2
RV
Cardiac
7.37
pH
27
PCO2
15
[HCO3 ]
116
PO2
1.00
FiO2
pH
7.38
PCO2
46
[HCO3 ]
26
PO2
40
RV
Arrest
LV
RV
pH
7.00
PCO2
75
[HCO3 ]
18
PO2
17
FIGURE 6-14
Pseudorespiratory alkalosis. This entity
develops in patients with profound depression of cardiac function and pulmonary
perfusion but relative preservation of alveolar ventilation. Patients include those with
advanced circulatory failure and those
undergoing cardiopulmonary resuscitation.
The severely reduced pulmonary blood flow
limits the amount of carbon dioxide delivered to the lungs for excretion, thereby
increasing the venous carbon dioxide tension (PCO2). In contrast, the increased ventilation-to-perfusion ratio causes a larger
than normal removal of carbon dioxide per
unit of blood traversing the pulmonary circulation, thereby giving rise to arterial
hypocapnia [12,13]. Note a progressive
widening of the arteriovenous difference in
pH and PCO2 in the two settings of cardiac
dysfunction. The hypobicarbonatemia in
the setting of cardiac arrest represents a
complicating element of lactic acidosis.
Despite the presence of arterial hypocapnia,
pseudorespiratory alkalosis represents a
special case of respiratory acidosis, as
absolute carbon dioxide excretion is
decreased and body carbon dioxide balance
is positive. Furthermore, the extreme oxygen deprivation prevailing in the tissues
might be completely disguised by the reasonably preserved arterial oxygen values.
Appropriate monitoring of acid-base composition and oxygenation in patients with
advanced cardiac dysfunction requires
mixed (or central) venous blood sampling
in addition to arterial blood sampling.
Management of pseudorespiratory alkalosis
must be directed at optimizing systemic
hemodynamics [1,13].
6.11
Metabolic Acidosis
150 125
100
80 70 60
PaCO2
mm Hg
50
40
30
120 100 90 80 70
20
60
50
40
40
30
30
20
Normal
20
M
e
ac tab
ido oli
sis c
50
10
10
6.8
6.9
7.0
7.1
7.2
7.3
7.4
7.5
7.6
7.7
FIGURE 6-15
Ninety-five percent confidence intervals for metabolic acidosis.
Metabolic acidosis is the acid-base disturbance initiated by a
decrease in plasma bicarbonate concentration ([HCO3]). The resultant acidemia stimulates alveolar ventilation and leads to the secondary hypocapnia characteristic of the disorder. Extensive observations in humans encompassing a wide range of stable metabolic
acidosis indicate a roughly linear relationship between the steadystate decrease in plasma bicarbonate concentration and the associated decrement in arterial carbon dioxide tension (PaCO2). The
slope of the steady state PaCO2 versus [HCO3] relationship has
been estimated as approximately 1.2 mm Hg per mEq/L decrease
in plasma bicarbonate concentration. Such empiric observations
have been used for construction of 95% confidence intervals for
graded degrees of metabolic acidosis, represented by the area in
color in the acid-base template. The black ellipse near the center of
the figure indicates the normal range for the acid-base parameters
[3]. Assuming a steady state is present, values falling within the
area in color are consistent with but not diagnostic of simple metabolic acidosis. Acid-base values falling outside the area in color
denote the presence of a mixed acid-base disturbance [4]. [H+]
hydrogen ion concentration.
Arterial blood pH
SIGNS AND SYMPTOMS OF METABOLIC ACIDOSIS

Respiratory
System
Hyperventilation
Respiratory distress
and dyspnea
Decreased strength
of respiratory
muscles and
promotion of
muscle fatigue
Metabolism
Impairment of cardiac
contractility, arteriolar
dilation, venoconstriction,
and centralization of
blood volume
Reductions in cardiac
output, arterial blood
pressure, and hepatic
and renal blood flow
Sensitization to reentrant
arrhythmias and reduction
in threshold for ventricular
fibrillation
Increased sympathetic
discharge but attenuation of
cardiovascular responsiveness
to catecholamines
Increased
metabolic demands
Insulin resistance
Inhibition of
anaerobic glycolysis
Reduction in adenosine
triphosphate synthesis
Hyperkalemia
Increased
protein degradation
Central
Nervous System
Skeleton
Impaired metabolism
Osteomalacia
Inhibition of cell
Fractures
volume regulation
Progressive obtundation
Coma
FIGURE 6-16
Signs and symptoms of metabolic acidosis.
Among the various clinical manifestations,
particularly pernicious are the effects of
severe acidemia (blood pH < 7.20) on the cardiovascular system. Reductions in cardiac
output, arterial blood pressure, and hepatic
and renal blood flow can occur and lifethreatening arrhythmias can develop. Chronic
acidemia, as it occurs in untreated renal tubular acidosis and uremic acidosis, can cause
calcium dissolution from the bone mineral
and consequent skeletal abnormalities.
6.12
Normal
A 10
HCO3
24
Na+
140
Metabolic acidosis
Normal anion gap
High anion gap
(hyperchloremic)
(normochloremic)
A 10
A 30
HCO3 4
HCO3 4
Cl
106
Na+
140
Cl
126
Na+
140
Cl
106
Causes
Causes
Renal acidification defects
Endogenous acid load
Proximal renal tubular acidosis
Ketoacidosis
Classic distal tubular acidosis
Diabetes mellitus
Hyperkalemic distal tubular acidosis Alcoholism
Early renal failure
Starvation
Gastrointestinal loss of bicarbonate
Uremia
Diarrhea
Lactic acidosis
Small bowel losses
Exogenous toxins
Ureteral diversions
Osmolar gap present
Anion exchange resins
Methanol
Ingestion of CaCl2
Ethylene glycol
Osmolar gap absent
Acid infusion
Salicylates
HCl
Paraldehyde
Arginine HCl
Lysine HCl
FIGURE 6-17
Causes of metabolic acidosis tabulated according to the prevailing
pattern of plasma electrolyte composition. Assessment of the plasma unmeasured anion concentration (anion gap) is a very useful
first step in approaching the differential diagnosis of unexplained
metabolic acidosis. The plasma anion gap is calculated as the difference between the sodium concentration and the sum of chloride
and bicarbonate concentrations. Under normal circumstances, the
plasma anion gap is primarily composed of the net negative
charges of plasma proteins, predominantly albumin, with a smaller
contribution from many other organic and inorganic anions. The
normal value of the plasma anion gap is 12 4 (mean 2 SD)
mEq/L, where SD is the standard deviation. However, recent introduction of ion-specific electrodes has shifted the normal anion gap
to the range of about 6 3 mEq/L. In one pattern of metabolic acidosis, the decrease in bicarbonate concentration is offset by an
increase in the concentration of chloride, with the plasma anion
gap remaining normal. In the other pattern, the decrease in bicarbonate is balanced by an increase in the concentration of unmeasured anions (ie, anions not measured routinely), with the plasma
chloride concentration remaining normal.
Lactic acidosis
Glucose
Gluconeogenesis
Cori
cycle
Muscle
Brain
Skin
RBC
Liver
Kidney cortex
Anaerobic glycolysis
H+ + Lactate
Overproduction
Lactic acidosis
Underutilization
FIGURE 6-18
Lactate-producing and lactate-consuming tissues under basal conditions and pathogenesis of lactic acidosis. Although all tissues pro-
duce lactate during the course of glycolysis, those listed contribute

substantial quantities of lactate to the extracellular fluid under normal aerobic conditions. In turn, lactate is extracted by the liver and
to a lesser degree by the renal cortex and primarily is reconverted to
glucose by way of gluconeogenesis (a smaller portion of lactate is
oxidized to carbon dioxide and water). This cyclical relationship
between glucose and lactate is known as the Cori cycle. The basal
turnover rate of lactate in humans is enormous, on the order of 15
to 25 mEq/kg/d. Precise equivalence between lactate production and
its use ensures the stability of plasma lactate concentration, normally
ranging from 1 to 2 mEq/L. Hydrogen ions (H+) released during lactate generation are quantitatively consumed during the use of lactate
such that acid-base balance remains undisturbed. Accumulation of
lactate in the circulation, and consequent lactic acidosis, is generated
whenever the rate of production of lactate is higher than the rate of
utilization. The pathogenesis of this imbalance reflects overproduction of lactate, underutilization, or both. Most cases of persistent lactic acidosis actually involve both overproduction and underutilization of lactate. During hypoxia, almost all tissues can release lactate
into the circulation; indeed, even the liver can be converted from the
premier consumer of lactate to a net producer [1,14].

Glucose
Glycolysis
PFK
low ATP
ADP
NAD+
NADH
Pyruvate
LDH
Gluconeogenesis
PD
H
NAD+
NADH
PC
low ATP
ADP
Oxaloacetate
Lactate
+
NADH
high
Cytosol
NAD+
Mitochondrial membrane
Mitochondria
high NADH+
NAD
Acetyl-CoA
TCA
cycle
FIGURE 6-19
Hypoxia-induced lactic acidosis. Accumulation of lactate during
hypoxia, by far the most common clinical setting of the disorder,
originates from impaired mitochondrial oxidative function that
reduces the availability of adenosine triphosphate (ATP) and NAD+

(oxidized nicotinamide adenine dinucleotide) within the cytosol. In
turn, these changes cause cytosolic accumulation of pyruvate as a
consequence of both increased production and decreased utilization. Increased production of pyruvate occurs because the reduced
cytosolic supply of ATP stimulates the activity of 6-phosphofructokinase (PFK), thereby accelerating glycolysis. Decreased utilization of pyruvate reflects the fact that both pathways of its consumption depend on mitochondrial oxidative reactions: oxidative
decarboxylation to acetyl coenzyme A (acetyl-CoA), a reaction catalyzed by pyruvate dehydrogenase (PDH), requires a continuous
supply of NAD+; and carboxylation of pyruvate to oxaloacetate, a
reaction catalyzed by pyruvate carboxylase (PC), requires ATP. The
increased [NADH]/[NAD+] ratio (NADH refers to the reduced
form of the dinucleotide) shifts the equilibrium of the lactate dehydrogenase (LDH) reaction (that catalyzes the interconversion of
pyruvate and lactate) to the right. In turn, this change coupled with
the accumulation of pyruvate in the cytosol results in increased
accumulation of lactate. Despite the prevailing mitochondrial dysfunction, continuation of glycolysis is assured by the cytosolic
regeneration of NAD+ during the conversion of pyruvate to lactate.
Provision of NAD+ is required for the oxidation of glyceraldehyde
3-phosphate, a key step in glycolysis. Thus, lactate accumulation
can be viewed as the toll paid by the organism to maintain energy
production during anaerobiosis (hypoxia) [14]. ADPadenosine
diphosphate; TCA cycletricarboxylic acid cycle.
CAUSES OF LACTIC ACIDOSIS

Type A:
Impaired Tissue Oxygenation
Shock
Severe hypoxemia
Generalized convulsions
Vigorous exercise
Exertional heat stroke
Hypothermic shivering
Massive pulmonary emboli
Severe heart failure
Profound anemia
Mesenteric ischemia
Carbon monoxide poisoning
Cyanide poisoning
Type B: Preserved Tissue Oxygenation

Diseases and conditions
Diabetes mellitus
Hypoglycemia
Renal failure
Hepatic failure
Severe infections
Alkaloses
Malignancies (lymphoma,
leukemia, sarcoma)
Thiamine deficiency
Acquired
immunodeficiency syndrome
Pheochromocytoma
Iron deficiency
D-Lactic acidosis
Congenital enzymatic defects
6.13
Drugs and toxins

Epinephrine,
norepinephrine,
vasoconstrictor agents
Salicylates
Ethanol
Methanol
Ethylene glycol
Biguanides
Acetaminophen
Zidovudine
Fructose, sorbitol,
and xylitol
Streptozotocin
Isoniazid
Nitroprusside
Papaverine
Nalidixic acid
FIGURE 6-20
Conventionally, two broad types of lactic
acidosis are recognized. In type A, clinical
evidence exists of impaired tissue oxygenation. In type B, no such evidence is apparent.
Occasionally, the distinction between the
two types may be less than obvious. Thus,
inadequate tissue oxygenation can at times
defy clinical detection, and tissue hypoxia
can be a part of the pathogenesis of certain
causes of type B lactic acidosis. Most cases
of lactic acidosis are caused by tissue hypoxia arising from circulatory failure [14,15].
6.14
Inadequate tissue
oxygenation?
No
Cause-specific measures
Yes
Oxygen-rich mixture
and ventilator support,
if needed
No
Antibiotics (sepsis)
Dialysis (toxins)
Discontinuation of incriminated
drugs
Insulin (diabetes)
Glucose (hypoglycemia, alcoholism)
Operative intervention (trauma,
tissue ischemia)
Thiamine (thiamine deficiency)
Low carbohydrate diet and
antibiotics (D-lactic acidosis)
Circulatory failure?
Yes
Volume repletion
Preload and afterload
reducing agents
Myocardial stimulants
(dobutamine, dopamine)
Avoid vasoconstrictors
Severe/Worsening
metabolic acidemia?
No
Continue therapy
Manage predisposing
conditions
Yes
Alkali administration to
maintain blood pH 7.20
FIGURE 6-21
Lactic acidosis management. Management
of lactic acidosis should focus primarily on
securing adequate tissue oxygenation and on
aggressively identifying and treating the
underlying cause or predisposing condition.
Monitoring of the patients hemodynamics,
oxygenation, and acid-base status should be
used to guide therapy. In the presence of
severe or worsening metabolic acidemia,
these measures should be supplemented by
judicious administration of sodium bicarbonate, given as an infusion rather than a
bolus. Alkali administration should be
regarded as a temporizing maneuver adjunctive to cause-specific measures. Given the
ominous prognosis of lactic acidosis, clinicians should strive to prevent its development by maintaining adequate fluid balance,
optimizing cardiorespiratory function, managing infection, and using drugs that predispose to the disorder cautiously. Preventing
the development of lactic acidosis is all the
more important in patients at special risk
for developing it, such as those with diabetes mellitus or advanced cardiac, respiratory, renal, or hepatic disease [1,1416].
Diabetic ketoacidosis and nonketotic hyperglycemia

A
Increased hepatic
glucose production
Glucagon
Insulin
deficiency
B
Triglycerides
Increased
lipolysis
Increased hepatic
ketogenesis
Increased lipolysis
in adipocytes
Decreased glucose
utilization in skeletal
muscle
Increased ketogenesis
Ketonemia
(metabolic acidosis)
Increased gluconeogenesis
Increased glycogenolysis
Decreased glucose uptake
Increased protein breakdown

Decreased amino acid uptake
Growth hormone
Norepinephrine
Cortisol
Counterregulation
Epinephrine
Decreased ketone uptake
Decreased glucose excretion

Hyperglycemia
(hyperosmolality)
Decreased glucose uptake
FIGURE 6-22
Role of insulin deficiency and the counterregulatory hormones, and their respective
sites of action, in the pathogenesis of hyperglycemia and ketosis in diabetic ketoacidosis (DKA).A, Metabolic processes affected
by insulin deficiency, on the one hand, and
excess of glucagon, cortisol, epinephrine,
norepinephrine, and growth hormone, on
the other. B, The roles of the adipose tissue,
liver, skeletal muscle, and kidney in the
pathogenesis of hyperglycemia and ketonemia. Impairment of glucose oxidation in
most tissues and excessive hepatic production of glucose are the main determinants
of hyperglycemia. Excessive counterregulation and the prevailing hypertonicity, metabolic acidosis, and electrolyte imbalance
superimpose a state of insulin resistance.
Prerenal azotemia caused by volume depletion can contribute significantly to severe
hyperglycemia. Increased hepatic production of ketones and their reduced utilization
by peripheral tissues account for the
ketonemia typically observed in DKA.
Insulin deficiency/resistance
Severe
Mild
Pure DKA
profound
ketosis
Mixed forms
DKA + NKH
Pure NKH
profound
hyperglycemia
Mild
Severe
Excessive counterregulation
Feature
Pure DKA
Incidence
Mortality
Onset
Age of patient
Type I diabetes
Type II diabetes
First indication of diabetes
Volume depletion
Renal failure (most commonly of prerenal nature)
Severe neurologic
abnormalities
Subsequent therapy with
insulin
Glucose
Ketone bodies
Effective osmolality
pH
[HCO3]
[Na+]
[K+]
510 times higher

510%
Rapid (<2 days)
Usually < 40 years
Common
Rare
Often
Mild/moderate
Mild, inconstant
Mixed forms Pure NKH

510 times lower
1060%
Slow (> 5 days)
Usually > 40 years
Rare
Common
Often
Severe
Always present
Rare
Always
Frequent
(coma in 2550%)
Not always
< 800 mg/dL

2 + in 1:1 dilution
< 340 mOsm/kg
Decreased
Decreased
Normal or low
Variable
> 800 mg/dL

< 2+ in 1:1 dilution
> 340 mOsm/kg
Normal
Normal
Normal or high
Variable
6.15
FIGURE 6-23
Clinical features of diabetic ketoacidosis (DKA) and nonketotic
hyperglycemia (NKH). DKA and NKH are the most important
acute metabolic complications of patients with uncontrolled diabetes mellitus. These disorders share the same overall pathogenesis that includes insulin deficiency and resistance and excessive
counterregulation; however, the importance of each of these
endocrine abnormalities differs significantly in DKA and NKH.
As depicted here, pure NKH is characterized by profound hyperglycemia, the result of mild insulin deficiency and severe counterregulation (eg, high glucagon levels). In contrast, pure DKA is
characterized by profound ketosis that largely is due to severe
insulin deficiency, with counterregulation being generally of lesser importance. These pure forms define a continuum that
includes mixed forms incorporating clinical and biochemical features of both DKA and NKH. Dyspnea and Kussmauls respiration result from the metabolic acidosis of DKA, which is generally absent in NKH. Sodium and water deficits and secondary
renal dysfunction are more severe in NKH than in DKA. These
deficits also play a pathogenetic role in the profound hypertonicity characteristic of NKH. The severe hyperglycemia of NKH,
often coupled with hypernatremia, increases serum osmolality,
thereby causing the characteristic functional abnormalities of the
central nervous system. Depression of the sensorium, somnolence, obtundation, and coma, are prominent manifestations of
NKH. The degree of obtundation correlates with the severity of
serum hypertonicity [17].
MANAGEMENT OF DIABETIC KETOACIDOSIS AND NONKETOTIC HYPERGLYCEMIA
Insulin
Fluid Administration
Potassium repletion
Alkali
1. Give initial IV bolus of 0.2 U/kg actual body weight.

2. Add 100 U of regular insulin to 1 L of normal saline (0.1
U/mL), and follow with continuous IV drip of 0.1 U/kg
actual body weight per h until correction of ketosis.
3. Give double rate of infusion if the blood glucose level
does not decrease in a 2-h interval (expected decrease
is 4080 mg/dL/h or 10% of the initial value.)
4. Give SQ dose (1030 U) of regular insulin when ketosis
is corrected and the blood glucose level decreases to
300 mg/dL, and continue with SQ insulin injection
every 4 h on a sliding scale (ie, 5 U if below 150, 10 U if
150200, 15 U if 200250, and 20 U if 250300 mg/dL).
Shock absent: Normal saline (0.9% NaCl)

at 7 mL/kg/h for 4 h, and half this
rate thereafter
Shock present: Normal saline and plasma
expanders (ie,albumin, low molecular
weight dextran) at maximal possible rate
Start a glucose-containing solution
(eg, 5% dextrose in water) when blood
glucose level decreases to 250 mg/dL.
Potassium chloride should be

added to the third liter of IV
infusion and subsequently
if urinary output is at least
3060 mL/h and plasma [K+]
< 5 mEq/L.
Add K+ to the initial 2 L of IV
fluids if initial plasma [K+]
< 4 mEq/L and adequate
diuresis is secured.
Half-normal saline (0.45% NaCl) plus

12 ampules (44-88 mEq) NaHCO3
per liter when blood pH < 7.0 or
total CO2 < 5 mmol/L; in hyperchloremic acidosis, add NaHCO3
when pH < 7.20; discontinue
NaHCO3 in IV infusion when total
CO2>810 mmol/L.
CO2carbon dioxide; IVintravenous; K+potassium ion; NaClsodium chloride; NaHCO3sodium bicarbonate; SQsubcutaneous.
FIGURE 6-24
Diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH)
management. Administration of insulin is the cornerstone of management for both DKA and NKH. Replacement of the prevailing water,
sodium, and potassium deficits is also required. Alkali are administered only under certain circumstances in DKA and virtually never in
NKH, in which ketoacidosis is generally absent. Because the fluid

deficit is generally severe in patients with NKH, many of whom have
preexisting heart disease and are relatively old, safe fluid replacement
may require monitoring of central venous pressure, pulmonary capillary wedge pressure, or both [1,17,18].
6.16

FEATURES OF THE RENAL TUBULAR ACIDOSIS (RTA) SYNDROMES
Feature
Proximal RTA
Classic Distal RTA
Hyperkalemic Distal RTA
Plasma bicarbonate
ion concentration
Plasma chloride
ion concentration
Plasma potassium
ion concentration
Plasma anion gap
Glomerular filtration rate
1418 mEq/L
Variable, may be
< 10 mEq/L
Increased
1520 mEq/L
Mildly to severely increased
Normal
Normal or
slightly decreased
5.5
5.5
Normal
>15%
Mildly to
severely decreased
Normal
Normal or
slightly decreased
>6.0
>6.0
Decreased
<5%
Decreased
Absent
Absent
Present
Usually present
High dose
Normal
Present
Present
Present
Absent
Low dose
Normal
Absent
Absent
Absent
Absent
Low dose
Urine pH during acidosis

Urine pH after acid loading
U-B PCO2 in alkaline urine
Fractional excretion of
HCO3 at normal [HCO3]p
Tm HCO3
Nephrolithiasis
Nephrocalcinosis
Osteomalacia
Fanconis syndrome*
Alkali therapy
-
Increased
Mildly decreased
Increased
Normal
Normal to
moderately decreased
5.5
5.5
Decreased
<5%
Tm HCO3maximum reabsorption of bicarbonate; U-B PCO2difference between partial pressure of carbon

dioxide values in urine and arterial blood.
*This syndrome signifies generalized proximal tubule dysfunction and is characterized by impaired reabsorption of
glucose, amino acids, phosphate, and urate.
FIGURE 6-25
Renal tubular acidosis (RTA) defines a
group of disorders in which tubular hydrogen ion secretion is impaired out of proportion to any reduction in the glomerular filtration rate. These disorders are characterized by normal anion gap (hyperchloremic)
metabolic acidosis. The defects responsible
for impaired acidification give rise to three
distinct syndromes known as proximal RTA
(type 2), classic distal RTA (type 1), and
hyperkalemic distal RTA (type 4).
Lumen
CA
HCO3 + H+
+
Na
CO2 + OH
HCO3
H 2O
3HCO3
1Na+
H+
Na+
Na+
Glucose
Amino acids
Phosphate
Blood
B. CAUSES OF PROXIMAL RENAL

TUBULAR ACIDOSIS
CA
CO2
H2CO3
Proximal tubule cell
6.17
3Na
2K+
Indicates possible cellular mechanisms responsible

for Type 2 proximal RTA
FIGURE 6-26
A and B, Potential defects and causes of proximal renal tubular
acidosis (RTA) (type 2). Excluding the case of carbonic anhydrase
inhibitors, the nature of the acidification defect responsible for
bicarbonate (HCO3) wastage remains unknown. It might represent
defects in the luminal sodium ion hydrogen ion (Na+-H+)
exchanger, basolateral Na+-3HCO3 cotransporter, or carbonic
anhydrase activity. Most patients with proximal RTA have additional defects in proximal tubule function (Fanconis syndrome);
this generalized proximal tubule dysfunction might reflect a defect
in the basolateral Na+-K+ adenosine triphosphatase. K+potassium
ion; CAcarbonic anhydrase. Causes of proximal renal tubular
acidosis (RTA) (type 2). An idiopathic form and cystinosis are the
most common causes of proximal RTA in children. In adults, multiple myeloma and carbonic anhydrase inhibitors (eg, acetazolamide) are the major causes. Ifosfamide is an increasingly
common cause of the disorder in both age groups.
Selective defect (isolated bicarbonate wasting)

Primary (no obvious associated disease)
Genetically transmitted
Transient (infants)
Due to altered carbonic anhydrase activity
Acetazolamide
Sulfanilamide
Mafenide acetate
Idiopathic
Osteopetrosis with carbonic
anhydrase II deficiency
York-Yendt syndrome
Generalized defect (associated with multiple
dysfunctions of the proximal tubule)
Sporadic
Genetically transmitted systemic disease
Tyrosinemia
Wilsons disease
Lowe syndrome
Hereditary fructose intolerance (during
administration of fructose)
Cystinosis
Pyruvate carboxylate deficiency
Metachromatic leukodystrophy
Methylmalonic acidemia
Conditions associated with chronic hypocalcemia
and secondary hyperparathyroidism
Vitamin D deficiency or resistance
Vitamin D dependence
Dysproteinemic states
Multiple myeloma
Monoclonal gammopathy
Drug- or toxin-induced
Outdated tetracycline
3-Methylchromone
Streptozotocin
Lead
Mercury
Arginine
Valproic acid
Gentamicin
Ifosfamide
Tubulointerstitial diseases
Renal transplantation
Sjgrens syndrome
Other renal diseases
Nephrotic syndrome
Amyloidosis
Miscellaneous
Paroxysmal
nocturnal hemoglobinuria
Hyperparathyroidism
6.18
B. CAUSES OF CLASSIC DISTAL RENAL

TUBULAR ACIDOSIS
Lumen
Intercalated cell (CCT & MCT)
CA
Cl
OH
H+

Sporadic
HCO3
CO2
+
Blood
H2 O
K+
Cl
Cl
Indicates possible cellular mechanisms responsible

for Type 1 distal RTA
FIGURE 6-27
A and B, Potential defects and causes of classic distal renal tubular
acidosis (RTA) (type 1). Potential cellular defects underlying classic
distal RTA include a faulty luminal hydrogen ionadenosine triphosphatase (H+ pump failure or secretory defect), an abnormality in the
basolateral bicarbonate ionchloride ion exchanger, inadequacy of
carbonic anhydrase activity, or an increase in the luminal membrane
permeability for hydrogen ions (backleak of protons or permeability
defect). Most of the causes of classic distal RTA likely reflect a secretory defect, whereas amphotericin B is the only established cause of a
permeability defect. The hereditary form is the most common cause
of this disorder in children. Major causes in adults include autoimmune disorders (eg, Sjgrens syndrome) and hypercalciuria [19].
CAcarbonic anhydrase.
Autoimmune disorders
Hypergammaglobulinemia
Hyperglobulinemic purpura
Cryoglobulinemia
Familial
Sjgrens syndrome
Thyroiditis
Pulmonary fibrosis
Chronic active hepatitis
Primary biliary cirrhosis
Systemic lupus erythematosus
Vasculitis
Genetically transmitted systemic disease
Ehlers-Danlos syndrome
Hereditary elliptocytosis
Sickle cell anemia
Marfan syndrome
Carbonic anhydrase I deficiency
or alteration
Osteopetrosis with carbonic
anhydrase II deficiency
Neuroaxonal dystrophy
Disorders associated
with nephrocalcinosis
Primary or familial hyperparathyroidism
Milk-alkali syndrome
Hyperthyroidism
Idiopathic hypercalciuria
Sporadic
Hereditary fructose intolerance
(after chronic fructose ingestion)
Medullary sponge kidney
Fabrys disease
Wilsons disease
Drug- or toxin-induced
Amphotericin B
Toluene
Analgesics
Lithium
Cyclamate
Balkan nephropathy
Tubulointerstitial diseases
Chronic pyelonephritis
Obstructive uropathy
Leprosy
Hyperoxaluria
Principal cell
Lumen
6.19
B. CAUSES OF HYPERKALEMIC
DISTAL RENAL TUBULAR ACIDOSIS
Blood
Na+
3Na+
2K+
Potential
difference
Aldosterone
K+
receptor
Cl
Intercalated cell
Aldosterone
receptor
HCO3
CO2
CA
H+
Cl
OH
H+
K+
H2 O
Cl
Cl
Indicates possible cellular mechanisms in aldosterone deficiency

Indicates defects related to aldosterone resistance
FIGURE 6-28
A and B, Potential defects and causes of hyperkalemic distal renal
tubular acidosis (RTA) (type 4). This syndrome represents the most
common type of RTA encountered in adults. The characteristic
hyperchloremic metabolic acidosis in the company of hyperkalemia
emerges as a consequence of generalized dysfunction of the collecting tubule, including diminished sodium reabsorption and impaired
hydrogen ion and potassium secretion. The resultant hyperkalemia
causes impaired ammonium excretion that is an important contribution to the generation of the metabolic acidosis. The causes of
this syndrome are broadly classified into disorders resulting in
aldosterone deficiency and those that impose resistance to the
action of aldosterone. Aldosterone deficiency can arise from
Deficiency of aldosterone
Associated with glucocorticoid deficiency
Addisons disease
Bilateral adrenalectomy
Enzymatic defects
21-Hydroxylase deficiency
3--ol-Dehydrogenase deficiency
Desmolase deficiency
Acquired immunodeficiency syndrome
Isolated aldosterone deficiency
Corticosterone methyl
oxidase deficiency
Transient (infants)
Sporadic
Heparin
Deficient renin secretion
Diabetic nephropathy
Tubulointerstitial renal disease
Nonsteroidal antiinflammatory drugs
-adrenergic blockers
Acquired immunodeficiency syndrome
Angiotensin I-converting enzyme inhibition
Endogenous
Captopril and related drugs
Angiotensin AT, receptor blockers
Resistance to aldosterone action

(with salt wasting)
Childhood forms with
obstructive uropathy
Adult forms with
renal insufficiency
Spironolactone
(without salt wasting)
Combined aldosterone deficiency
and resistance
Deficient renin secretion
Cyclosporine nephrotoxicity
Uncertain renin status
Voltage-mediated defects
Sickle cell anemia
Lithium
Triamterene
Amiloride
Trimethoprim, pentamidine
hyporeninemia, impaired conversion of angiotensin I to angiotensin

II, or abnormal aldosterone synthesis. Aldosterone resistance can
reflect the following: blockade of the mineralocorticoid receptor;
destruction of the target cells in the collecting tubule (tubulointerstitial nephropathies); interference with the sodium channel of the
principal cell, thereby decreasing the lumen-negative potential difference and thus the secretion of potassium and hydrogen ions
(voltage-mediated defect); inhibition of the basolateral sodium ion,
potassium ionadenosine triphosphatase; and enhanced chloride
ion permeability in the collecting tubule, with consequent shunting
of the transepithelial potential difference. Some disorders cause
combined aldosterone deficiency and resistance [20].
6.20

FIGURE 6-29
Treatment of acute metabolic acidosis. Whenever possible, causespecific measures should be at the center of treatment of metabolic
acidosis. In the presence of severe acidemia, such measures should
be supplemented by judicious administration of sodium bicarbonate. The goal of alkali therapy is to return the blood pH to a safer
level of about 7.20. Anticipated benefits and potential risks of
alkali therapy are depicted here [1].
Management of acute metabolic acidosis
Alkali therapy for severe

acidemia (blood pH<7.20)
Cause-specific measures
Benefits
Prevents or reverses acidemiarelated hemodynamic compromise.
Reinstates cardiovascular
responsiveness to catecholamines.
"Buys time," thus allowing causespecific measures and endogenous
reparatory processes to take effect.
Provides a measure of safety against
additional acidifying stresses.
Risks
Hypernatremia/
hyperosmolality
Volume overload
"Overshoot" alkalosis
Hypokalemia
Decreased plasma ionized
calcium concentration
Stimulation of organic
acid production
Hypercapnia
Metabolic Alkalosis
150 125
100
80 70 60
PaCO2
mm Hg
50
40
30
120 100 90 80 70
20
60
50
40
50
40
30
30
20
Normal
20
10
10
6.8
6.9
7.0
7.1
7.2
7.3
7.4
Arterial blood pH
7.5
7.6
7.7
FIGURE 6-30
Ninety-five percent confidence intervals for metabolic alkalosis.
Metabolic alkalosis is the acid-base disturbance initiated by an
increase in plasma bicarbonate concentration ([HCO3]). The
resultant alkalemia dampens alveolar ventilation and leads to the
secondary hypercapnia characteristic of the disorder. Available
observations in humans suggest a roughly linear relationship
between the steady-state increase in bicarbonate concentration
and the associated increment in the arterial carbon dioxide tension (PaCO2). Although data are limited, the slope of the steadystate PaCO2 versus [HCO3] relationship has been estimated as
about a 0.7 mm Hg per mEq/L increase in plasma bicarbonate
concentration. The value of this slope is virtually identical to
that in dogs that has been derived from rigorously controlled
observations [21]. Empiric observations in humans have been
used for construction of 95% confidence intervals for graded
degrees of metabolic alkalosis represented by the area in color in
the acid-base template. The black ellipse near the center of the
figure indicates the normal range for the acid-base parameters
[3]. Assuming a steady state is present, values falling within the
area in color are consistent with but not diagnostic of simple
metabolic alkalosis. Acid-base values falling outside the area in
color denote the presence of a mixed acid-base disturbance [4].
[H+]hydrogen ion concentration.
Excess alkali
Alkali gain
Enteral
Source?
Parenteral
Gastric
H+ loss
Intestinal
Renal
H+ shift
Milk alkali syndrome

Calcium supplements
Absorbable alkali
Nonabsorbable alkali plus K+
exchange resins
Ringer's solution
Bicarbonate
Blood products
Nutrition
Dialysis
Vomiting
Suction
Villous adenoma
Congenital chloridorrhea
6.21
FIGURE 6-31
Pathogenesis of metabolic alkalosis. Two
crucial questions must be answered when
evaluating the pathogenesis of a case of
metabolic alkalosis. 1) What is the source
of the excess alkali? Answering this question addresses the primary event responsible
for generating the hyperbicarbonatemia. 2)
What factors perpetuate the hyperbicarbonatemia? Answering this question addresses
the pathophysiologic events that maintain
the metabolic alkalosis.
Chloruretic diuretics
Inherited transport defects
Mineralocorticoid excess
Posthypercapnia
K+ depletion
Reduced GFR
Mode of perpetuation?
Increased
renal acidification
Cl responsive defect
Cl resistant defect
Baseline
Vomiting
Maintenance
Low NaCl and KCl intake
[HCO3 ],
mEq/L
45
Correction
High NaCl and KCl intake
40
35
30
25
[Cl ],
mEq/L
105
100
95
0
Cl
200
Cumulative balance, mEq

Na+
400
100
0
K+
200
400
2
8
Days
10
12
14
16
18
FIGURE 6-32
Changes in plasma anionic pattern and body electrolyte balance
during development, maintenance, and correction of metabolic
alkalosis induced by vomiting. Loss of hydrochloric acid from the
stomach as a result of vomiting (or gastric drainage) generates the
hypochloremic hyperbicarbonatemia characteristic of this disorder.
During the generation phase, renal sodium and potassium excretion increases, yielding the deficits depicted here. Renal potassium
losses continue in the early days of the maintenance phase.
Subsequently, and as long as the low-chloride diet is continued, a
new steady state is achieved in which plasma bicarbonate concentration ([HCO3]) stabilizes at an elevated level, and renal excretion
of electrolytes matches intake. Addition of sodium chloride (NaCl)
and potassium chloride (KCl) in the correction phase repairs the
electrolyte deficits incurred and normalizes the plasma bicarbonate
and chloride concentration ([Cl-]) levels [22,23].
6.22
Baseline
Vomiting
Maintenance
Low NaCl and KCl intake
Urine pH
8.0
Baseline
Correction
High NaCl and KCl intake
6.0
Maintenance
Low NaCl intake
Correction
Low KCl intake
[HCO3 ],
mEq/L
7.0
Diuresis
5.0
High KCl intake
40
35
30
75
105
[Cl ],
mEq/L
50
25
100
Urine net acid excretion,
mEq/d
100
95
0
Urine net acid
excretion, mEq/d
Urine HCO3 excretion,

mEq/d
25
75
50
125
100
75
50
25
0
25
200
Cl
10
12
14
16
18
Days
FIGURE 6-33
Changes in urine acid-base composition during development, maintenance, and correction of vomiting-induced metabolic alkalosis.
During acid removal from the stomach as well as early in the phase
after vomiting (maintenance), an alkaline urine is excreted as acid
excretion is suppressed, and bicarbonate excretion (in the company
of sodium and, especially potassium; see Fig. 6-32) is increased,
with the net acid excretion being negative (net alkali excretion).
This acid-base profile moderates the steady-state level of the resulting alkalosis. In the steady state (late maintenance phase), as all filtered bicarbonate is reclaimed the pH of urine becomes acidic, and
the net acid excretion returns to baseline. Provision of sodium
chloride (NaCl) and potassium chloride (KCl) in the correction
phase alkalinizes the urine and suppresses the net acid excretion, as
bicarbonaturia in the company of exogenous cations (sodium and
potassium) supervenes [22,23]. HCO3bicarbonate ion.
Cumulative balance, mEq

K+
Na+
400
50
100
0
100
2
10
12
Days
FIGURE 6-34
Changes in plasma anionic pattern, net acid excretion, and body
electrolyte balance during development, maintenance, and correction of diuretic-induced metabolic alkalosis. Administration of a
loop diuretic, such as furosemide, increases urine net acid excretion
(largely in the form of ammonium) as well as the renal losses of
chloride (Cl-), sodium (Na+), and potassium (K+). The resulting
hyperbicarbonatemia reflects both loss of excess ammonium chloride in the urine and an element of contraction (consequent to
diuretic-induced sodium chloride [NaCl] losses) that limits the
space of distribution of bicarbonate. During the phase after diuresis (maintenance), and as long as the low-chloride diet is continued,
a new steady state is attained in which the plasma bicarbonate concentration ([HCO3]) remains elevated, urine net acid excretion
returns to baseline, and renal excretion of electrolytes matches
intake. Addition of potassium chloride (KCl) in the correction
phase repairs the chloride and potassium deficits, suppresses net
acid excretion, and normalizes the plasma bicarbonate and chloride
concentration ([Cl-]) levels [23,24]. If extracellular fluid volume
has become subnormal folllowing diuresis, administration of NaCl
is also required for repair of the metabolic alkalosis.
6.23
Maintenance of Cl-responsive metabolic alkalosis

GFR
HCO3 reabsorption
Mediating factors
Cl depletion
Na+
Cl
Na+
Na+
H+, NH+4
GFR
K+ depletion
ECF volume depletion
Na+
3HCO3
HCO3
Cl
Basic mechanisms
P-cell
+
K
+
K
Hypercapnia
K
Na
Na+ reabsorption and consequent H+ and K+ secretion
K+
Cl
-cell
H+
NH4
K+
HCO3 reabsorption
NH4 , K
Na+
2Cl
NH4+ synthesis and

luminal entry
H 2O
Na+
HCO3
+
K Cl
Cl
-cell
NH4+
NH3
NH3
NH3
HCO3
Cl
Cl
H+ secretion
H+
K+
H+
Cl
HCO3
H+ secretion coupled to K+ reabsorption
HCO3 secretion
NH3
NH4+ entry in medulla and secretion

in medullary collecting duct
NH4+
Net acid excretion maintained at control
FIGURE 6-35
Maintenance of chloride-responsive metabolic alkalosis.
Increased renal bicarbonate reabsorption frequently coupled
with a reduced glomerular filtration rate are the basic mechanisms that maintain chloride-responsive metabolic alkalosis.
These mechanisms have been ascribed to three mediating factors: chloride depletion itself, extracellular fluid (ECF) volume
depletion, and potassium depletion. Assigning particular roles to
each of these factors is a vexing task. Notwithstanding, here

depicted is our current understanding of the participation of
each of these factors in the nephronal processes that maintain
chloride-responsive metabolic alkalosis [2224]. In addition to
these factors, the secondary hypercapnia of metabolic alkalosis
contributes importantly to the maintenance of the prevailing
hyperbicarbonatemia [25].
6.24

Maintenance of Cl-resistant metabolic alkalosis
HCO3 reabsorption
Basic mechanism
K+ depletion
Mineralocorticoid excess
Na+
3HCO3
HCO3
Cl
Mediating factors
P-cell
Na+
Na+
H+, NH+4
Na+
Cl
K
K
NH+4, K
Na+
2Cl
NH4+ synthesis and

luminal entry
H 2O
NH+4
K+
HCO3 reabsorption
Cl
Na+
HCO3
+
K Cl
NH+4
NH3
NH3
NH3
Virtually absent
(< 10 mEq/L)
Abundant
(> 20 mEq/L)
NH4+entry in medulla and secretion

in medullary collecting duct
Vomiting, gastric suction

Postdiuretic phase of loop
and distal agents
Posthypercapnic state
Villous adenoma of the colon
Congenital chloridorrhea
Post alkali loading
Urinary [K+]
Low (< 20 mEq/L)
FIGURE 6-36
Maintenance of chloride-resistant metabolic alkalosis. Increased
renal bicarbonate reabsorption is the sole basic mechanism that
maintains chloride-resistant metabolic alkalosis. As its name
implies, factors independent of chloride intake mediate the height-
Abundant
(> 30 mEq/L)
Na+ reabsorption and consequent H+ and K+ secretion
Cl
-cell
Urinary [Cl]
K
Na
Laxative abuse
Other causes of profound K+ depletion
Diuretic phase of loop and distal agents

Bartter's and Gitelman's syndromes
Cushing's syndrome
Exogenous mineralocorticoid agents
Secondary aldosteronism
malignant hypertension
renovascular hypertension
primary reninism
Liddle's syndrome
Cl
HCO3
Cl
H+
K+
-cell
HCO
H+ secretion coupled to K+ reabsorption
H+ secretion
H+
Cl
3
NH3
NH+4
ened bicarbonate reabsorption and include mineralocorticoid

excess and potassium depletion. The participation of these factors
in the nephronal processes that maintain chloride-resistant metabolic alkalosis is depicted [2224, 26].
FIGURE 6-37
Urinary composition in the diagnostic evaluation of metabolic alkalosis. Assessing the urinary composition can be an important aid in
the diagnostic evaluation of metabolic alkalosis. Measurement of urinary chloride ion concentration ([Cl-]) can help distinguish between
chloride-responsive and chloride-resistant metabolic alkalosis. The
virtual absence of chloride (urine [Cl-] < 10 mEq/L) indicates significant chloride depletion. Note, however, that this test loses its diagnostic significance if performed within several hours of administration of chloruretic diuretics, because these agents promote urinary
chloride excretion. Measurement of urinary potassium ion concentration ([K+]) provides further diagnostic differentiation. With the
exception of the diuretic phase of chloruretic agents, abundance of
both urinary chloride and potassium signifies a state of mineralocorticoid excess [22].
6.25
SIGNS AND SYMPTOMS OF METABOLIC ALKALOSIS

Central
Nervous System
Headache
Lethargy
Stupor
Delirium
Tetany
Seizures
Potentiation of hepatic
encephalopathy
Respiratory System
Neuromuscular System
Metabolic Effects
Supraventricular and
ventricular arrhythmias
Potentiation of
digitalis toxicity
Positive inotropic
ventricular effect
Hypoventilation with
attendant hypercapnia
and hypoxemia
Chvosteks sign
Trousseaus sign
Weakness (severity
depends on degree of
potassium depletion)
Increased organic acid and

ammonia production
Hypokalemia
Hypocalcemia
Hypomagnesemia
Hypophosphatemia
FIGURE 6-38
Signs and symptoms of metabolic alkalosis. Mild to moderate
metabolic alkalosis usually is accompanied by few if any symptoms, unless potassium depletion is substantial. In contrast, severe
metabolic alkalosis ([HCO3] > 40 mEq/L) is usually a symptomatic
disorder. Alkalemia, hypokalemia, hypoxemia, hypercapnia, and
decreased plasma ionized calcium concentration all contribute to
Ingestion of
large amounts
of calcium
Augmented body
content of calcium
Urine
alkalinization
Augmented body
bicarbonate stores
Nephrocalcinosis
Hypercalcemia
Renal
vasoconstriction
Renal
insufficiency
Reduced renal
bicarbonate
excretion
Decreased urine
calcium excretion
Polyuria
Polydipsia
Urinary concentration defect
Cortical and medullary
renal cysts
these clinical manifestations. The arrhythmogenic potential of alkalemia is more pronounced in patients with underlying heart disease
and is heightened by the almost constant presence of hypokalemia,
especially in those patients taking digitalis. Even mild alkalemia
can frustrate efforts to wean patients from mechanical ventilation
[23,24].
Ingestion of
large amounts of
absorbable alkali
Increased urine calcium

excretion (early phase)
Renal (Associated
Potassium Depletion)
Metabolic
alkalosis
Increased renal
reabsorption of calcium
Increased renal H+ secretion
FIGURE 6-39
Pathophysiology of the milk-alkali syndrome. The milk-alkali syndrome comprises the triad
of hypercalcemia, renal insufficiency, and metabolic alkalosis and is caused by the ingestion
of large amounts of calcium and absorbable alkali. Although large amounts of milk and
absorbable alkali were the culprits in the classic form of the syndrome, its modern version
is usually the result of large doses of calcium carbonate alone. Because of recent emphasis
on prevention and treatment of osteoporosis with calcium carbonate and the availability of
this preparation over the counter, milk-alkali syndrome is currently the third leading cause
of hypercalcemia after primary hyperparathyroidism and malignancy. Another

common presentation of the syndrome originates from the current use of calcium carbonate in preference to aluminum as a phosphate binder in patients with chronic renal
insufficiency. The critical element in the
pathogenesis of the syndrome is the development of hypercalcemia that, in turn,
results in renal dysfunction. Generation and
maintenance of metabolic alkalosis reflect
the combined effects of the large bicarbonate load, renal insufficiency, and hypercalcemia. Metabolic alkalosis contributes to
the maintenance of hypercalcemia by
increasing tubular calcium reabsorption.
Superimposition of an element of volume
contraction caused by vomiting, diuretics, or
hypercalcemia-induced natriuresis can worsen each one of the three main components
of the syndrome. Discontinuation of calcium
carbonate coupled with a diet high in sodium chloride or the use of normal saline and
furosemide therapy (depending on the severity of the syndrome) results in rapid resolution of hypercalcemia and metabolic alkalosis. Although renal function also improves,
in a considerable fraction of patients with
the chronic form of the syndrome serum
creatinine fails to return to baseline as a
result of irreversible structural changes in
the kidneys [27].
6.26
Clinical syndrome
Affected gene
Affected chromosome
Localization of tubular defect

TAL
Bartter's syndrome
Type 1
NKCC2
15q15-q21
TAL
CCD
Type 2
ROMK
11q24
TSC
16q13
Gitelman's syndrome
Tubular
lumen
Na+
K+,NH+4
Cl
Loop diuretics
H+
DCT
Peritubular
space
Cell
3Na
2K+
ATPase
K
3HCO3
Na+
Tubular
lumen
Na
Cl
Thiazides
Peritubular
space
Cell
3Na+
+
2K+
ATPase
Tubular
lumen
Peritubular
space
Cell
Na+
Cl
3Na
K
Cl
K+
ATPase +
2K
K
Cl
K+
3Na+
2+
Ca
2+
Ca
Ca2+
Mg2+
Thick ascending limb (TAL)
Distal convoluted tuble (DCT)
Cortical collecting duct (CCD)
FIGURE 6-40
Clinical features and molecular basis of tubular defects of Bartters and Gitelmans syndromes. These rare disorders are characterized by chloride-resistant metabolic alkalosis,
renal potassium wasting and hypokalemia, hyperreninemia and hyperplasia of the juxtaglomerular apparatus, hyperaldosteronism, and normotension. Regarding differentiating features, Bartters syndrome presents early in life, frequently in association with
growth and mental retardation. In this syndrome, urinary concentrating ability is usually decreased, polyuria and polydipsia are present, the serum magnesium level is normal,
and hypercalciuria and nephrocalcinosis

are present. In contrast, Gitelmans syndrome is a milder disease presenting later
in life. Patients often are asymptomatic,
or they might have intermittent muscle
spasms, cramps, or tetany. Urinary concentrating ability is maintained; hypocalciuria, renal magnesium wasting, and
hypomagnesemia are almost constant features. On the basis of certain of these clinical features, it had been hypothesized
that the primary tubular defects in
Bartters and Gitelmans syndromes reflect
impairment in sodium reabsorption in the
thick ascending limb (TAL) of the loop of
Henle and the distal tubule, respectively.
This hypothesis has been validated by
recent genetic studies [28-31]. As illustrated here, Bartters syndrome now has been
shown to be caused by loss-of-function
mutations in the loop diureticsensitive
sodium-potassium-2chloride cotransporter
(NKCC2) of the TAL (type 1 Bartters
syndrome) [28] or the apical potassium
channel ROMK of the TAL (where it recycles reabsorbed potassium into the lumen
for continued operation of the NKCC2
cotransporter) and the cortical collecting
duct (where it mediates secretion of potassium by the principal cell) (type 2
Bartters syndrome) [29,30]. On the other
hand, Gitelmans syndrome is caused by
mutations in the thiazide-sensitive Na-Cl
cotransporter (TSC) of the distal tubule
[31]. Note that the distal tubule is the
major site of active calcium reabsorption.
Stimulation of calcium reabsorption at
this site is responsible for the hypocalciuric effect of thiazide diuretics.
Management of
metabolic alkalosis
For alkali gain
For H+ loss
Eliminate source
of excess alkali
For H+ shift
Discontinue administrationof
bicarbonate or its precursors.
via gastric route
Administer antiemetics;
discontinue gastric suction;
administer H2 blockers or
H+-K+ ATPase inhibitors.
via renal route
Discontinue or decrease loop
and distal diuretics; substitute
with amiloride, triamterene, or
spironolactone; discontinue
or limit drugs with mineralocorticoid activity.
Potassium repletion
For decreased GFR
Interrupt perpetuating
mechanisms
For Cl responsive
acidification defect
For Cl resistant
acidification defect
ECF volume repletion;

renal replacement therapy
6.27
FIGURE 6-41
Metabolic alkalosis management. Effective
management of metabolic alkalosis requires
sound understanding of the underlying
pathophysiology. Therapeutic efforts should
focus on eliminating or moderating the
processes that generate the alkali excess and
on interrupting the mechanisms that perpetuate the hyperbicarbonatemia. Rarely, when
the pace of correction of metabolic alkalosis must be accelerated, acetazolamide or an
infusion of hydrochloric acid can be used.
Treatment of severe metabolic alkalosis can
be particularly challenging in patients with
advanced cardiac or renal dysfunction. In
such patients, hemodialysis or continuous
hemofiltration might be required [1].
Administer NaCl and KCl
Adrenalectomy or other surgery,

potassiuim repletion, administration
of amiloride, triamterene, or
spironolactone.
References
1. Adrogu HJ, Madias NE: Management of life-threatening acid-base
disorders. N Engl J Med, 1998, 338:2634, 107111.
2. Madias NE, Adrogu HJ: Acid-base disturbances in pulmonary medicine. In Fluid, Electrolyte, and Acid-Base Disorders. Edited by Arieff
Al, DeFronzo RA. New York: Churchill Livingstone; 1995:223253.
3. Madias NE, Adrogu HJ, Horowitz GL, et al.: A redefinition of normal acid-base equilibrium in man: carbon dioxide tension as a key
determinant of plasma bicarbonate concentration. Kidney Int 1979,
16:612618.
4. Adrogu HJ, Madias NE: Mixed acid-base disorders. In The
Principles and Practice of Nephrology. Edited by Jacobson HR,
Striker GE, Klahr S. St. Louis: Mosby-Year Book; 1995:953962.
5. Krapf R: Mechanisms of adaptation to chronic respiratory acidosis in
the rabbit proximal tubule. J Clin Invest 1989, 83:890896.
6. Al-Awqati Q: The cellular renal response to respiratory acid-base disorders. Kidney Int 1985, 28:845855.
7. Bastani B: Immunocytochemical localization of the vacuolar H+ATPase pump in the kidney. Histol Histopathol 1997, 12:769779.
8. Teixeira da Silva JC Jr, Perrone RD, Johns CA, Madias NE: Rat kidney band 3 mRNA modulation in chronic respiratory acidosis. Am J
Physiol 1991, 260:F204F209.
9. Respiratory pump failure: primary hypercapnia (respiratory acidosis).
In Respiratory Failure. Edited by Adrogu HJ, Tobin MJ. Cambridge,
MA: Blackwell Science; 1997:125134.
10. Krapf R, Beeler I, Hertner D, Hulter HN: Chronic respiratory alkalosis: the effect of sustained hyperventilation on renal regulation of acidbase equilibrium. N Engl J Med 1991, 324:13941401.
11. Hilden SA, Johns CA, Madias NE: Adaptation of rabbit renal cortical
Na+-H+-exchange activity in chronic hypocapnia. Am J Physiol 1989,
257:F615F622.
12. Adrogu HJ, Rashad MN, Gorin AB, et al.: Arteriovenous acid-base
disparity in circulatory failure: studies on mechanism. Am J Physiol
1989, 257:F1087F1093.
13. Adrogu HJ, Rashad MN, Gorin AB, et al.: Assessing acid-base status
in circulatory failure: differences between arterial and central venous
blood. N Engl J Med 1989, 320:13121316.
14. Madias NE: Lactic acidosis. Kidney Int 1986, 29:752774.
15. Kraut JA, Madias NE: Lactic acidosis. In Textbook of Nephrology.
Edited by Massry SG, Glassock RJ. Baltimore: Williams and Wilkins;
1995:449457.
16. Hindman BJ: Sodium bicarbonate in the treatment of subtypes of
acute lactic acidosis: physiologic considerations. Anesthesiology 1990,
72:10641076.
17. Adrogu HJ: Diabetic ketoacidosis and hyperosmolar nonketotic syndrome. In Therapy of Renal Diseases and Related Disorders. Edited
by Suki WN, Massry SG. Boston: Kluwer Academic Publishers;
1997:233251.
18. Adrogu HJ, Barrero J, Eknoyan G: Salutary effects of modest fluid
replacement in the treatment of adults with diabetic ketoacidosis.
JAMA 1989, 262:21082113.
19. Bastani B, Gluck SL: New insights into the pathogenesis of distal
renal tubular acidosis. Miner Electrolyte Metab 1996, 22:396409.
20. DuBose TD Jr: Hyperkalemic hyperchloremic metabolic acidosis:
pathophysiologic insights. Kidney Int 1997, 51:591602.
21. Madias NE, Bossert WH, Adrogu HJ: Ventilatory response to chronic metabolic acidosis and alkalosis in the dog. J Appl Physiol 1984,
56:16401646.
22. Gennari FJ: Metabolic alkalosis. In The Principles and Practice of
Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St Louis:
Mosby-Year Book; 1995:932942.
6.28
23. Sabatini S, Kurtzman NA: Metabolic alkalosis: biochemical mechanisms, pathophysiology, and treatment. In Therapy of Renal Diseases
and Related Disorders Edited by Suki WN, Massry SG. Boston:
Kluwer Academic Publishers; 1997:189210.
24. Galla JH, Luke RG: Metabolic alkalosis. In Textbook of Nephrology.
Edited by Massry SG, Glassock RJ. Baltimore: Williams & Wilkins;
1995:469477.
25. Madias NE, Adrogu HJ, Cohen JJ: Maladaptive renal response to
secondary hypercapnia in chronic metabolic alkalosis. Am J Physiol
1980, 238:F283289.
26. Harrington JT, Hulter HN, Cohen JJ, Madias NE: Mineralocorticoidstimulated renal acidification in the dog: the critical role of dietary
sodium. Kidney Int 1986, 30:4348.
27. Beall DP, Scofield RH: Milk-alkali syndrome associated with calcium
carbonate consumption. Medicine 1995, 74:8996.
28. Simon DB, Karet FE, Hamdan JM, et al.: Bartters syndrome,
hypokalaemic alkalosis with hypercalciuria, is caused by mutations in
the Na-K-2Cl cotransporter NKCC2. Nat Genet 1996, 13:183188.
29. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogeneity of Bartters syndrome revealed by mutations in the K+ channel,
ROMK. Nat Genet 1996, 14:152156.
30. International Collaborative Study Group for Bartter-like Syndromes.
Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome:
evidence for genetic heterogeneity. Hum Mol Genet 1997, 6:1726.
31. Simon DB, Nelson-Williams C, et al.: Gitelmans variant of Bartters
syndrome, inherited hypokalaemic alkalosis, is caused by mutations
in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 1996,
12:2430.
Disorders of
Phosphate Balance
Moshe Levi
Mordecai Popovtzer
he physiologic concentration of serum phosphorus (phosphate) in

normal adults ranges from 2.5 to 4.5 mg/dL (0.801.44 mmol/L).
A diurnal variation occurs in serum phosphorus of 0.6 to 1.0
mg/dL, the lowest concentration occurring between 8 AM and 11 AM.
A seasonal variation also occurs; the highest serum phosphorus concentration is in the summer and the lowest in the winter. Serum phosphorus
concentration is markedly higher in growing children and adolescents
than in adults, and it is also increased during pregnancy [1,2].
Of the phosphorus in the body, 80% to 85% is found in the skeleton. The rest is widely distributed throughout the body in the form of
organic phosphate compounds. In the extracellular fluid, including in
serum, phosphorous is present mostly in the inorganic form. In serum,
more than 85% of phosphorus is present as the free ion and less than
15% is protein-bound.
Phosphorus plays an important role in several aspects of cellular
metabolism, including adenosine triphosphate synthesis, which is the
source of energy for many cellular reactions, and 2,3-diphosphoglycerate
concentration, which regulates the dissociation of oxygen from hemoglobin. Phosphorus also is an important component of phospholipids in
cell membranes. Changes in phosphorus content, concentration, or
both, modulate the activity of a number of metabolic pathways.
Major determinants of serum phosphorus concentration are dietary
intake and gastrointestinal absorption of phosphorus, urinary excretion
of phosphorus, and shifts between the intracellular and extracellular
spaces. Abnormalities in any of these steps can result either in
hypophosphatemia or hyperphosphatemia [37].
The kidney plays a major role in the regulation of phosphorus
homeostasis. Most of the inorganic phosphorus in serum is ultrafilterable at the level of the glomerulus. At physiologic levels of serum
phosphorus and during a normal dietary phosphorus intake, approximately 6 to 7 g/d of phosphorous is filtered by the kidney. Of that
CHAPTER
7.2
amount, 80% to 90% is reabsorbed by the renal tubules and

the rest is excreted in the urine. Most of the filtered phosphorus is reabsorbed in the proximal tubule by way of a sodium
gradient-dependent process (Na-Pi cotransport) located on the
apical brush border membrane [810]. Recently two distinct
Na-Pi cotransport proteins have been cloned from the kidney
(type I and type II Na-Pi cotransport proteins). Most of the

hormonal and metabolic factors that regulate renal tubular
phosphate reabsorption, including alterations in dietary phosphate content and parathyroid hormone, have been shown to
modulate the proximal tubular apical membrane expression of
the type II Na-Pi cotransport protein [1116].
FIGURE 7-1
Summary of phosphate metabolism for
a normal adult in neutral phosphate balance. Approximately 1400 mg of phosphate
is ingested daily, of which 490 mg is excreted in the stool and 910 mg in the urine.
The kidney, gastrointestinal (GI) tract, and
bone are the major organs involved in
phosphorus homeostasis.
Bone
GI intake
1400 mg/d
Digestive juice
phosphorus
210 mg/d
Formation
210 mg/d
Resorption
210 mg/d
Extracellular fluid
Total absorbed
intestinal phosphorus
1120 mg/d
Urine
910 mg/d
Stool
490 mg/d
FIGURE 7-2
Major determinants of extracellular fluid or serum inorganic phosphate (Pi) concentration include dietary Pi intake, intestinal Pi
absorption, urinary Pi excretion and shift into the cells.
Major determinants of ECF or serum

inorganic phosphate (Pi) concentration
Dietary intake
Intestinal
absorption
Serum Pi
Urinary excretion
Cells
Disorders of Phosphate Balance
7.3
Renal Tubular Phosphate Reabsorption

100%
PCT
55-75%
DCT
5-10%
PST
10-20%
FIGURE 7-3
Renal tubular reabsorption of phosphorus. Most of the inorganic
phosphorus in serum is ultrafilterable at the level of the glomerulus.
At physiologic levels of serum phosphorus and during a normal
dietary phosphorus intake, most of the filtered phosphorous is reabsorbed in the proximal convoluted tubule (PCT) and proximal
straight tubule (PST). A significant amount of filtered phosphorus
is also reabsorbed in distal segments of the nephron [7,9,10].
CCTcortical collecting tubule; IMCDinner medullary collecting
duct or tubule; PSTproximal straight tubule.
CCT
2-5%
IMCD
<1%
0.2%-20% Urine
Lumen
Blood
Pi
Na+
Na
3 Na+
?An
Na+
Pi
Pi
Pi
Gluconeogenesis
[HPO4=
Glycolysis
H2PO4 ]
Pi+ADP ATP
P +ADP ATP
Na-K
ATPase
Respiratory chain
Oxidative phosphorylation
65mV
65mV
FIGURE 7-4
Cellular model for renal tubular reabsorption of phosphorus in the
proximal tubule. Phosphate reabsorption from the tubular fluid is
sodium gradientdependent and is mediated by the sodium gradient
dependent phosphate transport (Na-Pi cotransport) protein located
on the apical brush border membrane. The sodium gradient for phosphate reabsorption is generated by then sodium-potassium adenosine
triphosphatase (Na-K ATPase) pump located on the basolateral membrane. Recent studies indicate that the Na-Pi cotransport system is
electrogenic [8,11]. ADPadenosine diphosphate; Ananion.
7.4
FACTORS REGULATING RENAL PROXIMAL TUBULAR

PHOSPHATE REABSORPTION
Cellular model of proximal tubule Pi-reabsorption

Lumen
Parathyroid hormone
dietary Pi content
Blood
HPO42
3Na
HPO42
Na+
A
FIGURE 7-5
Celluar model of proximal tubular phosphate reabsorption. Major
physiologic determinants of renal tubular phosphate reabsorption are
alterations in parathyroid hormone activity and alterations in dietary
phosphate content. The regulation of renal tubular phosphate reabsorption occurs by way of alterations in apical membrane sodiumphosphate (Na-Pi) cotransport 3Na+-HPO24 activity [1114].
Decreased transport
Increased transport
High phosphate diet

Parathyroid hormone and parathyroidhormonerelated protein
Glucocorticoids
Chronic metabolic acidosis
Acute respiratory acidosis
Aging
Calcitonin
Atrial natriuretic peptide
Fasting
Hypokalemia
Hypercalcemia
Diuretics
Phosphatonin
Low phosphate diet

Growth hormone
Insulin
Thyroid hormone
1,25-dihydroxy-vitamin D3
Chronic metabolic alkalosis
High calcium diet
High potassium diet
Stanniocalcin
FIGURE 7-6
Factors regulating renal proximal tubular phosphate reabsorption.
FIGURE 7-7 (see Color Plate)

Effects of a diet low in phosphate on renal
tubular phosphate reabsorption in rats. A,
Chronic high Pi diet. B, Acute low Pi diet.
C, Colchicine and high Pi diet. D,
Colchicine and low Pi diet. In response to a
low phosphate diet, a rapid adaptive
increase occurs in the sodium-phosphate
(Na-Pi) cotransport activity of the proximal
tubular apical membrane (A, B). The
increase in Na-Pi cotransport activity is
mediated by rapid upregulation of the type
II Na-Pi cotransport protein, in the absence
of changes in Na-Pi messenger RNA
(mRNA) levels. This rapid upregulation is
dependent on an intact microtubular network because pretreatment with colchicine
prevents the upregulation of Na-Pi cotransport activity and Na-Pi protein expression
(C, D). In this immunofluorescence micrograph, the Na-Pi protein is stained green
(fluorescein) and the actin cytoskeleton is
stained red (rhodamine). Colocalization of
green and red at the level of the apical
membrane results in yellow color [14].
7.5

Effects of parathyroid hormone (PTH) on
renal tubular phosphate reabsorption in
rats. In response to PTH administration to
parathyroidectomized rats, a rapid decrease
occurs in the sodium-phosphate (Na-Pi)
cotransport activity of the proximal tubular
apical membrane. The decrease in Na-Pi
cotransport activity is mediated by rapid
downregulation of the type II Na-Pi
cotransport protein. In this immunofluorescence micrograph, the Na-Pi protein is
stained green (fluorescein) and the actin
cytoskeleton is stained red (rhodamine).
Colocalization of green and red at the level
of the apical membrane results in yellow
color [13]. A, parathyroidectomized (PTX)
effects. B, effects of PTX and PTH.
600
GlcCer,
ng/mg
Cholesterol,
nmol/mg
490
440
390
PDMP
Control
DEX
PDMP
Control
DEX
1600
1100
600
Low Pi diet
and/or young
Control
High Pi diet
and/or aged
FIGURE 7-9
Renal cholesterol content modulates renal tubular phosphate reabsorption. In aged rats versus young rats and rats fed a diet high in
phosphate versus a diet low in phosphate, an inverse correlation
exists between the brush border membrane (BBM) cholesterol content (A) and Na-Pi cotransport activity (B). Studies in isolated BBM
vesicles and recent studies in opossum kidney cells grown in culture
indicate that direct alterations in cholesterol content per se modulate Na-Pi cotransport activity [15]. CONcontrols.
Na-Pi,
pmol/5s/mg
Na-Pi,
pmol/5s/mg
1600
FIGURE 7-10
Renal glycosphingolipid content modulates renal tubular phosphate
reabsorption. In rats treated with dexamethasone (DEX) and in rats
fed a potassium-deficient diet, an inverse correlation exists between
brush border membrane (BBM) glucosylceramide (GluCer)and
ganglioside GM3, content and Na-Pi cotransport activity. Treatment
of rats with a glucosylceramide synthase inhibitor PDMP lowers
BBM glucosylceramide content (A) and increases Na-Pi cotransport
activity (B) [16].
7.6
Hypophosphatemia/Hyperphosphatemia
FIGURE 7-11
Major causes of hypophosphatemia. (From
Angus [1]; with permission.)
MAJOR CAUSES OF HYPOPHOSPHATEMIA

Internal redistribution
Decreased intestinal absorption
Increased urinary excretion
Increased insulin, particularly

during refeeding
Acute respiratory alkalosis
Hungry bone syndrome
Inadequate intake
Antacids containing aluminum
or magnesium
Steatorrhea and chronic diarrhea
Primary and secondary

hyperparathyroidism
Vitamin D deficiency or resistance
Fanconis syndrome
Miscellaneous: osmotic diuresis,
proximally acting diuretics, acute
volume expansion
CAUSES OF MODERATE HYPOPHOSPHATEMIA

Pseudohypophosphatemia
Mannitol
Bilirubin
Acute leukemia
Decreased dietary intake
Decreased intestinal absorption
Vitamin D deficiency
Malabsorption
Steatorrhea
Secretory diarrhea
Vomiting
PO34-binding antacids
Shift from serum into cells
Sepsis
Heat stroke
Neuroleptic malignant syndrome
Hepatic coma
Salicylate poisoning
Gout
Panic attacks
Psychiatric depression
Hormonal effects
Insulin
Glucagon
Epinephrine
Androgens
Cortisol
Anovulatory hormones
Nutrient effects
Glucose
Fructose
Glycerol
Lactate
Amino acids
Xylitol
FIGURE 7-12
Causes of moderate hypophosphatemia. (From Popovtzer, et al. [6];
with permission.)
Cellular uptake syndromes

Recovery from hypothermia
Burkitts lymphoma
Histiocytic lymphoma
Acute myelomonocytic leukemia
Acute myelogenous leukemia
Chronic myelogenous leukemia
in blast crisis
Treatment of pernicious anemia
Erythropoietin therapy
Erythrodermic psoriasis
Hungry bone syndrome
After parathyroidectomy
Acute leukemia
Increased excretion into urine

Hyperparathyroidism
Renal tubule defects
Fanconis syndrome
X-linked hypophosphatemic rickets
Hereditary hypophosphatemic rickets
with hypercalciuria
Polyostotic fibrous dysphasia
Panostotic fibrous dysphasia
Neurofibromatosis
Kidney transplantation
Oncogenic osteomalacia
Recovery from hemolytic-uremic
syndrome
Aldosteronism
Licorice ingestion
Volume expansion
Inappropriate secretion of antidiuretic
hormone
Mineralocorticoid administration
Corticosteroid therapy
Diuretics
Aminophylline therapy
CAUSES OF SEVERE HYPOPHOSPHATEMIA

Acute renal failure: excessive P binders
Chronic alcoholism and alcohol
withdrawal
Dietary deficiency and PO34-binding
antacids
Hyperalimentation
Neuroleptic malignant syndrome
Recovery from diabetic ketoacidosis
Recovery from exhaustive exercise
Kidney transplantation
Severe thermal burns
Therapeutic hypothermia
Reyes syndrome
After major surgery
Periodic paralysis
Acute malaria
Drug therapy
Ifosfamide
Cisplatin
Acetaminophen intoxication
Cytokine infusions
Tumor necrosis factor
Interleukin-2
7.7
CAUSES OF HYPOPHOSPHATEMIA IN PATIENTS

WITH NONKETOTIC HYPERGLYCEMIA OR
DIABETIC KETOACIDOSIS
Decreased net
intestinal phosphate
absorption
Decreased phosphate
intake
Increased urinary
phosphate excretion
Glucosuria-induced
osmotic diuresis
Acidosis
Acute movement of
extracellular phosphate into the cells
Insulin therapy
FIGURE 7-14
Causes of hypophosphatemia in patients with nonketotic hyperglycemia or diabetic ketoacidosis.
FIGURE 7-13
Causes of severe hypophosphatemia. (From Popovtzer, et al. [6];
with permission.)
CAUSES OF HYPOPHOSPHATEMIA
IN PATIENTS WITH ALCOHOLISM
Decreased net
intestinal phosphate
absorption
Poor dietary intake of
phosphate and vitamin D
Use of phosphate binders
to treat recurring gastritis
Chronic diarrhea
Increased urinary
phosphate excretion
Alcohol-induced
reversible proximal
tubular defect
Secondary hyperparathyroidism induced by
vitamin D deficiency
CAUSES OF HYPOPHOSPHATEMIA IN PATIENTS

WITH RENAL TRANSPLANTATION
Acute movement of
extracellular phosphate into the cells
Insulin release induced by
intravenous solutions
containing dextrose
Acute respiratory alkalosis
caused by alcohol
withdrawal, sepsis,
or hepatic cirrhosis
Refeeding of the patient
who is malnourished
Increased urinary phosphate excretion

Persistent hyperparathyroidism (hyperplasia or adenoma)
Proximal tubular defect (possibly induced by glucocorticoids, cyclosporine, or both)
FIGURE 7-16
Causes of hypophosphatemia in patients with renal transplantation.
FIGURE 7-15
Causes of hypophosphatemia in patients with alcoholism.
MAJOR CONSEQUENCES OF HYPOPHOSPHATEMIA

Decreased erythrocyte 2,3-diphosphoglycerate levels, which result in increased affinity
of hemoglobin for oxygen and reduced oxygen release at the tissue level
Decreased intracellular adenosine triphosphate levels, which result in impairment of
cell functions dependent on energy-rich phosphate compounds
FIGURE 7-17
Major consequences of hypophosphatemia.
7.8
SIGNS AND SYMPTOMS OF HYPOPHOSPHATEMIA

Central
nervous system
dysfunction
Metabolic
encephalopathy
owing to tissue
ischemia
Irritability
Paresthesias
Confusion
Delirium
Coma
Cardiac
dysfunction
Pulmonary
dysfunction
Skeletal and
smooth muscle
dysfunction
Impaired
myocardial
contractility
Congestive heart
failure
Weakness of the
diaphragm
Respiratory failure
Proximal myopathy
Dysphagia and ileus
Rhabdomyolysis
Hematologic
dysfunction
Bone disease
Erythrocytes
Increased bone
resorption
Increased
erythrocyte
Rickets and osteorigidity
malacia caused by
decreased bone
Hemolysis
mineralization
Leukocytes
Impaired
phagocytosis
Decreased
granulocyte
chemotaxis
Platelets
Defective clot
retraction
Thrombocytopenia
Renal effects
Decreased
glomerular
filtration rate
Decreased tubular
transport
maximum for
bicarbonate
Decreased renal
gluconeogenesis
Decreased titratable
acid excretion
Hypercalciuria
Hypermagnesuria
Metabolic
effects
Low parathyroid
hormone levels
Increased 1,25-dihydroxy-vitamin D3
levels
Increased creatinine
phosphokinase
levels
Increased aldolase
levels
FIGURE 7-18
Signs and symptoms of hypophosphatemia. (Adapted from Hruska
and Slatopolsky [2] and Hruska and Gupta [7].)
FIGURE 7-19
Pseudofractures (Loosers transformation zones) at the margins of
the scapula in a patient with oncogenic osteomalacia. Similar to the
genetic X-linked hypophosphatemic rickets, a circulating phosphaturic factor is believed to be released by the tumor, causing phosphate wasting and reduced calcitriol formation by the kidney. Note
the radiolucent ribbonlike decalcification extending into bone at a
right angle to its axillary margin. Pseudofractures are pathognomonic of osteomalacia with a low remodeling rate.

Histologic appearance of trabecular bone from a patient with
oncogenic osteomalacia. Undecalcified bone section with impaired
mineralization and a wide osteoid (organic matrix) seam stained
with von Kossas stain is illustrated. Note the wide bands of
osteoid around the mineralized bone. Absence of osteoblasts on
the circumference of the trabecular bone portion indicates a low
remodeling rate.
7.9
FIGURE 7-21(see Color Plate)

Microscopic appearance of bone section from a patient with vitamin D deficiency caused by malabsorption. The bone section was
stained with Masson trichrome stain. Hypophosphatemia and
hypocalcemia were present. Note the trabecular bone consisting
of very wide osteoid areas (red) characteristic of osteomalacia.
FIGURE 7-22
Usual dosages for phosphorus repletion.
USUAL DOSAGES FOR PHOSPHORUS REPLETION

Severe symptomatic hypophosphatemia (plasma phosphate
concentration < 1 mg/dL)
10 mg/kg/d, intravenously, until the
plasma phosphate concentration
reaches 2 mg/dL
Phosphate depletion
Hypophosphatemic rickets
24 g/d (64 to 128 mmol/d), orally,

in 3 to 4 divided doses
14 g/d (32 to 128 mmol/d), orally,

in 3 to 4 divided doses
FIGURE 7-23
Phosphate preparations for oral use.
PHOSPHATE PREPARATIONS FOR ORAL USE

Preparation
Phosphate, mg
Sodium, mEq
Potassium, mEq
250
13
1.1
K-Phos Neutral, tablet

(Beach Pharmaceuticals, Conestee, SC)
Neutra-Phos, capsule or 75-mL solution
(Baker Norton Pharmaceuticals, Miami, FL)
Neutra-Phos K, capsule or 75-mL solution
(Baker Norton Pharmaceuticals, Miami, FL)
250
7.1
7.1
250
14.2
FIGURE 7-24
Phosphate preparations for intravenous use.
(From Popovtzer, et al. [6]; with permission.)
PHOSPHATE PREPARATIONS FOR INTRAVENOUS USE
Phosphate preparation
Composition, mg/mL
Potassium
236 mg K2HPO4
224 mg KH2PO4
142 mg Na2HPO4
276 mg NaH2HPO4.H2O
10.0 mg Na2HPO
2.7 mg NaH2PO4.H2O
11.5 mg Na2HPO4
2.6 mg KH2PO4
Sodium
Neutral sodium
Neutral sodium, potassium
Phosphate,
mmol/mL
3 mmol/mL of phosphate corresponds to 93 mg of phosphorus.
Sodium,
mEq/mL
Potassium,
mEq/mL
3.0
4.4
3.0
4.0
0.09
0.2
1.10
0.2
0.02
7.10
CAUSES OF HYPERPHOSPHATEMIA
Pseudohyperphosphatemia
Increased endogenous loads
Reduced urinary excretion
Miscellaneous
Multiple myeloma
Extreme hypertriglyceridemia
In vitro hemolysis
Tumor lysis syndrome

Rhabdomyolysis
Bowel infarction
Malignant hyperthermia
Heat stroke
Acid-base disorders
Organic acidosis
Lactic acidosis
Ketoacidosis
Respiratory acidosis
Chronic respiratory alkalosis
Renal failure
Hypoparathyroidism
Hereditary
Acquired
Pseudohypoparathyroidism
Growth hormone
Insulin-like growth factor-1
Glucocorticoid withdrawal
Mg2+ deficiency
Tumoral calcinosis
Diphosphonate therapy
Hyopophosphatasia
Fluoride poisoning
-Blocker therapy
Verapamil
Hemorrhagic shock
Sleep deprivation
Increased exogenous phosphorus

load or absorption
Phosphorus-rich cows milk in premature
neonates
PO34-containing enemas
Intravenous phosphorus supplements
White phosphorus burns
Acute phosphorus poisoning
FIGURE 7-25
Causes of hyperphosphatemia. (From Knochel and Agarwal [5];
with permission.)
CLINICAL MANIFESTATIONS OF
HYPERPHOSPHATEMIA
Consequences of secondary
changes in calcium, parathyroid
hormone, vitamin D metabolism
and hypocalcemia:
Neuromuscular irritability
Tetany
Hypotension
Increased QT interval
Consequences of ectopic
calcification:
Periarticular and soft tissue calcification
Vascular calcification
Ocular calcification
Conduction abnormalities
Pruritus
FIGURE 7-26
Clinical manifestations of hyperphosphatemia.
TREATMENT OF HYPERPHOSPHATEMIA
Acute hyperphosphatemia in
patients with adequate renal
function
Chronic hyperphosphatemia in
patients with end-stage renal
disease
Saline diuresis that causes phosphaturia
Dietary phosphate restriction

Phosphate binders to decrease gastrointestinal phosphate reabsorption
FIGURE 7-27
Treatment of hyperphosphatemia.
A
FIGURE 7-28
Periarticular calcium phosphate deposits in a patient with endstage renal disease who has severe hyperphosphatemia and a high
level of the product of calcium and phosphorus. Note the partial
A
FIGURE 7-29
Resolution of soft tissue calcifications. The palms of the hands of
the patient in Figure 7-28 with end-stage renal disease are shown
before (A) and after (B) treatment of hyperphosphatemia. The
7.11
B
resolution of calcific masses after dietary phosphate restriction and
oral phosphate binders. Left shoulder joint before (A) and after (B)
treatment. (From Pinggera and Popovtzer [17]; with permission.)
B
patient has a high level of the product of calcium and phosphorus.
(From Pinggera and Popovtzer [17]; with permission.)
7.12
FIGURE 7-30
A, B, Bone sections from the same patient as in Figures 7-28 and 7-29, illustrating osteitis
fibrosa cystica caused by renal secondary hyperparathyroidism with hyperphosphatemia.
FIGURE 7-31
Roentgenographic appearance of femoral arterial vascular calcification in a patient on dialysis who has severe hyperphosphatemia. The
patient has a high level of the product of calcium and phosphorus.

Microscopic appearance of a cross section of a calcified artery in a
patient with end-stage renal disease undergoing chronic dialysis. The
patient has severe hyperphosphatemia and a high level of the product of calcium and phosphorus. Note the intimal calcium phosphate
deposit with a secondary occlusion of the arterial lumen.
FIGURE 7-33
Massive periarticular calcium phosphate deposit (around the hip joint) in a patient with
genetic tumoral calcinosis. The patient exhibits hyperphosphatemia and increased renal
tubular phosphate reabsorption. Normal parathyroid hormone levels and elevated calcitriol
levels are present. The same disease affects two of the patients brothers.
7.13
FIGURE 7-34
Massive periarticular calcium phosphate deposit in the plantar
joints in the same patient in Figure 7-33 who has genetic tumoral
calcinosis.

Complications of the use of aluminum-based phosphate binders to
control hyperphosphatemia. Appearance of bone section from a
patient with end-stage renal disease who was treated with oral aluminum gels to control severe hyperphosphatemia. A bone biopsy
was obtained 6 months after a parathyroidectomy was performed.
Note the wide areas of osteoid filling previously resorbed bone.

The same bone section as in Figure 7-35 but under polarizing lenses, illustrating the partially woven appearance of osteoid typical of
chronic renal failure.

The same bone section as in Figure 7-35 with positive aluminum
stain of the trabecular surface. These findings are consistent with
aluminum-related osteomalacia.
Acknowledgments
The authors thank Sandra Nickerson and Teresa Autrey for secretarial assistance and the Medical Media Department at the Dallas
VA Medical Center for the illustrations.
7.14
References
1.
Agus ZS: Phosphate metabolism. In UpToDate, Inc.. Edited by Burton

D. Rose, 1998.
2.
Hruska KA, Slatopolsky E: Disorders of phosphorus, calcium, and

magnesium metabolism. In Diseases of the Kidney, edn 6. Edited by
Schrier RW, Gottschalk CW. Boston: Little and Brown; 1997.
10. Suki WN, Rouse D: Renal Transport of calcium, magnesium, and

phosphate. In The Kidney, edn 5. Edited by Brenner BM.
Philadelphia: WB Saunders; 1996.
11. Levi M, Kempson, SA, Ltscher M, et al.: Molecular regulation of
renal phosphate transport. J Membrane Biol 1996, 154:19.
3.
Levi M, Knochel JP: The management of disorders of phosphate

metabolism. In Therapy of Renal Diseases and Related Disorders.
Edited by Massry SG, Suki WN. Boston, Martinus Nijhoff; 1990.
12. Levi M, Ltscher M, Sorribas V, et al.: Cellular mechanisms of acute

and chronic adaptation of rat renal phosphate transporter to alterations in dietary phosphate. Am J Physiol 1994, 267:F900F908.
4.
Levi M, Cronin RE, Knochel JP: Disorders of phosphate and magnesium metabolism. In Disorders of Bone and Mineral Metabolism.
Edited by Coe FL, Favus MJ. New York: Raven Press; 1992.
13. Kempson SA, Ltscher M, Kaissling B, et al.: Effect of parathyroid

hormone on phosphate transporter mRNA and protein in rat renal
proximal tubules. Am J Physiol 1995, 268:F784F791.
5.
Knochel JP, Agarwal R: Hypophosphatemia and hyperphosphatemia.

In The Kidney, edn 5. Edited by Brenner BM. Philadelphia: WB
Saunders; 1996.
6.
Popovtzer M, Knochel JP, Kumar R: Disorders of calcium, phosphorus,

vitamin D, and parathyroid hormone activity. In Renal Electrolyte
Disorders, edn 5. Edited by Schrier RW. Philadelphia: LippincottRaven; 1997.
14. Ltscher M, Biber J, Murer H, et al.: Role of microtubules in the

rapid upregulation of rat renal proximal tubular Na-Pi cotransport
following dietary P restriction. J Clin Invest 1997, 99:13021312.
15. Levi M, Baird B, Wilson P: Cholesterol modulates rat renal brush border
membrane phosphate transport. J Clin Invest 1990, 85:231237.
7.
Hruska K, Gupta A: Disorders of phosphate homeostasis. In

Metabolic Bone Disease, edn 3. Edited by Avioli LV, SM Krane.
New York: Academic Press; 1998.
8.
Murer H, Biber J: Renal tubular phosphate transport: cellular mechanisms. In The Kidney: Physiology and Pathophysiology, edn 2. Edited
by Seldin DW, Giebisch G. New York: Raven Press; 1997.
9.
Berndt TJ, Knox FG: Renal regulation of phosphate excretion. In

The Kidney: Physiology and Pathophysiology, edn 2. Edited by Seldin
DW, Giebisch G. New York: Raven Press; 1992.
16. Levi M, Shayman J, Abe A, et al.: Dexamethasone modulates rat renal

brush border membrane phosphate transporter mRNA and protein
abundance and glycosphingolipid composition. J Clin Invest 1995,
96:207216.
17. Pinggera WF, Popovtzer MM: Uremic osteodystrophy: the therapeutic
consequences of effective control of serum phosphorus. JAMA 1972,
222:16401642.
Acute Renal Failure:

Causes and Prognosis
Fernando Liao
Julio Pascual
here are many causesmore than fifty are given within this
present chapterthat can trigger pathophysiological mechanisms leading to acute renal failure (ARF). This syndrome is
characterized by a sudden decrease in kidney function, with a consequence of loss of the hemostatic equilibrium of the internal medium.
The primary marker is an increase in the concentration of the nitrogenous components of blood. A second marker, oliguria, is seen in 50%
to 70% of cases.
In general, the causes of ARF have a dynamic behavior as they
change as a function of the economical and medical development of
the community. Economic differences justify the different spectrum in
the causes of ARF in developed and developing countries. The setting
where ARF appears (community versus hospital), or the place where
ARF is treated (intensive care units [ICU] versus other hospital areas)
also show differences in the causes of ARF.
While functional outcome after ARF is usually good among the surviving patients, mortality rate is high: around 45% in general series
and close to 70% in ICU series. Although it is unfortunate that these
mortality rates have remained fairly constant over the past decades, it
should be noted that todays patients are generally much older and
display a generally much more severe condition than was true in the
past. These age and severity factors, together with the more aggressive
therapeutical possibilities presently available, could account for this
apparent paradox.
As is true for any severe clinical condition, a prognostic estimation
of ARF is of great utility for both the patients and their families, the
medical specialists (for analysis of therapeutical maneuvers and
options), and for society in general (demonstrating the monetary costs
of treatment). This chapter also contains a brief review of the prognostic tools available for application to ARF.
CHAPTER
8.2
Acute Renal Failure
Causes of Acute Renal Failure

Sudden causes
affecting
Induce
Prerenal
Renal
perfusion
Parenchymal
structures
Urine
output
Called
GFR
Parenchymatous
Obstructive
A
c
u
t
e
r
e
n
a
l
f
a
i
l
u
r
e
FIGURE 8-1
Characteristics of acute renal failure. Acute renal failure is a
syndrome characterized by a sudden decrease of the glomerular
filtration rate (GFR) and consequently an increase in blood
nitrogen products (blood urea nitrogen and creatinine). It is
associated with oliguria in about two thirds of cases. Depending
on the localization or the nature of the renal insult, ARF is classified as prerenal, parenchymatous, or obstructive (postrenal).
CAUSES OF PARENCHYMATOUS
ACUTE RENAL FAILURE
Acute tubular necrosis
Hemodynamic: cardiovascular surgery,* sepsis,* prerenal causes*
Toxic: antimicrobials,* iodide contrast agents,* anesthesics, immunosuppressive or
antineoplastic agents,* Chinese herbs, Opiaceous, Extasis, mercurials, organic
solvents, venoms, heavy metals, mannitol, radiation
Intratubular deposits: acute uric acid nephropathy, myeloma, severe hypercalcemia,
primary oxalosis, sulfadiazine, fluoride anesthesics
Organic pigments (endogenous nephrotoxins):
Myoglobin rhabdomyolisis: muscle trauma; infections; dermatopolymyositis;
metabolic alterations; hyperosmolar coma; diabetic ketoacidosis; severe
hypokalemia; hyper- or hyponatremia; hypophosphatemia; severe hypothyroidism; malignant hyperthermia; toxins such as ethylene glycol, carbon
monoxide, mercurial chloride, stings; drugs such as fibrates, statins, opioids
and amphetamines; hereditary diseases such as muscular dystrophy,
metabolopathies, McArdle disease and carnitine deficit
Hemoglobinuria: malaria; mechanical destruction of erythrocytes with extracorporeal
circulation or metallic prosthesis, transfusion reactions, or other hemolysis;
heat stroke; burns; glucose-6-phosphate dehydrogenase; nocturnal paroxystic
hemoglobinuria; chemicals such as aniline, quinine, glycerol, benzene, phenol,
hydralazine; insect venoms
Acute tubulointerstitial nephritis (see Fig. 8-4)
CAUSES OF PRERENAL ACUTE RENAL FAILURE

Decreased effective extracellular volume
Renal losses: hemorrhage, vomiting, diarrhea, burns, diuretics
Redistribution: hepatopathy, nephrotic syndrome, intestinal obstruction, pancreatitis,
peritonitis, malnutrition
Decreased cardiac output: cardiogenic shock, valvulopathy, myocarditis, myocardial
infarction, arrhythmia, congestive heart failure, pulmonary emboli, cardiac tamponade
Peripheral vasodilation: hypotension, sepsis, hypoxemia, anaphylactic shock, treatment
with interleukin L2 or interferons, ovarian hyperstimulation syndrome
Renal vasoconstriction: prostaglandin synthesis inhibition, -adrenergics, sepsis, hepatorenal syndrome, hypercalcemia
Efferent arteriole vasodilation: converting-enzyme inhibitors
FIGURE 8-2
Causes of prerenal acute renal failure (ARF). Prerenal ARF, also
known as prerenal uremia, supervenes when glomerular filtration
rate falls as a consequence of decreased effective renal blood supply.
The condition is reversible if the underlying disease is resolved.
Vascular occlusion
Principal vessels: bilateral (unilateral in solitary functioning kidney) renal artery
thrombosis or embolism, bilateral renal vein thrombosis
Small vessels: atheroembolic disease, thrombotic microangiopathy, hemolytic-uremic
syndrome or thrombotic thrombocytopenic purpura, postpartum acute renal
failure, antiphospholipid syndrome, disseminated intravascular coagulation,
scleroderma, malignant arterial hypertension, radiation nephritis, vasculitis
Acute glomerulonephritis
Postinfectious: streptococcal or other pathogen associated with visceral abscess,
endocarditis, or shunt
Henoch-Schonlein purpura
Essential mixed cryoglobulinemia
ImmunoglobulinA nephropathy
Mesangiocapillary
With antiglomerular basement membrane antibodies with lung disease
(Goodpasture is syndrome) or without it
Idiopathic, rapidly progressive, without immune deposits
Cortical necrosis, abruptio placentae, septic abortion, disseminated intravascular
coagulation
FIGURE 8-3
Causes of parenchymal acute renal failure (ARF). When the sudden decrease in glomerular filtration rate that characterizes ARF is
secondary to intrinsic renal damage mainly affecting tubules,
interstitium, glomeruli and/or vessels, we are facing a parenchymatous ARF. Multiple causes have been described, some of them
constituting the most frequent ones are marked with an asterisk.
8.3
Acute Renal Failure: Causes and Prognosis
MOST FREQUENT CAUSES OF ACUTE

TUBULOINTERSTITIAL NEPHRITIS
Antimicrobials
Penicillin
Ampicillin
Rifampicin
Sulfonamides
Analgesics, anti-inflammatories
Fenoprofen
Ibuprofen
Naproxen
Amidopyrine
Glafenine
Other drugs
Cimetidine
Allopurinol
CAUSES OF OBSTRUCTIVE ACUTE RENAL FAILURE
Congenital anomalies
Ureterocele
Bladder diverticula
Posterior urethral valves
Neurogenic bladder
Acquired uropathies
Benign prostatic hypertrophy
Urolithiasis
Papillary necrosis
Iatrogenic ureteral ligation
Malignant diseases
Prostate
Bladder
Urethra
Cervix
Colon
Breast (metastasis)
Immunological
Rejection
Infections (at present quite rare)
Neoplasia
Myeloma
Lymphoma
Acute leukemia
Idiopathic
Isolated
Associated with uveitis
FIGURE 8-4
Most common causes of tubulointerstitial nephritis. During the last
years, acute tubulointerstitial nephritis is increasing in importance as
a cause of acute renal failure. For decades infections were the most
important cause. At present, antimicrobials and other drugs are the
most common causes.
ATN
43.1%
Prerenal
40.6%
ATN
45%
Other parenchymal
6.4%
Obstructive
10%
Obstructive
3.4%
ATIN
1.6%
Arterial disease
1%
Prerenal
21%
Acute-on-chronic
13%
n = 202
19771980
n = 748
1991
FINDINGS OF THE MADRID STUDY
Condition
Prerenal acute renal failure
Acute on chronic renal failure
Obstructive acute renal failure
Glomerulonephritis (primary or secondary)
Acute tubulointerstitial nephritis
Vasculitis
Other vascular acute renal failure
Total
Incidence (per million persons per year)
95% CI
88
46
29
23
6.3
3.5
3.5
2.1
7997
4052
2434
1927
4.88.3
1.75.3
1.75.3
0.83.4
209
Infections
Schistosomiasis
Tuberculosis
Candidiasis
Aspergillosis
Actinomycosis
Other
Accidental urethral
catheter occlusion
FIGURE 8-5
Causes of obstructive acute renal failure. Obstruction at any level of
the urinary tract frequently leads to acute renal failure. These are the
most frequent causes.
Other parenchymal
4.5%
Arterial disease
2.5%
Retroperitoneal fibrosis
Idiopathic
Associated with
aortic aneurysm
Trauma
Iatrogenic
Drug-induced
Gynecologic non-neoplastic
Pregnancy-related
Uterine prolapse
Endometriosis
Acute uric acid nephropathy
Drugs
-Aminocaproic acid
Sulfonamides
195223
FIGURE 8-6
This figure shows a comparison of the percentages of the different types of acute renal failure
(ARF) in a western European country in
19771980 and 1991: A, distribution in a typical Madrid hospital; B, the Madrid ARF Study
[1]. There are two main differences: 1) the
appearance of a new group in 1991, acute
on chronic ARF, in which only mild forms
(serum creatinine concentrations between 1.5
and 3.0 mg/dL) were considered, for methodological reasons; 2) the decrease in prerenal
ARF suggests improved medical care. This low
rate of prerenal ARF has been observed by
other workers in an intensive care setting [2].
The other types of ARF remain unchanged.
FIGURE 8-7
Incidences of different forms of acute renal
failure (ARF) in the Madrid ARF Study [1].
Figures express cases per million persons per
year with 95% confidence intervals (CI).
8.4
Acute Renal Failure
Sclerodermal crisis 1
Tumoral obstruction 1
Secondary glomerulonephritis 1
Vasculitis 1
ATN
43%
Other
15%
Prerenal
27%
Malignant hypertension 2.1

Myeloma 2.1
Acute tubulointerstitial nephritis 2.1
Not recorded
15%
Atheroembolic disease 4.2
FIGURE 8-9
Discovering the cause of acute renal
failure (ARF). This is a great challenge
for clinicians. This algorithm could help
to determine the cause of the increase in
blood urea nitrogen (BUN) or serum
creatinine (SCr) in a given patient.
Bun/SCr
increase
Normal or big kidneys
(excluding amiloidosis and
polycystic kidney disease
Small kidneys
SCr < 0.5 mg/dL/d

Previous
SCr increased
and/or
and/or
and/or
and/or
SCr > 0.5 mg/dL/d

Previous
SCr normal
ARF
CRF
Urinary tract
dilatation
Echography
SCr < 0.5 mg/dL/d
Normal
Flare of previous
disease
Acute-on-chronic
renal failure
Repeat
echograph
after 24 h
Normal
No
Data indicating
glomerular
or systemic
disease?
Prerenal
factors?
Parenchymatous
glomerular or
systemic ARF
Yes
Vascular
ARF
Yes
Great or
small vessel
disease?
No
Acute
tubulointerstitial
nephritis
Yes
Data indicating
interstitial
disease?
No
Yes
Crystals or
tubular
deposits?
No
Tumor lysis
Sulfonamides
Amyloidosis
Other
FIGURE 8-8
The most frequent causes of acute renal
failure (ARF) in patients with preexisting
chronic renal failure are acute tubular
necrosis (ATN) and prerenal failure. The
distribution of causes of ARF in these
patients is similar to that observed in
patients without previous kidney diseases.
(Data from Liao et al. [1])
No
Yes
Obstructive
ARF
Improvement
with specific
treatment?
Yes
Prerenal
ARF
No
Acute
tubular
necrosis
BIOPSY RESULTS IN THE MADRID STUDY

Disease
Patients, n
Primary GN
Extracapillary
Acute proliferative
Endocapillary and extracapillary
Focal sclerosing
Secondary GN
Antiglomerular basement membrane
Acute postinfectious
Diffuse proliferative (systemic lupus erythematosus)
Vasculitis
Necrotizing
Wegeners granulomatosis
Not specified
Acute tubulointerstitial nephritis
Atheroembolic disease
Kidney myeloma
Cortical necrosis
Malignant hypertension
ImmunoglobulinA GN + ATN
Hemolytic-uremic syndrome
Not recorded
12
6
3
2
1
6
3
2
1*
10
5*
3
2
4*
4
2
2*
1
1
1
1
2
8.5
FIGURE 8-10
Biopsy results in the Madrid acute renal failure (ARF) study. Kidney
biopsy has had fluctuating roles in the diagnostic work-up of ARF.
After extrarenal causes of ARF are excluded, the most common
cause is acute tubular necrosis (ATN). Patients with well-established
clinical and laboratory features of ATN receive no benefit from renal
biopsy. This histologic tool should be reserved for parenchymatous
ARF cases when there is no improvement of renal function after 3
weeks evolution of ARF. By that time, most cases of ATN have
resolved, so other causes could be influencing the poor evolution.
Biopsy is mandatory when a potentially treatable cause is suspected,
such as vasculitis, systemic disease, or glomerulonephritis (GN) in
adults. Some types of parenchymatous non-ATN ARF might have
histologic confirmation; however kidney biopsy is not strictly necessary in cases with an adequate clinical diagnosis such as myeloma,
uric acid nephropathy, or some types of acute tubulointerstitial
nephritis . Other parenchymatous forms of ARF can be accurately
diagnosed without a kidney biopsy. This is true of acute post-streptococcal GN and of hemolytic-uremic syndrome in children. Kidney
biopsy was performed in only one of every 16 ARF cases in the
Madrid ARF Study [1]. All patients with primary GN, 90% with
vasculitis and 50% with secondary GN were diagnosed by biopsy at
the time of ARF. As many as 15 patients were diagnosed as having
acute tubulointerstitial nephritis, but only four (27%) were biopsied.
Only four of 337 patients with ATN (1.2%) underwent biopsy.
(Data from Liao et al. [1].)
* One patient with acute-on-chronic renal failure.
Predisposing Factors for Acute Renal Failure

Renal insult
Advanced age
Very
elderly
Elderly
Young
11%
12%
17%
11%
7%
Proteinuria
20%
Volume
depletion
29%
Other
Obstructive
Prerenal
Acute tubular
necrosis
21%
30%
Myeloma
Diuretic use
39%
Diabetes
mellitus
Previous cardiac
or renal insufficiency
Higher probability
for ARF
FIGURE 8-11
Factors that predispose to acute renal failure (ARF). Some of them
act synergistically when they occur in the same patient. Advanced
age and volume depletion are particularly important.
(n=103)
48%
(n=256)
56%
(n=389)
FIGURE 8-12
Causes of acute renal failure (ARF) relative to age. Although the cause of ARF is
usually multifactorial, one can define the
cause of each case as the most likely contributor to impairment of renal function.
One interesting approach is to distribute
the causes of ARF according to age. This
figure shows the

main causes of
ARF, dividing a
population diagnosed with ARF
into the very elderly (at least 80
years), elderly (65
to 79), and young
(younger than 65).
Essentially, acute
tubular necrosis
(ATN) is less
frequent (P=0.004)
and obstructive
ARF more frequent
(P<0.001) in the
very old than in
the youngest
patients. Prerenal
diseases appear
with similar
frequency in the
three age groups.
(Data from Pascual
et al. [3].)
8.6
Acute Renal Failure
Epidemiology of Acute Renal Failure

EPIDEMIOLOGY OF ACUTE RENAL FAILURE
Investigator, Year
Country (City)
Eliahou et al., 1973 [4]

Abraham et al., 1989 [5]
McGregor et al., 1992 [6]
Israel
Kuwait
United Kingdom
(Glasgow)
Spain (Cuenca)
United Kingdom
(Bristol and Devon)
Spain (Madrid)
Sanchez et al., 1992 [7]

Feest et al., 1993 [8]
Madrid ARF Study
Group, 1996 [1]
Study Period
(Study Length)
Study Population
(millions)
Incidence
(pmp/y)
19651966 (2 yrs)
19841986 (2 yrs)
19861988 (2 yrs)
2.2
0.4
0.94
52
95
185
19881989 (2 yrs)
19861987 (2 yrs)
0.21
0.44
254
175
19911992 (9 mo)
4.23
209
FIGURE 8-14
Number of patients needing dialysis for acute renal failure (ARF),
expressed as cases per million population per year (pmp/y). This has
been another way of assessing the incidence of the most severe cases
of ARF. Local situations, mainly economics, have an effect on dialysis facilities for ARF management. In 1973 Israeli figures showed a
lower rate of dialysis than other countries at the same time. The
very limited access to dialysis in developing countries supports this
hypothesis. At present, the need for dialysis in a given area depends
on the level of health care offered there. In two different countries
(eg, the United Kingdom and Spain) the need for dialysis for ARF
was very much lower when only secondary care facilities were available. At this level of health care, both countries had the same rate
of dialysis. The Spanish data of the EDTA-ERA Registry in 1982
gave a rate of dialysis for ARF of 59 pmp/y. This rate was similar to
that found in the Madrid ARF Study 10 years later. These data suggest that, when a certain economical level is achieved, the need of
ARF patients for dialysis tends to stabilize.
EPIDEMIOLOGY OF ACUTE RENAL FAILURE:

NEED OF DIALYSIS
Investigator, Year
Country
Lunding et al., 1964 [9]

Eliahou et al., 1973 [4]
Lachhein et al., 1978 [10]
Wing et al., 1983 [11]
Scandinavia
Israel
West Germany
European Dialysis and
Transplant Association
Spain
Kuwait
Spain
United Kingdom
United Kingdom
United Kingdom
Spain
Wing et al., 1983 [11]

Abraham et al., 1989 [5]
Sanchez et al., 1992 [7]
McGregor et al., 1992 [6]
Gerrard et al., 1992 [12]
Feest et al., 1993 [8]
Madrid ARF Study Group [1]
FIGURE 8-13
Prospective studies. Prospective epidemiologic
studies of acute renal failure (ARF) in large
populations have not often been published .
The first study reported by Eliahou and
colleagues [4] was developed in Israel in the
1960s and included only Jewish patients.
This summary of available data suggests a
progressive increase in ARF incidence that at
present seems to have stabilized around 200
cases per million population per year
(pmp/y). No data about ARF incidence are
available from undeveloped countries.
Cases (pmp/y)
28
17*
30
29
59
31
21
31
71
22
57
* Very restrictive criteria.

Only secondary care facilities.
HISTORICAL PATTERNS OF ACUTE RENAL FAILURE

Proportion of Cases, %
Surgical
Medical
Obstetric
France 1973
India
19651974
France
19811986
India
19811986
South Africa
19861988
46
30
24
11
67
22
30
70
2
30
61
9
8
77
15
FIGURE 8-15
Historical perspective of acute renal failure
(ARF) patterns in France, India, and South
Africa. In the 1960s and 1970s, obstetrical
causes were a great problem in both France
and India and overall incidences of ARF were
similar. Surgical cases were almost negligible in
India at that time, probably because of the relative unavailability of hospital facilities. During
the 1980s surgical and medical causes were
similar in both countries. In India, the increase
in surgical cases may be explained by advances
in health care, so that more surgical procedures
could be done. The decrease in surgical cases
in France, despite the fact that surgery had
become very sophisticated, could be explained
by better management of surgical patients.
8.7

FIGURE 8-15 (Continued)
Changes in classification criteriainclusion of a larger percentage
of medical cases than a decade beforecould be an alternative
explanation. In addition, obstetric cases had almost disappeared in
France in the 1980s, but they were still an important cause of ARF
in India. In a South African study that excluded the white population the distribution of ARF causes was almost identical to that
observed in India 20 years earlier. In conclusion, 1) the economic
level of a country determines the spectrum of ARF causes observed;

2) when a developing country improves its economic situation, the
spectrum moves toward that observed in developed countries; and
3) great differences can be detected in ARF causes among developing countries, depending on their individual economic power. (Data
from Kleinknecht [13]; Chugh et al. [14]; Seedat et al. [15].)
Percentage of total ARF cases
25
HD
68%
20
15
Diarrhea
Hemolysis
Obstetric
10
CRRT
1%
HD
60%
CRRT
33%
PD
31%
EDTA (1982)
0
19651974
19751980
Years
2221 patients
UF
1%
PD
5%
Madrid study (1992)
270 patients
19811986
FIGURE 8-16
Changing trends in the causes of acute renal failure (ARF) in the
Third-World countries. Trends can be identified from the analysis of
medical and obstetric causes by the Chandigarh Study [14]. Chugh
and colleagues showed how obstetric (septic abortion) and hemolytic
(mainly herbicide toxicity) causes tended to decrease as economic
power and availability of hospitalization improved with time. These
causes of ARF, however, did not completely disappear. By contrast,
diarrheal causes of ARF, such as cholera and other gastrointestinal diseases, remained constant. In conclusion, gastrointestinal causes of ARF
will remain important in ARF until structural and sanitary measures
(eg, water treatment) are implemented. Educational programs and
changes in gynecological attention, focused on controlled medical
abortion and contraceptive measures, should be promoted to eradicate
other forms of ARF that constitute a plague in Third World countries.
FIGURE 8-17
Evolution of dialysis techniques for acute renal failure (ARF) in Spain.
A, The percentages of different modalities of dialysis performed in
Spain in the early 1980s. B, The same information obtained a decade.
At this latter time, 90% of conventional hemodialysis (HD) was performed using bicarbonate as a buffer. These rates are those
of a developed country. In developing countries, dialysis should be
performed according to the available facilities and each individual
doctors experience in the different techniques. PDperitoneal dialysis; CRRTcontinuous renal replacement technique;
UFisolated ultrafiltration. (A, Data from the EDTA-ERA Registry
[11]; B data from the Madrid ARF Study [1].)
Hospital-Related Epidemiologic Data

FIGURE 8-18
Serum creatinine (SCr) at hospital admission has diagnostic and
prognostic implications for acute renal failure (ARF). A, Of the
patients included in an ARF epidemiologic study 39% had a
normal SCr concentration (less than 1.5 mg/dL) at hospital
admission. It is worth noting that only 22% of the patients had
clearly established ARF (SCr greater than 3 mg/dL) when admitted (no acute-on-chronic case was included). Mortality was
significantly higher in patients with normal SCr at admission.
P<0.001
60
50
%
40
30
20
10
0
(Continued on next page)

SCr<1.5 mg/dL
Mortality
SCr>3.0 mg/dL
Mortality
8.8
Acute Renal Failure
ARF
Community-acquired
(SCr at admission>3 mg/dL)
Hospital-acquired
(SCr at admission<1.5 mg/dL)
ATN
Prerenal
Obstructive
41.8
47.5
77.3
58.2
52.5
22.7
Total
49.7
50.3

B, With the same two groups, acute tubular necrosis (ATN)
predominated among the hospital-induced ARF group, whereas
the obstructive form was the main cause of community-acquired
ARF. In conclusion, the hospital could be considered an ARF
generator, particularly of the most severe forms. Nonetheless,
these iatrogenic ARF cases are usually innocent, and are an
unavoidable consequence of diagnostic and therapeutic maneuvers.
Medical dept.
34%
ICUs
27%
Trauma
2%
Nephrology
13%
Surgical dept.
23%
Gynecology
1%
FIGURE 8-19
Acute renal failure: initial hospital location and mortality. A,
Initial departmental location of ARF patients in a hospital in a
Western country. The majority of the cases initially were seen in
medical, surgical, and intensive care units (ICUs). The cases
initially treated in nephrology departments were community
acquired, whereas the ARF patients in the other settings generally
acquired ARF in those settings. Obstetric-gynecologic ARF cases
have almost disappeared. ARF of traumatic origin is also rare, for
EPIDEMIOLOGIC VARIABLES
Investigator, Year
Hou et al., 1983*
Shusterman et al., 1987*
Lauzurica et al., 1989*
First period
Second period
Abraham et al., 1989
Madrid Study, 1992
* Case-control studies.
Acute Renal Failure in Hospitalized Patients

(per 1000 admissions)
49.0
19.0
16.0
6.5
1.3
1.5
Mortality, %
80
70
60
50
40
30
20
10
0
*
All cases
ICUs
Medical
Surgical
*P<0.001 respect to all cases
Nephrol
two reasons: 1) polytrauma patients are now treated in the ICU

and 2) early and effective treatments applied today to trauma
patients at the accident scene, and quick transfer to hospital, have
decreased this cause of ARF. B, Mortality was greater for patients
initially treated in the ICU and lower in the nephrology setting
than rates observed in other departments. These figures were
obtained from 748 ARF patients admitted to 13 different adult
hospitals. (Data from Liao et al. [1].)
FIGURE 8-20
Epidemiologic variable. The incidence of hospital-acquired acute
renal failure (ARF) depends on what epidemiologic method is used.
In case-control studies the incidence varied between 49 and 19 per
thousand. When the real occurrence was measured in large populations over longer intervals, the incidence of hospital-acquired ARF
decreased to 1.5 per thousand admissions. (Data from
[1,5,16,17,18].)
8.9
Prognosis
HISTORICAL PERSPECTIVE OF MEDICAL PROGNOSIS APPLIED IN ACUTE RENAL FAILURE
Criteria
Derivation
Applications
Advantages
Drawbacks
Classical
Doctors experience
Individual prognosis
Easy
Traditional
Present
Univariate statistical analysis

Multivariate statistical analysis
Computing facilities
Risk stratification
Risk stratification
Individual prognosis?
Future
Multivariate analysis
Computing facilities
Risk stratification
Individual prognosis
Patients quality of life evaluation
Functional prediction
Easy
Measurable
Theoretically, all factors influencing outcome
are considered
Measurable
All factors considered
Doctors inexperience
Unmeasurable
Only one determinant of prognosis is considered
Complexity (variable, depending on model)
FIGURE 8-21
Estimating prognosis. The criteria for estimating prognosis in
acute renal failure can be classified into four periods. The
Classical or heuristic way is similar to that used since the
Hippocratic aphorisms. The Traditional one based on simple
statistical procedures, is not useful for individual prognosis. The
Present form is more or less complex, depending on what method
is used, and it is possible, thanks to computing facilities and the
Renal insult
Ideally, none
development of multivariable analysis. Theoretically, few of these

methods can give an individual prognosis [19]. They have not
been used for triage. The next step will need a great deal of
work to design and implement adequate tools to stratify risks
and individual prognosis. In addition, the estimate of residual
renal function and survivors quality of life, mainly for older
people, are future challenges.
100
Cumulative trend
Mean
ARF
Outcome
Mortality, %
80
60
40
20
0
Prognosis
FIGURE 8-22
Ideally, prognosis should be established as the problem, the episode
of acute renal failure (ARF), starts. Correct prognostic estimation
gives the real outcome for a patient or group of patients as precisely
as possible. In this ideal scenario, this fact is illustrated by giving
the same surface area for the concepts of outcome and prognosis.
11
10 2 3 3 1
1951 55
34
60
11
16
57
65
20
13
11 131110
10 8 Number
9
6 55 478 6
5 64
5
of
3
2
publications
70
Year
75
80
85
1990
FIGURE 8-23
Mortality trends in acute renal failure (ARF). This figure shows the
evolution of mortality during a 40-year period, starting in 1951. The
graphic was elaborated after reviewing the outcome of 32,996 ARF
patients reported in 258 published papers. As can be appreciated,
mortality rate increases slowly but constantly during this follow-up,
despite theoretically better availability of therapeutic armamentarium
(mainly antibiotics and vasoactive drugs), deeper knowledge of dialysis techniques, and wider access to intensive care facilities. This
improvement in supporting measures allows the physician to keep
alive, for longer periods of time patients who otherwise would have
died. A complementary explanation could be that the patients treated now are usually older, sicker, and more likely to be treated more
aggressively. (From Kierdorf et al. [20]; with permission.)
8.10
Acute Renal Failure
Prognostic
systems used
in ARF
Specific
ARF
methods
ICU
methods
Apache
system
APACHE II
SAPS
APACHE III
SAPS I
OSF
MPM
MPM I
SAPS II
MPM II
OSF
MODS
Liano
SOFA
Rasmussen
Lohr
Schaefer
Brivet
Sensitivity, %
FIGURE 8-24
Ways of estimating prognosis in acute renal failure (ARF). This can be
done using either general intensive care unit (ICU) score systems or
methods developed specifically for ARF patients. ICU systems include
Acute Physiological and Chronic Health Evaluation (APACHE)
[21,22], Simplified Physiologic Score (SAPS)[23,24], Mortality
Prediction Model (MPM) [25,26], and Organ System Failure scores
(OSF) [27]. Multiple Organ Dysfunction Score (MODS) [28] and
100
100
80
80
60
60
APACHE II
APACHE III
SAPS
SAPS-R
SAPS-E
SS
MPM
40
20
40
Rasmussen
Liao
Lohr
Schaefer
20
0
0
Sepsis-Related Organ Failure Assessment Score (SOFA) [29] are those

that seem most suitable for this purpose. APACHE II used to be most
used. Other systems (white boxes) have been used in ARF.
On the other hand, at least 17 specific ARF prognostic methods
have been developed [20,30]. The figure shows only those that
have been used after their publication [31], plus one recently published system which is not yet in general use [2].
20
40
60
1- Specificity, %
80
100
20
40
60
80
1- Specificity, %
100
FIGURE 8-25
Comparison of prognostic methods for acute renal failure (ARF) by ROC curve analysis [31]. A method is better when its ROC-curve moves to the upper left square determined by the sensitivity and the reciprocal of the specificity. A, ROC curves of seven
prognostic methods usually employed in

the ICU setting. The best curve comes
from the APACHE III method, which has
an area under the ROC curve of 0.74
0.04 (SE). B, Four ROC curves
corresponding to prognostic methods
specifically developed for ARF patients
are depicted. The best curve in this panel
comes from the Liao method for ARF
prognosis. Its area under the curve is
0.78 0.03 (SE). APACHEAcute
Physiology and Chronic Health
Evaluation, (II second version [21]; III
third version [22]); SAPSSimplified
Acute Physiology Score [23]; SAPS-R
SAPS-reduced [33]; SAPS-ESAPSExtended [32]; SSSickness Score [33];
MPMMortality Prediction Model [25];
ROC curveReceiving Operating
Characteristic curve; SEStandard
Error. (From Douma [31];
with permission.)
8.11
Hypotension
Catabolism
Hemolysis
Hepatic disease
Kind of surgery
Hyperkalemia
Need for dialysis
Assisted respiration
Site of war injuries
Disseminated intravascular coagulopathy
Pancreatitis
Antibiotics
Timing of treatment
FIGURE 8-26
Individual factors that have been associated with acute renal failure
(ARF) outcome. Most of these innumerable variables have been
related to an adverse outcome, whereas few (nephrotoxicity as a
cause of ARF and early treatment) have been associated with more
favorable prognosis. For a deep review of variables studied with
univariate statistical analysis [34, 35]. NSAIDnonsteroidal antiinflammatory drugs; BUNblood urea nitrogen.
40
20
0
100
40
Survivors
10
15
20 25 30 35 40
Days of ARF evolution
80
Persistent hypotension
69
60
P<0.001
40
33
100
20
20
60
Mortality, %
Assisted repiration
80
60
P<0.001
40
32
Yes
Jaundice
100
80
80
No
67
60
P<0.001
40
40
20
No
Oliguria
100
Mortality, %
Co
ma
n
A
res ssis
pir ted
ati
on
Jau
nd
ice
co No
nsc rm
iou al
sne
ss
Sed
ati
on
ten
sio
ria
Hy
po
igu
55
0
Yes
Ol
50
20
0
0
FIGURE 8-28
Precipitating condition of acute renal failure (ARF). The initial
clinical condition observed in ARF patients is shown. Oliguria:
urine output of less than 400 mL per day; hypotension: systolic
blood pressure lower than 100 mm Hg for at least 10 hours per
day independent of the use of vasoactive drugs; jaundice: serum
bilirubin level higher than 2 mg/dL; coma: Glasgow coma score of
5 or less. The presence of these factors is associated with poorer
outcome (see Fig. 8-29). (Data from Liao et al. [1].)
45
FIGURE 8-27
Duration and resolution of acute renal failure (ARF). Most of the
episodes of ARF resolved in the first month of evolution. Mean
duration of ARF was 14 days. Seventy-eight percent of the patients
with ARF who died did so within 2 weeks after the renal insult.
Similarly, 60% of survivors had recovered renal function at that time.
After 30 days, 90% of the patients had had a final resolution of the
ARF episode, one way or the other. Patients who finally lost renal
function and needed to be included in a chronic periodic dialysis
program usually had severe forms of glomerulonephritis, vasculitis,
or systemic disease. (From Liao et al. [1]; with permission.)
Mortality, %
ARF patients, %
60
80
60
8 patients to
chronic
hemodialysis
Nonsurvivors
80
Mortality, %
Age
Jaundice
Sepsis
Burns
Trauma
NSAIDs
BUN increments
Coma
Oliguria
Obstetric origin
Malignancies
Cardiovascular disease
X-ray contrast agents
Acidosis
Cumulative frequencies of resolved cases, %
100
ACUTE RENAL FAILURE: VARIABLES

STUDIED WITH UNIVARIATE ANALYSIS
80
60
52
40
P<0.02
36
20
0
Yes
No
Yes
No
FIGURE 8-29
Mortality associated with the presence or absence of oliguria, persistent hypotension, assisted respiration and jaundice (as defined in
Fig. 8-28). The presence of an unfavorable factor was significantly
associated with higher mortality. (Data from Liao et al. [1].)
8.12
Acute Renal Failure
100
77
80
Mortality rate, %
FIGURE 8-30
Consciousness level and mortality. Coma patients had a Glasgow
coma score of 5 or lower. Sedation refers to the use of this kind of
treatment, primarily in patients with assisted respiration. Both situations are associated with significantly higher mortality (P<0.001)
than that observed in either patients with a normal consciousness
level or the total population. (Data from Liao et al. [1].)
92
60
45
40
30
20
0
Normal
Sedation
Coma
All cases
Original
disease
3
Previous health
condition
Kind and severity

of kidney insult
SIR
Depending on 2 and 3
No
SIR
S
Isolated
ARF
ARF in a MODS
complex
Death
Recovery
Depending on:
*2,3, & 1
*No. of failing organs
*Recovery process
Recovery
FIGURE 8-31
Outcome of acute renal failure (ARF). Two groups of factors play
a role on ARF outcome. The first includes factors that affect the
patient: 1) previous health condition; 2) initial diseaseusually,
the direct or indirect (eg, treatments) cause of kidney failure; 3)
the kind and severity of kidney injury. While 1 is a conditioning
element, 2 and 3 trigger the second group of factors: the response
of the patient to the insult. If this response includes a systemic
inflammatory response syndrome (SIRS) like that usually seen in
intensive care patients (eg, sepsis, pancreatitis, burns), a multiple
organ dysfunction syndrome (MODS) frequently appears and
consequently outcome is associated with a higher fatality rate
(thick line). On the contrary, if SIRS does not develop and isolated
ARF predominates, death (thin line, right) is less frequent than
survival (thick line).
FIGURE 8-32
Individual severity index (ISI). The ISI was published in its second
version in 1993 [36]. The ISI estimates the probability of death.
Nephrotoxic indicates an ARF of that origin; the other variables
have been defined in preceding figures. The numbers preceding
these keys denote the contribution of each one to the prognosis
and are the factor for multiplying the clinical variables; 0.210 is
the equation constant. Each clinical variable takes a value of 1 or
0, depending, respectively, on its presence or absence (with the
exception of the age, which takes the value of the patients decade).
The parameters are recorded when the nephrologist sees the patient
the first time. Calculation is easy: only a card with the equation
values, a pen, and paper are necessary. A real example is given.
INDIVIDUAL SEVERITY INDEX

ISI=0.032 (age-decade) 0.086 (male) 0.109 (nephrotoxic) 0.109 (oliguria)
0.116 (hypotension) 0.122 (jaundice) 0.150 (coma) 0.154 (consciousness)
0.182 (assisted respiration) 0.210
Case example
A 55-year-old man was seen because of oliguria following pancreatic surgery. At
that moment he was hypotensive and connected to a respirator, and jaundice
was evident. He was diagnosed with acute tubular necrosis. His ISI was calculated
as follows:
ISI=0.032(6) 0.086 0.109 0.116 0.122 0.182 0.210 = 0.845
Acute GN
ATN
66
No recovery
11
11
31
31
Partial recovery
32
32
24
No recovery
47
35
Partial recovery
63
63
Total recovery
1 yr
5 yr
25
29
5 yr
HUS/ACN
8
25
63
75
Total recovery
1 yr
Acute TIN
No recovery
Partial recovery
24
57
57
41
No recovery
91
Total recovery
5 yr
Dead
174
FIGURE 8-33
Outcome of acute renal failure (ARF). Long-term outcome of ARF
has been studied only in some series of intrinsic or parenchymatous
ARF. The figure shows the different long-term prognoses for intrinsic ARF of various causes. Left, The percentages of recovery rate of
renal function 1 year after the acute episode of renal failure. Right,
The situation of renal function 5 years after the ARF episode.
Acute tubulointerstitial nephritis (TIN) carries the better prognosis:
the vast majority of patients had recovered renal function after 1
and 5 years. Two thirds of the patients with acute tubule necrosis
(ATN) recovered normal renal function, 31% showed partial
recovery, and 6% experienced no functional recovery. Some
patients with ATN lost renal function over the years. Patients with
ARF due to glomerular lesions have a poorer prognosis; 24% at 1
year and 47% at 5 years show terminal renal failure. The poorest
evolution is observed with severe forms of acute cortical necrosis
or hemolytic-uremic syndrome. GNglomerulonephritis; HUS
hemolytic-uremic syndrome; ACNacute cortical necrosis.
(Data from Bonomini et al. [37].)
67
27
1 yr
8.13
Partial recovery
1 yr
Dead
113
Dead
50
Alive
225
Alive
143
Alive
53
< 65 yr
(n = 399)
6579 yr
(n = 256)
> 80 yr
(n = 103)
9
5 yr
FIGURE 8-34
Age as a prognostic factor in acute renal failure (ARF). There is a
tendency to treat elders with ARF less aggressively because of the
presumed worse outcomes; however, prognosis may be similar to
that found in the younger population. In the multicenter prospective longitudinal study in Madrid, relative risk for mortality in
patients older than 80 years was not significantly different (1.09 as
compared with 1 for the group younger than 65 years). Age probably is not a poor prognostic sign, and outcome seems to be within
acceptable limits for elderly patients with ARF. Dialysis should not
be withheld from patients purely because of their age.
8.14
Acute Renal Failure
VARIABLES ASSOCIATED WITH PROGNOSIS:

MULTIVARIATE ANALYSIS (16 STUDIES)
PROGNOSIS IN ACUTE RENAL FAILURE

19601969
Assisted respiration
Hypotension or inotropic support
Age
Cardiac failure/complications
Jaundice
Diuresis volume
Coma
Male sex
Sepsis
Chronic disease
Neoplastic disease
Other organ failures
Serum creatinine
Other conditions
Summary
Clinical variables
Laboratory variables
11
10
8
6
6
5
5
4
3
3
2
2
2
12
No.
Mortality (%)
Mean age (y)
Median APACHE II score
Range
119
51
50.9
32
(2245)
19801989
124
63
63
35
(2549)
NS
< 0.0001
< 0.0001
FIGURE 8-36
Prognosis in acute renal failure (ARF). This figure shows the utility
of a prognostic system for evaluating the severity of ARF over
time, using the experience of Turney [38]. He compared the age,
mortality, and APACHE II score of ARF patients treated at one
hospital between 1960 and 1969 and 1980 and 1989. In the latter
period there were significant increases in both the severity of the
illness as measured by APACHE II and age. Although there was a
tendency to a higher mortality rate in the second period, this
tendency was not great enough to be statistically significant.
20
6
FIGURE 8-35
Outcome of acute renal failure (ARF). A great number of variables
have been associated with outcome in ARF by multivariate analysis. This figure gives the frequency with which these variables
appear in 16 ARF studies performed with multivariable analysis
(all cited in [30]).
70
68
Time
60
Mortality, %
50
42
40
30
20
10
22 6
Apache II score
Admission in ICU
Before dialysis
24 h after dialysis
48 h after dialysis
Nonsurvivors
24
22
25
24
Survivors
22
22
22
22
22 6
Dialysis patients
Nondialysis patients
FIGURE 8-37
APACHE score. The APACHE II score is not a good method for
estimating prognosis in acute renal failure (ARF) patients. A,
Data from Verde and coworkers show how mortality was higher
in their ICU patients with ARF needing dialysis than in those
without need of dialysis, despite the fact that the APACHE II
score before dialysis was equal in both groups [39]. B, Similar
data were observed by Schaefers group [40], who found that the
median APACHE II score was similar in both the surviving or

nonsurviving ARF patients treated in an intensive care unit.
Recently Brivet and associates have found that APACHE II score
influences ARF prognosis when included as a factor in a more
complex logistic equation [2]. Although not useful for prognostic
estimations, APACHE II score has been used in ARF for risk
stratification.
Mortality, %
Severity index
P<0.001
0.8
P<0.001
66
0.57
0.6
60
40
33
0.35
0.4
Severity index
80
0.2
20
Dialysis
No dialysis
200
Number of cases
FIGURE 8-38
Analysis of the severity and mortality in acute renal failure (ARF)
patients needing dialysis. This figure is an example of the uses of a
severity index for analyzing the effect of treatment on the outcome
of ARF. Looking at the mortality rate, it is clear that it is higher in
patients who need dialysis than in those who do not. It could lead
to the sophism that dialysis is not a good treatment; however, it is
also clear that the severity index score for ARF was higher in
patients who needed dialysis. Severity index is the mean of the
individual severity index of each of the patients in each group [36].
150
100
50
Ot
he
r
US
ICT
C
DI
Inf
ec t
ion
Re
spi
r
dis ato
eas ry
Ca
e
rdi
ac
dis
eas
Ga
e
str
o
ble inte
ed sti
ing na
l
Sh
oc
k
Or
igin
al d
ise
a se
8.15
FIGURE 8-39
Causes of death. The causes of death from acute renal failure
(ARF) were analyzed in 337 patients in the Madrid ARF Study [1].
In this work all the potential causes of death were recorded; thus,
more than one cause could be present in a given patient. In fact,
each dead patient averaged two causes, suggesting multifactorial
origin. This could be the expression of a high presence of multiple
organ dysfunction syndrome (MODS) among the nonsurviving
patients. The main cause of death was the original disease, which
was present in 55% of nonsurviving patients. Infection and shock
were the next most common causes of death, usually concurrent in
septic patients. It is worth noting that, if we exclude from the
mortality analysis patients who died as a result of the original
disease, the corrected mortality due to the ARF episode itself
and its complications, drops to 27%. GIgastrointestinal;
DICdisseminated intravascular coagulation.
References
1. Liao F, Pascual J the Madrid ARF Study Group: Epidemiology of
acute renal failure: A prospective, multicenter, community-based
study. Kidney Int 1996, 50:811818.
2. Brivet FG, Kleinknecht DJ, Loirat P, et al.: Acute renal failure in intensive care unitscauses, outcome and prognostic factors of hospital
mortality: A prospective, multicenter study. Crit Care Med 1995,
24:192197.
3. Pascual J, Liao F, the Madrid ARF Study Group: Causes and prognosis of acute renal failure in the very old. J Am Geriatr Soc 1998,
46:15.
4. Eliahou HE, Modan B, Leslau V, et al.: Acute renal failure in the community: An epidemiological study. Acute Renal Failure Conference,
Proceedings. New York 1973.
5. Abraham G, Gupta RK, Senthilselvan A, et al.: Cause and prognosis
of acute renal failure in Kuwait: A 2-year prospective study. J Trop
Med Hyg 1989, 92:325329.
6. McGregor E, Brown I, Campbell H, et al.: Acute renal failure. A
prospective study on incidence and outcome (Abstract). XXIX
Congress of EDTA-ERA, Paris, 1992, p 54.
7. Sanchez Rodrguez L, Martn Escobar E, Lozano L, et al.: Aspectos
epidemiolgicos del fracaso renal agudo en el rea sanitaria de
Cuenca. Nefrologa 1992, 12(Suppl 4):8791.
8. Feest TG, Round A, Hamad S: Incidence of severe acute renal failure
in adults: Results of a community based study. Br Med J 1993,
306:481483.
9. Lunding M, Steiness I, Thaysen JH: Acute renal failure due to tubular

necrosis. Immediate prognosis and complications. Acta Med Scand
1964, 176:103119.
10. Lachhein L, Kielstein R, Sauer K, et al.: Evaluation of 433 cases of
acute renal failure. Proc EDTA 1978, 14:628629.
11. Wing AJ, Broyer M, Brunner FP, et al.: Combined report on regular
dialysis and transplantation in Europe XIII-1982. Proc EDTA 1983,
20:578.
12. Gerrard JM, Catto GRD, Jones MC: Acute renal failure: An iceberg
revisited (Abstract). Nephrol Dial Transplant 1992, 7:458.
13. Kleinknecht D: Epidemiology of acute renal failure in France today.
In Acute Renal Failure in the Intensive Therapy Unit. Edited by Bihari
D, Neild G. London:Springer-Verlag; 1990:1321.
14. Chugh S, Sakhuja V, Malhotra HS, Pereira BJG: Changing trends in
acute renal failure in Third-World countriesChandigarh study.
Q J Med 1989, 272:11171123.
15. Seedat YK, Nathoo BC: Acute renal failure in blacks and Indians in
South AfricaComparison after 10 years. Nephron 1993,
64:198201.
16. Hou SH, Bushinsky DA, Wish JB, et al.: Hospital-acquired renal
insufficiency: A prospective study. Am J Med 1983, 74:243248.
17. Shusterman N, Strom BL, Murray TG, et al.: Risk factors and outcome of hospital-acquired acute renal failure. Am J Med 1987,
83:6571.
8.16
Acute Renal Failure
18. Lauzurica R, Caralps A: Insuficiencia renal aguda producida en el

hospital: Estudio prospectivo y prevencin de la misma. Med Cln
(Barc) 1989, 92:331334.
29. Vincent JL, Moreno R, Takala J, et al.: The SOFA (sepsis-related

organ failure assessment) score to describe organ dysfunction/failure.
Intensive Care Med 1996, 22:707710.
19. Liao F, Solez K, Kleinknecht D: Scoring the patient with ARF. In

Critical Care Nephrology. Edited by Ronco C, Bellomo R.
Dordrecht:Kluwer Academic; 1998; Section 23.1: 15351545.
30. Liao F, Pascual J: Acute renal failure, critical illness and the artificial
kidney: Can we predict outcome? Blood Purif 1997, 15:346353.
20. Kierdorf H, Sieberth HG: Continuous treatment modalities in acute

renal failure. Nephrol Dial Transplant 1995; 10:20012008.
31. Douma CE, Redekop WK, Van der Meulen JHP, et al.: Predicting
mortality in intensive care patients with acute renal failure treated
with dialysis. J Am Soc Nephrol 1997, 8:111117.
21. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: A
severity of disease classification system. Crit Care Med 1985,
13:818829.
32. Viviand X, Gouvernet J, Granthil C, Francois G: Simplification of the

SAPS by selecting independent variables. Intensive Care Med 1991,
17:164168.
22. Knaus WA, Wagner DP, Draper EA, et al.: The APACHE III prognostic
system: Risk prediction of hospital mortality for critically ill hospitalized
adults. Chest 1991, 100:16191636.
33. Bion JF, Aitchison TC, Edlin SA, Ledingham IM: Sickness scoring and
response to treatment as predictors of outcome from critical illness.
Intensive Care Med 1988, 14:167172.
23. Le Gall JR, Loirat P, Alperovitch A, et al.: A simplified acute physiology

score for ICU patients. Crit Care Med 1984, 12:975977.
34. Chew SL, Lins RL, Daelemans R, De Broe ME: Outcome in acute
renal failure. Nephrol Dial Transplant 1993, 8:101107.
24. Le Gall, Lemeshow S, Saulnier F: A new Simplified Acute Phisiology

Score (SAPS II) based on a European/North American multicenter
study. JAMA 1993, 270:29572963.
25. Lemeshow S, Teres D, Pastides H, et al.: A method for predicting
survival and mortality of ICU patients using objectively derived
weights. Crit Care Med 1985, 13:519525.
26. Lemeshow S, Teres D, Klar J, et al.: Mortality probability models
(MPM II) based on an international cohort of intensive care unit
patients. JAMA 1993, 270:24782486.
35. Liao F: Severity of acute renal failure: The need of measurement.

Nephrol Dial Transplant 1994, 9(Suppl. 4):229238.
36. Liao F, Gallego A, Pascual J, et al.: Prognosis of acute tubular necrosis: An extended prospectively contrasted study. Nephron 1993,
63:2123.
37. Bonomini V, Stefoni S, Vangelista A: Long-term patient and renal
prognosis in acute renal failure. Nephron 1984, 36:169172.
38. Turney JH: Why is mortality persistently high in acute renal failure?
Lancet 1990, 335:971.
27. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: Prognosis in
acute organ-system failure. Ann Surg 1985, 202:685693.
39. Verde E, Ruiz F, Vozmediano MC, et al.: Valor predictivo del

APACHE II en el fracaso renal agudo de las unidades de cuidados
intensivos (Abstract). Nefrologa 1996, 16(Suppl. 19):32.
28. Marshall JC, Cook DJ, Christou NV, et al.: Multiple organ dysfunction
score: A reliable descriptor of a complex clinical outcome. Crit Care
Med 1995, 23:16381652.
40. Schaefer JH, Jochimsen F, Keller F, et al.: Outcome prediction of acute

renal failure in medical intensive care. Intensive Care Med 1991,
17:1924.
Renal Histopathology, Urine

Cytology, and Cytopathology
of Acute Renal Failure
Lorraine C. Racusen
Cynthia C. Nast
auses of acute renal failure can be divided into three categories:

1) prerenal, due to inadequate perfusion; 2) postrenal, due to
obstruction of outflow; and 3) intrinsic, due to injury to renal
parenchyma. Among the latter, diseases of, or injury to, glomeruli,
vessels, interstitium, or tubules may lead to a decrease in glomerular
filtration rate (GFR).
Glomerular diseases that lead to acute renal failure are the proliferative
glomerulonephritides, including postinfectious and membranoproliferative glomerulonephritis secondary to glomerular deposition of
immune complexes. If glomerular injury is severe enough to damage
the glomerular basement membrane, leakage of fibrin and other
plasma proteins stimulates formation of cellular extracapillary
crescents composed of epithelial cells and monocytes and
macrophages. Crescents may form as a result of an inflammatory
reaction to immune complexes formed to nonglomerular antigens;
antibody reaction to intrinsic glomerular antigens, as in antiglomerular
basement membrane disease; and, in the absence of immune
complexes, the pauci-immune processes, which include the small
vessel vasculitides, including Wegeners granulomatosis and microscopic
polyarteritis. Immunohistologic examination and electron microscopy
play important roles in the diagnosis of these processes. Extensive
crescent formation is accompanied by rapidly progressive acute renal
failure. The urine sediment in these diseases often contains red blood
cells and red cell casts.
Vascular diseases (involving veins, arteries, or arterioles and capillaries) can lead to hypoperfusion and acute renal failure. Venous thrombosis, most often due to trauma or a nephrotic state, and arterial thrombosis due to trauma or vasculitis, cause parenchymal ischemia and
CHAPTER
9.2
Acute Renal Failure
infarction. Small vessel vasculitides involve small arteries, arterioles, and glomerular capillaries, causing injury and necrosis in the
glomerular tuft, which may result in crescent formation.
Thrombotic microangiopathies result from endothelial injury
damage in small arteries and arterioles, producing thrombosis,
obstruction to blood flow, and glomerular hypoperfusion. Urine
sediment in these diseases often shows hematuria or cellular casts,
reflecting ischemia.
Interstitial inflammatory processes lead to acute renal failure
via compression of peritubular capillaries or injury to tubules.
Causes of acute interstitial nephritis include infection, and
immune-mediated reactions. With infection, polymorphonuclear leukocytes may be seen in tubules as well as in interstitium. Inflammatory infiltrates in hypersensitivity reactions,
often due to drug exposure, feature eosinophils. Immunohistologic studies may reveal the presence of immune complexes;
immune complex deposition around tubules occurs as a primary
process or associated with immune glomerular injury. Tubulitis

is seen when the inflammatory reaction extends into the tubular epithelium. Epithelial cell injury is often produced by such
inflammatory processes. The urine sediment reveals white
blood cells and white cell casts, which may include numerous
polymorphonuclear leukocytes or eosinophils.
The most common cause of acute renal failure is injury to
tubule epithelium. Primary tubule cell injury typically results
from ischemia, toxic injury, or both. Cell injury results in disruption of the epithelium and its normal reabsorptive functions, and may lead to obstruction of tubule lumens. Cell exfoliation often occurs, and intact cells and cell fragments and
debris can be seen in the urine sediment; these may be in the
form of casts. Necrotic cells may be seen in situ along the
tubule epithelium or in the tubule lumen, but often overt cell
necrosis is not prominent. Apoptosis of tubule cells is seen
after injury as well.
Glomerular Diseases

Early postinfectious glomerulonephritis. Numerous polymorphonuclear leukocytes in glomerular capillary loops contribute to the
hypercellular appearance of the glomerulus. There is also a segmental
increase in mesangial cells (hematoxylin and eosin, original magnification 400). This reactive inflammatory process occurs in response
to glomerular deposition of immune complexes, including the large
subepithelial hump-like deposits which are typical of post-infectious glomerulonephritis. The glomerulonephritis is usually selflimited and reversible, and especially with appropriate treatment of
the underlying infection, long-term prognosis is excellent [1].

A large epithelial crescent fills Bowmans space and compresses the
capillary loops in the glomerular tuft. This silver stain highlights
the glomerular mesangium and the basement membrane of the
glomerular capillaries (silver stain, original magnification 400).
The patient presented with hematuria and acute renal failure.
Immunostains were negative in this case, a finding consistent with
a pauci-immune process. The differential diagnosis includes small
vessel vasculitis, and anti-neutrophil cytoplasmic antibody may
be positive. Crescentic glomerulonephritis may also occur with
anti-glomerular basement membrane antibody disease, or as a
complication of immune complex glomerulonephritis [2].
Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure
9.3

Urine sediment of a patient with acute renal failure revealing red
blood cells and some red blood cell casts (original magnification
600). Biopsy in this case revealed crescentic glomerulonephritis.
However, hematuria may be seen in any proliferative glomerulonephritis or with parenchymal infarcts. The casts assume the
cylindrical shape of the renal tubules, and confirm an intrarenal
source of the blood in the urine. Fragmented or dysmorphic red
blood cells may be seen when the red cells have traversed through
damaged glomerular capillaries.
Vascular Diseases
An early thrombus is seen in a small renal artery in a patient with
patchy cortical infarction (original magnification 250). The
patient presented with acute renal failure. The thrombosis may be
due to a hypercoaggulable state (eg, disseminated intravascular
coaggulation) or endothelial injury (eg, hemolytic uremic syndrome). If the cortical necrosis is patchy, recovery of adequate
renal function may occur [3].

A parenchymal infarct in a patient with renal vein thrombosis (hematoxylin and eosin, original magnification 200). A few surviving
tubules and a rim of inflammatory cells are seen at the periphery of
the infarct. Infarcts may also be seen with arterial thromboses, and
with severe injury to the microvasculature, as occurs in thrombotic
microangiopathies [3]. If the process is extensive, acute cortical
necrosis may occur, often leading to irreversible renal failure.
9.4
Acute Renal Failure
A
A fine-needle aspirate in renal infarction. A, Low magnification shows
many degenerating cells with a dirty background containing cellular
debris and scattered neutrophils. Compare to acute tubular necrosis,
which has only scattered degenerated or necrotic cells without the
extensive necrosis and cell debris. Neutrophils may be numerous if the
B
edge of an infarct is aspirated (May-Grunwald Giemsa, original magnification 40). B, Diffusely degenerated and necrotic cells with condensed and disrupted cytoplasm and pyknotic nuclei, and an adjacent
neutrophil. No significant numbers of viable tubule epithelial cells
remain (May-Grunwald Giemsa, original magnification 160).
A small artery with severe inflammation in a patient with a small
vessel vasculitis. The wall of the vessel is infiltrated by lymphocytes,
plasma cells, and eosinophils (hematoxylin and eosin, original magnification 250). The patient was p-ANCA positive. ANCA may
play a pathogenic role in the vasculitis process [4]. Vasculitis in the
kidney is often part of a systemic syndrome, but may occur as an
apparently renal-limited process.

Microangiopathic changes in a small artery, with endothelial
activation, evidenced by the large endothelial cells with hyperchromatic nuclei and vacuolization. There is intimal edema with some
cell proliferation, and a prominent band of fibrinoid necrosis is
seen; the latter appears dark red-pink on this hematoxylin-eosin
stain, and represents insudation of fibrin and plasma proteins
into the wall of the injured vessel (original magnification 250).
The differential diagnosis includes hemolytic uremic syndrome,
thrombotic thrombocytopenic purpura, malignant hypertension,
scleroderma, and drug toxicity, the latter due most commonly to
mitomycin C or cyclosporine/FK506 [5].
9.5

A cast of necrotic tubular cells in urine sediment (Papanicolaou
stain, original magnification 400). The most likely causes of
damage to the renal tubules with such findings in the urinary
sediment are severe ischemia/infarction, or tubular necrosis due to
exposure to toxins which injure the renal tubules. The latter include
antibiotics, including aminoglycosides and cephalosporins, and
chemotherapeutic agents.
Interstitial Disease

Interstitial nephritis with edema and a mononuclear inflammatory
infiltrate. Eosinophils in the infiltrate suggest a possible hypersensitivity reaction (hematoxylin and eosin, original magnification
400). Drugs are the most common cause of such a reaction, which
often presents with acute renal failure [6]. Inflammatory cells and
cell casts may be seen in the urine sediment in these cases, as
inflammatory cells infiltrate the tubular epithelium.

Tubulitis, with infiltration of mononuclear cells into the tubular
epithelium (hematoxylin and eosin, original magnification 400).
There is a mononuclear infiltrate and edema in the surrounding
interstitium. Tubule cells may show evidence of lethal or sublethal
injury as the inflammatory cells release damaging enzymes. Tubulitis
is often seen in interstitial nephritis especially if the targets of the
inflammatory reaction are tubular cell antigens or antigens deposited
around the tubules. Immunofluorescence may reveal granular or linear deposits of immunoglobulin and complement around the tubules.
9.6
Acute Renal Failure

Polymorphonuclear leukocytes forming a cast in a cortical tubule
(hematoxylin and eosin, original magnification 400). Note edema
and inflammation in adjacent interstitium. These intratubular cells
are highly suggestive of acute infection, and may be seen in distal as
well as proximal nephron as part of an ascending infection. Intratubular PML may also be seen in vasculitis and other necrotizing
glomerular processes, in which these cells escape across damaged
areas of the inflamed glomerular tuft.
A
Fine-needle aspirate of acute infectious interstitial nephritis (acute
pyelonephritis). A 25-gauge needle attached to a 10-cc syringe was
utilized to withdraw the aspirate into 4 cc of RPMI-based medium. The specimen was then cytocentrifuged and stained with
May-Grunwald Giemsa. A, The renal aspirate contains large
numbers of intrarenal neutrophils, which are focally undergoing
degenerative changes with cytoplasmic vacuolization and nuclear
B
breakdown. In bacterial infection there are many infiltrating neutrophils and there may be associated necrosis of tubule epithelial
cells (original magnification 80). B, A neutrophil contains
phagocytosed bacteria within the cytoplasm; bacteria stain with
Giemsa, so are readily detectable in this setting. Adjacent tubule
epithelial cells have cytoplasmic granules but do not phagocytize
bacteria (original magnification 160).
Numerous polymorphonuclear leukocytes (PML) in the urine sediment
of a patient with acute pyelonephritis (hematoxylin and eosin, original
magnification 400). Some red blood cells and tubular cells are seen
in the background of this cytospin preparation. PML may be found in
the urine with acute infection of the lower urinary tract as well, or as a
contaminant from vaginal secretions in females. PML casts, on the
other hand, are evidence that the cells are from the kidney.
A
Fine-needle aspirate from patient with intrarenal cytomegalovirus
(CMV) infection. A, There are activated and transformed lymphocytes with immature nuclear chromatin and abundant blue cytoplasm that infiltrate the kidney in response to the infection; large
granular lymphocytes (NK cells) may be seen as well, but few neutrophils. Similar activated lymphocytes, NK cells, and atypical
monocytes can be observed within the peripheral blood. The tubule
epithelial cells are virtually never seen to contain CMV inclusions in
aspirate material, in contrast to core biopsy specimens. All intrarenal
9.7
B
viral infections have a similar appearance, and immunostaining or in
situ hybridization is required to identify specific viruses (MayGrunwald Giemsa, original magnification 80). B, Tubular epithelial cells stained with antibody to CMV immediate and early nuclear
proteins in active intrarenal CMV infection. With an immunoalkaline phosphatase method, cytoplasmic and prominent nuclear staining for these early proteins are observed in the tubular epithelium. In
very early infection, neutrophils also may have cytoplasmic staining
for these proteins (original magnification 240).
Numerous eosinophils in an interstitial inflammatory infiltrate.
Eosinophils may be diffuse within the infiltrate, but may also be
clustered, forming eosinophilic abscesses, as in this area (hematoxylin and eosin, original magnification 400). Eosinophils may
also be demonstrated in the urine sediment. Drugs most commonly
producing acute interstitial nephritis as part of a hypersensitivity
reaction include: penicillins, sulfonamides, and nonsteroidal antiinflammatory drugs [6]. The patient had recently undergone a course
of therapy with methicillin. The interstitial nephritis may be part of a
systemic reaction which includes fever, rash, and eosinophilia.
9.8
Acute Renal Failure
A
Fine-needle aspirate of acute allergic interstitial nephritis. A, The
aspirate contains numerous lymphocytes, occasional activated
lymphocytes, and eosinophils without fully transformed lymphocytes,
corresponding to the inflammatory component within the tubulointerstitium observed on routine renal biopsy. Monocytes often are
B
present (May-Grunwald Giemsa, original magnification 80).
B, Higher magnification showing the typical infiltrating cells,
including a monocyte, activated lymphocyte, and an eosinophil.
A neutrophil is present, likely owing to blood contamination
(May-Grunwald Giemsa, original magnification 160).
Tubular Diseases

Severe vacuolization of tubular cells in injured tubular epithelium
(hematoxylin and eosin, original magnification 400). The vacuoles
reflect cell injury and derangement of homeostatic mechanisms that
maintain the normal intracellular milieu. In this case, the vacuoles
developed on exposure to intravenous immunoglobulin in a sucrose
vehicle; the morphology is reminiscent of the severe changes produced by osmotic agents. While generally a nonspecific marker of
cell injury, a distinctive pattern of isometric vacuolization, in
which there are numerous intracellular vacuoles of uniform size
(not shown here) is very typical of cyclosporine/FK506 effect [6].

Necrotic tubular cells and cell debris in tubular lumina. One tubule
shows extensive cell loss, with tubular epithelium lined only by a very
flattened layer of cytoplasm. The dilated lumen contains numerous
necrotic tubular cells with pyknotic nuclei. Several tubules contain cell
debris and one contains red blood cells (hematoxylin and eosin, original magnification 250). Such changes are more often seen with
toxic than with ischemic injury [6], unless the latter is very severe.

This micrograph shows sites of cell exfoliation, attenuation of
remaining cells, and reactive and regenerative changes (hematoxylin and eosin, original magnification 400). Exfoliation
occurs with disruption of cell-cell and cell-substrate adhesion, and
may involve viable as well as non-viable cells [7]. Reactive and
regenerative changes may include basophilia of cell cytoplasm,
increased nuclear:cytoplasmic ratio, heterogeneity of nuclear size
and appearance, hyperchromatic nuclei and mitotic figures.
A
Fine-needle aspirate showing acute tubular cell injury and necrosis.
A, The aspirate shows scattered tubular epithelial cells with swelling
and focal degenerative changes, and a minimal associated inflammatory infiltrate. There is no significant background cell debris (MayGrunwald Giemsa, original magnification 40). B, One tubular
cell is degenerated with reduction in cell size, condensed gray-blue
9.9

Outer medulla shows in situ cell necrosis and loss in medullary thick
ascending limb (hematoxylin and eosin, original magnification
250). Tubules contain cells and cell debris. Changes reflect
ischemic injury. Impaction of cells and cast material may lead to
tubular obstruction, especially in narrow regions of the nephron.
Adhesion molecules on the surface of exfoliated cells may contribute
to aggregation of cells within the tubule and adhesion of detached
cells to in situ tubular cells [8].
B
cytoplasm, and a pyknotic nucleus. Another cell has more advanced
necrosis with additional cytoplasmic disruption and a very small
pyknotic nucleus. Compare the adjacent swollen damaged tubular
cell which has not yet undergone necrosis (May-Grunwald Giemsa,
original magnification 160).
9.10
Acute Renal Failure

Urine sediment from a patient with acute tubular injury showing
tubular cells and cell casts (Papanicolaou stain, original magnification 250). Many of these cells are morphologically intact, even
by electron microscopy. Studies have shown that a significant
percentage of the cells shed into the urine may exclude vital dyes,
and may even grow when placed in culture, indicating that they
remain viable. Such cells clearly detached from tubular basement
membrane as a manifestation of sub-lethal injury [7].
A
Myoglobin casts in the tubules of a patient who abused cocaine. A,
Hematoxylin and eosin stained casts have a dark red, coarsely granular appearance (original magnification 250). B, Immunoperoxidase stain for myoglobin confirms positive staining in the casts
B
(original magnification 250). These casts may obstruct the
nephron, especially with dehydration and low tubular fluid flow
rates. Rhabdomyolysis with formation of intrarenal myoglobin casts
may also occur with severe trauma, crush injury, or extreme exercise.
9.11

Apoptosis of tubular cells following tubular cell injury. Note the
shrunken cells with condensed nuclei and cytoplasm in the central
tubule. The patient had presumed ischemic injury (hematoxylin and
eosin, original magnification 400). The role of apoptosis in injury
to the renal tubule remains to be defined. The process may be difficult to quantitate, since apoptotic cells may rapidly disintegrate. In
experimental models, the degree of apoptosis versus coaggulative
necrosis occurring following injury is related to the severity and
duration of injury, with milder injury showing more apoptosis [9].
Disintegrating
fragments
Shrunken cell with
peripheral condensed nuclear
chromatin and intact
organelles
Phagocytosed
apoptic cell
fragments
FIGURE 9-26
Apoptosis-schematic of histologic changes in tubular epithelium.
The process begins with condensation of the cytoplasm and of the
nucleus, a process which involves endonucleases, which digest the
DNA into ladder-like fragments characteristic of this process. The
cell disintegrates into discrete membrane-bound fragments, so-called
apoptotic bodies. These fragments may be rapidly extruded into
the tubular lumen or phagocytosed by neighboring epithelial cells
or inflammatory cells. (Modified from Arends, et al. [10];
with permission.)
9.12
Acute Renal Failure
Ischemia
Vascular endothelial
injury
Altered
permeability
Toxins
Inflammatory
infiltrate
Tubular cell injury
Sublethal
Upregulation of
adhesion molecules
Interstitial
edema
Tubular cell
swelling
Compression of
peritubular capillaries
Loss of surface area

and cell polarity
Apoptosis
Altered adhesion
Lethal
Changes of repair
and regeneration
Increased epithelial
permeability
Loss of tubular
integrity
Exfoliation
Loss of normal
transport function
Vacuolization
of smooth
muscle
cells
Arteriolar
vasoconstriction
Impaction in the
tubules
Loss of
distal flow
Glomerular
collapse
"Backleak" of
filtrate
Increased renal
vascular
resistance
Aggregation of
erythrocytes,fibrin
and/or leukocytes
in peritubular
capillaries
In situ
necrosis
Obstruction
Cast formation
Increased
intratubular
pressure
Tubular dilatation
Decrease in glomerular
filtration rate
Reduced renal
blood flow
FIGURE 9-27
A schematic showing the relationship between morphologic and
functional changes with injury to the renal tubule due to ischemia
or nephrotoxins. Morphologic changes are shown in italics.
Histology reflects the altered hemodynamics, epithelial derangements, and obstruction which contribute to loss of renal function.
(Modified from Racusen [11]; with permission.)
References
1.
2.
3.
4.
5.
6.
Popovic-Rolovic M, Kostic M, Antic-Peco A, et al.: Medium and

long-term prognosis of patients with acute post-streptococcal
glomerulonephritis. Nephron 1991, 58:393399.
Jennette JC: Crescentic glomerulonephritis. In Heptinstalls Pathology
of the Kidney, edn. 5. Edited by Jennette JC, JL Olson, M Schwarz,
FG Silva. New York:Lippincott-Raven, 1998.
Racusen LC, Solez K: Renal cortical necrosis, infarction and
atheroembolic disease. In Renal Pathology. Edited by Tisher C,
B Brenner. Philadelphia:Lippincott-Raven, 1993:811.
Evert BH, Jennette JC, Falk RJ: The pathogenic role of antineutrophil
cytoplasmic autoantibodies. Am J Kidney Dis 1991, 8:188195.
Remuzzi G, Ruggenenti P: The hemolytic uremic syndrome. Kidney
Int 1995, 47:219.
Nadasdy T, Racusen LC: Renal injury caused by therapeutic and
diagnostic agents, and abuse of analgesics and narcotics. In Heptinstalls
Pathology of the Kidney, edn. 5. Edited by Jennette JC, JL Olson,
MM Schwartz, FG Silva. New York:Lippincott-Raven, 1998.
7. Racusen LC, Fivush BA, Li Y-L, et al.: Dissociation of tubular

detachment and tubular cell death in clinical and experimental
acute tubular necrosis. Lab Invest 1991, 64:546556.
8. Goligorsky MS, Lieberthal W, Racusen L, Simon EE: Integrin receptors in renal tubular epithelium: New insights into pathophysiology
of acute renal failure. Am J Physiol 1993, 264:F1F8.
9. Schumer KM, Olsson CA, Wise GJ, Buttyan R: Morphologic,
biochemical and molecular evidence of apoptosis during the
reperfusion phase after brief periods of renal ischemia.
Am J Pathol 1992, 140:831838.
10. Arends MJ, Wyllie AH: Apoptosis: Mechanisms and role in
pathology. Int Rev Exp Pathol 1991, 32:225254.
11. Racusen LC: Pathology of acute renal failure: Structure/function
correlations. Advances in Renal Replacement Therapy, 1997
4(Suppl. 2): 316.
Acute Renal Failure in

the Transplanted Kidney
Kim Solez
Lorraine C. Racusen
cute renal failure (ARF) in the transplanted kidney represents a

high-stakes area of nephrology and of transplantation practice.
A correct diagnosis can lead to rapid return of renal function;
an incorrect diagnosis can lead to loss of the graft and severe sequelae
for the patient. The diagnostic possibilities are many (Fig. 10-1) and
treatments quite different, although the clinical presentations of newonset functional renal impairment and of persistent nonfunctioning
after transplant may be identical.
In transplant-related ARF percutaneous kidney allograft biopsy
is crucial in differentiating such diverse entities as acute rejection
(Figs. 10-2 to 10-9), acute tubular necrosis (Figs. 10-10 to 10-14),
cyclosporine toxicity (Figs. 10-15 and 10-16), posttransplant lymphoproliferative disorder (Fig. 10-17), and other, rarer, conditions.
In the case of acute rejection, standardization of transplant biopsy
interpretation and reporting is necessary to guide therapy and to establish an objective endpoint for clinical trials of new immunosuppressive
agents. The Banff Classification of Renal Allograft Pathology [1] is an
internationally accepted standard for the assessment of renal allograft
biopsies sponsored by the International Society of Nephrology
Commission of Acute Renal Failure. The classification had its origins in
a meeting held in Banff, Alberta, in the Canadian Rockies, in August,
1991, where subsequent meetings have been held every 2 years. Hot
topics likely to influence the Banff Classification of Renal Allograft
Pathology in 1999 and beyond are shown in Figs. 10-17 to 10-19.
CHAPTER
10
10.2
Acute Renal Failure
Acute Rejection
FIGURE 10-1
Diagnostic possibilities in transplant-related acute renal failure.
DIAGNOSTIC POSSIBILITIES IN TRANSPLANTRELATED ACUTE RENAL FAILURE
M
ild
i m
(w ntim od
it a er
of h an l ar ate,
tu y ter se
bu de it ve
lit gr is re
is) ee
M
tu ode
bu ra
lit te
is
re
ve itis
Se bul
tu
None
Borderline
M
ild
tu
bu
lit
is
Lesions-tubulitis, intimal arteritis
1. Acute (cell-mediated) rejection

2. Delayed-appearing antibody-mediated rejection
3. Acute tubular necrosis
4. Cyclosporine or FK506 toxicity
5. Urine leak
6. Obstruction
7. Viral infection
8. Post-transplant lymphoproliferative disorder
9. Vascular thrombosis
10. Prerenal azotemia
Mild
Moderate
Severe
Rejection
FIGURE 10-2
Diagnosis of rejection in the Banff classification makes use of two
basic lesions, tubulitis and intimal arteritis. The 19931995 Banff
classification depicted in this figure is the standard in use in virtually
all current clinical trials and in many individual transplant units. In
this construct, rejection is regarded as a continuum of mild, moderate,
and severe forms. The 1997 Banff classification is similar, having the
same threshold for rejection diagnosis, but it recognizes three different
histologic types of acute rejection: tubulointersititial, vascular, and
transmural. The quotation marks emphasize the possible overlap of
features of the various types (eg, the finding of tubulitis should not
dissuade the pathologist from conducting a thorough search for
intimal arteritis).
No tubulitis
FIGURE 10-3
Tubulitis is not absolutely specific for acute rejection. It can be
found in mild forms in acute tubular necrosis, normally functioning
kidneys, and in cyclosporine toxicity and in conditions not related
to rejection. Therefore, quantitation is necessary. The number of
lymphocytes situated between and beneath tubular epithelial cells is
compared with the number of tubular cells to determine the severity
of tubulitis. Four lymphocytes per most inflamed tubule cross section or per ten tubular cells is required to reach the threshold for
diagnosing rejection. In this figure, the two tubule cross sections in
the center have eight mononuclear cells each. Rejection with intimal
arteritis or transmural arteritis can occur without any tubulitis
whatsoever, although usually in well-established rejection both
tubulitis and intimal arteritis are observed.
Acute Renal Failure in the Transplanted Kidney
10.3

In this figure the tubules with lymphocytic invasion are atrophic
with thickened tubular basement membranes. There are 13 or 14
lymphocytes per tubular cross section. This is an example of how a
properly performed periodic acid-Schiff (PAS) stain should look.
The Banff classification is critically dependent on proper performance
of PAS staining. The invading lymphocytes are readily apparent and
countable in the tubules. In the Banff 1997 classification one avoids
counting lymphocytes in atrophic tubules, as tubulitis there is more
nonspecific than in nonatrophed tubules. (From Solez et al. [1];
with permission.)
FIGURE 10-5
Intimal arteritis in a case of acute rejection. Note that more than
20 lymphocytes are present in the thickened intima. With this
lesion, however, even a single lymphocyte in this site is sufficient
to make the diagnosis. Thus, the pathologist must search for subtle
intimal arteritis lesions, which are highly reliable and specific for
rejection. (From Solez et al. [1]; with permission.)
FIGURE 10-6
Artery in longitudinal section shows a more florid intimal arteritis
than that in Figure 10-5. Aggregation of lymphocytes is also seen
in the lumen, but this is a nonspecific change. The reporting for
some clinical trials has involved counting lymphocytes in the most
inflamed artery, but this has not been shown to correlate with clinical
severity or outcome, whereas the presence or absence of the lesion
has been shown to have such a correlation. (From Solez et al. [1];
with permission.)
FIGURE 10-7
Transmural arteritis with fibrinoid change. In addition to the influx of
inflammatory cells there has been proliferation of modified smooth
muscle cells migrated from the media to the greatly thickened intima.
Note the fibrinoid change at lower left and the penetration of the
media by inflammatory cells at the upper right. Patients with these
types of lesions have a less favorable prognosis, greater graft loss, and
poorer long-term function as compared with patients with intimal
arteritis alone. These sorts of lesions are also common in antibodymediated rejection (see Fig. 10-9).
10.4
Acute Renal Failure
Arterial lesions in acute rejection

1
Adventitia
3
10
Media
2
11
Endothelium
6
Lumen
4
FIGURE 10-8
Diagram of arterial lesions of acute rejection.
The initial changes (15) before intimal
arteritis (6) occurs are completely nonspecific.
These early changes are probably mechanistically related to the diagnostic lesions but can
occur as a completely self-limiting phenomenon unrelated to clinical rejection. Lesions 7
to 10 are those characteristic of transmural
rejection. Lesion 1 is perivascular inflammation; lesion 2, myocyte vacuolization; lesion
3, apoptosis; lesion 4, endothelial activation
and prominence; lesion 5, leukocyte adherence to the endothelium; lesion 6 (specific),
penetration of inflammatory cells under the
endothelium (intimal arteritis); lesion 7,
inflammatory cell penetration of the media;
lesion 8, necrosis of medial smooth muscle
cells; lesion 9, platelet aggregation; lesion 10,
fibrinoid change; and lesion 11 is thrombosis.

Antibody-mediated rejection with aggregates of polymorphonuclear
leukocytes (polymorphs) in peritubular capillaries. This lesion is a
feature of both classic hyperacute rejection and of later appearing
antibody-mediated rejection, which is by far the more common entity.
Antibody- and cell-mediated rejection can coexist, so one may find
both tubulitis and intimal arteritis along with this lesion; however
many cases of antibody-mediated rejection have a paucity of tubulitis
[2]. The polymorph aggregates can be subtle, another reason for
looking with care at the biopsy that appears to show nothing.
Acute Tubular Necrosis

Acute tubular necrosis in the allograft. Unlike acute tubule necrosis
in native kidney, in this condition actual necrosis appears in the
transplanted kidney but in a very small proportion of tubules,
often less than one in 300 tubule cross sections. Where the necrosis
does occur it tends to affect the entire tubule cross section, as in
the center of this field [3].

A completely necrotic tubule in the center of the picture in a case of
acute tubular necrosis (ATN) in an allograft. The tubule is difficult to
identify because, in contrast to the appearance in native kidney ATN,
no residual tubular cells survive; the epithelium is 100% necrotic.
10.5

Calcium oxalate crystals seen under polarized light. These are very
characteristic of transplant acute tubular necrosis (ATN), probably
because they relate to some degree to the duration of uremia, which
is often much longer in transplant ATN (counting the period of
uremia before transplantation) than in native ATN. With prolonged
uremia elevation of plasma oxalate is greater and more persistent
and consequently tissue deposition is greater [4].
FEATURES OF TRANSPLANT ACUTE TUBULAR

NECROSIS (ATN) WHICH DIFFERENTIATE IT
FROM NATIVE KIDNEY ATN
1. Apparently intact proximal tubular brush border
2. Occasional foci of necrosis of entire tubular cross sections
3. More extensive calcium oxalate deposition
4. Significantly fewer tubular casts
5. Significantly more interstitial inflammation
6. Less cell-to-cell variation in size and shape (tubular cell unrest)
FIGURE 10-13
Calcium oxalate crystals seen by electron microscopy in transplant
acute tubular necrosis.
FIGURE 10-14
Features of transplant acute tubular necrosis that differentiate it
from the same condition in native kidney [3].
10.6
Acute Renal Failure
Cyclosporine Toxicity
FIGURE 10-15
Cyclosporine nephrotoxicity with new-onset hyaline arteriolar
thickening in the renin-producing portion of the afferent arteriole
[5]. This lesion can be highly variable in extent and severity from
section to section of the biopsy specimen, and it represents one of
the strong arguments for examining multiple sections. The lesion is
reversible if cyclosporine levels are reduced. Tacrolimus (FK506)
produces an identical picture.

Bland hyaline arteriolar thickening of donor origin in a renal allograft
recipient never treated with cyclosporine. This phenomenon provides
a strong argument for doing implantation biopsies; otherwise, donor
changes can be mistaken for cyclosporine toxicity.
Posttransplant Lymphoproliferative Disorder

FIGURE 10-17
Posttransplant lymphoproliferative disorder (PTLD). The least
satisfying facet of the 1997 Fourth Banff Conference on Allograft
Pathology was the continued lack of good tools for the renal
pathologist trying to distinguish the more subtle forms of PTLD
from rejection. PTLD is rare, but, if misdiagnosed and treated with
increased (rather than decreased) immunosuppression, it can quickly
lead to death. The fact that both rejection and PTLD can occur
simultaneously makes the challenge even greater [6]. It is hoped
that newer techniques will make the diagnosis of this important
condition more accurate in the future [79]. This figure shows
an expansile plasmacytic infiltrate in a case of PTLD. However,
most cases of PTLD are the result of Epstein-Barr virusinduced
lymphoid proliferation.
10.7
Subclinical Rejection
Subclinical rejection. Subclinical rejection characterized by moderate
to severe tubulitis may be found in as many as 35% of normally
functioning grafts. Far from representing false-positive readings, such
findings now appear to represent bona fide smoldering rejection that,
if left untreated, is associated with increased incidence of chronic
renal functional impairment and graft loss [10,11]. The important
debate for the future is when to perform protocol biopsies to identify
subclinical rejection and how best to treat it. This picture shows
severe tubulitis in a normally functioning graft 15 months after
transplantation. In the tubule in the center are 30 lymphocytes
(versus 14 tubule cells). A year and a half later the patient developed
renal functional impairment.
Thrombotic Microangiopathy
FIGURE 10-19
Thrombotic microangiopathy in renal allografts. A host of different
conditions and influences can lead to arteriolar and capillary thrombosis in renal allografts and these are as various as the first dose reaction to OKT3, HIV infection, episodes of cyclosporine toxicity, and
antibody-mediated rejection [2, 12, 13]. It is hoped that further study
will allow for more accurate diagnosis in patients manifesting this
lesion. The figure shows arteriolar thrombosis and ischemic capillary
collapse in a case of transplant thrombotic microangiopathy.
10.8
Acute Renal Failure
Peritubular Capillary Basement

Membrane Changes in Chronic Rejection
A
Peritubular capillary basement membrane ultrastructural changes,
A, and staining for VCAM-1 as specific markers for chronic rejection, B [1416]. Splitting and multilayering of peritubular capillary
basement membranes by electron microscopy holds promise as a
relatively specific marker for chronic rejection [14,15]. VCAM-1
staining by immunohistology in these same structures may also be
B
of diagnostic utility [16]. Ongoing studies of large numbers of
patients using these parameters will test the value of these parameters which may eventually be added to the Banff classification.
A, Multilayering of peritubular capillary basement membrane in a
case of chronic rejection; B, shows staining of peritubular capillaries
for VCAM-1 by immunoperoxidase in chronic rejection.
References
1. Solez K, Axelsen RA, Benediktsson H, et al.: International standardization of criteria for the histologic diagnosis of renal allograft rejection:
The Banff working classification of kidney transplant pathology.
Kidney Int 1993, 44:411422.
2. Trpkov K, Campbell P, Pazderka F, et al.: Pathologic features of acute
renal allograft rejection associated with donor-specific antibody,
analysis using the Banff grading schema. Transplantation 1996,
61(11):15861592.
3. Solez K, Racusen LC, Marcussen N, et al.: Morphology of ischemic
acute renal failure, normal function, and cyclosporine toxicity in
cyclosporine-treated renal allograft recipients. Kidney Int 1993,
43(5):10581067.
4. Salyer WR, Keren D:Oxalosis as a complication of chronic renal
failure. Kidney Int 1973, 4(1):6166.
5. Strom EH, Epper R, Mihatsch MJ: Cyclosporin-associated arteriolopathy: The renin producing vascular smooth muscle cells are more
sensitive to cyclosporin toxicity. Clin Nephrol 1995, 43(4):226231.
6. Trpkov K, Marcussen N, Rayner D, et al.: Kidney allograft with a
lymphocytic infiltrate: Acute rejection, post-transplantation lymphoproliferative disorder, neither, or both entities? Am J Kidney Dis 1997,
30(3):449454.
7. Sasaki TM, Pirsch JD, DAlessandro AM, et al.: Increased 2-microglobulin (B2M) is useful in the detection of post-transplant lymphoproliferative disease (PTLD). Clin Transplant 1997, 11(1):2933.
8. Chetty R, Biddolph S, Kaklamanis L, et al.: bcl-2 protein is strongly
expressed in post-transplant lymphoproliferative disorders. J Pathol
1996, 180(3):254258.
9. Wood A, Angus B, Kestevan P, et al.: Alpha interferon gene deletions

in post-transplant lymphoma. Br J Haematol 1997, 98(4):10021003.
10. Nickerson P, Jeffrey J, McKenna R, et al.: Do renal allograft function
and histology at 6 months posttransplant predict graft function at 2
years? Transplant Proc 1997, 29(6):25892590.
11. Rush D: Subclinical rejection. Presentation at Fourth Banff
Conference on Allograft Pathology, March 712, 1997.
12. Wiener Y, Nakhleh RE, Lee MW, et al.: Prognostic factors and early
resumption of cyclosporin A in renal allograft recipients with thrombotic microangiopathy and hemolytic uremic syndrome. Clin
Transplant 1997, 11(3):157162.
13. Frem GJ, Rennke HG, Sayegh MH: Late renal allograft failure
secondary to thrombotic microangiopathyhuman immunodeficiency
virus nephropathy. J Am Soc Nephrol 1994, 4(9):16431648.
14. Monga G, Mazzucco G, Messina M, et al.: Intertubular capillary
changes in kidney allografts: A morphologic investigation on 61 renal
specimens. Mod Pathol 1992, 5(2):125130.
15. Mazzucco G, Motta M, Segoloni G, Monga G: Intertubular capillary
changes in the cortex and medulla of transplanted kidneys and their
relationship with transplant glomerulopathy: An ultrastructural study
of 12 transplantectomies. Ultrastruct Pathol 1994, 18(6):533537.
16. Solez K, Racusen LC, Abdulkareem F, et al.: Adhesion molecules and
rejection of renal allografts. Kidney Int 1997, 51(5):14761480.
Renal Injury Due To

Environmental Toxins,
Drugs, and Contrast Agents
Marc E. De Broe
he kidneys are susceptible to toxic or ischemic injury for several reasons. Thus, it is not surprising that an impressive list of
exogenous drugs and chemicals can cause clinical acute renal
failure (ARF) [1]. On the contrary, the contribution of environmental
toxins to ARF is rather limited. In this chapter, some of the most common drugs and exogenous toxins encountered by the nephrologist in
clinical practice are discussed in detail.
The clinical expression of the nephrotoxicity of drugs and chemicals is highly variable and is influenced by several factors. Among
these is the direct toxic effect of drugs and chemicals on a particular
type of nephron cell, the pharmacologic activity of some substances
and their effects on renal function, the high metabolic activity (ie, vulnerability) of particular segments of the nephron, the multiple transport systems, which can result in intracellular accumulation of drugs
and chemicals, and the high intratubule concentrations with possible
precipitation and crystallization of particular drugs.
CHAPTER
11
11.2
Acute Renal Failure
General Nephrotoxic Factors

FIGURE 11-1
Sites of renal damage, including factors that
contribute to the kidneys susceptibility to
damage. ACEangiotensin-converting
enzyme; NSAIDnonsteroidal anti-inflammatory drugs; HgCl2mercuric chloride.
The nephron
S1
Cortex
Sites of renal damage
Medullary ray
S1
Outer
stripe
Inner
stripe
Inner
medula
ACE inhibitors
NSAIDs
Aminoglycosides
Acyclovir
Cisplatinum
HgCl2
S3
S2
Outer medulla
S2
Lithium
S3
Ischemia
Vulnerability of the kidney

Important blood flow (1/4 cardiac output)
High metabolic activity
Largest endothelial surface by weight
Multiple enzyme systems
Transcellular transport
Concentration of substances
Protein unbinding
High O2 consumption/delivery ratio
in outer medulla
Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents
11.3
DRUGS AND CHEMICALS ASSOCIATED WITH ACUTE RENAL FAILURE

Mechanisms
M1 Reduction in renal perfusion through alteration of intrarenal hemodynamics
M2 Direct tubular toxicity
M3 Heme pigmentinduced toxicity (rhabdomyolysis)
M1
M2
M3
M4
M5*
M6
Drugs
Cyclosporine, tacrolimus
Amphotericin B, radiocontrast agents
Angiotensin-converting enzyme inhibitors, interleukin-2
Methotrexate
Aminoglycosides, cisplatin, foscarnet, heavy metals, intravenous immunoglobulin, organic solvents, pentamidine
Cocaine
Ethanol, lovastatin**
Sulfonamides
Acyclovir, Indinavir, chemotherapeutic agents, ethylene glycol***
Allopurinol, cephalosporins, cimetidine, ciprofloxacin, furosemide, penicillins, phenytoin, rifampin, thiazide diuretics
Conjugated estrogens, mitomycin, quinine
M4 Intratubular obstruction by precipitation of the agents or its metabolites or byproducts

M5 Allergic interstitial nephritis
M6 Hemolytic-uremic syndrome
* Many other drugs in addition to the ones listed can cause renal failure by this mechanism.
Interleukin-2 produces a capillary leak syndrome with volume contractions.
Uric acid crystals form as a result of tumor lysis.
The mechanism of this agent is unclear but may be due to additives.
** Acute renal failure is most likely to occur when lovastatin is given in combination with cyclosporine.
*** Ethylene glycolinduced toxicity can cause calcium oxalate crystals.
FIGURE 11-2
Drugs and chemicals associated with acute renal failure. (Apapted from Thadhani, et al. [2].)
11.4
Acute Renal Failure
Aminoglycosides
1. Filtration
2. Binding
Glomerulus
3. Adsorptive
pinocytosis
Proximal tubule
4. Lysosomal trapping
and storage
+
+
Lysosomal phospholipidosis
ABOVE
threshold:
lysosomal
swelling,
disruption
or leakage
*
*
BELOW
threshold:
exocytosis
shuttle
*
*
*
Cell necrosis
regeneration
FIGURE 11-3
Renal handling of aminoglycosides: 1) glomerular filtration;
2) binding to the brush border membranes of the proximal
tubule; 3) pinocytosis; and 4) storage in the lysosomes [3].
Nephrotoxicity and otovestibular toxicity remain frequent side
effects that seriously limit the use of aminoglycosides, a still important class of antibiotics. Aminoglycosides are highly charged, polycationic, hydrophilic drugs that cross biologic membranes little, if
at all [4,5]. They are not metabolized but are eliminated unchanged
almost entirely by the kidneys. Aminoglycosides are filtered by the
glomerulus at a rate almost equal to that of water. After entering
the luminal fluid of proximal renal tubule, a small but toxicologically important portion of the filtered drug is reabsorbed and
stored in the proximal tubule cells. The major transport of aminoglycosides into proximal tubule cells involves interaction with
acidic, negatively charged phospholipid-binding sites at the level
of the brush border membrane.
Regression of
drug-induced
changes
Aminoglycoside
* Hydrolase
Toxins
After charge-mediated binding, the drug is taken up into the cell

in small invaginations of the cell membrane, a process in which
megalin seems to play a role [6]. Within 1 hour of injection, the
drug is located at the apical cytoplasmic vacuoles, called endocytotic vesicles. These vesicles fuse with lysosomes, sequestering the
unchanged aminoglycosides inside those organelles.
Once trapped in the lysosomes of proximal tubule cells, aminoglycosides electrostatically attached to anionic membrane phospholipids interfere with the normal action of some enzymes (ie, phospholipases and sphingomyelinase). In parallel with enzyme inhibition, undigested phospholipids originating from the turnover of cell
membranes accumulate in lysosomes, where they are normally
digested. The overall result is lysosomal phospholipidosis due to
nonspecific accumulation of polar phospholipids as myeloid bodies, so called for their typical electron microscopic appearance.
(Adapted from De Broe [3].)
B
FIGURE 11-4
Ultrastructural appearance of proximal tubule cells in aminoglycoside-treated patients (4 days
of therapeutic doses). Lysosomes (large arrow) contain dense lamellar and concentric structures. Brush border, mitochondria (small arrows) and peroxisomes are unaltered. At higher
magnification the structures in lysosomes show a periodic pattern. The bar in A represents 1
m, in part B, 0.1 m [7].
B
Administration of aminoglycosides for days induces progression
of lysosomal phospholipidosis. The overloaded lysosomes continue
to swell, even if the drug is then withdrawn. In vivo this overload
may result in loss of integrity of the membranes of lysosomes and
release of large amounts of lysosomal enzymes, phospholipids, and
aminoglycosides into the cytosol, but this has not been proven.
Thus, these aminoglycosides can gain access to and injure other
organelles, such as mitochondria, and disturb their functional
integrity, which leads rapidly to cell death. As a consequence
of cell necrosis, A, intratubular obstruction by cell debris increased
intratubule pressure, a decrease in the glomerular filtration rate
and cellular infiltration, B, may ensue. In parallel with these lethal
processes in the kidney, a striking regeneration process is observed
that is characterized by a dramatic increase in tubule cell turnover
and proliferation, C, in the cortical interstitial compartment.
FIGURE 11-6
A, Relationship between constant serum levels and concomitant
renal cortical accumulation of gentamicin after a 6 hour intravenous infusion in rats. The rate of accumulation is expressed in
micrograms of aminoglycoside per gram of wet kidney cortex per
hour, due to the linear accumulation in function of time. Each
point represents one rat whose aminoglycosides were measured
in both kidneys at the end of the infusion and the serum levels
assayed twice during the infusion [8].
Vmax= 149.83 + 9.08 g/g/h

Km= 15.01+1.55 g/ml
150

100
Renal cortical gentamicin
accumulation rate, g/g/h
Renal cortical gentamicin accumulation rate, g/g/h
200
50
60
40
20
V= 6.44 + 4.88 C
r= 0.96
0
5
10
15
Serum gentamicin concentration, g/ml
0
0
11.5
10
20
30
40
50
60
70
80
Serum gentamicin concentration, g/ml
90
100
11.6
Acute Renal Failure
One injection a day

Three injections a day
800
**
Continuous infusion
Total daily dose:
10 mg/kg i.p.
600
400
**
**
**
**
200
0
1
2
4
Days of administration
40
40
Gentamicin
35
Netilmicin
35
Serum levels, g/ml
4.5 mg/kg/d
5 mg/kg/d
30
30
25
25
20
20
Single injection
15
Single injection
15
10
10
Continuous infusion
Continuous infusion
12
16 20
40
24
12
16
20 24
90
Tobramycin
35
Amikacin
80
15 mg/kg/d
4.5 mg/kg/d
70
30
Serum levels, g/ml
One injection a day
250
Continuous infusion (n6)
P< 0.025
P< 0.025
N.S.
P< 0.05
Gentamicin
4.5 mg/kg
Netilmicin
5 mg/kg
Tobramycin
4.5 mg/kg/d
Amikacin
15 mg/kg/d
200
150
100
50
0
60
25
50
20
40
Single injection
15
Single injection
30
10
20
Continuous infusion
Continuous infusion
10
0
0

B, Kidney cortical concentrations of gentamicin in rats given equal
daily amounts of aminoglycoside in single injections, three injections,
or by continuous infusion over 8 days. Each block represents the
mean of seven rats SD. Significance is shown only between cortical
levels achieved after continuous infusion and single injections (asteriskP < 0.05; double asteriskP < 0.01) [9].
In rats, nephrotoxicity of gentamicin is more pronounced when the
total daily dose is administered by continuous infusion rather than as a
single injection. Thus, a given daily drug does not produce the same
degree of toxicity when it is given by different routes. Indeed, renal
cortical uptake is less efficient at high serum concentration than at
low ones. A single injection results in high peak serum levels that overcome the saturation limits of the renal uptake mechanism. The high
plasma concentrations are followed by fast elimination and, finally,
absence of the drug for a while. This contrasts with the continuous
low serum levels obtained with more frequent dosing when the uptake
at the level of the renal cortex is not only more efficient but remains
available throughout the treatment period. Vmaxmaximum velocity.
Renal cortical concentration after one day, g/g
Renal cortical gentamicin accumulation, g/g
1000
12
16 20
0
0
24
Time, hrs
12 16 20 24
FIGURE 11-7
Course of serum concentrations, A, and of renal cortical concentrations, B, of gentamicin, netilmicin, tobramycin, and amikacin after
dosing by a 30-minute intravenous injection or continuous infusion
over 24 hours [10,11].
Two trials in humans found that the dosage schedule had a critical effect on renal uptake of gentamicin, netilmicin [10], amikacin,
and tobramycin [11]. Subjects were patients with normal renal
function (serum creatinine concentration between 0.9 and 1.2
mg/dL, proteinuria lower than 300 mg/24 h) who had renal cancer
and submitted to nephrectomy. Before surgery, patients received
gentamicin (4.5 mg/kg/d), netilmicin (5 mg/kg/d), amikacin (15
mg/kg/d), or tobramycin (4.5 mg/kg/d) as a single injection or as a
continuous intravenous infusion over 24 hours. The single-injection
schedule resulted in 30% to 50% lower cortical drug concentrations of netilmicin, gentamicin, and amikacin as compared with
continuous infusion. For tobramycin, no difference in renal accumulation could be found, indicating the linear cortical uptake of
this particular aminoglycoside [8]. These data, which supported
decreased nephrotoxic potential of single-dose regimens, coincided
with new insights in the antibacterial action of aminoglycosides
(concentration-dependent killing of gram-negative bacteria and
prolonged postantibiotic effect) [12]. N.S.not significant.
RISK FACTORS FOR AMINOGLYCOSIDE NEPHROTOXICITY

Patient-Related Factors
Aminoglycoside-Related Factors
Other Drugs
Older age*
Preexisting renal disease
Female gender
Magnesium, potassium, or
calcium deficiency*
Intravascular volume depletion*
Hypotension*
Hepatorenal syndrome
Sepsis syndrome
Recent aminoglycoside therapy
Amphotericin B
Cephalosporins
Cisplatin
Clindamycin
Larger doses*
Treatment for 3 days or more*
Dose regimen*
* Similar to experimental data.
PREVENTION OF AMINOGLYCOSIDE
NEPHROTOXICITY
Identify risk factor
Patient related
Drug related
Other drugs
Give single daily dose of gentamicin, netilmicin, or amikacin
Reduce the treatment course as much as possible
Avoid giving nephrotoxic drugs concurrently
Make interval between aminoglycoside courses as long as possible
Calculate glomerular filtration rate out of serum creatinine concentration
Cyclosporine
Foscarnet
Furosemide
Piperacillin
Radiocontrast agents
Thyroid hormone
11.7
FIGURE 11-8
Risk factors for aminoglycoside nephrotoxicity. Several risk factors have been
identified and classified as patient related,
aminoglycoside related, or related to concurrent administration of certain drugs.
The usual recommended aminoglycoside
dose may be excessive for older patients
because of decreased renal function and
decreased regenerative capacity of a damaged kidney. Preexisting renal disease
clearly can expose patients to inadvertent
overdosing if careful dose adjustment is
not performed. Hypomagnesemia,
hypokalemia, and calcium deficiency may
be predisposing risk factors for consequences of aminoglycoside-induced damage [13]. Liver disease is an important
clinical risk factor for aminoglycoside
nephrotoxicity, particularly in patients
with cholestasis [13]. Acute or chronic
endotoxemia amplifies the nephrotoxic
potential of the aminoglycosides [14].
FIGURE 11-9
Prevention of aminoglycoside nephrotoxicity. Coadministration
of other potentially nephrotoxic drugs enhances or accelerates the
nephrotoxicity of aminoglycosides. Comprehension of the pharmacokinetics and renal cell biologic effects of aminoglycosides,
allows identification of aminoglycoside-related nephrotoxicity risk
factors and makes possible secondary prevention of this important
clinical nephrotoxicity.
11.8
Acute Renal Failure
Amphotericin B
Water
Lipid
Phospholipid
Cholesterol
C20-C33 heptaene segment
Amphotericin B
Pore
C
O
N
H
FIGURE 11-10
Proposed partial model for the amphotericin B (AmB)induced
pore in the cell membrane. AmB is an amphipathic molecule: its
structure enhances the drugs binding to sterols in the cell membranes and induces formation of aqueous pores that result in weakening of barrier function and loss of protons and cations from the
cell. The drug acts as a counterfeit phospholipid, with the C15
hydroxyl, C16 carboxyl, and C19 mycosamine groups situated at
the membrane-water interface, and the C1 to C14 and C20 to C33
chains aligned in parallel within the membrane. The heptaene
chain seeks a hydrophobic environment, and the hydroxyl groups
seek a hydrophilic environment. Thus, a cylindrical pore is formed,
the inner wall of which consists of the hydroxyl-substituted carbon
chains of the AmB molecules and the outer wall of which is formed
by the heptaene chains of the molecules and by sterol nuclei [15].
FIGURE 11-11
Risk factors for development of amphotericin B (AmB) nephrotoxicity. Nephrotoxicity of AmB is a major problem associated with clinical use of this important drug. Disturbances in both glomerular
and tubule function are well described. The nephrotoxic effect of
AmB is initially a distal tubule phenomenon, characterized by a loss
of urine concentration, distal renal tubule acidosis, and wasting of
potassium and magnesium, but it also causes renal vasoconstriction
leading to renal ischemia. Initially, the drug binds to membrane
sterols in the renal vasculature and epithelial cells, altering its membrane permeability. AmB-induced vasoconstriction and ischemia to
very vulnerable sections of the nephron, such as medullary thick
ascending limb, enhance the cell death produced by direct toxic
action of AmB on those cells. This explains the salutary effect on
AmB nephrotoxicity of salt loading, furosemide, theophylline, or
calcium channel blockers, all of which improve renal blood flow or
inhibit transport in the medullary thick ascending limb.
RISK FACTORS IN THE DEVELOPMENT OF

AMPHOTERICIN NEPHROTOXICITY
Age
Concurrent use of diuretics
Abnormal baseline renal function
Larger daily doses
Hypokalemia
Hypomagnesemia
Other nephrotoxic drugs (aminoglycosides, cyclosporine)
Indication for amphotericin B therapy

Clinical evaluation:
Is patient salt depleted?
yes
Correction:
Correct salt depletion
Avoid diuretics
Liberalize dietary sodium
Will salt loading exacerbate underlying disease?
yes
Weigh risk-benefit ratio

Seek alternatives
Does patient require concommitant antibiotics?
yes
Select drug with high salt content
Is potassium (K) or magnesium (Mg) depleted?
yes
Correct abnormalities
No
Begin amphotericin B with sodium supplement, 150 mEq/d
Begin amphotericin B therapy
Routine Monitoring:
Clinical evaluation (cardiovascular/respiratory status; body weight; fluid intake and excretion)
Laboratory tests (renal function; serum electrolyte levels; 24 -hours urinary electrolyte excretion)
Clinical evaluation: Is patient vomiting?
yes
Increase salt load
No
Correction:
Laboratory evaluation:
Is serum creatinine
creratinine>3
>3mg/dL
mg/dLor
orisisrenal
renaldeterioration
deteriorationrapid?
rapid?
Is K level ,3.5 mEq/L or Mg level <1.6 mEq/L?
No
Continue amphotericin B therapy and routine monitoring

Close follow-up of serum electrolytes
11.9
yes
Interrupt amphotericin B therapy,

resume on improvement
yes
Use oral or intravenous

supplementation
FIGURE 11-12
Proposed approach for management of
amphotericin B (AmB) therapy. Several new
formulations of amphotericin have been
developed either by incorporating amphotericin into liposomes or by forming complexes to phospholipid. In early studies,
nephrotoxicity was reduced, allowing an
increase of the cumulative dose. Few studies
have established a therapeutic index
between antifungal and nephrotoxic effects
of amphotericin. To date, the only clinically
proven intervention that reduces the incidence and severity of nephrotoxicity is salt
supplementation, which should probably be
given prophylactically to all patients who
can tolerate it. (From Bernardo JF, et al.
11.10
Acute Renal Failure
Cyclosporine

Intravascular coagulation in a cyclosporine-treated renal transplant
recipient. Cyclosporine produces a dose-related decrease in renal
function in experimental animals and humans [17] that is attributed to the drugs hemodynamic action to produce vasoconstriction
of the afferent arteriole entering the glomerulus. When severe
enough, this can decrease glomerular filtration rate. Although the
precise pathogenesis of the renal hemodynamic effects of
cyclosporine are unclear, endothelin, inhibition of nitric oxide,
release of vasoconstrictor prostaglandins such as thromboxane A2,

and activation of the sympathetic nervous system, are among the
candidates for cyclosporine-induced vasoconstriction [18].
The diagnosis of cyclosporine-induced acute renal dysfunction
is not difficult when the patient has no other reason for reduced
renal function (eg, psoriasis, rheumatoid arthritis). In renal transplant recipients, however, the situation is completely different. In
this clinical setting, the clinician must differentiate between cyclosporine injury and acute rejection. The incidence of this acute
cyclosporine renal injury can be enhanced by extended graft preservation, preexisting histologic lesions, donor hypotension, or preoperative complications. The gold standard for this important distinction remains renal biopsy.
In addition, cyclosporine has been associated with hemolytic-uremic syndrome with thrombocytopenia, red blood cell fragmentation, and intravascular (intraglomerular) coagulation. Again, this
drug-related intravascular coagulation has to be differentiated from
that of acute rejection. The absence of clinical signs and of rejection-related interstitial edema and cellular infiltrates can be helpful.
Vanrenterghem and coworkers [19] found a high incidence of
venous thromboembolism shortly after (several of them within
days) cadaveric kidney transplantation in patients treated with
cyclosporine, in contrast to those treated with azathioprine. Recent
studies [20] have shown that impaired fibrinolysis, due mainly to
excess plasminogen activator inhibitor (PAI-1), may also contribute
to this imbalance in coagulation and anticoagulation during
cyclosporine treatment.
Lithium-Induced Acute Renal Failure

SIGNS AND SYMPTOMS OF
TOXIC EFFECTS OF LITHIUM
Toxic Effect
Mild
Moderate
Severe
Plasma Lithium Level

11.5 mmol/L
1.62.5 mmol/L
>2.5 mmol/L
Signs and Symptoms

Impaired concentration, lethargy,
irritability, muscle weakness,
tremor, slurred speech, nausea
Disorientation, confusion,
drowsiness, restlessness, unsteady
gait, coarse tremor, dysarthria,
muscle fasciculation, vomiting
Impaired consciousness (with
progression to coma), delirium,
ataxia, generalized fasciculations,
extrapyramidal symptoms,
convulsions, impaired renal
function
FIGURE 11-14
Symptoms and signs of toxic effects of lithium. Lithium can cause
acute functional and histologic (usually reversible) renal injury.
Within 24 hours of administration of lithium to humans or animals, sodium diuresis occurs and impairment in the renal concentrating capacity becomes apparent. The defective concentrating
capacity is caused by vasopressin-resistant (exogenous and endogenous) diabetes insipidus. This is in part related to lithiums inhibition of adenylate cyclase and impairment of vasopressin-induced
generation of cyclic adenosine monophosphatase.
Lithium-induced impairment of distal urinary acidification has
also been defined.
Acute lithium intoxication in humans and animals can cause
acute renal failure. The clinical picture features nonspecific signs of
degenerative changes and necrosis of tubule cells [21]. The most
distinctive and specific acute lesions lie at the level of the distal
tubule [22]. They consist of swelling and vacuolization of the cytoplasm of the distal nephron cells plus periodic acid-Schiffpositive
granular material in the cytoplasm (shown to be glycogen) [23].
Most patients receiving lithium have side effects, reflecting the
drugs narrow therapeutic index.
FIGURE 11-15
Drug interactions with lithium [24]. Acute renal failure, with or
without oliguria, can be associated with lithium treatment, and with
severe dehydration. In this case, acute renal failure can be considered a prerenal type; consequently, it resolves rapidly with appropriate fluid therapy. Indeed, the histologic appearance in such cases is
remarkable for its lack of significant abnormalities. Conditions that
stimulate sodium retention and consequently lithium reabsorption,
such as low salt intake and loss of body fluid by way of vomiting,
diarrhea, or diuretics, decreasing lithium clearance should be avoided. With any acute illness, particularly one associated with gastrointestinal symptoms such as diarrhea, lithium blood levels should be
closely monitored and the dose adjusted when necessary. Indeed,
most episodes of acute lithium intoxication are largely predictable,
and thus avoidable, provided that precautions are taken [25].
Removing lithium from the body as soon as possible the is the
mainstay of treating lithium intoxication. With preserved renal function, excretion can be increased by use of furosemide, up to 40 mg/h,
obviously under close monitoring for excessive losses of sodium and
water induced by this loop diuretic. When renal function is impaired
in association with severe toxicity, extracorporeal extraction is the
most efficient way to decrease serum lithium levels. One should,
however, remember that lithium leaves the cells slowly and that plasma levels rebound after hemodialysis is stopped, so that longer dialysis treatment or treatment at more frequent intervals is required.
DRUG INTERACTIONS WITH LITHIUM
Salt depletion strongly impairs renal elimination of lithium.

Salt loading increases absolute and fractional lithium clearance.
Diuretics
Acetazolamide
Thiazides
Increased lithium clearance

Increased plasma lithium level due to decreased
lithium clearance
Acute increased lithium clearance
Usually no change in plasma lithium level; may be
used to treat lithium-induced polyuria
Loop diuretics
Amiloride
Nonsteroidal
anti-inflammatory drugs
Increased plasma lithium level due to decreased

renal lithium clearance (exceptions are aspirin
and sulindac)
Decreased plasma lithium level due to increased
renal lithium clearance
May increase plasma lithium level
Bronchodilators (aminophylline, theophylline)

Angiotensin-converting
enzyme inhibitors
Cyclosporine
11.11
Decreased lithium clearance
Inhibitors of the Renin-Angiotensin System

Pre-kallikrein
Angiotensinogen
Renin
Activated factor XII
Kininogen
+ Kallikrenin
Angiotensin I
+
Angiotensin
converting
enzyme
Kininase II
Angiotensin II
+ : stimulation
Bradykinin
+
Arachidonic acid
Inactive peptide
+
Increased aldosterone release

Potentiation of sympathetic activity
Increased Ca2+ current
Vasoconstriction
Prostaglandins
Vasodilation
Cough?
FIGURE 11-16
Soon after the release of this useful class of antihypertensive drugs, the syndrome of functional acute renal insufficiency was described as a class effect. This phenomenon was first
observed in patients with renal artery stenosis, particularly when the entire renal mass was
affected, as in bilateral renal artery stenosis or in renal transplants with stenosis to a solitary kidney [26]. Acute renal dysfunction appears to be related to loss of postglomerular
efferent arteriolar vascular tone and in

general is reversible after withdrawing the
angiotensin-converting enzyme (ACE)
inhibitor [27].
Inhibition of the ACE kinase II results
in at least two important effects: depletion
of angiotensin II and accumulation of
bradykinin [28]. The role of the latter effect
on renal perfusion pressure is not clear, A.
To understand the angiotensin I converting enzyme inhibitorinduced drop in
glomerular filtration rate, it is important
to understand the physiologic role of the
renin-angiotensin system in the regulation
of renal hemodynamics, B. When renal perfusion drops, renin is released into the plasma and lymph by the juxtaglomerular cells
of the kidneys. Renin cleaves angiotensinogen to form angiotensin I, which is cleaved
further by converting enzyme to form
angiotensin II, the principal effector molecule in this system. Angiotensin II participates in glomerular filtration rate regulation
in a least two ways. First, angiotensin II
increases arterial pressuredirectly and
acutely by causing vasoconstriction and
more chronically by increasing body fluid
volumes through stimulation of renal sodium retention; directly through an effect on
the tubules, as well as by stimulating thirst
11.12
Acute Renal Failure
+: vasoconstriction
B1. Normal condition
: vasodilation
Autoregulation
+
Afferent
arteriole
Efferent
arteriole
Glomerulus
Myogenic reflex (Laplace)

Tubuloglomerular feedback
B2. Perfusion pressure reduced
but still within autoregulatory range
(congestive heart failure,
renal artery stenosis,
diuretic therapy,
nephrotic syndrome cirrhosis,
sodium restriction depletion,
advanced age [age >80])
Tubule
PGE2
+
Local
angiotensin II
B3. Perfusion pressure

seriously reduced
(prerenal azotemia)
PGE2
Intraglomerular
pressure
+
Sympathetic activity
angiotensin II
+
Local
angiotensin II

and indirectly via aldosterone. Second, angiotensin II preferentially constricts the efferent
arteriole, thus helping to preserve glomerular capillary hydrostatic pressure and, consequently, glomerular filtration rate.
When arterial pressure or body fluid volumes are sensed as subnormal, the reninangiotensin system is activated and plasma renin activity and angiotensin II levels
increase. This may occur in the context of clinical settings such as renal artery stenosis,
dietary sodium restriction or sodium

depletion as during diuretic therapy, congestive heart failure, cirrhosis, and
nephrotic syndrome. When activated, this
reninangiotensin system plays an important role in the maintenance of glomerular
pressure and filtration through preferential angiotensin IImediated constriction
of the efferent arteriole. Thus, under such
conditions the kidney becomes sensitive
to the effects of blockade of the reninangiotensin system by angiotensin Iconverting enzyme inhibitor or angiotensin II
receptor antagonist.
The highest incidence of renal failure in
patients treated with ACE inhibitors was
associated with bilateral renovascular
disease [27]. In patients with already
compromised renal function and congestive
heart failure, the incidence of serious
changes in serum creatinine during ACE
inhibition depends on the severity of the
pretreatment heart failure and renal failure.
Volume management, dose reduction,
use of relatively short-acting ACE
inhibitors, diuretic holiday for some days
before initiating treatment, and avoidance
of concurrent use of nonsteroidal antiinflammatory drug (hyperkalemia) are
among the appropriate measures for
patients at risk.
Acute interstitial nephritis associated with
angiotensin Iconverting enzyme inhibition
has been described [29]. (Adapted from
Opie [30]; with permission.)
Nonsteroidal Anti-inflammatory Drugs

Patients at risk for NSAID-induced acute renal failure
Renin-angiotensin axis
Angiotensin II
Adrenergic nervous system

Catecholamines
Renal vasoconstriction
Renal function
"Normalized" renal function
Inhibition
by NSAID
Compensatory vasodilation induced by renal

prostaglandin synthesis
FIGURE 11-17
Mechanism by which nonsteroidal anti-inflammatory drugs
(NSAIDs) disrupt the compensatory vasodilatation response of
renal prostaglandins to vasoconstrictor hormones in patients with
prerenal conditions. Most of the renal abnormalities encountered
clinically as a result of NSAIDs can be attributed to the action of
these compounds on prostaglandin production in the kidney [31].
Sodium chloride and water retention are the most common side
effects of NSAIDs. This should not be considered drug toxicity
because it represents a modification of a physiologic control
mechanism without the production of a true functional disorder
in the kidney.
FIGURE 11-18
Conditions associated with risk for nonsteroidal anti-inflammatory
drugs (NSAID)-induced acute renal failure. NSAIDs can induce
acute renal decompensation in patients with various renal and
extrarenal clinical conditions that cause a decrease in blood perfusion to the kidney [32]. Renal prostaglandins play an important
role in the maintenance of homeostasis in these patients, so disruption of counter-regulatory mechanisms can produce clinically
important, and even severe, deterioration in renal function.
PREDISPOSING FACTORS FOR NSAIDINDUCED ACUTE RENAL FAILURE

Severe heart disease (congestive heart failure)
Severe liver disease (cirrhosis)
Nephrotic syndrome (low oncotic pressure)
Chronic renal disease
Age 80 years or older
Protracted dehydration (several days)
Physiologic stimulus
Inflammatory stimuli
COX-1
constitutive
Stomach Kidney
Intestine Platelets
Endothelium
PGE2
TxA2
PGI2
Physiologic functions
Inhibition
by NSAID
11.13
COX-2
inducible
Inflammatory sites
(macrophages,
synoviocytes)
Inflammatory PGs
Proteases
Inflammation
O2 -
FIGURE11-19
Inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) on
pathways of cyclo-oxygenase (COX) and prostaglandin synthesis
[33]. The recent demonstration of the existence of functionally distinct isoforms of the cox enzyme has major clinical significance, as
it now appears that one form of cox is operative in the gastric
mucosa and kidney for prostaglandin generation (COX-1) whereas
an inducible and functionally distinct form of cox is operative in
the production of prostaglandins in the sites of inflammation and
pain (COX-2) [33]. The clinical therapeutic consequence is that an
NSAID with inhibitory effects dominantly or exclusively upon the
cox isoenzyme induced at a site of inflammation may produce the
desired therapeutic effects without the hazards of deleterious effects
on the kidneys or gastrointestinal tract. PGprostaglandin;
TxA2thromboxane A2.
11.14
Acute Renal Failure
EFFECTS OF NSAIDS ON RENAL FUNCTION

Renal Syndrome
Mechanism
Risk Factors
Prevention/Treatment [34]
Sodium retension
and edema
Prostaglandin
NSAID therapy (most

common side effect)
Stop NSAID
Hyperkalemia
Prostaglandin
Potassium to
distal tubule
Aldosterone/reninangiotensin
Renal disease
Heart failure
Diabetes
Multiple myeloma
Potassium therapy
Potassium-sparing
diuretic
Stop NSAID
Avoid use in high-risk patients
Acute deterioration of
renal function
Prostaglandin and
disruption of
hemodynamic balance
Liver disease
Renal disease
Heart failure
Dehydration
Old age
Nephrotic syndrome with:

Papillary necrosis
Lymphocyte recruitment and activation

Direct toxicity
Fenoprofen
Combination aspirin
and acetaminophen
abuse
Stop NSAID
Avoid use in high-risk patients
Stop NSAID
Dialysis and steroids (?)
Stop NSAID
Avoid long-term
analgesic use
FIGURE 11-20
Summary of effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function [31].
All NSAIDs can cause another type of renal dysfunction that is associated with various
levels of functional impairment and characterized by the nephrotic syndrome together with
interstitial nephritis.
Characteristically, the histology of this form of NSAIDinduced nephrotic syndrome
consists of minimal-change glomerulonephritis with tubulointerstitial nephritis. This is an
unusual combination of findings and in the

setting of protracted NSAID use is virtually
pathognomic of NSAID-related nephrotic
syndrome.
A focal diffuse inflammatory infiltrate
can be found around the proximal and distal tubules. The infiltrate consists primarily
of cytotoxic T lymphocytes but also contains other T cells, some B cells, and plasma
cells. Changes in the glomeruli are minimal
and resemble those of classic minimalchange glomerulonephritis with marked
epithelial foot process fusion.
Hyperkalemia, an unusual complication
of NSAIDs, is more likely to occur in
patients with pre-existing renal impairment,
cardiac failure, diabetes, or multiple myeloma or in those taking potassium supplements, potassium-sparing diuretic therapy,
or intercurrent use of an angiotensin-converting enzyme inhibitor. The mechanism of
NSAID hyperkalemiasuppression of
prostaglandin-mediated renin releaseleads
to a state of hyporeninemic hypoaldosteronism. In addition, NSAIDs, particularly
indomethacin, may have a direct effect on
cellular uptake of potassium.
The renal saluretic response to loop
diuretics is partially a consequence of
intrarenal prostaglandin production. This
component of the response to loop diuretics
is mediated by an increase in renal
medullary blood flow and an attendant
reduction in renal concentrating capacity.
Thus, concurrent use of an NSAID may
blunt the diuresis induced by loop diuretics.
Contrast MediumAssociated Nephrotoxicity

RISK FACTORS THAT PREDISPOSE TO CONTRAST
ASSOCIATED NEPHROPATHY
Confirmed
Suspected
Disproved

Severe congestive
heart failure
Amount and frequency
of contrast media
Volume depletion
or hypotension
Hypertension
Generalized atherosclerosis
Abnormal liver
function tests
Hyperuricemia
Proteinuria
Myeloma
Diabetes without
nephropathy
FIGURE 11-21
Risk factors that predispose to contrast-associated nephropathy. In
random populations undergoing radiocontrast imaging the incidence
of contrasts associated nephropathy defined by a change in serum
creatinine of more than 0.5 mg/dL or a greater than 50% increase
over baseline, is between 2% and 7%. For confirmed high-risk
patients (baseline serum creatinine values greater than 1.5 mg/dL) it
rises to 10% to 35%. In addition, there are suspected risk factors
that should be taken into consideration when considering the value
of contrast-enhanced imaging.
Hypersomolar radiocontrast medium
PGE2
ANF
Systemic
Endothelin
ATPase
hypoxemia
Vasopressin
Adenosine Blood viscosity Osmotic load
to distal tubule
PGI2
RBF RBF
Calcium
antagonists
Theophylline
Net O2 consumption
Net O2 delivery
Cell injury
TH protein
Intrarenal number
of macrophages, T cells
Stimulation of mesangium
Tubular obstruction
RBF
GFR
Superoxidase
dismutase
Reactive O2 species
lipid peroxidase
Contrast associated nephropathy
FIGURE 11-22
A proposed model of the mechanisms involved in radiocontrast
mediuminduced renal dysfunction. Based on experimental mod-
PREVENTION OF CONTRAST
ASSOCIATED NEPHROPATHY
Hydrate patient before the study (1.5 mL/kg/h) 12 h before and after.
Hemodynamically stabilize hemodynamics.
Minimize amount of contrast medium administered.
Use nonionic, iso-osmolar contrast media for patients at high risk (see Figure 11-21).
FIGURE 11-23
Prevention of contrast-associated nephropathy. The goal of management is the prevention of contrast-associated nephropathy.
11.15
els, a consensus is developing to the effect that contrast-associated nephropathy involves combined toxic and hypoxic insults
to the kidney [35]. The initial glomerular vasoconstriction that
follows the injection of radiocontrast medium induces the
liberation of both vasoconstrictor (endothelin, vasopressin) and
vasodilator (prostaglandin E2 [PGE2], adenosine, atrionatiuretic
factor {ANP}) substances. The net effect is reduced oxygen delivery to tubule cells, especially those in the thick ascending limb
of Henle. Because of the systemic hypoxemia, raised blood viscosity, inhibition of sodium-potassiumactivated ATPase and the
increased osmotic load to the distal tubule at a time of reduced
oxygen delivery, the demand for oxygen increases, resulting in
cellular hypoxia and, eventually cell death. Additional factors
that contribute to the acute renal dysfunction of contrast-associated nephropathy are the tubule obstruction that results from
increased secretion of Tamm-Horsfall proteins and the liberation
of reactive oxygen species and lipid peroxidation that accompany cell death. As noted in the figure, calcium antagonists and
theophylline (adenosine receptor antagonist) are thought to
act to diminish the degree of vasoconstriction induced by contrast medium.
The clinical presentation of contrast-associated nephropathy
involves an asymptomatic increase in serum creatinine within 24
hours of a radiographic imaging study using contrast medium,
with or without oliguria [36].
We have recently reviewed the clinical outcome of 281 patients
with contrast-associated nephropathy according to the presence
or absence of oliguric acute renal failure at the time of diagnosis.
Of oliguric acute renal failure patients, 32% have persistent
elevations of serum creatinine at recovery and half require permanent dialysis. In the absence of oliguric acute renal failure
the serum creatinine value does not return to baseline in 24%
of patients, approximately a third of whom require permanent
dialysis. Thus, this is not a benign condition but rather one
whose defined risks are not only permanent dialysis but also
death. GFRglomerular filtration rate; RBFrenal blood flow;
THTamm Horsfall protein.
Thus it is important to select the least invasive diagnostic procedure that provides the most information, so that the patient can
make an informed choice from the available clinical alternatives.
Since radiographic contrast imaging is frequently performed
for diabetic nephropathy, congestive heart failure, or chronic
renal failure, concurrent administration of renoprotective
agents has become an important aspect of imaging. A list of
maneuvers that minimize the risk of contrast-associated
nephropathy is contained in this table. The correction of
prestudy volume depletion and the use of active hydration
before and during the procedure are crucial to minimizing the
risk of contrast-associated nephropathy. Limiting the total
volume of contrast medium and using nonionic, isoosmolar
media have proven to be protective for high-risk patients.
Pretreatment with calcium antagonists is an intriguing but
unsubstantiated approach.
11.16
Acute Renal Failure
References
1. Bennett WM, Porter GA: Overview of clinical nephrotoxicity. In
Toxicology of the Kidney, edn 2. Edited by Hook JB, Goldstein RS.
Raven Press, 1993:6197.
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Diagnostic Evaluation of
the Patient with Acute
Renal Failure
Brian G. Dwinnell
Robert J. Anderson
cute renal failure (ARF) is abrupt deterioration of renal function sufficient to result in failure of urinary elimination of
nitrogenous waste products (urea nitrogen and creatinine).
This deterioration of renal function results in elevations of blood urea
nitrogen and serum creatinine concentrations. While there is no disagreement about the general definition of ARF, there are substantial
differences in diagnostic criteria various clinicians use to define ARF
(eg, magnitude of rise of serum creatinine concentration). From a clinical perspective, for persons with normal renal function and serum
creatinine concentration, glomerular filtration rate must be dramatically reduced to result in even modest increments (eg, 0.1 to 0.3
mg/dL) in serum creatinine concentration. Moreover, several studies
demonstrate a direct relationship between the magnitude of serum
creatinine increase and mortality from ARF. Thus, the clinician must
carefully evaluate all cases of rising serum creatinine.
The process of urine formation begins with delivery of blood to the
glomerulus, filtration of the blood at the glomerulus, further processing of the filtrate by the renal tubules, and elimination of the formed
urine by the renal collecting system. A derangement of any of these
processes can result in the clinical picture of rapidly deteriorating
renal function and ARF. As the causes of ARF are multiple and since
subsequent treatment of ARF depends on a clear delineation of the
cause, prompt diagnostic evaluation of each case of ARF is necessary.
CHAPTER
12
12.2
Acute Renal Failure
RATIONALE FOR ORGANIZED

APPROACH TO ACUTE RENAL FAILURE
PRESENTING FEATURES OF ACUTE RENAL FAILURE
Common
Rising BUN or creatinine
Oligoanuria
Less common
Symptoms of uremia
Characteristic laboratory abnormalities
Common
Present in 1%2% of hospital admissions
Develops after admission in 1%5% of noncritically ill patients
Develops in 5%20% after admission to an intensive care unit
Multiple causes
Prerenal
Postrenal
Renal
Therapy dependent upon diagnosing cause
Prerenal: improve renal perfusion
Postrenal: relieve obstruction
Renal: identify and treat specific cause
Poor outcomes
Twofold increased length of stay
Two- to eightfold increased mortality
Substantial morbidity
FIGURE 12-1
Rationale for an organized approach to acute renal failure (ARF).
An organized approach to the patient with ARF is necessary, as this
disorder is common and is caused by several insults that operate via
numerous mechanisms. Successful amelioration of the renal failure
state depends on early identification and treatment of the cause of
the disorder [17]. If not diagnosed and treated and reversed quickly, it can lead to substantial morbidity and mortality.
FIGURE 12-2
Presenting features of acute renal failure (ARF). ARF usually comes
to clinical attention by the finding of either elevated (or rising)
blood urea nitrogen (BUN) or serum creatinine concentration. Less
commonly, decreased urine output ( less than 20 mL per hour) heralds the presence of ARF. It is important to acknowledge, however,
that at least half of all cases of ARF are nonoliguric [26]. Thus,
healthy urine output does not ensure normal renal function. Rarely,
ARF comes to the attention of the clinician because of symptoms
of uremia (eg, anorexia, nausea, vomiting, confusion, pruritus) or
laboratory findings compatible with renal failure (metabolic acidosis, hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, hypermagnesemia, anemia).
Blood Urea Nitrogen, Creatinine, and Renal Failure

OVERVIEW OF BLOOD UREA NITROGEN AND SERUM CREATININE
Source
Constancy of production
Renal handling
Value as marker for
glomerular filtration rate
Correlation with
uremic symptoms
Blood Urea Nitrogen
Serum Creatinine
Protein that can be of exogenous

or endogenous origin
Variable
Completely filtered; significant
tubular reabsorption
Modest
Nonenzymatic hydrolysis of creatine

released from skeletal muscle
More stable
Completely filtered; some tubular secretion
Good
Poor
Good in steady state
FIGURE 12-3
Overview of blood urea nitrogen (BUN) and serum creatinine. Given the central role of
BUN and serum creatinine in determining the presence of renal failure, an understanding
of the metabolism of these substances is needed. Urea nitrogen derives from the breakdown of proteins that are delivered to the liver. Thus, the urea nitrogen production rate
can vary with exogenous protein intake and

endogenous protein catabolism. Urea nitrogen is a small, uncharged molecule that is
not protein bound, and as such, it is readily
filtered at the renal glomerulus. Urea nitrogen undergoes renal tubular reabsorption
by specific transporters. This tubular reabsorption limits the value of BUN as a marker for glomerular filtration. However, the
BUN usually correlates with the symptoms
of uremia. By contrast, the production of
creatinine is usually more constant unless
there has been a marked reduction of skeletal muscle mass (eg, loss of a limb, prolonged starvation) or diffuse muscle injury.
Although creatinine undergoes secretion
into renal tubular fluid, this is very modest
in degree. Thus, a steady-stable serum creatinine concentration is usually a relatively
good marker of glomerular filtration rate as
noted in Figure 12-5.
Diagnostic Evaluation of the Patient with Acute Renal Failure
BLOOD UREA NITROGEN (BUN)-CREATININE RATIO

> 10
< 10
Increased protein intake

Catabolic state
Fever
Sepsis
Trauma
Corticosteroids
Tissue necrosis
Tetracyclines
Diminished urine flow
Prerenal state
Postrenal state
Starvation
Advanced liver disease
Postdialysis state
Drugs that impair tubular secretion
Cimetidine
Trimethoprim
Rhabdomyolysis
FIGURE 12-4
The blood urea nitrogen (BUN)-creatinine ratio. Based on the information in Figure 12-3, the BUN-creatinine ratio often deviates from
the usual value of about 10:1. These deviations may have modest
diagnostic implications. As an example, for reasons as yet unclear,
tubular reabsorption of urea nitrogen is enhanced in low-urine flow
states. Thus, a high BUN-creatinine ratio often occurs in prerenal
and postrenal (see Fig. 12-6) forms of renal failure. Similarly,
enhanced delivery of amino acids to the liver (as with catabolism,
corticosteroids, etc.) can enhance urea nitrogen formation and
increase the BUN-creatinine ratio. A BUN-creatinine ratio lower
than 10:1 can occur because of decreased urea nitrogen formation
(eg, in protein malnutrition, advanced liver disease), enhanced creatinine formation (eg, with rhabdomyolysis), impaired tubular secretion
of creatinine (eg, secondary to trimethoprim, cimetidine), or relatively enhanced removal of the small substance urea nitrogen by dialysis.
FIGURE 12-5
Correlation of steady-state serum creatinine concentration and
glomerular filtration rate (GFR).
CORRELATION OF STEADY-STATE SERUM

CREATININE CONCENTRATION AND
GLOMERULAR FILTRATION RATE (GFR)
Creatinine (mg/dL)
12.3
GFR (mL/min)
1
2
4
8
16
100
50
25
12.5
6.25
Renal Failure
Favors
acute
Favors
chronic
Normal
Kidney size
Small
Normal
Carbamylated hemoglobin
High
Absent
Broad casts on urinalysis
Present
Absent
History of kidney disease,

hypertension,
abnormal urinalysis
Present
Often
present
Anemia, metabolic acidosis,

hyperkalemia, hyperphosphatemia
Usually
present
Usually
complete
Reversibility with time
Sometimes,
partial
FIGURE 12-6
Categories of renal failure. Once the presence of renal failure is
ascertained by elevated blood urea nitrogen (BUN) or serum creatinine value, the clinician must decide whether it is acute or chronic.
When previous values are available for review, this judgment is
made relatively easily. In the absence of such values, the factors
depicted here may be helpful. Hemoglobin potentially undergoes
nonenzymatic carbamylation of its terminal valine [8]. Thus, similar to the hemoglobin A1C value as an index of blood sugar control, the level of carbamylated hemoglobin is an indicator of the
degree and duration of elevated BUN, but, this test is not yet widely available. The presence of small kidneys strongly suggests that
renal failure is at least in part chronic. From a practical standpoint,
because even chronic renal failure often is partially reversible, the
clinician should assume and evaluate for the presence of acute
reversible factors in all cases of acute renal failure.
12.4
Acute Renal Failure
Categorization of Causes of Acute Renal Failure

Acute renal failure
Prerenal
causes
Vascular
disorders
Renal
causes
Glomerulonephritis
Postrenal
causes
Interstitial
nephritis
Ischemia
Tubular
necrosis
Toxins
Pigments
FIGURE 12-7
Acute renal failure (ARF). This figure depicts the most commonly used schema to classify
and diagnostically approach the patient with ARF [1, 6, 9]. The most common general
cause of ARF (60% to 70% of cases) is prerenal factors. Prerenal causes include those secondary to renal hypoperfusion, which occurs in the setting of extracellular fluid loss (eg,
with vomiting, nasogastric suctioning, gastrointestinal hemorrhage, diarrhea, burns, heat
stroke, diuretics, glucosuria), sequestration of extracellular fluid (eg, with pancreatitis,
VASOMOTOR MECHANISMS CONTRIBUTING TO ACUTE RENAL FAILURE

Decreased Renal
Perfusion Pressure
Extracellular fluid volume loss
or sequestration
Impaired cardiac output
Antihypertensive medications
Sepsis
Afferent Arteriolar Constriction
Efferent Arteriolar Dilation
Sepsis
Medications (NSAIDs, cyclosporine,
contrast medium, amphotericin,
alpha-adrenergic agonists)
Hypercalcemia
Postoperative state
Converting enzyme inhibitors

Angiotensin II receptor antagonists
abdominal surgery, muscle crush injury,

early sepsis), or impaired cardiac output. In
most prerenal forms of ARF, one or more
of the vasomotor mechanisms noted in
Figure 12-8 is operative. The diagnostic criteria for prerenal ARF are delineated in
Figure 12-9. Once prerenal forms of ARF
have been ruled out, postrenal forms (ie,
obstruction to urine flow) should be considered. Obstruction to urine flow is a less
common (5% to 15% of cases) cause of
ARF but is nearly always amenable to therapy. The site of obstruction can be
intrarenal (eg, crystals or proteins obstructing the terminal collecting tubules) or
extrarenal (eg, blockade of the renal pelvis,
ureters, bladder, or urethra). The diagnosis
of postrenal forms of ARF is supported by
data outlined in Figure 12-10. After preand postrenal forms of ARF have been considered, attention should focus on the kidney. When considering renal forms of ARF,
it is helpful to think in terms of renal
anatomic compartments (vasculature,
glomeruli, interstitium, and tubules). Acute
disorders involving any of these compartments can lead to ARF.
FIGURE 12-8
Vasomotor mechanisms contributing to acute
renal failure (ARF). Most prerenal forms of
ARF have operational one or more of the
vasomotor mechanisms depicted here [6].
Collectively, these factors lead to diminished
glomerular filtration and ARF. NSAIDs
nonsteroidal anti-inflammatory drugs.
DIAGNOSIS OF POSSIBLE PRERENAL CAUSES OF ACUTE RENAL FAILURE

History
Examination
Laboratory/Other
Extracellular fluid loss or sequestration from skin, gastrointestinal

and/or renal source (see Fig. 12-15)
Orthostatic lightheadedness
Thirst
Oliguria
Symptoms of heart failure
Edema
Orthostatic hypotension
and tachycardia
Dry mucous membranes
No axillary moisture
Decreased skin turgor
Evidence of congestive
heart failure
Presence of edema
Normal urinalysis
Urinary indices compatible with normal
tubular function (see Fig. 12-14)
Elevated BUN-creatinine ratio
Improved renal function with correction
of the underlying cause
Rarely, chest radiography, cardiac ultrasound, gated blood pool scan, central
venous and/or Swan-Ganz wedge
pressure recordings
DIAGNOSIS OF POSSIBLE POSTRENAL CAUSES OF ACUTE RENAL FAILURE

History
Examination
Laboratory/Other
Very young or very old age

Nocturia
Decreased size or force of urine stream
Anticholinergic or alpha-adrenergic
agonist medications
Bladder, prostate, pelvic, or
intra-abdominal cancer
Fluctuating urine volume
Oligoanuria
Suprapubic pain
Urolithiasis
Medication known to produce
crystalluria (sulfonamides, acyclovir,
methotrexate, protease inhibitors)
Distended bladder
Enlarged prostate
Abnormal pelvic examination
Abnormal urinalysis
Elevated BUN-creatinine ratio
Elevated postvoiding
residual volume
Abnormal renal ultrasound,
CT or MRI findings
Improvement after drainage
POSTOPERATIVE ACUTE RENAL FAILURE

Frequency
Predisposing Factors
Preventive Strategies
Elective surgery 1%5%

Emergent or vascular
surgery 5%10%
Comorbidity results in decreased

renal reserve
The surgical experience decreases
renal function (volume shifts,
vasoconstriction)
A second insult usually occurs
(sepsis, reoperation, nephrotoxin,
volume/cardiac issue)
Avoid nephrotoxins
Minimize hospital-acquired infections
(invasive equipment)
Selective use of volume expansion,
vasodilators, inotropes
Preoperative hemodynamic optimization
in selected cases
Increase tissue oxygenation delivery to
supranormal levels in selected cases
12.5
FIGURE 12-9
Diagnosis of possible prerenal causes of
acute renal failure (ARF). Prerenal events
are the most common factors that lead to
contemporary ARF. The historical, physical
examination, and laboratory and other
investigations involved in identifying a prerenal form of ARF are outlined here [1].
BUNblood urea nitrogen.
FIGURE 12-10
Diagnosis of possible postrenal causes of
acute renal failure (ARF). Postrenal causes
of ARF are less common (5% to 15% of
ARF population) but are nearly always
amenable to therapy. This figure depicts the
historical, physical examination and tests
that can lead to an intrarenal (crystal deposition) or extrarenal (blockade of the collecting system) form of obstructive uropathy [1, 6, 9, 10]. BUNblood urea nitrogen; CTcomputed tomography;
MRImagnetic resonance imaging.
FIGURE 12-11
Postoperative acute renal failure (ARF).
The postoperative setting of ARF is very
common. This figure depicts data on the
frequency, predisposing factors, and potential strategies for preventing postoperative
ARF [11, 12].
12.6
Acute Renal Failure
Diagnostic Steps in Evaluating Acute Renal Failure

STEPWISE APPROACH TO DIAGNOSIS OF ACUTE RENAL FAILURE
Step 1
Step 2
Step 3
History
Record review
Physical examination
Urinary bladder catherization
(if oligoanuric)
Urinalysis (see Fig. 12-15)
Consider urinary diagnostic

Consider selected
indices (see Fig. 12-16)
therapeutic trials
Consider need for further
evaluation to exclude
urinary tract obstruction
Consider need for more data
to assess intravascular volume
or cardiac output status
Consider need for additional
blood tests
Consider need for evaluation of
renal vascular status
Step 4
Consider renal biopsy
Consider empiric therapy
for suspected diagnosis
FIGURE 12-12
Stepwise approach to diagnosis of acute renal failure (ARF). The multiple causes, predisposing factors, and clinical settings demand a logical, sequential approach to each case of
ARF. This figure presents a four-step approach to assessing ARF patients in an effort to
delineate the cause in a timely and cost-effective manner. Step 1 involves a focused history,
record review, and examination. The salient features of these analyses are noted in more
detail in Figure 12-13. In many cases, a single bladder catheterization is needed to assess
the degree of residual volume, which should be less than 30 to 50 mL. Urinalysis is a critical part of the initial evaluation of all patients with ARF. Generally, a relatively normal
urinalysis suggests either a prerenal or postrenal cause, whereas a urinalysis containing
cells and casts is most compatible with a renal cause. A detailed schema of urinalysis interpretation in the setting of ARF is depicted in Figure 12-15. Usually, after Step 1 the clinician has a reasonably good idea of the likely cause of the ARF. Sometimes, the information
noted under Step 2 is needed to ascertain definitively the cause of the ARF. More details of
Step 2 are depicted in Figure 12-14. Oftentimes, urinary diagnostic indices (see Fig. 12-16),
are helpful in differentiating between prerenal (intact tubular function) and acute
tubular necrosis (impaired tubular function)
as the cause of renal failure. Sometimes,
further evaluation (usually ultrasonography,
less commonly computed tomography or
magnetic resonance imaging) is needed to
exclude the possibility of bilateral ureteric
obstruction (or single ureteric obstruction
in patients with a single kidney).
Occasionally, additional studies such as
central venous pressure or left ventricular
filling pressure determinations are needed
to better assess whether prerenal factors are
contributing to the ARF. When the cause of
the ARF continues to be difficult to ascertain and renal vascular disorders (see Fig.
12-17 and 12-18), glomerulonephritis (see
Fig. 12-19) or acute interstitial nephritis
(see Fig. 12-20) remain possibilities, additional blood analyses and other tests
described in Figures 12-18 through 12-20
may be indicated. Sometimes, selected therapeutic trials (eg, volume expansion,
maneuvers to increase cardiac index,
ureteric stent or nephrostomy tube relief of
obstruction) are necessary to document the
cause of ARF definitively. Empiric therapy
(eg, corticosteroids for suspected acute
allergic interstitial nephritis) is given as
both a diagnostic and a therapeutic maneuver in selected cases. Rarely, despite all
efforts, the cause of the ARF remains
unknown and renal biopsy is necessary to
establish a definitive diagnosis.
FIRST STEP IN EVALUATION OF ACUTE RENAL FAILURE
History
Disorders that suggest or predispose to renal failure: hypertension, diabetes mellitus,
human immunodeficiency virus, vascular disease, abnormal urinalyses, family history
of renal disease, medication use, toxin or environmental exposure, infection, heart failure, vasculitis, cancer
Disorders that suggest or predispose to volume depletion: vomiting, diarrhea, pancreatitis, gastrointestinal bleeding, burns, heat stroke, fever, uncontrolled diabetes mellitus,
diuretic use, orthostatic hypotension, nothing-by-mouth status, nasogastric suctioning
Disorders that suggest or predispose to obstruction: stream abnormalities, nocturia, anticholingeric medications, stones, urinary tract infections, bladder or prostate disease,
intra-abnominal malignancy, suprapubic or flank pain, anuria, fluctuating urine volumes
Symptoms of renal failure: anorexia, vomiting, reversed sleep pattern, puritus
Record review
Recent events (procedures, surgery)
Medications (see Fig. 12-22)
Vital signs
Intake and output
Body weights
Blood chemistries and hemogram
Skin: rash suggestive of allergy, palpable purpura of vasculitis, livedo reticularis and
digital infarctions suggesting atheroemboli
Eyes: hypertension, diabetes mellitus, Hollenhorst plaques, vasculitis, candidemia
Lungs: rales, rubs
Heart: evidence of heart failure, pericardial disease, jugular venous pressure
Vascular system: bruits, pulses, abdominal aortic aneurysm
Abdomen: flank or suprapubic masses, ascites, costovertebral angle pain
Extremities: edema, pulses, compartment syndromes
Nervous system: focal findings, asterixis, mini-mental status examination
Consider bladder catheterization
Urinalysis (see Fig. 12-13)
FIGURE 12-13
First step in evaluation of acute renal failure.
SECOND STEP IN EVALUATION

OF ACUTE RENAL FAILURE
Urine diagnostic indices (see Fig. 12-16)
Consider need for further evaluation for obstruction
Ultrasonography, computed tomography, or magnetic resonance imaging
Consider need for additional blood tests
Vasculitis/glomerulopathy: human immunodeficiency virus infections, antineutrophilic cytoplasmic antibodies, antinuclear antibodies, serologic tests for hepatitis, systemic bacterial endocarditis and streptococcal infections, rheumatoid factor,
complement, cryoglobins
Plasma cell disorders: urine for light chains, serum analysis for abnormal proteins
Drug screen/level, additional chemical tests
Consider need for evaluation of renal vascular supply
Isotope scans, Doppler sonography, angiography
Consider need for more data to assess volume and cardiac status
Swan-Ganz catheterization
FIGURE 12-14
Second step in evaluation of acute renal failure.
12.7
12.8
Acute Renal Failure
Urinalysis in acute renal failure
Normal
Prerenal,
postrenal,
high oncotic
pressure
(dextran,
mannitol)
Abnormal
RBC
RBC casts
Proteinuria
WBC
WBC casts
Eosinophils
RTE cells
Pigmented
casts
Crystalluria
Low grade
proteinuria
Glomerulopathy,
vasculitis,
thrombotic
microangiopathy
Pyelonephritis,
interstitial
nephritis
Allergic
interstitial
nephritis,
atheroemboli,
glomerulopathy
ATN,
myoglobinuria,
hemoglobinuria
Uric acid,
drugs or toxins
Plasma cell
dyscrasia
FIGURE 12-15
Urinalysis in acute renal failure (ARF). A normal urinalysis suggests
a prerenal or postrenal form of ARF; however, many patients with
ARF of postrenal causes have some cellular elements on urinalysis.
Relatively uncommon causes of ARF that usually present with
oligoanuria and a normal urinalysis are mannitol toxicity and large
doses of dextran infusion. In these disorders, a hyperoncotic state
occurs in which glomerular capillary oncotic pressure, combined
with the intratubular hydrostatic pressure, exceeds the glomerular
capillary hydrostatic pressure and stop glomerular filtration. Red
blood cells (RBCs) can be seen with all renal forms of ARF. When
RBC casts are present, glomerulonephritis or vasculitis is most likely.
Urinary diagnostic indices

in acute renal failure
Prerenal
Hyaline casts
>1.020
>500
<20
<1
<7
<7
Renal
Urinalysis
Specific gravity
Uosm (mOsm/kg H2O)
Una (mEq/L)
FE Na (%)
FE uric acid (%)
FE lithium (%)
Abnormal
~1.010
>300
>40
>2
>15
>20
White blood cells (WBCs) can also be present in small numbers in

the urine of patients with ARF. Large numbers of WBCs and WBC
casts strongly suggest the presence of either pyelonephritis or acute
interstitial nephritis. Eosinolphiluria (Hansels stain) is often present
in either allergic interstitial nephritis or atheroembolic disease [13,
14]. Renal tubular epithelial (RTE) cells and casts and pigmented
granular casts typically are present in pigmenturia-associated ARF
(see Fig. 12-21) and in established acute tubular necrosis (ATN).
The presence of large numbers of crystals on urinalysis, in conjunction with the clinical history, may suggest uric acid, sulfonamides, or
protease inhibitors as a cause of the renal failure.
FIGURE 12-16
Urinary diagnostic indices in acute renal failure (ARF). These
indices have traditionally been used in the setting of oliguria, to
help differentiate between prerenal (intact tubular function) and
acute tubular necrosis (ATN, impaired tubular function). Several
caveats to interpretation of these indices are in order [1]. First, none
of these is completely sensitive or specific in differentiating the prerenal from the ATN form of ARF. Second, often a continuum exists
between early prerenal conditions and late prerenal conditions that
lead to ischemic ATN. Most of the data depicted here are derived
from patients relatively late in the progress of ARF when the serum
creatinine concentrations were 3 to 5 mg/dL. Third, there is often a
relatively large gray area, in which the various indices do not give
definitive results. Finally, some of the indices (eg, fractional excretion of endogenous lithium [FE lithium]) are not readily available in
the clinical setting. The fractional excretion (FE) of a substance is
determined by the formula: U/P substance U/P creatinine 100.
U/Purine-plasma ratio.
12.9
Vascular Mechanisms Involved in Acute Renal Failure

VASCULAR CAUSES OF ACUTE RENAL FAILURE
Arterial
Venous
Large vessels
Renal artery stenosis
Thrombosis
Cross-clamping
Emboli
Atheroemboli
Endocarditis
Atrial fibrillation
Mural thrombus
Tumor
Occlusion
Clot
Tumor
FIGURE 12-17
Vascular causes of acute renal failure (ARF). Once prerenal and
postrenal causes of ARF have been excluded, attention should be
focused on the kidney. One useful means of classifying renal causes
of ARF is to consider the anatomic compartments of the kidney.
Thus, disorders of the renal vasculature (see Fig. 12-18), glomerulus (see Fig. 12-19), interstitium (see Fig. 12-20) and tubules can all
result in identical clinical pictures of ARF [1]. This figure depicts
the disorders of the renal arterial and venous systems that can
result in ARF [15].
Small vessels
Cortical necrosis malignant hypertension
Scleroderma
Vasculitis
Antiphospholipid syndrome
Thrombotic microangiopathies
Thrombotic thrombocytopenic purpura
Postpartum
Medications (mitomycin C, cyclosporine, tacrolimus)
DIAGNOSIS OF POSSIBLE VASCULAR CAUSE OF ACUTE RENAL FAILURE

History
Examination
Laboratory/Other
Factors that predispose to vascular disease

(smoking, hypertension, diabetes mellitus,
hyperlipidemia)
Claudication, stroke, myocardial infarction
Surgical procedure on aorta
Catheterization procedure involving aorta
Selected clinical states (scleroderma, pregnancy)
Selected medications, toxins (cyclosporine,
mitomycin C, cocaine, tacrolimus)
Constitutional symptoms
Marked hypertension
Atrial fibrillation
Scleroderma
Palpable purpura
Abdominal
aortic aneurysm
Diminished pulses
Infarcted toes
Hollendhorst plaques
Vascular bruits
Stigmata of
bacterial endocarditis
Illeus
Thrombocytopenia
Microangiopathic hemolysis
Coagulopathy
Urinalysis with hematuria and
low-grade proteinuria
Abnormal renal isotope scan
and/or Doppler ultrasonography
Renal angiography
Renal or extrarenal tissue analysis
FIGURE 12-18
Diagnosis of a possible vascular cause of
acute renal failure (ARF). This figure depicts
the historical, physical examination, and
testing procedures that often lead to diagnosis of a vascular cause of ARF [1, 15, 16].
12.10
Acute Renal Failure
Acute Glomerulonephritis
DIAGNOSIS OF A POSSIBLE ACUTE GLOMERULAR
PROCESS AS THE CAUSE OF ACUTE RENAL FAILURE
History
Examination
Laboratory/Other
Recent infection
Sudden onset of edema, dyspnea
Systemic disorder
(eg, lupus erythematosus, Wegeners
granulomatosis, Goodpastures syndrome)
No evidence of other causes of renal failure
Hypertension
Edema
Rash
Arthropathy
Prominent
pulmonary findings
Stigmata of bacterial
endocarditis or
visceral abscess
Urinalysis with hematuria, red cell

casts, and proteinuria
Serologic or culture evidence of
recent infection
Laboratory evidence of immunemediated process (low complement,
cryoglobulinemia, antinuclear antibody, anti-DNA, rheumatoid factor,
antiglomerular basement membrane antibody, antineutrophilic
cytoplasmic antibody)
Renal tissue examination
FIGURE 12-19
Diagnosis of a possible acute glomerular
process as the cause of acute renal failure
(ARF). Acute glomerulonephritis is a relatively rare cause of ARF in adults. In the
pediatric age group, acute glomerulonephritis and a disorder of small renal arteries
(hemolytic-uremic syndrome) are relatively
common causes. This figure depicts the historical, examination, and laboratory findings that collectively may support a diagnosis of acute glomerulonephritis as the cause
of ARF [16, 17].
Interstitial Nephritis
DIAGNOSIS OF POSSIBLE ACUTE INTERSTITIAL
NEPHRITIS AS THE CAUSE OF ACUTE RENAL FAILURE
History
Examination
Laboratory/Other
Medication exposure
Severe pyelonephritis
Systemic infection
Fever
Rash
Back or flank pain
Abnormal urinalysis (white blood cells or cell casts,

eosinophils, eosinophilic casts, low-grade proteinuria,
sometimes hematuria)
Eosinophilia
Urinary diagnositc indices compatible with a renal cause
of renal failure (see Fig. 12-16)
Uptake on gallium or indium scan
Renal biopsy
FIGURE 12-20
Diagnosis of possible acute interstitial
nephritis as the cause of acute renal failure
(ARF). This figure outlines the historical,
physical examination and other investigative methods that can lead to identification
of acute interstitial nephritis as the cause
of ARF [18].
12.11
Acute Tubular Necrosis

DIAGNOSIS OF POSSIBLE PIGMENT-ASSOCIATED FORMS OF ACUTE RENAL FAILURE
Myoglobinuria
Hemoglobinuria
History
Examination
Laboratory
History
Examination
Laboratory
Trauma to muscles
Condition known
to predispose to
nontraumatic
rhabdomyolysis
Muscle pain
or stiffness
Dark urine
Can be normal
Muscle edema,
weakness, pain
Neurovascular
entrapment or compartment syndromes
in severe cases
Flank pain
Serum creatinine disproportionately

elevated related to BUN
Elevated (10-fold) enzymes
(CK, SGOT, LDH, adolase)
Elevations of plasma potassium,
uric acid, phosphorus, and
hypocalcemia
Urinalysis with pigmented granular
casts, () stick reaction for blood
in the absence of hematuria, and
myoglobin test if available
Clear plasma
Condition associated with

intravascular hemolysis
(red cell trauma, antibodymediated hemolysis, direct red
cell toxicity, sickle cell disease)
Can be normal
Pallor
Flank pain
Normocytic anemia
High red cell LDH fraction
Reticulocytosis
Low haptoglobin
Urinalysis with pigmented
granular casts, () stick
reaction for blood in absence
of hemataria and reddish
brown or pink plasma
FIGURE 12-21
Diagnosis of possible pigment-associated forms of acute renal failure
(ARF). Once prerenal and postrenal forms of ARF have been ruled
out and renal vascular, glomerular, and interstitial processes seem
unlikely, a diagnosis of acute tubular necrosis (ATN) is probable. A
diagnosis of ATN is thus one of exclusion (of other causes of ARF).
In the majority of cases when ATN is present, one or more of the
three predisposing conditions have been identified to be operational.
These conditions include renal ischemia due to a prolonged prerenal
state, nephrotoxin exposure, and sometimes pigmenturia. A diagnosis
of ATN is supported by the absence of other causes of ARF, the presence of one or more predisposing factors, and the presence of urinary
diagnostic indices and urinalysis suggested of ATN (see Figs. 12-15
and 12-16). A pigmenturic disorder (myloglobinuria or hemoglobinuria) can predispose to ARF. This figure depicts the historical, physical examination, and supporting diagnostic tests that often lead to a
diagnosis of pigment-associated ARF [19]. BUNblood urea nitrogen; CKcreatinine kinase; SGOTserum glutamic-oxaloacetic
transaminase; LDHlactic dehydrogenase.
Nephrotoxin Acute Renal Failure

NEPHROTOXIC ACUTE RENAL FAILURE
Prerenal
Diuretics
Interleukin 2
CEIs
Antihypertensive agents
Tubular toxicity
Aminoglyosides
Cisplatin
Vancomycin
Foscarnet
Pentamidine
Radiocontrast
Amphotercin
Heavy metals
Vasoconstriction
NSAIDs
Radiocontrast agents
Cyclosporine
Tacrolimus
Amphotericin
Endothelial injury
Cyclosporine
Mitomycin C
Tacrolimus
Cocaine
Conjugated estrogens
Quinine
Crystalluria
Sulfonamides
Methotrexate
Acyclovir
Triamterene
Ethylene glycol
Protease inhibitors
Glomerulopathy
Gold
Penicillamine
NSAIDs
Multiple
FIGURE 12-22
Nephrotoxin acute renal failure (ARF). A variety of nephrotoxins
have been implicated in causing 20% to 30% of all cases of ARF.
These potential nephrotoxins can act through a variety of mechanisms to induce renal dysfunction [6, 20, 21]. CEIconverting
enzyme inhibitor; NSAIDnonsteroidal anti-inflammatory drugs.
12.12
Acute Renal Failure
References
1. Anderson RJ, Schrier RW: Acute renal failure. In Diseases of the
Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown;
1997:10691113.
2. Hou SH, Bushinsky D, Wish JB, Harrington JT: Hospital-acquired
renal insufficiency: A prospective study. Am J Med 1983,
74:243248.
3. Shusterman N, Strom BL, Murray TG, et al.: Risk factors and outcome of hospital-acquired acute renal failure. Am J Med 1987,
83:6571.
4. Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure
on mortality. JAMA 1996, 275:14891494.
~ F, Pascual J: Epidemiology of acute renal failure: A prospective,
5. Liano
12. Kellerman PS: Perioperative care of the renal patient. Arch Intern Med
1994, 154:16741681.
13. Nolan CR, Anger MS, Kelleher SP: Eosinophiluria a new method of
detection and definition of the clinical spectrum. N Engl J Med 1986,
315:15161519.
14. Wilson DM, Salager TL, Farkouh ME: Eosinophiluria in atheroembolic renal disease. Am J Med 1991, 91:186191.
15. Abuelo JG: Diagnosing vascular causes of acute renal failure. Ann
Intern Med 1995, 123:601614.
16. Falk RJ, Jennette JC: ANCA small-vessel vasculitis. J Am Soc Nephrol
1997, 8:314322.
6. Thadhani R, Pascual M, Bonventre JV: Acute renal failure. New Engl

J Med 1996, 334:14481460.
17. Kobrin S, Madacio MP: Acute poststreptococcal glomerulonephritis

and other bacterial infection-related glomerulonephritis. In Diseases
of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little,
Brown; 1997:15791594.
7. Feest TG, Round A, Hamad S: Incidence of severe acute renal failure

in adults: Results of a community-based study. Br Med J 1993,
306:481483.
18. Eknoyan G: Acute tubulointerstitial nephritis. In Diseases of the

Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown;
1997:12491272.
8. Davenport A: Differentiation of acute from chronic renal impairment

by detection of carbamylated hemoglobin. Lancet 1993,
341:16141616.
9. Mendell JA, Chertow GM: A practical approach to acute renal failure. Med Clin North Am 1997, 81:731748.
10. Kopp JB, Miller KD, Mican JM, et al.: Crystalluria and urinary tract
abnormalities associated with indinovir. Ann Intern Med 1997,
127:119125.
19. Don BR, Rodriguez RA, Humphreys MH: Acute renal failure associated with pigmenturia as crystal deposits. In Diseases of the Kidney.
Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown;
1997:12731302.
multicenter, community-based study. Kid Int 1996, 50:811818.
11. Charlson ME, MacKenzie CR, Gold JP, Shires T: Postoperative

changes in serum creatinine. Ann Surg 1989, 209:328335.
20. Chaudbury O, Ahmed Z: Drug-induced nephrotoxicity. Med Clin

North Am 1997, 81:705717.
21. Palmer B, Henrich WL: Nephrotoxicity of nonsteroidal anti-inflammatory agents, analgesics, and angiotensin converting enzyme inhibitors. In
Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston:
Little, Brown; 1997:11671188.
Pathophysiology of Ischemic
Cytoskeletal Aspects
Bruce A. Molitoris
Robert Bacallao
schemia remains the major cause of acute renal failure (ARF) in the
adult population [1]. Clinically a reduction in glomerular filtration
rate (GFR) secondary to reduced renal blood flow can reflect
prerenal azotemia or acute tubular necrosis (ATN). More appropriate
terms for ATN are acute tubular dysfunction or acute tubular injury,
as necrosis only rarely is seen in renal biopsies, and renal tubular cell
injury is the hallmark of this process. Furthermore, the reduction in GFR
during acute tubular dysfunction can now, in large part, be related to
tubular cell injury. Ischemic ARF resulting in acute tubular dysfunction secondary to cell injury is divided into initiation, maintenance,
and recovery phases. Recent studies now allow a direct connection to
be drawn between these clinical phases and the cellular phases of
ischemic ARF (Fig. 13-1). Thus, renal function can be directly related
to the cycle of cell injury and recovery.
Renal proximal tubule cells are the cells most injured during renal
ischemia (Fig. 13-2) [2,3]. Proximal tubule cells normally reabsorb 70%
to 80% of filtered sodium ions and water and also serve to selectively
reabsorb other ions and macromolecules. This vectorial transport across
the cell from lumen to blood is accomplished by having a surface membrane polarized into apical (brush border membrane) and basolateral
membrane domains separated by junctional complexes (Fig. 13-3) [4].
Apical and basolateral membrane domains are biochemically and
functionally different with respect to many parameters, including
enzymes, ion channels, hormone receptors, electrical resistance,
membrane transporters, membrane lipids, membrane fluidity, and
cytoskeletal associations. This epithelial cell polarity is essential for
normal cell function, as demonstrated by the vectorial transport of
sodium from the lumen to the blood (see Fig. 13-3). The establishment
CHAPTER
13
13.2
Acute Renal Failure
and maintenance of this specialized organization is a dynamic

and ATP dependent multistage process involving the formation
and maintenance of cell-cell and cell-substratum attachments
and the targeted delivery of plasma membrane components to
the appropriate domains [5]. These processes are very dependent
on the cytoskeleton, in general, and the cytoskeletal membrane
interactions mediated through F-actin (see Fig. 13-2, 13-3), in
particular.
Ischemia in vivo and cellular ATP depletion in cell culture
models (chemical ischemia) are known to produce characteristic surface membrane structural, biochemical, and functional
abnormalities in proximal tubule cells. These alterations occur
in a duration-dependent fashion and are illustrated in Figures
13-2 and 13-3 and listed in Figure 13-4. Ischemia-induced
alterations in the actin cytoskeleton have been postulated to
mediate many of the aforementioned surface membrane
changes [2,6,7]. This possible link between ischemia-induced
actin cytoskeletal alterations and surface membrane structural
and functional abnormalities is suggested by several lines. First,
the actin cytoskeleton is known to play fundamental roles in
surface membrane formation and stability, junctional complex
formation and regulation, Golgi structure and function, and
cellextracellular membrane attachment [2,4,5,8]. Second,
proximal tubule cell actin cytoskeleton is extremely sensitive to
ischemia and ATP depletion [9,10]. Third, there is a strong
correlation between the time course of actin and surface membrane alterations during ischemia or ATP depletion [2,9,10].
Finally, many of the characteristic surface membrane changes
RELATIONSHIP BETWEEN THE CLINICAL AND CELLULAR

PHASES OF ISCHEMIC ACUTE RENAL FAILURE
Clinical Phases
Cellular Phases
Prerenal azotemia
Initiation
Maintenance
Recovery
Vascular and cellular adaptation
ATP depletion, cell injury
Repair, migration, apoptosis, proliferation
Cellular differentiation
induced by ischemia can be mimicked by F-actin disassembly

mediated by cytochalasin D [11]. Although these correlations
are highly suggestive of a central role for actin alterations in the
pathophysiology of ischemia-induced surface membrane damage they fall short in providing mechanistic data that directly
relate actin cytoskeletal changes to cell injury.
Proximal tubule cell injury during ischemia is also known to
be principally responsible for the reduction in GFR. Figure 13-5
illustrates the three known pathophysiologic mechanisms that
relate proximal tubule cell injury to a reduction in GFR.
Particularly important is the role of the cytoskeleton in mediating
these three mechanisms of reduced GFR. First, loss of apical
membrane into the lumen and detachment of PTC result in substrate for cast formation. Both events have been related to actin
cytoskeletal and integrin polarity alterations [1215]. Cell
detachment and the loss of integrin polarity are felt to play a
central role in tubular obstruction (Fig. 13-6). Actin cytoskeletalmediated tight junction opening during ischemia occurs and
results in back-leak of glomerular filtrate into the blood. This
results in ineffective glomerular filtration (Fig. 13-7). Finally,
abnormal proximal sodium ion reabsorption results in large
distal tubule sodium delivery and a reduction in GFR via tubuloglomerular feedback mechanisms [2,16,17].
In summary, ischemia-induced alterations in proximal tubule
cell surface membrane structure and function are in large part
responsible for cell and organ dysfunction. Actin cytoskeletal
dysregulation during ischemia has been shown to be responsible for much of the surface membrane structural damage.
FIGURE 13-1
Relationship between the clinical and cellular phases of ischemic
acute renal failure. Prerenal azotemia results from reduced renal
blood flow and is associated with reduced organ function (decreased
glomerular filtration rate), but cellular integrity is maintained
through vascular and cellular adaptive responses. The initiation
phase occurs when renal blood flow decreases to a level that results
in severe cellular ATP depletion that, in turn, leads to acute cell
injury. Severe cellular ATP depletion causes a constellation of cellular
alterations culminating in proximal tubule cell injury, cell death, and
organ dysfunction [2]. During the clinical phase known as maintenance, cells undergo repair, migration, apoptosis, and proliferation in
an attempt to re-establish and maintain cell and tubule integrity [3].
This cellular repair and reorganization phase results in slowly
improving cell and organ function. During the recovery phase,
cell differentiation continues, cells mature, and normal cell and
organ function return [18].
Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects
MV
ZO
ZA
MT
x
HD
ECM
13.3
FIGURE 13-2
Ischemic acute renal failure in the rat kidney. Light A, B, transmission electron, C, D, and immunofluorescence E, F, microscopy of control renal cortical sections, A, C, E, and after moderate ischemia induced by 25 minutes of renal artery occlusion,
B, D, F. Note the extensive loss of apical membrane structure,
B, D, in proximal (PT) but not distal tubule cells. This has been
shown to correlate with extensive alterations in F-actin as shown
by FITC-phalloidin labeling, E, F. G, Drawing of a proximal
tubule cell under physiologic conditions. Note the orderly
arrangement of the actin cytoskeleton and its extensive interaction with the surface membrane at the zonula occludens (ZO,
tight junction) zonula adherens (ZA, occludens junction), interactions with ankyrin to mediate Na+, K+-ATPase [2] stabilization
and cell adhesion molecule attachment [5,8]. The actin cytoskeleton also mediates attachment to the extracellular matrix
(ECM) via integrins [12,15]. Microtubules (MT) are involved in
the polarized delivery of endocytic and exocytic vesicles to the
surface membrane. Finally, F-actin filaments bundle together via
actin-bundling proteins [19] to mediate amplification of the apical surface membrane via microvilli (MV). The actin bundle
attaches to the surface membrane by the actin-binding proteins
myosin I and ezrin [19,20].
13.4
Acute Renal Failure
Proximal tubule cell
ADP
+P
1
ATP
+
K
Ischemia
d
ate
nti
e
r
iffe
+
Na
+
ADP
K
ATP
Recovery
Inj
ure
Na+
+
K
ATP
+P
1
Death
Apoptosis
ADP
+P
1
ECM
Na+
d
Un
d
ate
nti
e
r
iffe
ISCHEMIA INDUCED PROXIMAL TUBULE CELL ALTERATIONS

Alterations
Surface Membrane Alterations
1. Microvilli fusion, internalization, fragmentation and luminal shedding resulting in loss of
surface membrane area and tubular obstruction
2. Loss of surface membrane polarity for lipids and proteins
3. Junctional complex dissociation with unregulated paracellular permeability (backleak)
4. Reduced PTC vectorial transport
Actin Cytoskeletal Alterations
1. Polymerization of actin throughout the cell cytosol
2. Disruption and delocalization of F-actin structures including stress fibers, cortical actin
and the junctional ring
3. Accumulation of intracellular F-actin aggregates containing surface membrane proteinsmyosin I, the tight junction proteins ZO-1, ZO-2, cingulin
4. Disruption and dissociation of the spectrin cytoskeleton
5. Disruption of microtubules during early reflow in vivo
6. The cytoskeleton of proximal tubule cells, as compared to distal tubule cells, is more
sensitive to ischemia in vivo and ATP depletion in vitro
Necrosis
References
[21]
[2,22,23]
[6,2427]
[28]
[6,16,29]
[2,7,16]
[20,30]
[31,32]
[33]
[6,16,34]
FIGURE 13-3
Fate of an injured proximal tubule cell.
The fate of a proximal tubule cell after an
ischemic episode depends on the extent and
duration of the ischemia. Cell death can
occur immediately via necrosis or in a more
programmed fashion (apoptosis) hours to
days after the injury. Fortunately, most cells
recover either in a direct fashion or via
an intermediate undifferentiated cellular
pathway. Again, the severity of the injury
determines the route taken by a particular
cell. Adjacent cells are often injured to
varying degrees, especially during mild to
moderate ischemia. It is believed that the
rate of organ functional recovery relates
directly to the severity of cell injury during
the initiation phase. ECMextracellular
membrane; Na+sodium ion; K+potassium ion; P1phosphate.
FIGURE 13-4
Ischemia induced proximal tubule cell
alterations.
13.5
Efferent arteriole
Glomerular
plasma flow
Glomerular
hydrostatic
pressure
Glomerular
filtration
Intratubular
pressure
Afferent
arteriolar
constriction
Glomerular
pressure
D
Obstruction
Obstructing
cast
Backleak
Leakage of
filtrate
D
RG
RGD
RG
D
Afferent arteriole
FIGURE 13-5
Mechanisms of proximal tubule cellmediated reductions in glomerular filtration rate
(GFR) following ischemic injury. A, GFR
depends on four factors: 1) adequate blood
flow to the glomerulus; 2) an adequate
glomerular capillary pressure as determined
by afferent and efferent arteriolar resistance; 3) glomerular permeability; and
4) low intratubular pressure. B, Afferent
arteriolar constriction diminishes GFR by
reducing blood flowand, therefore,
glomerular capillary pressure. This occurs
in response to a high distal sodium delivery
and is mediated by tubular glomerular
feedback. C, Obstruction of the tubular
lumen by cast formation increases tubular
pressure and, when it exceeds glomerular
capillary pressure, a marked decrease or no
filtration occurs. D, Back-leak occurs when
the paracellular space between cells is open
for the flux of glomerular filtrate to leak
back into the extracellular space and into
the blood stream. This is believed to occur
through open tight junctions.
D
RG
D
RG
Normal
D
RG
RGD
FIGURE 13-6
Overview of potential therapeutic effects of cyclic integrin-binding
peptides. A, During ischemic injury, tubular obstruction occurs as a
result of loss of apical membrane, cell contents, and detached cells
released into the lumen. B, Also, basolateral integrins diffuse to the
apical region of the cell. Biotinylated cyclic peptides containing the
sequence cRGDDFV bind to desquamated cells in the ascending
limb of the loop of Henle and in proximal tubule cells in ischemic
rat kidneys. The desquamated cells can adhere to injured cells or
aggregate, causing tubule obstruction.
13.6
Acute Renal Failure
cRGDDFLG
1400
cRGDDFV
cRDADFV
Control
1200
GFR, l/min
1000
800
***
x
**
x
Day 2
Day 3
*
**
x
600

C, When cyclic peptides that contain the RGD canonical binding
site of integrins are perfused intra-arterially, the peptides ameliorate the extent of acute renal failure, as demonstrated by a higher
glomerular filtration rate (GFR) in rats receiving peptide containing
the RGD sequence. B, Proposed mechanism of renal protection by
cyclic RGD peptides. By adhering to the RGD binding sites of the
integrins located on the apical plasma membrane or distributed
randomly on desquamated cells, the cyclic peptide blocks cellular
aggregation and tubular obstruction [1215]. (Courtesy of MS
Goligorski, MD.)
400
200
0
Pre-Op
Day 1
TER vs. Time
80
ATP depleted
ATP depleted
70
Control
Repletion buffer added
TER, -cm2
60
50
40
30
20
10
0
0
10
20
30
40
Time,min
60
90
120
150
FIGURE 13-7
Functional and morphologic changes in tight junction integrity associated with ischemic injury or intracellular ATP depletion. A and B,
Ruthenium red paracellular permeability in rat proximal tubules.
A, In control kidneys, note the electron-dense staining of the brush
border, which cuts off at the tight junctions (tj, arrows). B, Sections
from a perfusion-fixed kidney after 20 minutes of renal artery crossclamp [35]. The electron-dense staining can be seen at cell contact
sites beyond the tight junction (arrows). The paracellular pathway
is no longer sealed by the tight junction, permitting backleak of
the electron-dense ruthenium red. C, Changes in the transepithelial
resistance (TER) versus time during ATP depletion and ATP repletion [36]. Paracellular resistance to electron movement
13.7

(the TER falls to zero with ATP depletion).
The cellular junctional complex that controls
the TER is the tight junction. When the TER
falls to zero, this suggests that tight junction
structural integrity has been compromised. D
and E, Staining of renal epithelial cells with
antibodies that bind to a component of the
tight junction, ZO-1 [37]. D, ZO-1 staining in
untreated Mardin-Darby carnine kidney
(MDCK) cells. ZO-1 is located at the periphery of cells at cell contact sites, forming a continuous linear contour. E, In ATPdepleted
cells the staining pattern is discontinuous.
F and G, Ultrastructural analysis of the tight
junction in MDCK cells. In untreated MDCK
cells, electron micrographs of the tight junction shows a continuous ridge like structure in
freeze fracture preparations [38]. In ATP
depleted cells the strands are disrupted, forming aggregates (arrows). Note that the continuous strands are no longer present and large
gaps are observable.
Acknowledgment
These studies were in part supported by the National Institute
of Diabetes and Digestive and Kidney Diseases Grants DK
41126 (BAM) and DK4683 (RB) and by an American Heart
Association Established Investigator Award (BAM), a VA

Merrit Review Grant (BAM), and a NKF Clinical Scientist
Award (RB).
13.8
Acute Renal Failure
References
1.
~o F, Pascual J, Madrid Acute Renal Failure Study Group:

Lian
Epidemiology of acute renal failure: A prospective, multicenter,
community-based study. Kidney Int 1996, 50:811818.
2.
Molitoris BA, Wagner MC: Surface membrane polarity of proximal

tubular cells: Alterations as a basis for malfunction. Kidney Int 1996,
49:15921597.
3.
Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl

J Med 1996, 334:14481457.
4.
Drubin DG, Nelson WJ: Origins of cell polarity. Cell 1996,

84:335344.
5.
Mays RW, Nelson WJ, Marrs JA: Generation of epithelial cell polarity:
Roles for protein trafficking, membrane-cytoskeleton, and E-cadherinmediated cell adhesion. Cold Spring Harbor Symposia on
Quantitative Biol 1995, 60:763773.
6.
7.
8.
Bacallao R, Garfinkel A, Monke S, et al.: ATP depletion: A novel

method to study junctional properties in epithelial tissues. I.
Rearrangement of the actin cytoskeleton. J Cell Sci 1994,
107:33013313.
Kroshian VM, Sheridan AM, Lieberthal W: Functional and cytoskeletal
changes induced by sublethal injury in proximal tubular epithelial
cells. Am J Physiol 1994, F21F30.
Fish EM, Molitoris BA: Alterations in epithelial polarity and the
pathogenesis of disease states. N Engl J Med 1994, 330:15801588.
9.
Glaumann B, Glauman H, Berezesky IK, et al.: Studies on the cellular

recovery from injury II. Ultrastructural studies on the recovery of the
pars convoluta of the proximal tubule of the rat kidney from temporary ischemia. Virchows Arch B 1977, 24:118.
10. Kellerman PS, Norenberg SL, Jones GM: Early recovery of the actin
cytoskeleton during renal ischemic injury in vivo. Am J Kidney Dis
1996, 16:3342.
11. Kellerman PS, Clark RAF, Hoilien CA, et al.: Role of microfilaments
in the maintenance of proximal tubule structural and functional
integrity. Am J Physiol 1990, 259:F279F285.
12. Noiri E, Gailit J, Gurrath M, et al.: Cyclic RGD peptides ameliorate
ischemic acute renal failure in rats. Kidney Int 1994, 46:10501058.
13. Noiri E, Goligorsky MS, Som P: Radiolabeled RGD peptides as diagnostic tools in acute renal failure and tubular obstruction. J Am Soc
Nephrol 1996, 7:26822688.
14. Romanov V, Noiri E, Czerwinski G, et al.: Two novel probes reveal
tubular and vascular RGD binding sites in the ischemic rat kidney.
Kidney Int 1997, 52:92102.
15. Goligorsky MS, Noiri E, Romanov V, et al.: Therapeutic potential of
RGD peptides in acute renal failure. Kidney Int 1997, 51:14871493.
16. Molitoris BA, Dahl R, Geerdes AE: Cytoskeleton disruption and
apical redistribution of proximal tubule Na+,K+-ATPase during
ischemia. Am J Physiol 1992, 263:F488F495.
17. Alejandro V, Scandling JD, Sibley RK, et al.: Mechanisms of filtration
failure during postischemic injury of the human kidney: A study of
the reperfused renal allograft. J Clin Invest 1995, 95:820831.
18. Bacallao R, Fine LG: Molecular events in the organization of renal
tubular epithelium: From nephrogenesis to regeneration. Am J Physiol
1989, 257:F913F924.
19. Molitoris BA: Putting the actin cytoskeleton into perspective: pathophysiology of ischemic alterations. Am J Physiol 1997,
272:F430F433.
20. Wagner MC, Molitoris BA: ATP depletion alters myosin Ib cellular
location in LLC-PK1 cells. Am J Physiol 1997, 272:C1680C1690.
21. Venkatachalam MA, Jones DB, Rennke HG, et al.: Mechanism of
proximal tubule brush border loss and regeneration following mild
ischemia. Lab Invest 1981, 45:355365.
22. Ritter D, Dean AD, Guan ZH, et al.: Polarized distribution of renal
natriuretic peptide receptors in normal physiology and ischemia.
Am J Physiol 1995, 269:F918F925.
23. Alejandro VSJ, Nelson WJ, Huie P, et al.: Postischemic injury, delayed
function and Na+/K+-ATPase distribution in the transplanted kidney.
Kidney Int 1995, 48:13081315.
24. Donohoe JF, Venkatachalam MA, Benard DB, et al.: Tubular leakage
and obstruction after renal ischemia: Structural-functional correlations. Kidney Int 1978, 13:208222.
25. Molitoris BA, Falk SA, Dahl RH: Ischemic-induced loss of epithelial
polarity. Role of the tight junction. J Clin Invest 1989, 84:13341339.
26. Mandel LJ, Bacallao R, Zampighi G: Uncoupling of the molecular
fence and paracellular gate functions in epithelial tight junctions.
Nature 1993, 361:552555.
27. Kwon O, Nelson J, Sibley RK, et al.: Backleak, tight junctions and
cell-cell adhesion in postischemic injury to the renal allograft
(Abstract). J Am Soc Nephrol 1996, 7:A2907.
28. Molitoris BA. Na+-K+-ATPase that redistributes to apical membrane
during ATP depletion remains functional. Am J Physiol 1993,
265:F693F597.
29. Kellerman PS: Exogenous adenosine triphosphate (ATP) proximal
tubule microfilament structure and function in vivo in a maleic acid
model of ATP depletion. J Clin Invest 1993, 92:19401949.
30. Tsukamoto T, Nigam SK: ATP depletion causes tight junction proteins
to form large, insoluble complexes with cytoskeletal proteins in renal
epithelial cells. J Biol Chem 1997, 273:F463F472.
31. Molitoris BA, Dahl R, Hosford M: Cellular ATP depletion induces
disruption of the spectrin cytoskeletal network. Am J Physiol 1996,
271:F790F798.
32. Edelstein CL, Ling H, Schrier RW: The nature of renal cell injury.
Kidney Int 1997, 51:13411351.
33. Abbate M, Bonventre JV, Brown D: The microtubule network of renal
epithelial cells is disrupted by ischemia and reperfusion. Am J Physiol
1994, 267:F971F978.
34. Sheridan AM, Schwartz JH, Kroshian VM, et al.: Renal mouse proximal tubular cells are more susceptible than MDCK cells to chemical
anoxia. Am J Physiol 1993, 265:F342F350.
35. Molitoris BA, Falk SA, Dahl RH: Ischemia-induced loss of epithelial
polarity. Role of the tight junction. J Clin Invest 1989, 84:13341339.
36. Doctor RB, Bacallao R, Mandel LJ: Method for recovering ATP
content and mitochondrial function after chemical anoxia in renal
cell cultures. Am J Physiol 1994, 266:C1803C1811.
37. Stevenson BR, Siliciano JD, Mooseker MS, et al.: Identification of
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103:755766.
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Pathophysiology
of Ischemic Acute
Renal Failure
Michael S. Goligorsky
Wilfred Lieberthal
cute renal failure (ARF) is a syndrome characterized by an

abrupt and reversible kidney dysfunction. The spectrum of
inciting factors is broad: from ischemic and nephrotoxic agents
to a variety of endotoxemic states and syndrome of multiple organ
failure. The pathophysiology of ARF includes vascular, glomerular
and tubular dysfunction which, depending on the actual offending
stimulus, vary in the severity and time of appearance. Hemodynamic
compromise prevails in cases when noxious stimuli are related to
hypotension and septicemia, leading to renal hypoperfusion with secondary tubular changes (described in Chapter 13). Nephrotoxic
offenders usually result in primary tubular epithelial cell injury,
though endothelial cell dysfunction can also occur, leading to the
eventual cessation of glomerular filtration. This latter effect is a consequence of the combined action of tubular obstruction and activation
of tubuloglomerular feedback mechanism. In the following pages we
shall review the existing concepts on the phenomenology of ARF
including the mechanisms of decreased renal perfusion and failure of
glomerular filtration, vasoconstriction of renal arterioles, how formed
elements gain access to the renal parenchyma, and what the sequelae
are of such an invasion by primed leukocytes.
CHAPTER
14
14.2
Acute Renal Failure
Vasoactive Hormones
Ischemic or toxic insult
Tubular injury and
dysfunction
Hemodynamic changes
Afferent arteriolar
vasoconstriction
Mesangial
contraction
Reduced GPF and P
Reduced glomerular
filtration surface area
available for filtration
and a fall in Kf
Reduced tubular
reabsorption of NaCl
Increased delivery of
NaCl to distal nephron
(macula densa) and
activation of TG feedback
FIGURE 14-1
Pathophysiology of ischemic and toxic acute renal
failure (ARF). The severe reduction in glomerular
filtration rate (GFR) associated with established
ischemic or toxic renal injury is due to the combined effects of alterations in intrarenal hemodynamics and tubular injury. The hemodynamic alterations associated with ARF include afferent arteriolar constriction and mesangial contraction, both of
Ischemic or toxic injury

to the kidney
Increase in
vasoconstrictors
Deficiency of
vasodilators
Angiotensin II
Endothelin
Thromboxane
Adenosine
Leukotrienes
Platelet-activating
factor
PGI2
EDNO
Imbalance in vasoactive hormones

causing persistent intrarenal
vasoconstriction
Persistent medullary hypoxia
Backleak of
glomerular filtrate
Backleak of urea,
creatinine,
and reduction in
"effective GFR"
Tubular obstruction
Compromises patency
of renal tubules and
prevents the recovery
of renal function
which directly reduce GFR. Tubular injury reduces

GFR by causing tubular obstruction and by allowing backleak of glomerular filtrate. Abnormalities in
tubular reabsorption of solute may contribute to
intrarenal vasoconstriction by activating the tubuloglomerular (TG) feedback system. GPFglomerular plasmaflow; Pglomerular pressure; Kf
glomerular ultrafiltration coefficient.
FIGURE 14-2
Vasoactive hormones that may be responsible for the hemodynamic abnormalities in acute
tubule necrosis (ATN). A persistent reduction in renal blood flow has been demonstrated
in both animal models of acute renal failure (ARF) and in humans with ATN. The mechanisms responsible for the hemodynamic alterations in ARF involve an increase in the
intrarenal activity of vasoconstrictors and a deficiency of important vasodilators. A number of vasoconstrictors have been implicated in the reduction in renal blood flow in ARF.
The importance of individual vasoconstrictor hormones in ARF probably varies to some
extent with the cause of the renal injury. A deficiency of vasodilators such as endotheliumderived nitric oxide (EDNO) and/or prostaglandin I2 (PGI2) also contributes to the renal
hypoperfusion associated with ARF. This imbalance in intrarenal vasoactive hormones
favoring vasoconstriction causes persistent intrarenal hypoxia, thereby exacerbating tubular injury and protracting the course of ARF.
14.3
Pathophysiology of Ischemic Acute Renal Failure
Glomerular basement
membrane
Glomerular capillary
endothelial cells
M
Glomerular epithelial
cells
M
Mesangial cell contraction
Angiotensin II
Endothelin1
Thromboxane
Sympathetic nerves
FIGURE 14-3
The mesangium regulates single-nephron glomerular filtration rate
(SNGFR) by altering the glomerular ultrafiltration coefficient (Kf).
This schematic diagram demonstrates the anatomic relationship
between glomerular capillary loops and the mesangium. The
mesangium is surrounded by capillary loops. Mesangial cells (M)
are specialized pericytes with contractile elements that can respond
to vasoactive hormones. Contraction of mesangium can close and
prevent perfusion of anatomically associated glomerular capillary
loops. This decreases the surface area available for glomerular filtration and reduces the glomerular ultrafiltration coefficient.
Mesangial cell relaxation

Prostacyclin
EDNO
Afferent arteriole
Periportal
cell
Extraglomerular
mesangial cells
Macula densa
cells
FIGURE 14-4
A, The topography of juxtaglomerular apparatus (JGA), including
macula densa cells (MD), extraglomerular mesangial cells (EMC),
and afferent arteriolar smooth muscle cells (SMC). Insets schematically illustrate, B, the structure of JGA; C, the flow of information
within the JGA; and D, the putative messengers of tubuloglomerular feedback responses. AAafferent arteriole; PPCperipolar cell;
EAefferent arteriole; GMCglomerular mesangial cells.
(Modified from Goligorsky et al. [1]; with permission.)
Glomerus
AA
AA
AA
MD
MD
SMC+GC
GMC
GMC
EA
EMC
G
EMC
GMC
EA
PPC
PPC
PPC
EMC
MD
Chloride
Adenosine
PGE2
Angiotensin
Nitric oxide
Osmolarity
Unknown?
EA
14.4
Acute Renal Failure
The normal tubuloglomerular (TG) feedback mechanism

4. Afferent arteriolar and mesangial
contraction reduce SNGFR back toward
control levels.
3. Renin is released from specialized

cells of JGA and the intrarenal renin
angiotensin system generates release
of angiotensin II locally.
2. The composition of filtrate

passing the macula densa is
altered and stimulates the JGA.
1. SNGFR increases
causing increase
in delivery of solute
to the distal nephron.
Role of TG feedback in ARF

4. Afferent arteriolar and mesangial
contraction reduce SNGFR below
normal levels.
1. Renal epithelial cell injury

reduces reabsorption
of NaCl by proximal tubules.
3. Local release of
angiotensin II
is stimulated.
2. The composition of filtrate

passing the macula densa is
altered and stimulates the JGA.
FIGURE 14-5
The tubuloglomerular (TG) feedback mechanism. A, Normal TG feedback. In the normal kidney, the TG feedback mechanism is
a sensitive device for the regulation of the
single nephron glomerular filtration rate
(SNGFR). Step 1: An increase in SNGFR
increases the amount of sodium chloride
(NaCl) delivered to the juxtaglomerular
apparatus (JGA) of the nephron. Step 2:
The resultant change in the composition of
the filtrate is sensed by the macula densa
cells and initiates activation of the JGA.
Step 3: The JGA releases renin, which
results in the local and systemic generation
of angiotensin II. Step 4: Angiotensin II
induces vasocontriction of the glomerular
arterioles and contraction of the mesangial
cells. These events return SNGFR back
toward basal levels. B, TG feedback in
ARF. Step 1: Ischemic or toxic injury to
renal tubules leads to impaired reabsorption
of NaCl by injured tubular segments proximal to the JGA. Step 2: The composition of
the filtrate passing the macula densa is
altered and activates the JGA. Step 3:
Angiotensin II is released locally. Step 4:
SNGFR is reduced below normal levels. It
is likely that vasoconstrictors other than
angiotensin II, as well as vasodilator hormones (such as PGI2 and nitric oxide) are
also involved in modulating TG feedback.
Abnormalities in these vasoactive hormones
in ARF may contribute to alterations in TG
feedback in ARF.
FIGURE 14-6
Metabolic basis for the adenosine hypothesis. A, Osswalds
hypothesis on the role of adenosine in tubuloglomerular feedback.
B, Adenosine metabolism: production and disposal via the salvage
and degradation pathways. (A, Modified from Osswald et al. [2];
with permission.)
Osswald's Hypothesis
Increased ATP hydrolysis (increased distal Na+ load)
Increased generation of adenosine
Activation of JGA
Afferent arteriolar vasoconstriction

Nerve endings
[Na+]
Na+
ATP
Adenosine
Adenosine
Renin
secretion
Renincontaining
cells
ANG II
Vascular
smooth
muscle
[Cl ]
GFR
ANG I
Signal Transmission
Mediator(s)
Effects
Adenosine nucleotide metabolism

ATP
ADP
AMP
Adenosine
A2
Receptors
Transporter
5'nu
cle
ot
id
a
se
se
AD
Pa
AT
Pas
A1
Phosphorylation
or
degradation
ATP
ADP
AMP
Salvage
pathway
14.5
Adenosine
Inosine
Hypoxanthine
Degradation
pathway
Uric acid
Xanthine
14.6
Acute Renal Failure

FIGURE 14-7
Elevated concentration of adenosine, inosine,
and hypoxanthine in the dog kidney and
urine after renal artery occlusion. (Modified
from Miller et al. [3]; with permission.)
Adenosine,
nmoles/mL
20
15
10
5
Hypoxanthine,
nmoles/mL
Inosine,
nmoles/mL
0
25
20
15
10
5
0
30
25
20
15
10
5
0
1
10
11
12
13
14
15
16
17
18
Volume collected, mL
Post Ischemia
Glomerul I
SNGFR: 17.41.7 nL/min
PFR: 66.65.6 nL/min
Anti-endothelin
Glomeruli II
SNGFR: 27.03.1 nL/min
PFR: 128.714.4 nL/min
FIGURE 14-8
Endothelin (ET) is a potent renal vasoconstrictor. Endothelin (ET)
is a 21 amino acid peptide of which three isoformsET-1, ET-2
and ET-3have been described, all of which have been shown to
be present in renal tissue. However, only the effects of ET-1 on the
kidney have been clearly elucidated. ET-1 is the most potent vasoconstrictor known. Infusion of ET-1 into the kidney induces profound and long lasting vasoconstriction of the renal circulation. A,
The appearance of the rat kidney during the infusion of ET-1 into
the inferior branch of the main renal artery. The lower pole of the
kidney perfused by this vessel is profoundly vasoconstricted and
hypoperfused. B, Schematic illustration of function in separate
populations of glomeruli within the same kidney. The entire kidney
underwent 25 minutes of ischemia 48 hours before micropuncture.
Glomeruli I are nephrons not exposed to endothelin antibody;
Glomeruli II are nephrons that received infusion with antibody
through the inferior branch of the main renal artery. SNGFRsingle nephron glomerular filtration rate; PFRglomerular renal plasma flow rate. (From Kon et al. [4]; with permission.)
FIGURE 14-9
Biosynthesis of mature endothelin-1 (ET-1). The mature ET-1
peptide is produced by a series of biochemical steps. The precursor of active ET is pre-pro ET, which is cleaved by dibasic pairspecific endopeptidases and carboxypeptidases to yield a
39amino acid intermediate termed big ET-1. Big ET-1, which
has little vasoconstrictor activity, is then converted to the mature
21amino acid ET by a specific endopeptidase, the endothelinconverting enzyme (ECE). ECE is localized to the plasma membrane of endothelial cells. The arrows indicate sites of cleavage
of pre-pro ET and big ET.
Preproendothelin1
NH2
COOH
53
74
92
LysArg
14.7
203
ArgArg
Dibasic pairspecific
endopeptidase(s)
Big endothelin
COOH
NH3
TrpVal
Leu Ser Ser

Cys Ser Cys
Met
Endothelin converting
enzyme (ECE)
NH3
Asp
Mature endothelin
Lys
Glu
Cys Val Tyr Phe Cys His Leu Asp Ile
Ile Trp COOH
ET
Plasma
Mature ET
ETB receptor
E
EC
Endothelium
NO
PGI2
Cyclic
GMP
Cyclic
AMP
ECE
Mature ET
ETA receptor
ETB receptor
Vascular
smooth
muscle
Vasoconstriction
Vasodilation
FIGURE 14-10
Regulation of endothelin (ET) action; the
role of the ET receptors. Pre-pro ET is produced and converted to big ET. Big ET is
converted to mature, active ET by endothelin-converting enzyme (ECE) present on the
endothelial cell membrane. Mature ET
secreted onto the basolateral aspect of the
endothelial cell binds to two ET receptors
(ETA and ETB); both are present on vascular smooth muscle (VSM) cells. Interaction
of ET with predominantly expressed ETA
receptors on VSM cells induces vasoconstriction. ETB receptors are predominantly
located on the plasma membrane of
endothelial cells. Interaction of ET-1 with
these endothelial ETB receptors stimulates
production of nitric oxide (NO) and prostacyclin by endothelial cells. The production
of these two vasodilators serves to counterbalance the intense vasoconstrictor activity
of ET-1. PGI2prostaglandin I2.
14.8
Acute Renal Failure
Ischemia
Number of rats
10
Vehicle
BQ123
BQ123(0.1mg/kg min, for 3h)
8
6
4
2
0
Basal
GFR, mL/h
150
24h
control
14
14
14
Ischemia
120
90
60
30
0
Plasma K+, mEq/L
Basal
10
24h
control
Ischemia
FIGURE 14-11
Endothelin-1 (ET-1) receptor blockade ameliorates severe ischemic
acute renal failure (ARF) in rats. The effect of an ETA receptor
antagonist (BQ123) on the course of severe postischemic ARF was
examined in rats. BQ123 (light bars) or its vehicle (dark bars) was
administered 24 hours after the ischemic insult and the rats were
followed for 14 days. A, Survival. All rats that received the vehicle
were dead by the 3rd day after ischemic injury. In contrast, all rats
that received BQ123 post-ischemia survived for 4 days and 75%
recovered fully. B, Glomerular filtration rate (GFR). In both groups
of rats GFR was extremely low (2% of basal levels) 24 hours after
ischemia. In BQ123-treated rats there was a gradual increase in
GFR that reached control levels by the 14th day after ischemia.
C, Serum potassium. Serum potassium increased in both groups but
reached significantly higher levels in vehicle-treated compared to the
BQ123-treated rats by the second day. The severe hyperkalemia
likely contributed to the subsequent death of the vehicle treated
rats. In BQ123-treated animals the potassium fell progressively after
the second day and reached normal levels by the fourth day after
ischemia. (Adapted from Gellai et al. [5]; with permission.)
6
4
2
0
Basal
24h
control
Posttreatment days
Lipid Membrane
Phospholipase A2
Arachidonic acid
NSAID
Cycloxygenase
PGG2
Prostaglandin
intermediates
Thromboxane
TxA2
PGH2
PGF2
PGI2
Prostacyclin
PGE2
FIGURE 14-12
Production of prostaglandins. Arachidonic acid is released from the
plasma membrane by phospholipase A2. The enzyme cycloxygenase
catalyses the conversion of arachidonate to two prostanoid intermediates (PGH2 and PGG2). These are converted by specific enzymes
into a number of different prostanoids as well as thromboxane
(TXA2). The predominant prostaglandin produced varies with the
cell type. In endothelial cells prostacyclin (PGI2) (in the circle) is the
major metabolite of cycloxygenase activity. Prostacyclin, a potent
vasodilator, is involved in the regulation of vascular tone. TXA2 is
not produced in endothelial cells of normal kidneys but may be produced in increased amounts and contribute to the pathophysiology
of some forms of acute renal failure (eg, cyclosporine Ainduced
nephrotoxicity). The production of all prostanoids and TXA2 is
blocked by nonsteroidal anti-inflammatory agents (NSAIDs), which
inhibit cycloxygenase activity.
FIGURE 14-13
Endothelin (ET) receptor blockade ameliorates acute cyclosporineinduced nephrotoxicity. Cyclosporine A (CSA) was administered
intravenously to rats. Then, an ET receptor anatgonist was infused
directly into the right renal artery. Glomerular filtration rate (GFR)
and renal plasma flow (RPF) were reduced by the CSA in the left
kidney. The ET receptor antagonist protected GFR and RPF from
the effects of CSA on the right side. Thus, ET contributes to the
intrarenal vasoconstriction and reduction in GFR associated with
acute CSA nephrotoxicity. (From Fogo et al. [6]; with permission.)
Aorta
Intraarterial
infusion of ETA
receptor antagonist
Cyclosporine A
in circulation
CSA
Right renal
artery
Left renal
artery
GFR and RPF:

near normal
GFR and RPF:

Reduced 20-25%
below normal
Right kidney
Left kidney
Normal basal state

Circulating levels of vasoconstrictors: Low
Afferent arteriolar tone
normal
Intrarenal levels of prostacyclin: Low
Intraglomerular P
normal
GFR normal
Intravascular volume depletion
Circulating levels of vasoconstrictors: High
normal or mildly reduced
Intrarenal levels of prostacyclin: High
Intraglomerular P
GFR
and NSAID administration
Circulating levels of vasoconstrictors: High
severely increased
Intrarenal levels of prostacyclin: Low
14.9
Intraglomerular P
severely reduced
GFR
severely reduced
FIGURE 14-14
Prostacyclin is important in maintaining
renal blood flow (RBF) and glomerular filtration rate (GFR) in prerenal states.
A, When intravascular volume is normal,
prostacyclin production in the endothelial
cells of the kidney is low and prostacyclin
plays little or no role in control of vascular
tone. B, The reduction in absolute or
effective arterial blood volume associated
with all prerenal states leads to an increase
in the circulating levels of a number of of
vasoconstrictors, including angiotensin II,
catecholamines, and vasopressin. The
increase in vasoconstrictors stimulates
phospholipase A2 and prostacyclin production in renal endothelial cells. This increase
in prostacyclin production partially counteracts the effects of the circulating vasoconstrictors and plays a critical role in
maintaining normal or nearly normal RBF
and GFR in prerenal states. C, The effect of
cycloxygenase inhibition with nonsteroidal
anti-inflammatory drugs (NSAIDs) in prerenal states. Inhibition of prostacyclin
production in the presence of intravascular
volume depletion results in unopposed
action of prevailing vasoconstrictors and
results in severe intrarenal vascasoconstriction. NSAIDs can precipitate severe acute
renal failure in these situations.
14.10
Acute Renal Failure
A. VASODILATORS USED IN EXPERIMENTAL ACUTE RENAL FAILURE (ARF)
Vasodilator
ARF Disorder
Time Given in
Relation to Induction
Propranolol
Ischemic
Before, during, after
Phenoxybenzamine
Clonidine
Bradykinin
Acetylcholine
Prostaglandin E1
Prostaglandin E2
Prostaglandin I2
Saralasin
Captopril
Verapamil
Nifedipine
Nitrendipine
Diliazem
Chlorpromazine
Atrial natriuretic
peptide
Toxic
Ischemic
Ischemic
Ischemic
Ischemic
Ischemic, toxic
Ischemic
Toxic, ischemic
Toxic, ischemic
Ischemic, toxic
Ischemic
Toxic
Toxic
Toxic
Ischemic, toxic

After
Before, during
Before, after
After
Before, during
Before
Before
Before
Before, during
Before
After
Observed Effect
Scr, BUN if given before,
during; no effect if given after
Prevented fall in RBF
Scr, BUN
RBF, GFR
RBF; no change in GFR
RBF; no change in GFR
GFR
GFR
RBF; no change in Scr, BUN
RBF; no change in Scr, BUN
RBF, GFR in most studies
GFR
GFR
GFR; recovery time
GFR; recovery time
RBF, GFR
BUNblood urea nitrogen; GFRglomerular filtration rate; RBFrenal blood flow; Scrserum creatinine.
B. VASODILATORS USED TO ALTER COURSE

OF CLINICAL ACUTE RENAL FAILURE (ARF)
Vasodilator
ARF Disorder
Observed Effect
Remarks
Dopamine
Phenoxybenzamine
Phentolamine
Prostaglandin A1
Prostaglandin E1
Dihydralazine
Verapamil
Diltiazem
Nifedipine
Atrial natriuretic
peptide
Ischemic, toxic
Ischemic, toxic
Ischemic, toxic
Ischemic
Ischemic
Ischemic, toxic
Ischemic
Transplant, toxic
Radiocontrast
Ischemic
Improved V, Scr if used early

No change in V, RBF
No change in V, RBF
No change in V, Scr
RBF, no change v, Ccr
RBF, no change V, Scr
Ccr or no effect
Ccr or no effect
No effect
Ccr
Combined with furosemide
Used with dopamine

Used with NE
Prophylactic use
Ccrcreatinine clearance; NEnorepinephrine; RBFrenal blood flow; Scrserum creatinine; Vurine flow rate.
FIGURE 14-15
Vasodilators used in acute renal failure (ARF). A, Vasodilators used in experimental
acute ARF. B, Vasodilators used to alter the course of clinical ARF. (From Conger [7];
with permission.)
14.11

NH2
NH2
NH
NADPH NADP+
O2
H 2O
NH2
NOH
NH2
Modular structure of nitric oxide synthases

H BH4 ARG CaM
FMN
FAD
+
1/
1
2 NADPH /2 NADP
O2
NH
Target domain
H 2O
NH
Dimerization site(s) 1314

+ NO
BH4
BH4
Oxygenase domain
NADPH
Reductase domain
1820
nNOS
23
nitric oxide
45 6 79 1012 151617
1618
1112
2123
2429
23 4 57
1921
2226
eNOS
+
COO
NH3
COO
NH3
A L-arginine
N -hydroxy-L-arginine
COO
NH3
L-citrulline
FIGURE 14-16
Chemical reactions leading to the generation of nitric oxide (NO),
A, and enzymes that catalize them, B. (Modified from Gross [8];
with permission.)
M
iNOS
1921
23 45 6 79 1011 13 1418
23 48
912
Mammalian P450 Reductases
Bacterial Flavodoxins
Plant Ferredoxin NADPH Reductases
B. mega P450
DHF Reductases
Mammalian Syntrophins (GLGF Motif)
B
L-arginine
L-citrulline
Nitric oxide
GTP
GC
Smooth muscle
Vasodilatation
cGMP
Target cell
death
Neurotransmission
Hemoglobin
CNS and PNS
NO3 + NO2
cGMP
Urine excretion
Leukocyte
migration
Endothelium-dependent
vasodilators
+
NO
+
L-Arginine
Platelet
aggregation
+ NOS
NO
Nitroglycerin
+
GTP
sGC +
cGMP
Relaxation
ANP
pGC
DNA damage
Activation of
apoptotic signal
Thiols
mM
Heme- & ironcontaining proteins
M
ROIs
nM
Inhibition of
iron-containing
enzymes
Immune cells
Shear stress
2226
1316
M
NO concentration
NOS
810 131415
1213
Guanylate cyclase
Time
Cell death
Apoptosis
Induction of stress proteins
Inactivation of enzymes
Antioxidant
cGMP (cellular signal)
Consequences
FIGURE 14-17
Major organ, A, and cellular, B, targets of nitric oxide (NO).
A, Synthesis and function of NO. B, Intracellular targets for NO
and pathophysiological consequences of its action. C, Endotheliumdependent vasodilators, such as acetylcholine and the calcium
ionophore A23187, act by stimulating eNOS activity thereby
increasing endothelium-derived nitric oxide (EDNO) production.
In contrast, other vasodilators act independently of the endothelium. Some endothelium-independent vasodilators such as nitroprusside and nitroglycerin induce vasodilation by directly releasing nitric
oxide in vascular smooth muscle cells. NO released by these agents,
like EDNO, induces vasodilation by stimulating the production of
cyclic guanosine monophosphate (cGMP) in vascular smooth muscle (VSM) cells. Atrial natriuretic peptide (ANP) is also an endothelium-independent vasodilator but acts differently from NO. ANP
directly stimulates an isoform of guanylyl cyclase (GC) distinct from
soluble GC (called particulate GC) in VSM. CNScentral nervous
system; GTPguanosine triphosphate; NOSnitric oxide synthase;
PGCparticulate guanylyl cyclase; PNSperipheral nervous system; ROIreduced oxygen intermediates; SGCsoluble guanylyl
cyclase. (A, From Reyes et al. [9], with permission; B, from Kim
et al. [10], with permission.)
14.12
Acute Renal Failure

FIGURE 14-18
Impaired production of endothelium-dependent nitric oxide (EDNO) contributes to the
vasoconstriction associated with established acute renal failure (ARF). Ischemia-reperfusion injury in the isolated erythrocyte-perfused kidney induced persistant intarenal vasoconstriction. The endothelium-independent vasodilators (atrial natriuretic peptide [ANP]
and nitroprusside) administered during the reflow period caused vasodilation and restored
the elevated intrarenal vascular resistance (RVR) to normal. In marked contrast, two
endothelium-dependent vasodilators (acetylcholine and A23187) had no effect on renal
vascular resistance after ischemia-reflow. These data suggest that EDNO production is
impaired following ischemic injury and that this loss of EDNO activity contributes to the
vasoconstriction associated with ARF. (Adapted from Lieberthal [11]; with permission.)
Ischemia (I)
alone
I + ANP
I+
nitroprusside
I+
Acetylcholine
I + A23187
0
20
40
80
60
Increase in RVR above control, %
60
150
O2
BUN
Hypoxia
40
P<.001
30
2.5
1.5
Hypoxia + L-Arg
P<.05
50
P<.01
Hypoxia
mg/dL
Percent LDH release
O2
P<.001
30
1.0
*
*
0.5
Control
20
30
Time, min
40
50
P<.001
50
40
30
NS
20
10
0
Normoxia Hypoxia
Wild type mice
Normoxia Hypoxia
iNOS knockout mice
SCR
10
Ischemia
AS
Vehicle
Control
10
LDH release, %
Cr
P<.001
20
0
3.0
40
50
Control
10
60
100
Hypoxia + L-NAME
P<.001
20
mg/dL
50
FIGURE 14-19
Deleterious effects of nitric oxide (NO) on the viability of renal
tubular epithelia. A, Hypoxia and reoxygenation lead to injury of
tubular cells (filled circles); inhibition of NO production improves
the viability of tubular cells subjected to hypoxia and reoxygenation (triangles in upper graph), whereas addition of L-arginine
enhances the injury (triangles in lower graph). B, Amelioration of
ischemic injury in vivo with antisense oligonucleotides to the
iNOS: blood urea nitrogen (BUN), and creatinine (CR) in rats subjected to 45 minutes of renal ischemia after pretreatment with antisense phosphorothioate oligonucleotides (AS) directed to iNOS or
with sense (S) and scrambled (SCR) constructs. C, Resistance of
proximal tubule cells isolated from iNOS knockout mice to hypoxia-induced injury. LDHlactic dehydrogenase. (A, From Yu et al.
[12], with permission; B, from Noiri et al. [13], with permission;
C, from Ling et al. [14], with permission.)
Radiocontrast
Medulla
Cortex
Percent of baseline
Iothalamate
100
100
50
50
Normal kidneys
Iothalamate
200
Compensatory increase in
PGI2 and EDNO release
Chronic renal
insufficiency
Increased
endothelin
Reduced or absent
increase in PGI2 or EDNO
150
100
100
50
50
Iothalamate
Mild vasoconstriction
Severe vasoconstriction
No loss of GFR
Acute renal failure
0
0
14.13
20
40
Minutes
No pretreatment
(n = 6)
60
20
40
Minutes
60
Pretreatment with
L-NAME (n = 6)
FIGURE 14-20
Proposed role of nitric oxide (NO) in radiocontrast-induced acute
renal failure (ARF). A, Administration of iothalamate, a radiocontrast dye, to rats increases medullary blood flow. Inhibitors of
either prostaglandin production (such as the NSAID,
indomethacin) or inhibitors of NO synthesis (such as L-NAME)
abolish the compensatory increase in medullary blood flow that
occurs in response to radiocontrast administration. Thus, the stimulation of prostaglandin and NO production after radiocontrast
administration is important in maintaining medullary perfusion
and oxygenation after administration of contrast agents. B,
Radiocontrast stimulates the production of vasodilators (such as
prostaglandin [PGI2] and endothelium-dependent nitric oxide
[EDNO]) as well as endothelin and other vasoconstrictors within
the normal kidney. The vasodilators counteract the effects of the

vasoconstrictors so that intrarenal vasoconstriction in response to
radiocontrast is usually modest and is associated with little or no
loss of renal function. However, in situations when there is preexisting chronic renal insufficiency (CRF) the vasodilator response
to radiocontrast is impaired, whereas production of endothelin and
other vasoconstrictors is not affected or even increased. As a result,
radiocontrast administration causes profound intrarenal vasoconstriction and can cause ARF in patients with CRF. This hypothesis
would explain the predisposition of patients with chronic renal
dysfunction, and especially diabetic nephropathy, to contrastinduced ARF. (A, Adapted from Agmon and Brezis [15], with permission; B, from Agmon et al. [16], with permission.)
FIGURE 14-21
Cellular calcium metabolism and potential targets of the elevated
cytosolic calcium. A, Pathways of calcium mobilization. B, Pathophysiologic mechanisms ignited by the elevation of cytosolic calcium concentration. (A, Adapted from Goligorsky [17], with permission; B, from Edelstein and Schrier [18], with permission.)
14.14
Acute Renal Failure
60
100
*
* * *
40
200
* Significant
vs. time 0
150
Hypoxia
60
300
80
20
10
NS
Post NE
Verapamil before NE
P<.001
40
P<.05
20
CIn, mL/min
Pl stained nuclei, %
Estimated [Ca2+]i , nM
400
Pre NE
0
60
NS
20
40
20
30
Time, min
FIGURE 14-22
Pathophysiologic sequelae of the elevated cytosolic calcium (C2+).
A, The increase in cytosolic calcium concentration in hypoxic rat
proximal tubules precedes the tubular damage as assessed by propidium iodide (PI) staining. B, Administration of calcium channel inhibitor
Verapamil after NE
P<.001
P<.02
Control
1h
24 h
verapamil before injection of norepinephrine (cross-hatched bars) significantly attenuated the drop in inulin clearance induced by norepinephrine alone (open bars). (A, Adapted from Kribben et al. [19], with
permission; B, adapted from Burke et al. [20], with permission.)
FIGURE 14-23
Dynamics of heat shock
proteins (HSP) in stressed
cells. Mechanisms of activation and feedback control of the inducible heat
shock gene. In the normal unstressed cell, heat
shock factor (HSF) is
rendered inactive by
association with the constitutively expressed
HSP70. After hypoxia or
ATP depletion, partially
denatured proteins (DP)
become preferentially
associated with HSC73,
releasing HSF and allowing trimerization and
binding to the heat shock
element (HSE) to initiate
the transcription of the
heat shock gene. After
translation, excess
inducible HSP (HSP72)
interacts with the trimerized HSF to convert it
back to its monomeric
state and release it from
the HSE, thus turning off
the response. (Adapted
from Kashgarian [21];
with permission.)
14.15
Free Radical Pathways in the Mitochondrion

Catalase/GPx complex?
Hydrogen
H2O 2
peroxide
Outer
membrane
Inner
membrane
H 2O 2
O2
Superoxide
anion
Mn-SOD
(tetramer)
Matrix
2O2
Hydrogen
peroxide
Hydroperoxyl
radical
HO2
HO2
(From glycolysis/
TCA cycle)
e
Hepatocyte
(and other cells)
Golgi
complex
O2
Tissue ECSOD
+
2H+
Endoplasmic
reticulum
Mitochondrion
Secretory vesicle
Heparin
sulfate
proteoglycans
Chromosome
(chrom) 4
Manganese
superoxide
dismatase
(Mn-SOD) mRNA
Extracellular
superoxide
dismutase
(EC-SOD)
mRNA
Catalase
mRNA
chrom 11
GPx
(tetramer)
Se
chrom 21
H2O+O2
+GSSG
Glutathione
peroxidase
(GPx) mRNA
Cu,ZnSOD
(dimer)
2O2
Glutathione
(dimer)
Glutathione
(monomer)
+2GSH
Peroxisome
Copperzinc
superoxide
dismutase
(Cu,ZnSOD) mRNA
Plasma
membrane
damaged
(enlarged below)
+O2
+2H+
Lipid peroxidation of plasma membrane
Perxisome reactions
Oxidative enzyme
(eg, urate oxidase)
Phospholipid
hydroperoxide
glutathione
peroxidase
(PHGPx)
LOH+
GSSG+
2GSH's + LOOH
OH
LO
Catalase
(tetramer)
H
LO
Heme
Inside
cell
LH
2H2O+O2
LH
Hydrogen
peroxide
+
O2
GPx
subunit
chrom 3
Catalase
subunit
2H+
H 2O 2
chrom 6
RH2
+
O2
Plasma ECSOD
Proteinase?
LH
LH
RH
Lipid
radical
L
LOO
LOOH
L
Vitamin E (a-Tocopherol)
inhibits lipid peroxidation
chain reaction
Lipid
peroxide
O
Lipid
LOOH
LH
e
Free
radical
LH
O
LOO
Outside
cell
Lipid
chain collpases
(now hydrophilic)
FIGURE 14-24
Cellular sources of reactive oxygen species (ROS) defense systems from free radicals. Superoxide and hydrogen peroxide are produced during normal cellular metabolism. ROS are constantly being produced by the
normal cell during a number of physiologic reactions. Mitochondrial respiration is an important source of
superoxide production under normal conditions and can be increased during ischemia-reflow or gentamycininduced renal injury. A number of enzymes generate superoxide and hydrogen peroxide during their catalytic
cycling. These include cycloxygenases and lipoxygenes that catalyze prostanoid and leukotriene synthesis.
Some cells (such as leukocytes, endothelial cells, and vascular smooth muscle cells) have NADH/ or NADPH
oxidase enzymes in the plasma membrane that are capable of generating superoxide. Xanthine oxidase, which
converts hypoxathine to xanthine, has been implicated as an important source of ROS after ischemia-reperfusion injury. Cytochrome p450, which is bound to the membrane of the endoplasmic reticulum, can be
increased by the presence of high concentrations of metabolites that are oxidized by this cytochrome or by
injurious events that uncouple the activity of the p450. Finally, the oxidation of small molecules including free
heme, thiols, hydroquinines, catecholamines, flavins, and tetrahydropterins, also contribute to intracellular
superoxide production. (Adapted from [22]; with permission.)
14.16
Acute Renal Failure

FIGURE 14-25
Evidence suggesting a role for reactive oxygen metabolites in acute
renal failure. The increased ROS production results from two
major sources: the conversion of hypoxanthine to xanthine by xanthine dehydrogenase and the oxidation of NADH by NADH oxidase(s). During the period of ischemia, oxygen deprivation results
in the massive dephosphorylation of adenine nucleotides to hypoxanthine. Normally, hypoxanthine is metabolized by xanthine dehydrogenase which uses NAD+ rather than oxygen as the acceptor of
electrons and does not generate free radicals. However, during
ischemia, xanthine dehydrogenase is converted to xanthine oxidase. When oxygen becomes available during reperfusion, the
metabolism of hypoxanthine by xanthine oxidase generates superoxide. Conversion of NAD+ to its reduced form, NADH, and the
accumulation of NADH occurs during ischemia. During the reperfusion period, the conversion of NADH back to NAD+ by NADH
oxidase also results in a burst of superoxide production. (From
Ueda et al. [23]; with permission.)
EVIDENCE SUGGESTING A ROLE FOR

REACTIVE OXYGEN METABOLITES IN
ISCHEMIC ACUTE RENAL FAILURE
Enhanced generation of reactive oxygen metabolites and xanthine oxidase and

increased conversion of xanthine dehydrogenase to oxidase occur in in vitro and in
vivo models of injury.
Lipid peroxidation occurs in in vitro and in vivo models of injury, and this can be prevented by scavengers of reactive oxygen metabolites, xanthine oxidase inhibitors, or
iron chelators.
Glutathione redox ratio, a parameter of oxidant stress decreases during ischemia and
markedly increases on reperfusion.
Scavengers of reative oxygen metabolites, antioxidants, xanthine oxidase inhibitors,
and iron chelators protect against injury.
A diet deficient in selenium and vitamin E increases susceptibility to injury.
Inhibition of catalase exacerbates injury, and transgenic mice with increased superoxide
dismutase activity are less susceptible to injury.
250
3.0
*P < 0.001
150
100
16*
*P < 0.001
2.0
1.5
1.0
8*
8*
50
6*
26
0.5
4*
13*
6*
5*
4*
8*
18
+Fe3+
Iron stores
(Ferritin)
Release of
free iron
Hydrogen
Peroxide
(H2O2)
Fe2+
Fe3+
OH
Hydroxyl
Radical
(OH)
HB
FO
FIGURE 14-26
Effect of different scavengers of reactive
oxygen metabolites and iron chelators on,
A, blood urea nitrogen (BUN) and, B, creatinine in gentamicin-induced acute renal
failure. The numbers shown above the error
bars indicate the number of animals in each
group. Benzsodium benzoate; Contcontrol group; DFOdeferoxamine; DHB
2,3 dihydroxybenzoic acid; DMSO
dimethyl sulfoxide; DMTUdimethylthiourea; Gentgentamicin group. (From
Ueda et al. [23]; with permission.)
+D
+D
nz
+Be
MS
+D
MT
+D
t
Con
Gen
HB
FO
+D
+D
nz
Superoxide
O2
+Be
MS
+D
+D
MT
Gen
Con
0.0
t
16
2.5
200
Creatinine, mg/dL
Plasma urea nitrogen, mg/dL
24
FIGURE 14-27
Production of the hydroxyl radical: the Haber-Weiss reaction. Superoxide is converted to
hydrogen peroxide by superoxide dismutase. Superoxide and hydrogen peroxide per se
are not highly reactive and cytotoxic. However, hydrogen peroxide can be converted to
the highly reactive and injurious hydroxyl radical by an iron-catalyzed reaction that
requires the presence of free reduced iron. The availability of free catalytic iron is a
critical determinant of hydroxyl radical production. In addition to providing a source of
hydroxyl radical, superoxide potentiates hydroxyl radical production in two ways: by
releasing free iron from iron stores such as ferritin and by reducing ferric iron and recycling the available free iron back to the ferrous form. The heme moiety of hemoglobin,
myoglobin, or cytochrome present in normal cells can be oxidized to metheme (Fe3+).
The further oxidation of metheme results in the production of an oxyferryl moiety
(Fe4+=O), which is a long-lived, strong oxidant which likely plays a role in the cellular
injury associated with hemoglobinuria and myoglobinuria.
Activated leukocytes produce superoxide and hydrogen peroxide via the activity of a
membrane-bound enzyme NADPH oxidase. This superoxide and hydrogen peroxide can
be converted to hydroxyl radical via the Haber-Weiss reaction. Also, the enzyme myeloperoxidase, which is specific to leukocytes, converts hydrogen peroxide to another highly
reactive and injurious oxidant, hypochlorous acid.
14.17
:OO + NO
:O2
:OONO 22 kcal/mol
...Large Gibbs energy
6.7 x 109 M1s1 [NO]
Initiation
ONOO
...Faster than SOD
LH + OH
Propagation L + O2
O 2 + H 2O 2
1 x 109 M1s1 [SOD]
H
O
O
O
O
N O
N O
N O
OH
...Peroxynitrous
OH
A
acid in trans
LOO
LOO + LH
LOOH + L
Termination L + L
LL
LOO + NO
LOONO
ONOO
Cortex
X: SOD, Cu2+, Fe3+
FIGURE 14-28
Cell injury: point of convergence between
the reduced oxygen intermediatesgenerating and reduced nitrogen intermediates
generating pathways, A, and mechanisms
of lipid peroxidation, B.
H2O + L
Medulla
XO
NO2
Tyr
116 KD
116 KD
66 KD
66 KD
NO2
OH
Nitrotyrosine
CI
LN
CI
LN
R
Unsaturated fatty acid
Free
R' radical
R'
O O
OO
Free
Control
Control Ischemia
L-Nil + Ischemia
R'
B
FIGURE 14-29
Detection of peroxynitrite production and lipid peroxidation in
ischemic acute renal failure. A, Formation of nitrotyrosine as an
indicator of ONOO- production. Interactions between reactive
oxygen species such as the hydroxyl radical results in injury to
the ribose-phosphate backbone of DNA. This results in singleand double-strand breaks. ROS can also cause modification and
deletion of individual bases within the DNA molecule. Interaction
between reactive oxygen and nitrogen species results in injury to
the ribose-phosphate backbone of DNA, nuclear DNA fragmentation (single- and double-strand breaks) and activation of poly(ADP)-ribose synthase. B, Immunohistochemical staining of kidneys with antibodies to nitrotyrosine. C, Western blot analysis of
nitrotyrosine. D, Reactions describing lipid peroxidation and formation of hemiacetal products. The interaction of oxygen radicals with lipid bilayers leads to the removal of hydrogen atoms
from the unsaturated fatty acids bound to phospholipid. This
radical
O2
OO
O O
O2
Lipid based
peroxyradical (LOO)
R'
OH
R'
HNE
HNE
Ab
OH
O
X
Protein
(X: Cys, His, Lys)
OH
X
Formation of stable
hemiacetal adducts
process is called lipid peroxidation. In addition to impairing the

structural and functional integrity of cell membranes, lipid peroxidation can lead to a self-perpetuating chain reaction in which
additional ROS are generated.
14.18
Acute Renal Failure
Cortex
Control
Control Ischemia
Medulla
L-Nil + Ischemia
E
E, Immunohistochemical staining of kidneys with antibodies to
HNEmodified proteins. F, Western blot analysis of HNE expression. Ccontrol; CIcentral ischemia; LNischemia with L-Nil
pretreatment (Courtesy of E. Noiri, MD.)
CI
LN
CI
LN
Leukocytes in Acute Renal Failure

Inactive leukocyte
Activated leukocyte
Leukocyte adhesion molecules

2 integrins (LFA1 or Mac1)
Selections
Endothelial adhesion molecules
ICAM
Ligand for leukocyte selections
FIGURE 14-30
Role of adhesion molecules in mediating
leukocyte attachment to endothelium.
A, The normal inflammatory response is
mediated by the release of cytokines that
induce leukocyte chemotaxis and activation.
The initial interaction of leukocytes with
endothelium is mediated by the selectins and
their ligands both of which are present on
leukocytes and endothelial cells,
Selectionmediated
rolling of leukocytes
Firm adhesion of
leukocytes
(integrinmediated)
Diapedesis
Tissue injury
Release of
oxidants
proteases
elastases

B. Selectin-mediated leukocyte-endothelial interaction results in
the rolling of leukocytes along the endothelium and facilitates the
firm adhesion and immobilization of leukocytes. Immobilization of
leukocytes to endothelium is mediated by the 2-integrin adhesion
molecules on leukocytes and their ICAM ligands on endothelial
cells. Immobilization of leukocytes is necessary for diapedesis of
leukocytes between endothelial cells into parenchymal tissue.
Leukocytes release proteases, elastases, and reactive oxygen radicals that induce tissue injury. Activated leukocytes also elaborate
cytokines such as interleukin 1 and tumor necrosis factor which
attract additional leukocytes to the site, causing further injury.
B. LEUKOCYTE ADHESION MOLECULES

AND THEIR LIGANDS POTENTIALLY
IMPORTANT IN ACUTE RENAL FAILURE
Major Families
Cell Distribution
Selectins
L-selectin
P-selectin
E-selectin
Carbohydrate ligands for selectins
Sulphated polysacharides
Oligosaccharides
Integrins
CD11a/CD18
CD11b/CD18
Immunoglobulin Glike ligands
for integrins
Intracellular adhesion molecules (ICAM)
125
Endothelium
Leukocytes
Leukocytes
Leukocytes
Endothelial cells
75
50
Anti-ICAM
antibody
Vehicle
2
Plasma creatinine
Blood urea nitrogen
Leukocytes
Endothelial cells
Endothelial cells
Anti-ICAM
antibody
Vehicle
100
1.5
1
0.5
25
0
0
0
24
48
72
Time following ischemia-reperfusion, d
0
24
48
72
96
Time following ischemia-reperfusion, d
Myeloperoxidase activity
Vehicle
Anti-ICAM
antibody
750
500
250
0
0
FIGURE 14-31
Neutralizing antiICAM antibody ameliorates the course of ischemic renal failure
with blood urea nitrogen, A, and plasma
creatinine, B. Rats subjected to 30 minutes
of bilateral renal ischemia or a sham-operation were divided into three groups that
received either anti-ICAM antibody or its
vehicle. Plasma creatinine levels are shown
at 24, 48, and 72 hours. ICAM antibody
ameliorates the severity of renal failure at
all three time points. (Adapted from Kelly
FIGURE 14-32
Neutralizing anti-ICAM-1 antibody reduces myeloperoxidase activity
in rat kidneys exposed to 30 minutes of ischemia. Myeloperoxidase
is an enzyme specific to leukocytes. Anti-ICAM antibody reduced
myeloperoxidase activity (and by inference the number of leukocytes) in renal tissue after 30 minutes of ischemia. (Adapted from
Kelly et al. [24]; with permission.)
1250
1000
14.19
4
24
48
Time after reperfusion, hrs
72
14.20
Acute Renal Failure
Mechanisms of Cell Death: Necrosis and Apoptosis

FIGURE 14-33
Apoptosis and necrosis: two distinct morphologic forms of cell death. A, Necrosis. Cells
undergoing necrosis become swollen and enlarged. The mitochondria become markedly
abnormal. The main morphoplogic features of mitochondrial injury include swelling and
flattening of the folds of the inner mitochondrial membrane (the christae). The cell plasma
membrane loses its integrity and allows the escape of cytosolic contents including lyzosomal proteases that cause injury and inflammation of the surrounding tissues. B, Apoptosis.
In contrast to necrosis, apoptosis is associated with a progressive decrease in cell size and
maintenance of a functionally and structurally intact plasma membrane. The decrease in
cell size is due to both a loss of cytosolic volume and a decrease in the size of the nucleus.
The most characteristic and specific morphologic feature of apoptosis is condensation of
nuclear chromatin. Initially the chromatin condenses against the nuclear membrane. Then
the nuclear membrane disappears, and the condensed chromatin fragments into many
pieces. The plasma membrane undergoes a process of budding, which progresses to
fragmentation of the cell itself. Multiple plasma membranebound fragments of condensed
DNA called apoptotic bodies are formed as a result of cell fragmentation. The apoptotic
cells and apoptotic bodies are rapidly phagocytosed by neighboring epithelial cells as well
as professional phagocytes such as macrophages. The rapid phagocytosis of apoptotic bodies with intact plasma membranes ensures that apoptosis does not cause any surrounding
inflammatory reaction.
[Ca2+]i ?
Signal transduction pathways
Mitochondrion
Mitochondrial permeability transition
Induction phase
Regulation by
Hcl-2 and
its relatives
?
Positive feedback loop

Consequences of permeability transition:
Disruption of m and mitochondrial biogenesis
Breakdown of energy metabolism
Uncoupling of respiratory chain
Calcium release frommitochondrial matrix
Hyperproduction of superoxide anion
Depletion of glutathione
Activation of
ICE/ced-3-like
proteases ?
Effector phase
?
NAD/NADH
Increase in ATP
[Ca2+]i depletion depletion
Cytoplasmic effects
Disruption of anabolic reactions
Dilatation of ER
Activation of proteases
Disruption of intracellular calcium
compartimentalization
Disorganization of cytoskeleton
Tyrosin kinases
G-proteins ?
Nucleus
Activation of endonucleases
Activation of repair enzymes
(ATP depletion)
Activation of poly(ADP) ribosly
transferase (NAD depletion)
Chromatinolysis, nucleolysis
Degradation phase
ROS
effects
FIGURE 14-34
Hypothetical schema of cellular events triggering apoptotic cell death. (From Kroemer
14.21
FIGURE 14-35
Phagocytosis of an apoptotic body by a renal tubular epithelial cell.
Epithelial cells dying by apoptosis are not only phagocytosed by
macrophages and leukocytes but by neighbouring epithelial cells as
well. This electron micrograph shows a normal-looking epithelial cell
containing an apoptotic body within a lyzosome. The nucleus of an
epithelial cell that has ingested the apoptotic body is normal (white
arrow). The wall of the lyzosome containing the apoptotic body (black
arrow) is clearly visible. The apoptotic body consists of condensed
chromatin surrounded by plasma membrane (black arrowheads).
Nucleosome
~200 bp
Internucleosome
"Linker" regions
DNA fragmentation
Apoptosis
Necrosis
Loss
of
histones
800 bp 600 bp
400 bp 200 bp
DNA electrophoresis
Apoptic
"ladder"
pattern
Necrotic
"smear"
pattern
FIGURE 14-36
DNA fragmentation in apoptosis vs necrosis. DNA is made up of nucleosomal units. Each
nucleosome of DNA is about 200 base pairs in size and is surrounded by histones. Between
nucleosomes are small stretches of DNA that are not surrounded by histones and are called
linker regions. During apoptosis, early activation of endonuclease(s) causes double-strand
breaks in DNA between nucleosomes. No fragmentation occurs in nucleosomes because the
DNA is protected by the histones. Because of the size of nucleosomes, the DNA is fragmented during apoptosis into multiples of 200 base pair pieces (eg, 200, 400, 600, 800).
When the DNA of apoptotic cells is electrophoresed, a characteristic ladder pattern is found.
In contrast, necrosis is associated with the early release of lyzosomal proteases, which
cause proteolysis of nuclear histones, leaving naked stretches of DNA not protected by
histones. Activation of endonucleases during necrosis therefore cause DNA cleavage at
multiple sites into double- and single-stranded DNA fragments of varying size.
Electrophoresis of DNA from necrotic cells results in a smear pattern.
14.22
Acute Renal Failure

FIGURE 14-37
Potential causes of apoptosis in acute renal failure (ARF). The
same cytotoxic stimuli that induce necrosis cause apoptosis. The
mechanism of cell death induced by a specific injury depends in
large part on the severity of the injury. Because most cells require
constant external signals, called survival signals, to remain viable,
the loss of these survival signals can trigger apoptosis. In ARF, a
deficiency of growth factors and loss of cell-substrate adhesion are
potential causes of apoptosis. The death pathways induced by
engagement of tumour necrosis factor (TNF) with the TNF receptor or Fas with its receptor (Fas ligand) are well known causes of
apoptosis in immune cells. TNF and Fas can also induce apoptosis
in epithelial cells and may contribute to cell death in ARF.
POTENTIAL CAUSES OF APOPTOSIS

IN ACUTE RENAL FAILURE
Loss of survival factors
Deficiency of renal growth factors (eg, IGF-1, EGF, HGF)
Loss of cell-cell and cell-matrix interactions
Receptor-mediated activators of apoptosis
Tumor necrosis factor
Fas/Fas ligand
Cytotoxic events
Ischemia; hypoxia; anoxia
Oxidant injury
Nitric oxide
Cisplati
Apoptotic Trigger
Commitment phase
Anti-apoptic factors
Pro-apoptic factors
BclXL
Bcl2
BAD
Bax
Execution phase
Crma
p35
Caspase activation
? Point of no return?
Proteolysis of multiple
intracellular substrates
Apoptosis
FIGURE 14-38
Apoptosis is mediated by a highly coordinated and genetically programmed pathway. The response to an apoptotic stimulus can be
divided into a commitment and execution phases. During the commitment phase the balance between a number of proapoptotic and
antiapoptotic mechanisms determine whether the cell survives or
dies by apoptosis. The BCL-2 family of proteins consists of at least
12 isoforms, which play important roles in this commitment phase.
Some of the BCL-2 family of proteins (eg, BCL-2 and BCL-XL) protect cells from apoptosis whereas other members of the same family
(eg, BAD and Bax) serve proapoptotic functions. Apoptosis is executed by a final common pathway mediated by a class of cysteine
proteases-caspases. Caspases are proteolytic enzymes present in cells
in an inactive form. Once cells are commited to undergo apoptosis,
these caspases are activated. Some caspases activate other caspases
in a hierarchical fashion resulting in a cascade of caspase activation.
Eventually, caspases that target specific substrates within the cell are
activated. Some substrates for caspases that have been identified
include nuclear membrane components (such as lamin), cytoskeletal
elements (such as actin and fodrin) and DNA repair enzymes and
transcription elements. The proteolysis of this diverse array of substrates in the cell occurs in a predestined fashion and is responsible
for the characteristic morphologic features of apoptosis.
Stress
Restoration of
fluid and
electrolyte
balance
ETR antagonists
Kf
Ca channel
inhibitors
ATP-Mg
ETR
antagonists
Ca channel
inhibitors
Loss of tubular
integrity and
function
Hemodynamic
compromise
RBF
PMN
infiltration
Dopamine
ANP
IGF-1
ICAM-1
antibody
RGD
Back
leak
Obstruction
Mannitol
Lasix
ANP
RGD
IGF-1l
T4
HGF
Avoidance and
discontinuation
of nephrotoxins
Survival factors
(HGF, IGF-1)
ATP-Mg
T4
NOS inhibitors
14.23
FIGURE 14-39
Therapeutic approaches, both experimental
and in clinical use, to prevent and manage
acute renal failure based on its pathogenetic
mechanisms. ETRET receptor; GFR
glomerular filtration rate; HGFhepatocyte
growth factor 1; IGF-1insulin-like growth
factor 1; Kfglomerular ultrafiltration coefficient; NOSnitric oxide synthase; PMN
polymorphonuclear leukocytes; RBFrenal
blood flow; T4thyroxine.
GFR and
maintenance
phase
Restoration
of renal
hemodynamics
Reparation of
tubular integrity
and function
Recovery
References
1. Goligorsky M, Iijima K, Krivenko Y, et al.: Role of mesangial cells in
macula densa-to-afferent arteriole information transfer. Clin Exp
Pharm Physiol 1997, 24:527531.
2. Osswald H, Hermes H, Nabakowski G: Role of adenosine in signal
transmission of TGF. Kidney Int 1982, 22(Suppl. 12):S136S142.
3. Miller W, Thomas R, Berne R, Rubio R: Adenosine production in the
ischemic kidney. Circ Res 1978, 43(3):390397.
4. Kon V, et al.: Glomerular actions of endothelin in vivo. J Clin Invest
1989, 83:17621767.
5. Gellai M, Jugus M, Fletcher T, et al.: Reversal of postischemic acute
renal failure with a selective endothelin A receptor antagonist in the
rat. J Clin Invest 1994, 93:900906.
6. Fogo, et al.: Endothelin receptor antagonism is protective in vivo in
acute cyclosporine toxicity. Kidney Int 1992, 42:770774.
7. Conger J: NO in acute renal failure. In: Nitric Oxide and the Kidney.
Edited by Goligorsky M, Gross S. New York:Chapman and Hall,
1997.
8. Gross S: Nitric oxide synthases and their cofactors. In: Nitric Oxide
and the Kidney. Edited by Goligorsky M, Gross S. New
York:Chapman and Hall, 1997.
9. Reyes A, Karl I, Klahr S: Role of arginine in health and in renal disease. Am J Physiol 1994, 267:F331F346.
10. Kim Y-M, Tseng E, Billiar TR: Role of NO and nitrogen intermediates
in regulation of cell functions. In: Nitric Oxide and the Kidney. Edited
by Goligorsky M, Gross S. New York:Chapman and Hall, 1997.
11. Lieberthal W:Renal ischemia and reperfusion impair endotheliumdependent vascular relaxation. Am J Physiol 1989, 256:F894F900.
12. Yu L, Gengaro P, Niederberger M, et al.: Nitric oxide: a mediator in
rat tubular hypoxia/reoxygenation injury. Proc Natl Acad Sci USA
1994, 91:16911695.
13. Noiri E, Peresleni T, Miller F, Goligorsky MS: In vivo targeting of
iNOS with oligodeoxynucleotides protects rat kidney against
ischemia. J Clin Invest 1996, 97:23772383.
14. Ling H, Gengaro P, Edelstein C, et al.: Injurious isoform of NOS in

mouse proximal tubular injury. Kidney Int, 1998, 53:1642
15. Agmon Y, et al.: Nitric oxide and prostanoids protect the renal outer
medulla from radiocontrast toxicity in the rat. J Clin Invest 1994,
94:10691075.
16. Agmon Y, Brezis M: NO and the medullary circulation. In: Nitric
Oxide and the Kidney. Edited by Goligorsky M, Gross S. New
York:Chapman and Hall, 1997.
17. Goligorsky MS: Cell biology of signal transduction. In: Hormones,
autacoids, and the kidney. Edited by Goldfarb S, Ziyadeh F. New
York:Churchill Livingstone, 1991.
18. Edelstein C, Schrier RW: The role of calcium in cell injury. In: Acute
Renal Failure: New Concepts and Therapeutic Strategies. Edited by
Goligorsky MS, Stein JH. New York:Churchill Livingstone, 1995.
19. Kribben A, Wetzels J, Wieder E, et al.:Evidence for a role of cytosolic
free calcium in hypoxia-induced proximal tubule injury. J Clin Invest
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intrarenal calcium channel blockers before or after renal ischemia.
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Acute Renal Failure: New Concepts and therapeutic strategies. Edited
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22. J NIH Research
23. Ueda N, Walker P, Shah SV: Oxidant stress in acute renal failure.
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Pathophysiology of
Nephrotoxic Acute
Renal Failure
Rick G. Schnellmann
Katrina J. Kelly
umans are exposed intentionally and unintentionally to a

variety of diverse chemicals that harm the kidney. As the list
of drugs, natural products, industrial chemicals and environmental pollutants that cause nephrotoxicity has increased, it has
become clear that chemicals with very diverse chemical structures produce nephrotoxicity. For example, the heavy metal HgCl2, the mycotoxin fumonisin B1, the immunosuppresant cyclosporin A, and the
aminoglycoside antibiotics all produce acute renal failure but are not
structurally related. Thus, it is not surprising that the cellular targets
within the kidney and the mechanisms of cellular injury vary with different toxicants. Nevertheless, there are similarities between chemicalinduced acute tubular injury and ischemia/reperfusion injury.
The tubular cells of the kidney are particularly vulnerable to toxicant-mediated injury due to their disproportionate exposure to circulating chemicals and transport processes that result in high intracellular concentrations. It is generally thought that the parent chemical or
a metabolite initiates toxicity through its covalent or noncovalent
binding to cellular macromolecules or through their ability to produce
reactive oxygen species. In either case the activity of the macromolecule(s) is altered resulting in cell injury. For example, proteins and
lipids in the plasma membrane, nucleus, lysosome, mitochondrion and
cytosol are all targets of toxicants. If the toxicant causes oxidative
stress both lipid peroxidation and protein oxidation have been shown
to contribute to cell injury.
In many cases mitochondria are a critical target and the lack of
adenosine triphosphate (ATP) leads to cell injury due to the dependence of renal function on aerobic metabolism. The loss of ATP leads
CHAPTER
15
15.2
Acute Renal Failure
to disruption of cellular ion homeostasis with decreased cellular

K+ content, increased Na+ content and membrane depolarization. Increased cytosolic free Ca2+ concentrations can occur in
the early or late phase of cell injury and plays a critical role leading to cell death. The increase in Ca2+ can activate calcium activated neutral proteases (calpains) that appear to contribute to
the cell injury that occurs by a variety of toxicants. During the
late phase of cell injury, there is an increase in Cl- influx, followed by the influx of increasing larger molecules that leads to
cell lysis. Two additional enzymes appear to play an important
role in cell injury, particularly oxidative injury. Phospholipase A2
consists of a family of enzymes in which the activity of the
cytosolic form increases during oxidative injury and contributes
to cell death. Caspases are a family of cysteine proteases that are
activated following oxidative injury and contribute to cell death.
Following exposure to a chemical insult those cells sufficiently

injured die by one of two mechanisms, apoptosis or oncosis.
Clinically, a vast number of nephrotoxicants can produce a
variety of clinical syndromes-acute renal failure, chronic renal
failure, nephrotic syndrome, hypertension and renal tubular
defects. The evolving understanding of the pathophysiology of
toxicant-mediated renal injury has implications for potential
therapies and preventive measures. This chapter outlines some
of the mechanisms thought to be important in toxicant-mediated renal cell injury and death that leads to the loss of tubular
epithelial cells, tubular obstruction, backleak of the glomerular filtrate and a decreased glomerular filtration rate. The recovery from the structural and functional damage following chemical exposures is dependent on the repair of sublethally-injured
and regeneration of noninjured cells.
Clinical Significance of Toxicant-Mediated

Acute Renal Failure
CLINICAL SIGNIFICANCE OF
TOXICANTMEDIATED RENAL FAILURE
Nephrotoxins may account for approximately 50% of all cases of acute and chronic
renal failure.
Nephrotoxic renal injury often occurs in conjunction with ischemic acute renal failure.
Acute renal failure may occur in 2% to 5% of hospitalized patients and 10% to 15% of
patients in intensive care units.
The mortality of acute renal failure is approximatley 50% which has not changed
significantly in the last 40 years.
Radiocontrast media and aminoglycosides are the most common agents associated
with nephrotoxic injury in hospitalized patients.
Aminoglycoside nephrotoxicity occurs in 5% to 15% of patients treated with
these drugs.
REASONS FOR THE KIDNEYS

SUSCEPTIBILITY TO TOXICANT INJURY
Receives 25% of the cardiac output
Sensitive to vasoactive compounds
Concentrates toxicants through reabsorptive and secretive processes
Many transporters result in high intracellular concentrations
Large luminal membrane surface area
Large biotransformation capacity
Baseline medullary hypoxia
FIGURE 15-2
Reasons for the kidneys susceptibility to toxicant injury.
FIGURE 15-1
Clinical significance of toxicant-mediated renal failure.
FACTORS THAT PREDISPOSE THE

KIDNEY TO TOXICANT INJURY
Preexisting renal dysfunction
Dehydration
Diabetes mellitus
Exposure to multiple nephrotoxins
FIGURE 15-3
Factors that predispose the kidney to toxicant injury.
Pathophysiology of Nephrotoxic Acute Renal Failure
15.3
EXOGENOUS AND ENDOGENOUS CHEMICALS THAT CAUSE ACUTE RENAL FAILURE

Antibiotics
Aminoglycosides (gentamicin, tobramycin,
amikacin, netilmicin)
Amphotericin B
Cephalosporins
Ciprofloxacin
Demeclocycline
Penicillins
Pentamidine
Polymixins
Rifampin
Sulfonamides
Tetracycline
Vancomycin
Chemotherapeutic agents
Adriamycin
Cisplatin
Methotraxate
Mitomycin C
Nitrosoureas
(eg, streptozotocin, Iomustine)
Radiocontrast media
Ionic (eg, diatrizoate, iothalamate)
Nonionic (eg, metrizamide)
Immunosuppressive agents
Cyclosporin A
Tacrolimus (FK 506)
Antiviral agents
Acyclovir
Cidovir
Foscarnet
Valacyclovir
Heavy metals
Cadmium
Gold
Mercury
Lead
Arsenic
Bismuth
Uranium
Organic solvents
Ethylene glycol
Carbon tetrachloride
Unleaded gasoline
Vasoactive agents
Nonsteroidal anti-inflammatory
drugs (NSAIDs)
Ibuprofen
Naproxen
Indomethacin
Meclofenemate
Aspirin
Piroxicam
Angiotensin-converting
enzyme inhibitors
Captopril
Enalopril
Lisinopril
Angiotensin receptor antagonists
Losartan
Other drugs
Acetaminophen
Halothane
Methoxyflurane
Cimetidine
Hydralazine
Lithium
Lovastatin
Mannitol
Penicillamine
Procainamide
Thiazides
Lindane
Endogenous compounds
Myoglobin
Hemoglobin
Calcium
Uric acid
Oxalate
Cystine
FIGURE 15-4
Exogenous and endogenous chemicals that cause acute renal failure.
Proximal convoluted tubule

(S1/S2 segments)
Aminoglycosides
Cephaloridine
Cadmium chloride
Potassium dichromate
Renal vessels
NSAIDs
ACE inhibitors
Cyclosporin A
Papillae
Phenacetin
Glomeruli
Interferon
Gold
Penicillamine
Proximal straight tubule
(S3 segment)
Cisplatin
Mercuric chloride
DichlorovinylLcysteine
Interstitium
Cephalosporins
Cadmium
NSAIDs
FIGURE 15-5
Nephrotoxicants may act at different sites in the kidney, resulting
in altered renal function. The sites of injury by selected nephrotoxicants are shown. Nonsteroidal anti-inflammatory drugs (NSAIDs),
angiotensin-converting enzyme (ACE) inhibitors, cyclosporin A,
and radiographic contrast media cause vasoconstriction. Gold,
interferon-alpha, and penicillamine can alter glomerular function
and result in proteinuria and decreased renal function. Many
nephrotoxicants damage tubular epithelial cells directly.
Aminoglycosides, cephaloridine, cadmium chloride, and potassium
dichromate affect the S1 and S2 segments of the proximal tubule,
whereas cisplatin, mercuric chloride, and dichlorovinyl-L-cysteine
affect the S3 segment of the proximal tubule. Cephalosporins, cadmium chloride, and NSAIDs cause interstitial nephritis whereas
phenacetin causes renal papillary necrosis.
15.4
Acute Renal Failure

Prerenal azotemia
Renal vasoconstriction
Intravascular
volume
Increased tubular pressure

n
e
p
h
r
o
t
o
x
i
t c
o a
n
t
E
x
p
o
s
u
r
e
Tubular obstruction
Intratubular
casts
Sympathetic
tone
"Back-leak" of glomerular filtrate

Functional
abnormalties
GFR
Capillary permeability
Endothelial injury
Tubular damage
Persistent medullary hypoxia
Physical constriction
of medullary vessels
Hemodynamic
Glomerular
hydrostatic
alterations
pressure
Intrarenal
vasoconstriction Perfusion pressure
Efferent tone
Afferent tone
Glomerular factors
Hypertension
Endothelin
Nitric oxide
Thromboxane
Prostaglandins
Renal and systemic

vasoconstriction
Intrarenal factors
Obstruction
Vascular smooth muscle

sensitivity to vasoconstrictors
Cyclosporin A
Angiotensin II
Tubular cell injury
Glomerular ultrafiltration
Postrenal failure
FIGURE 15-6
Mechanisms that contribute to decreased glomerular filtration rate
(GFR) in acute renal failure. After exposure to a nephrotoxicant,
one or more mechanisms may contribute to a reduction in the
GFR. These include renal vasoconstriction resulting in prerenal
azotemia (eg, cyclosporin A) and obstruction due to precipitation
of a drug or endogenous substances within the kidney or collecting
ducts (eg, methotrexate). Intrarenal factors include direct tubular
obstruction and dysfunction resulting in tubular backleak and
increased tubular pressure. Alterations in the levels of a variety of
vasoactive mediators (eg, prostaglandins following treatment with
nonsteroidal anti-inflammatory drugs) may result in decreased
renal perfusion pressure or efferent arteriolar tone and increased
afferent arteriolar tone, resulting in decreased in glomerular hydrostatic pressure. Some nephrotoxicants may decrease glomerular
function, leading to proteinuria and decreased renal function.
Striped interstitial
fibrosis
GFR
FIGURE 15-7
Renal injury from exposure to cyclosporin A. Cyclosporin A is one
example of a toxicant that acts at several sites within the kidney.
It can injure both endothelial and tubular cells. Endothelial injury
results in increased vascular permeability and hypovolemia, which
activates the sympathetic nervous system. Injury to the endothelium also results in increases in endothelin and thromboxane A2
and decreases in nitric oxide and vasodilatory prostaglandins.
Finally, cyclosporin A may increase the sensitivity of the vasculature to vasoconstrictors, activate the renin-angiotensin system, and
increase angiotensin II levels. All of these changes lead to vasoconstriction and hypertension. Vasoconstriction in the kidney contributes to the decrease in glomerular filtration rate (GFR), and
the histologic changes in the kidney are the result of local ischemia
and hypertension.
Renal Cellular Responses to Toxicant Exposures

Nephrotoxic insult
to the nephron
Uninjured cells
Compensatory
hypertrophy
Cellular
adaptation
Injured cells
Cellular
proliferation
Re-epithelialization
Cell death
Cellular
repair
Cellular adaptation
Differentiation
Structural and functional recovery of the nephron
FIGURE 15-8
The nephrons response to a nephrotoxic insult. After a population
of cells are exposed to a nephrotoxicant, the cells respond and ultimately the nephron recovers function or, if cell death and loss is
extensive, nephron function ceases. Terminally injured cells undergo cell death through oncosis or apoptosis. Cells injured sublethally undergo repair and adaptation (eg, stress response) in response
to the nephrotoxicant. Cells not injured and adjacent to the injured
area may undergo dedifferentiation, proliferation, migration or
spreading, and differentiation. Cells that were not injured may also
undergo compensatory hypertrophy in response to the cell loss and
injury. Finally the uninjured cells may also undergo adaptation in
response to nephrotoxicant exposure.

Loss of polarity, tight junction
integrity, cellsubstrate adhesion,
simplification of brush border
Intact tubular epithelium
Cell death
Toxic injury
Necrosis
Cast formation
and tubuler
obstruction
Na+/K+=ATPase
1 Integrin
RGD peptide
FIGURE 15-9
After injury, alterations can occur in the cytoskeleton and in
the normal distribution of membrane proteins such as Na+, K+ATPase and 1 integrins in sublethally injured renal tubular
cells. These changes result in loss of cell polarity, tight junction
integrity, and cell-substrate adhesion. Lethally injured cells
undergo oncosis or apoptosis, and both dead and viable cells
Migrating
spreading cells
Cell
proliferation
Basement
membrane
Toxicant inhibition
of cell repair
Apoptosis
Sloughing of viable
and nonviable cells
with intraluminal
cell-cell adhesion
Cytoskeleton
Extracellular matrix
Sublethally
injured cells
15.5
Toxicant inhibition
of cell migration/spreading
Toxicant inhibition
of cell proliferation
may be sloughed into the tubular lumen. Adhesion of sloughed

cells to other sloughed cells and to cells remaining adherent to
the basement membrane may result in cast formation, tubular
obstruction, and further compromise the glomerular filtration
rate. (Adapted from Fish and Molitoris [1], and Gailit et al. [2];
with permission.)
FIGURE 15-10
Potential sites where nephrotoxicants can interfere with the structural and functional recovery of nephrons.
15.6
Acute Renal Failure

140
Percent of control
120
100
Oncosis
Apoptosis
80
60
Cell number/confluence
Mitochondrial function
Active Na+ transport
+
Na -coupled glucose transport
GGT activity
40
20
0
0
Blebbing
Budding
Time after exposure, d
FIGURE 15-11
Inhibition and repair of renal proximal tubule cellular functions
after exposure to the model oxidant t-butylhydroperoxide.
Approximately 25% cell loss and marked inhibition of mitochondrial function active (Na+) transport and Na+-coupled glucose
transport occurred 24 hours after oxidant exposure. The activity
of the brush border membrane enzyme -glutamyl transferase
(GGT) was not affected by oxidant exposure. Cell proliferation
and migration or spreading was complete by day 4, whereas active
Na+ transport and Na+-coupled glucose transport did not return to
control levels until day 6. These data suggest that selective physiologic functions are diminished after oxidant injury and that a hierarchy exists in the repair process: migration or spreading followed
by cell proliferation forms a monolayer and antedates the repair of
physiologic functions. (Data from Nowak et al. [3].)
Necrosis
Phagocytosis
inflammation
Phagocytosis
by macrophages
or nearby cells
FIGURE 15-12
Apoptosis and oncosis are the two generally recognized forms of
cell death. Apoptosis, also known as programmed cell death and
cell suicide, is characterized morphologically by cell shrinkage, cell
budding forming apoptotic bodies, and phagocytosis by
macrophages and nearby cells. In contrast, oncosis, also known as
necrosis, necrotic cell death, and cell murder, is characterized morphologically by cell and organelle swelling, plasma membrane blebbing, cell lysis, and inflammation. It has been suggested that cell
death characterized by cell swelling and lysis not be called necrosis
or necrotic cell death because these terms describe events that
occur well after the cell has died and include cell and tissue breakdown and cell debris. (From Majno and Joris [4]; with permission.)
Mechanisms of Toxicant-Mediated Cellular Injury

Transport and biotransformation
Toxicant whose primary
mechanism of action is
ATP depletion
Toxicants in general
Apoptosis
Oncosis
Cell death
Cell death
Oncosis
Apoptosis
Toxicant concentration
Toxicant concentration
FIGURE 15-13
The general relationship between oncosis and apoptosis after
nephrotoxicant exposure. For many toxicants, low concentrations
cause primarily apoptosis and oncosis occurs principally at higher
concentrations. When the primary mechanism of action of the
nephrotoxicant is ATP depletion, oncosis may be the predominant
cause of cell death with limited apoptosis occurring.
GSH-Hg-GSH
GSH-Hg-GSH
CYS-Hg-CYS
GSH-Hg-GSH
-GT
?
GLY-CYS-Hg-CYS-GLY
Acivicin
CYS-Hg-CYS
Lumen
Dipeptidase
CYS-Hg-CYS Na
Neutral amino
acid transporter
R-Hg-R
CYS-Hg-CYS
GSH-Hg-GSH
Na+ -Ketoglutarate -Ketoglutarate
Dicarboxylate
Organic anion
transporter
transporter
Proximal
tubular cell
Blood
Urine
CYS-Hg-CYS Na
Organic anions
(PAH or
probenecid)
-Ketoglutarate
Na+
Dicarboxylic
acids
-Ketoglutarate
Biotransformation
Altered activity of
critical macromolecules
FIGURE 15-14
The importance of cellular transport in mediating toxicity.
Proximal tubular uptake of inorganic mercury is thought to be the
result of the transport of mercuric conjugates (eg, diglutathione
mercury conjugate [GSH-Hg-GSH], dicysteine mercuric conjugate
[CYS-Hg-CYS]). At the luminal membrane, GSH-Hg-GSH appears
to be metabolized by (-glutamyl transferase ((-GT) and a dipeptidase to form CYS-Hg-CYS. The CYS-Hg-CYS may be taken up by
an amino acid transporter. At the basolateral membrane, mercuric
conjugates appear to be transported by the organic anion transporter. (-Ketoglutarate and the dicarboxylate transporter seem to
play important roles in basolateral membrane uptake of mercuric
conjugates. Uptake of mercuric-protein conjugates by endocytosis
may play a minor role in the uptake of inorganic mercury transport. PAHpara-aminohippurate. (Courtesy of Dr. R. K. Zalups.)
R-Hg-R
CYS-Hg-CYS
GSH-Hg-GSH
Toxicant
High-affinity binding
to macromolecules
15.7
Reactive intermediate
Redox cycling
Covalent binding
to macromolecules
Increased reactive
oxygen species
Damage to critical
macromolecules
Oxidative damage to
critical macromolecules
FIGURE 15-15
Covalent and noncovalent binding versus oxidative stress mechanisms of cell injury. Nephrotoxicants are generally thought to produce cell injury and death through one of two mechanisms, either
alone or in combination. In some cases the toxicant may have a
high affinity for a specific macromolecule or class of macromolecules that results in altered activity (increase or decrease) of these
molecules, resulting in cell injury. Alternatively, the parent nephrotoxicant may not be toxic until it is biotransformed into a reactive
intermediate that binds covalently to macromolecules and in turn
alters their activity, resulting in cell injury. Finally, the toxicant may
increase reactive oxygen species in the cells directly, after being biotransformed into a reactive intermediate or through redox cycling.
The resulting increase in reactive oxygen species results in oxidative damage and cell injury.
Cell injury
Cell repair
Cell death
Plasma RSG
Plasma RSG
R-SG
R + SG
1.
R-SG
6.
Glomerular filtration
2.
R-SG 3.
4. -Glu
Na+
Plasma
R-Cys
7.
R-Cys
Na+
Plasma
R-NAC
8.
R-NAC
Na+
5.
R-Cys
12. NH3+H3CCOCO2H
10. 11. R-SH 13.
Covalent binding
Cell injury
R-NAC
Basolateral
membrane
9.
Brush border
membrane
R-Cys
R-NAC
Gly
FIGURE 15-16
This figure illustrates the renal proximal tubular uptake, biotransformation, and toxicity of glutathione and cysteine conjugates and mercapturic acids of haloalkanes and haloalkenes (R). 1) Formation of a
glutathione conjugate within the renal cell (R-SG). 2) Secretion of the
R-SG into the lumen. 3) Removal of the -glutamyl residue (-Glu)
by -glutamyl transferase. 4) Removal of the glycinyl residue (Gly) by
a dipeptidase. 5) Luminal uptake of the cysteine conjugate (R-Cys).
Basolateral membrane uptake of R-SG (6), R-Cys (7), and a mercapturic acid (N-acetyl cysteine conjugate; R-NAC)(8). 9) Secretion of
R-NAC into the lumen. 10) Acetylation of R-Cys to form R-NAC.
11) Deacetylation of R-NAC to form R-Cys. 12) Biotransformation
of the penultimate nephrotoxic species (R-Cys) by cysteine conjugate
-lyase to a reactive intermediate (R-SH), ammonia, and pyruvate.
13) Binding of the reactive thiol to cellular macromolecules (eg, lipids,
proteins) and initiation of cell injury. (Adapted from Monks and Lau
15.8
Acute Renal Failure
B
Representative
starting
material
Submitochondrial fractions
A. Untreated
B. TFEC (30 mg/kg)
Mr (kDa)
228
109
P99
P84
P66
P52
P42
70
Inter
Outer
Matrix
Inner
Inter
Outer
Matrix
Inner
44
FIGURE 15-17
Covalent binding of a nephrotoxicant
metabolite in vivo to rat kidney tissue, localization of binding to the mitochondria, and
identification of three proteins that bind to
the nephrotoxicant. A, Binding of tetrafluoroethyl-L-cysteine (TFEC) metabolites in vivo
to rat kidney tissue detected immunohistochemically. Staining was localized to the S3
segments of the proximal tubule, the segment
that undergoes necrosis. B, Immunoreactivity
in untreated rat kidneys. C, Isolation and
fractionation of renal cortical mitochondria
from untreated and TFEC treated rats and
immunoblot analysis revealed numerous proteins that bind to the nephrotoxicant (innerinner membrane, matrix-soluble matrix,
outer-outer membrane, inter-intermembrane
space). The identity of three of the proteins
that bound to the nephrotoxicant: P84,
mortalin (HSP70-like); P66, HSP 60; and
P42, aspartate aminotransferase. Mrrelative molecular weight. (From Hayden et al.
[6], and Bruschi et al. [7]; with permission.)
Lipid peroxidation and mitochondrial dysfunction

HH
HO
H
R
Lipid
H 2O
Hydrogen abstraction
R
Lipid radical
Diene conjugation
R
H
O2
R
OO H
LH
O O
HOO H
Fe(II)
Fe(III)
Malondialdehyde
O H
Lipid radical, conjugated diene
Oxygen addition
R
Lipid peroxyl radical
Hydrogen abstraction
L
R
Lipid hydroperoxide
Fenton reaction
HO
R
Lipid alkoxyl radical
Fragmentation
H
H
H
LH
L
H
O
Lipid aldehyde
H
H
Ethane
FIGURE 15-18
A simplified scheme of lipid peroxidation. The first step, hydrogen
abstraction from the lipid by a radical (eg, hydroxyl), results in the
formation of a lipid radical. Rearrangement of the lipid radical
results in conjugated diene formation. The addition of oxygen
results in a lipid peroxyl radical. Additional hydrogen abstraction
results in the formation of a lipid hydroperoxide. The Fenton reaction produces a lipid alkoxyl radical and lipid fragmentation,
resulting in lipid aldehydes and ethane. Alternatively, the lipid peroxyl radical can undergo a series of reactions that result in the formation of malondialdehyde.
15.9

50
Control
DCVC
DCVC + DEF (1 mM)
DCVC + DPPD (50M)
80
LDH release, %
40
LDH release, %
100
Control
TBHP (0.5 mmol)
TBHP + DEF (1 mM)
TBHP + DPPD (2 M)
30
20
10
60
40
20
0
0
Time, h
1.2
Time, h
2.0
+1 mM DEF
Lipid peroxidation,
nmol MDAmg protein1
Lipid peroxidation,
nmol MDAmg protein1
1.0
0.8
0.6
0.4
0.2
0.0
Control
TBHP
+1 mM DEF
+2 M DPPD
FIGURE 15-19
AD, Similarities and differences between oxidant-induced and
halocarbon-cysteine conjugateinduced renal proximal tubular
lipid peroxidation and cell death. The model oxidant t-butylhydroperoxide (TBHP) and the halocarbon-cysteine conjugate
dichlorovinyl-L-cysteine (DCVC) caused extensive lipid peroxidation after 1 hour of exposure and cell death (lactate dehydrogenase (LDH) release) over 6-hours exposure. The iron chelator
deferoxamine (DEF) and the antioxidant N,N-diphenyl-1,
4-phenylenediamine (DPPD) completely blocked both the lipid
ALTERATION OF RENAL TUBULAR CELL

ENERGETICS AFTER EXPOSURE TO TOXICANTS
Decreased oxygen delivery secondary to vasoconstriction
Inhibition of mitochondrial respiration
Increased tubular cell oxygen consumption
1.6
+50 M DPPD
1.2
0.8
0.4
0.0
Control
DCVC
peroxidation and cell death caused by TBHP. In contrast,

while DEF and DPPD completely blocked the lipid peroxidation
caused by DCVC, cell death was only delayed. These results
suggest that the iron-mediated oxidative stress caused by TBHP
is responsible for the observed toxicity, whereas the iron-mediated oxidative stress caused by DCVC accelerates cell death. One
reason that cells die in the absence of iron-mediated oxidative
stress is that DCVC causes marked mitochondrial dysfunction.
(Data from Groves et al. [8], and Schellmann [9].)
FIGURE 15-20
Mechanisms by which nephrotoxicants can alter renal tubular
cell energetics.
15.10
Acute Renal Failure

FIGURE 15-21
Some of the mitochondrial targets of nephrotoxicants: 1) nicotinamide adenine dinucleotide (NADH) dehydrogenase; 2) succinate dehydrogenase; 3) coenzyme
Qcytochrome C reductase; 4) cytochrome
C; 5) cytochrome C oxidase; 6) cytochrome
Aa3; 7) H+-Pi contransporter; 8) F0F1ATPase; 9) adenine triphosphate/diphosphate
(ATP/ADP) translocase; 10) protonophore
(uncoupler); 11) substrate transporters.
Substrates
11
Cephaloridine
Atractyloside
Ochratoxin A
TCA
cycle
ADP
Bromohydroquinone
9
ATP
DichlorovinylLcysteine
TetrafluoroethylLcysteine
PentachlorobutadienylLcysteine
Citrinin
Ochratoxin A
Hg2+
CN
H+
ATP
H+
H+
Oligomycin
4
5
H+
Pi
6
O2
Pi
H+
Matrix
H 2O
Ochratoxin A
10
PentachlorobutadienylLcysteine
H+
Citrinin
FCCP
Inner membrane
Outer membrane
Disruption of ion homeostasis

Na+
Na+
ATPase
ATP
Na+
Na+
ATPase
ATP
Cl
Cl
Cl
K+
K+
Cl
Antimycin A
K+
Na+
Na+
ATPase
Na+
ATPase
ATP
ATP
Cl
K+
Cl
Cl
Cl
K+
A Antimycin A
100
90
80
70
60
50
40
30
20
10
0
Na+
K+
B Antimycin A
K+
H 2O
Membrane
potential
QO2
K+
H 2O
ATP
FIGURE 15-22
Early ion movements after mitochondrial dysfunction. A, A control
renal proximal tubular cell. Within minutes of mitochondrial inhibition (eg, by antimycin A), ATP levels drop, resulting in inhibition of
the Na+, K+-ATPase. B, Consequently, Na+ influx, K+ efflux, membrane depolarization, and a limited degree of cell swelling occur.
Na+
Relative cellular changes
H 2O
Na+
5
Antimycin A
10
15
20
25
30
Time, min
FIGURE 15-23
A graphic of the phenomena diagrammed in Figure 15-22.
FIGURE 15-24
The late ion movements after mitochondrial dysfunction that leads
to cell death/lysis. A, Cl- influx occurs as a distinct step subsequent
to Na+ influx and K+ efflux. B, Following Cl- influx, additional
Na+ and water influx occur resulting in terminal cell swelling.
Ultimately cell lysis occurs.
Relative cellular changes
100
90
80
70
60
50
40
30
20
10
0
Na
15.11
FIGURE 15-25
A graph of the phenomena depicted in Figures 15-22 through 1524, illustrating the complete temporal sequence of events following
mitochondrial dysfunction. QO2oxygen consumption.
Cl
Membrane
potential
QO2
H 2O
Ca++
K+
ATP
10
Antimycin A
15
20
25
30
Time, min
Disregulation of regulatory enzymes

er
Ca2+
BIOCHEMICAL CHARACTERISTICS OF CALPAIN

ATP
2+
Ca
(1 mM)
Ca2+
(100 nM)
Mitochondria
ATP
Ca2+
FIGURE 15-26
A simplified schematic drawing of the regulation of cytosolic
free Ca2+.
Endopeptidase
Heterodimer: 80-kD catalytic subunit, 30-kD regulatory subunit
Calpain and -calpain are ubiquitously distributed cytosolic isozymes
Calpain and -calpain have identical regulatory subunits but distinctive catalytic
subunits
Calpain requires a higher concentration of Ca2+ for activation than -calpain
Phospholipids reduce the Ca2+ requirement
Substrates: cytoskeletal and membrane proteins and enzymes
FIGURE 15-27
Biochemical characteristics of calpain.
FIGURE 15-28
Calpain translocation. Proposed pathways of calpain activation
and translocation. Both calpain subunits may undergo calcium
(Ca2+)-mediated autolysis within the cytosol and hydrolyze cytosolic substrates. Calpains may also undergo Ca2+-mediated translocation to the membrane, Ca2+-mediated, phospholipid-facilitated
autolysis and hydrolyze membrane-associated substrates. The
autolyzed calpains may be released from the membrane and
hydrolyze cytosolic substrates. (From Suzuki and Ohno [10], and
Suzuki et al. [11]; with permission.)
Acute Renal Failure
35
40
30
35
LDH release, %
LDH release, %
15.12
25
20
15
30
25
20
15
10
10
0
CON
TFEC
+C12
BHQ
+C12
TBHP
+C12
FIGURE 15-29
A, B, Dissimilar types of calpain inhibitors block renal proximal
tubular toxicity of many agents. Renal proximal tubular suspensions were pretreated with the calpain inhibitor 2 (CI2) or
PD150606 (PD). CI2 is an irreversible inhibitor of calpains that
binds to the active site of the enzyme. PD150606 is a reversible
inhibitor of calpains that binds to the calcium (Ca2+)-binding
CON
TFEC
+PD
BHQ
+PD
TBHP
+PD
domain on the enzyme. The toxicants used were the haloalkane

cysteine conjugate tetrafluoroethyl-L-cysteine (TFEC), the alkylating quinone bromohydroquinone (BHQ), and the model oxidant tbutylhydroperoxide (TBHP). The release of lactate dehydrogenase
(LDH) was used as a marker of cell death. CONcontrol. (From
Waters et al. [12]; with permission.)
FIGURE 15-30
One potential pathway in which calcium (Ca2+) and calpains play a role in renal proximal
tubule cell death. These events are subsequent to mitochondrial inhibition and ATP depletion. 1) -Calpain releases endoplasmic reticulum (er) Ca2+ stores. 2) Release of er Ca2+
stores increases cytosolic free Ca2+ concentrations. 3) The increase in cytosolic free Ca2+
concentration mediates extracellular Ca2+ entry. (This may also occur as a direct result of er
Ca2+ depletion.) 4) The influx of extracellular Ca2+ further increases cytosolic free Ca2+
concentrations. 5) This initiates the translocation of nonactivated m-calpain to the plasma
membrane (6). 7) At the plasma membrane nonactivated m-calpain is autolyzed and
hydrolyzes a membrane-associated substrate. 8) Either directly or indirectly, hydrolysis of
the membrane-associated substrate results in influx of extracellular chloride ions (Cl-). The
influx of extracellular Cl- triggers terminal cell swelling. Steps ad represent an alternate
pathway that results in extracellular Ca2+ entry. (Data from Waters et al. [12,13,14].)
FIGURE 15-31
Biochemical characteristics of several identified phospholipase A2s.
PROPERTIES OF PHOSPHOLIPASE A2 GROUP

Characteristics
Secretory
Cytosolic
Localization
Molecular mass
Arachidonate preference
Ca2+ required
Ca2+ role
Secreted
~14 kDa

mM
Catalysis
Cytosolic
~85 kDa

(M
Memb. Assoc.
Ca2+-Independent
Cytosolic
~40 kDa

None
None
Membrane
unknown

None
None
15.13

50
80
LLC-cPLA2
LLC-vector
LDH release, % total
AA release, %
40
LLC-cPLA2
LLC-PK1
LLC-vector
70
30
20
10
60
50
40
30
20
10
0
30
60
90
120
0.0
LLC-cPLA2
LLC-sPLA2
LLC-vector
50
40
30
20
10
0
0.0
0.1
0.2
0.3
[H2O2], mmol
0.4
0.5
0.5
FIGURE 15-33
Potential role of caspases in cell death in LLC-PK1 cells exposed to
antimycin A. A, Time-dependent effects of antimycin A treatment on
caspase activity in LLC-PK1 cells. B, C, The effect of two capase
inhibitors on antimycin Ainduced DNA damage and cell death, respectively. Antimycin A is an inhibitor of mitochondrial electron transport.
r II
bito
rI
bito
Con
trol
Inhi
Inhi
0
Ant
imy
cin A
Cell death, %
0
r II
30
10
20
Time of antimycin A treatment,
min
bito
20
10
Con
trol
30
25
Inhi
50
50
rI
100
40
75
bito
150
100
Ant
imy
cin A
Residual double-stranded DNA, %
Increase in caspase activity,

units/mg protein
0.4
50
200
0.3
[H2O2], mmol
Inhi
LDH release, % total
60
0.2
FIGURE 15-32
The importance of the cytosolic phospholipase A2 in oxidant
injury. A, Time-dependent release of arachidonic acid (AA)
from LLC-PK1 cells exposed to hydrogen peroxide (0.5 mM).
B and C, The concentration-dependent effects of hydrogen peroxide on LLC-PK1 cell death (using lactate dehydrogenase [LDH]
release as marker) after 3 hours exposure. Cells were transfected
with 1) the cytosolic PLA2 (LLC-cPLA2), 2) the secretory PLA2
(LLC-sPLA2), 3) vector (LLC-vector), or 4) were not transfected
(LLC-PK1). Cells transfected with cytosolic PLA2 exhibited
greater AA release and cell death in response to oxidant exposure
than cells transfected with the vector or secretory PLA2 or not
transfected. These results suggest that activation of cytosolic
PLA2 during oxidant injury contributes to cell injury and death.
(From Sapirstein et al. [15]; with permission.)
80
70
0.1
Time, min
Inhibitor 1 is IL-1 converting enzyme inhibitor 1 (YVAD-CHO) and

inhibitor II is CPP32/apopain inhibitor (DEVD-CHO). These results
suggest that caspases are activated after mitochondrial inhibition and
that caspases may contribute to antimycin Ainduced DNA damage
and cell death. (From Kaushal et al. [16]; with permission.)
15.14
Acute Renal Failure
References
1.
Fish EM, Molitoris BA: Alterations in epithelial polarity and the

2.
Gailit J, Colfesh D, Rabiner I, et al.: Redistribution and dysfunction

of integrins in cultured renal epithelial cells exposed to oxidative
stress. Am J Physiol 1993, 264:F149.
3.
Nowak G, Aleo MD, Morgan JA, Schnellmann RG: Recovery of cellular functions following oxidant injury. Am J Physiol 1998, 274:F509.
4.
Majno G, Joris I: Apoptosis, oncosis and necrosis. Am J Pathol 1995,

146:3.
5.
Monks TJ, Lau SS: Renal transport processes and glutathione conjugatemediated nephrotoxicity. Drug Metab Dispos 1987, 15:437.
6.
Hayden PJ, Ichimura T, McCann DJ, et al.: Detection of cysteine conjugate metabolite adduct formation with specific mitochondrial proteins using antibodies raised against halothane metabolite adducts.
J Biol Chem 1991, 266:18415.
Bruschi SA, West KA, Crabb JW, et al.: Mitochondrial HSP60 (P1
protein) and a HSP70-like protein (mortalin) are major targets for
modification during S-(1,1,2,2-tetrafluoroethyl)-L-cysteineinduced
nephrotoxicity. J Biol Chem 1993, 268:23157.
Groves CE, Lock EA, Schnellmann RG: Role of lipid peroxidation in
renal proximal tubule cell death induced by haloalkene cysteine conjugates. Toxicol Appl Pharmacol 1991, 107:54.
Schnellmann RG: Pathophysiology of nephrotoxic cell injury. In
Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW.
Boston:Little Brown; 1997:1049.
7.
8.
9.
10. Suzuki K, Ohno S: Calcium activated neutral protease: Structure-function relationship and functional implications. Cell Structure Function
1990, 15:1.
11. Suzuki K, Sorimachi H, Yoshizawa T, et al.: Calpain: Novel family
members, activation, and physiologic function. Biol Chem HoppeSeyler 1995, 376:523.
12. Waters SL, Sarang SS, Wang KKW, Schnellmann RG: Calpains mediate calcium and chloride influx during the late phase of cell injury. J
Pharmacol Exp Ther 1997, 283:1177.
13. Waters SL, Wong JK, Schnellmann RG: Depletion of endoplasmic
reticulum calcium stores protects against hypoxia- and mitochondrial
inhibitorinduced cellular injury and death. Biochem Biophys Res
Commun 1997, 240:57.
14. Waters SL, Miller GW, Aleo MD, Schnellmann RG: Neurosteroid
inhibition of cell death. Am J Physiol 1997, 273:F869.
15. Sapirstein A, Spech RA, Witzgall R, Bonventre JV: Cytosolic phospholipase A2 (PLA2), but not secretory PLA2, potentiates hydrogen peroxide cytotoxicity in kidney epithelial cells. J Biol Chem 1996,
271:21505.
16. Kaushal GP, Ueda N, Shah SV: Role of caspases (ICE/CED3 proteases)
in DNA damage and cell death in response to a mitochondrial
inhibitor, antimycin A. Kidney Int 1997, 52:438.

Cellular Features of
Injury and Repair
Kevin T. Bush
Hiroyuki Sakurai
Tatsuo Tsukamoto
Sanjay K. Nigam
lthough ischemic acute renal failure (ARF) is likely the result of

many different factors, much tubule injury can be traced back
to a number of specific lesions that occur at the cellular level in
ischemic polarized epithelial cells. At the onset of an ischemic insult,
rapid and dramatic biochemical changes in the cellular environment
occur, most notably perturbation of the intracellular levels of ATP and
free calcium and increases in the levels of free radicals, which lead to
alterations in structural and functional cellular components characteristic of renal epithelial cells [17]. These alterations include a loss
of tight junction integrity, disruption of actin-based microfilaments,
and loss of the apical basolateral polarity of epithelial cells. The result
is loss of normal renal cell function [712].
After acute renal ischemia, the recovery of renal tubule function is
critically dependent on reestablishment of the permeability barrier,
which is crucial to proper functioning of epithelial tissues such as renal
tubules. After ischemic injury the formation of a functional permeability barrier, and thus of functional renal tubules, is critically dependent on the establishment of functional tight junctions. The tight junction is an apically oriented structure that functions as both the fence
that separates apical and basolateral plasma membrane domains and
the major paracellular permeability barrier (gate). It is not yet clear
how the kidney restores tight junction structure and function after
ischemic injury. In fact, tight junction assembly under normal physiological conditions remains ill-understood; however, utilization of the
CHAPTER
16
16.2
Acute Renal Failure
calcium switch model with cultured renal epithelial cells has

helped to elucidate some of the critical features of tight junction
bioassembly. In this model for tight junction reassembly, signaling events involving G proteins, protein kinase C, and calcium
appear necessary for the reestablishment of tight junctions
[1319]. Tight junction injury and recovery, like that which
occurs after ischemia and reperfusion, has similarly been modeled by subjecting cultured renal epithelial cells to ATP depletion (chemical anoxia) followed by repletion. While there are
many similarities to the calcium switch, biochemical studies
have recently revealed major differences, for example, in the
way tight junction proteins interact with the cytoskeleton [12].
Thus, important insights into the basic and applied biology of
tight junctions are likely to be forthcoming from further analysis of the ATP depletion-repletion model. Nevertheless, it is likely that, as in the calcium switch model, tight junction reassembly is regulated by classical signaling pathways that might
potentially be pharmacologically modulated to enhance recovery after ischemic insults.
More prolonged insults can lead to greater, but still sublethal,
injury. Key cellular proteins begin to break down. Many of these
(eg, the tight junction protein, occludin, and the adherens junction
protein, E-cadherin) are membrane proteins. Matrix proteins and

their integrin receptors may need to be resynthesized, along with
growth factors and cytokines, all of which pass through the endoplasmic reticulum (ER). The rate-limiting events in the biosynthesis and assembly of these proteins occur in the ER and are catalyzed by a set of ER-specific molecular chaperones, some of
which are homologs of the cytosolic heat-shock proteins [20]. The
levels of mRNAs for these proteins may increase 10-fold or more
in the ischemic kidney, to keep up with the cellular need to synthesize and transport these new membrane proteins, as well as
secreted ones.
If the ischemic insult is sufficiently severe, cell death and/or
detachment leads to loss of cells from the epithelium lining the
kidney tubules. To recover from such a severe insult, cell regeneration, differentiation, and possibly morphogenesis, are necessary. To a limited extent, the recovery of kidney tubule function
after such a severe ischemic insult can be viewed as a recapitulation of various steps in renal development. Cells must proliferate and differentiate, and, in fact, activation of growth factormediated signaling pathways (some of the same ones
involved in kidney development) appears necessary to ameliorate renal recovery after acute ischemic injury [2130].
The Ischemic Epithelial Cell

Functional renal tubules
Uninjured cells
Ischemic insult
Injured cells
ATP; [CA2+]i; Free radicals; Other changes?
Tight junction
disruption
Apical-basolateral
polarity disruption
Microfilament
disruption
Dysfunctional renal tubular epithelial cells

Remove insult
Continued insult
Cellular
repair
Cell loss
(detachment
or death)
Cell regenertation,
differentiation, and
morphogenesis
Remove insult
FIGURE 16-1
Ischemic acute renal failure (ARF). Flow chart illustrates the cellular basis of ischemic ARF. As described above, renal tubule epithelial cells undergo a variety of biochemical and structural changes in
response to ischemic insult. If the duration of the insult is sufficiently short, these alterations are readily reversible, but if the
insult continues it ultimately leads to cell detachment and/or cell
death. Interestingly, unlike other organs in which ischemic injury
often leads to permanent cell loss, a kidney severely damaged by
ischemia can regenerate and replace lost epithelial cells to restore
renal tubular function virtually completely, although it remains
unclear how this happens.
Acute Renal Failure: Cellular Features of Injury and Repair
FIGURE 16-2
Typical renal epithelial cell. Diagram of a typical renal epithelial
cell. Sublethal injury to polarized epithelial cells leads to multiple
lesions, including loss of the permeability barrier and apical-basolateral polarity [712]. To recover, cells must reestablish intercellular
junctions and repolarize to form distinct apical and basolateral
domains characteristic of functional renal epithelial cells. These
junctions include those necessary for maintaining the permeability
barrier (ie, tight junctions), maintaining cell-cell contact (ie,
adherens junctions and desmosomes), and those involved in cell-cell
communication (ie, gap junctions). In addition, the cell must establish and maintain contact with the basement membrane through its
integrin receptors. Thus, to understand how kidney cells recover
from sublethal ischemic injury it is necessary to understand how
renal epithelial cells form these junctions. Furthermore, after lethal
injury to tubule cells new cells may have to replace those lost during
the ischemic insult, and these new cells must differentiate into
epithelial cells to restore proper function to the tubules.
Brush
border
Tight
junction
Adherens
junction
Terminal web
Actin cortical ring
Desmosome
16.3
Intermediate
filaments
Gap
junction
Na+, K+, ATPase
Integrins
Extracellular matrix
Occludin
Symplekin
7H6
Cingulin
p130
ZO1
ZO2
Actin
filaments
Fodrin
Paracellular
space
FIGURE 16-3
The tight junction. The tight junction, the most apical component of the junctional complex
of epithelial cells, serves two main functions in epithelial cells: 1) It separates the apical and
basolateral plasma membrane domains of the cells, allowing for vectorial transport of ions
and molecules; 2) it provides the major framework for the paracellular permeability barrier,
allowing for generation of chemical and electrical gradients [31]. These functions are critically important to the proper functioning of renal tubules. The tight junction is comprised
of a number of proteins (cytoplasmic and transmembrane) that interact with a similar
group of proteins between adjacent cells to form the permeability barrier [16, 3237].
These proteins include the transmembrane protein occludin [35, 38] and the cytosolic proteins zonula occludens 1 (ZO-1), ZO-2 [36], p130, [39], cingulin [33, 40], 7H6 antigen
[34] and symplekin [41], although other as yet unidentified components likely exist. The
tight junction also appears to interact with the actin-based cytoskeleton, probably in part
through ZO-1fodrin interactions.
16.4
Acute Renal Failure
Reassembly of the Permeability Barrier

Reutilization of existing
junctional components
Synthesis of new
junctional components
Polarized renal
epithelial cells
Nonpolarized renal
epithelial cells
Nonpolarized renal
epithelial cells
Intact intercellular
junctions
Compromised
intercellular junctions
Damaged disassembled
intercellular junctions
Cell death
Apoptosis Necrosis
Deplete
ATP
Short-term
ATP depletion
01 h
Replete
ATP
Long-term
ATP depletion
2.5-4 h
Replete
ATP
Severe
ATP depletion
6+ h
FIGURE 16-4
Cell culture models of tight junction disruption and reassembly. The disruption of the permeability barrier, mediated by the tight junction, is a key lesion in the pathogenesis of tubular
dysfunction after ischemia and reperfusion. Cell culture models employing ATP depletion
and repletion protocols are a commonly used approach for understanding the molecular
occludin
ZO-1
fodrin
control
ATP depletion (1 hr)
ATP repletion (3hrs)
FIGURE 16-5
Immunofluorescent localization of proteins of the tight junction
after ATP depletion and repletion. The cytosolic protein zonula
Occludin
Occludin
Fodrin ZO1
ZO1
Fodrin
ZO2
Actin
filament
Ischemia
ATP depletion
ZO2
Actin
filament
Membrane vesicle?
mechanisms underlying tight junction dysfunction in ischemia and how tight junction
integrity recovers after the insult [6, 12, 42].
After short-term ATP depletion (1 hour or
less) in Madin-Darby canine kidney cells,
although some new synthesis probably
occurs, by and large it appears that reassembly of the tight junction can proceed with
existing (disassembled) components after
ATP repletion. This model of short-term ATP
depletion-repletion is probably most relevant
to transient sublethal ischemic injury of renal
tubule cells. However, in a model of
longterm ATP depletion (2.5 to 4 hours),
that probably is most relevant to prolonged
ischemic (though still sublethal) insult to the
renal tubule, it is likely that reestablishment
of the permeability barrier (and thus of
tubule function) depends on the production
(message and protein) and bioassembly of
new tight junction components. Many of
these components (membrane proteins) are
assembled in the endoplasmic reticulum.
occludens 1 (ZO-1), and the transmembrane protein occludin are

integral components of the tight junction that are intimately associated at the apical border of epithelial cells. This is demonstrated
here by indirect immunofluorescent localization of these two proteins in normal kidney epithelial cells. After 1 hour of ATP depletion this association appears to change, occludin can be found in
the cell interior, whereas ZO-1 remains at the apical border of the
plasma membrane. Interestingly, the intracellular distribution of
the actin-cytoskeletalassociated protein fodrin also changes after
ATP depletion. Fodrin moves from a random, intracellular distribution and appears to become co-localized with ZO-1 at the apical
border of the plasma membrane. These changes are completely
reversible after ATP repletion. These findings suggest that disruption of the permeability barrier could be due, at least in part, to
altered association of ZO-1 with occludin. In addition, the apparent co-localization of ZO-1 and fodrin at the level of the tight
junction suggests that ZO-1 is becoming intimately associated
with the cytoskeleton.
FIGURE 16-6
ATP depletion causes disruption of tight junctions. Diagram of the
changes induced in tight junction structure by ATP depletion. ATP
depletion causes the cytoplasmic tight junction proteins zonula
occludens 1 (ZO-1) and ZO-2 to form large insoluble complexes,
probably in association with the cytoskeletal protein fodrin [12],
though aggregation may also be significant. Furthermore, occludin,
the transmembrane protein of the tight junction, becomes localized
to the cell interior, probably in membrane vesicles. These kinds of
studies have begun to provide insight into the biochemical basis of
tight junction disruption after ATP depletion, although how the
tight junction reassembles during recovery of epithelial cells from
ischemic injury remains unclear.
Low calcium (LC)
16.5
FIGURE 16-7
Madin-Darby canine kidney (MDCK) cell calcium switch. Insight into the molecular mechanisms involved in the assembly of tight junctions (that may be at least partly applicable to the
ischemia-reperfusion setting) has been gained from the MDCK cell calcium switch model [43].
MDCK cells plated on a permeable support form a monolayer with all the characteristics of a
tight, polarized transporting epithelium. Exposing such cell monolayers to conditions of low
extracellular calcium (less than 5M) causes the cells to lose cell-cell contact and to round
up. Upon switching back to normal calcium media (1.8 mM), the cells reestablish cell-cell
contact, intercellular junctions, and apical-basolateral polarity. These events are accompanied
by profound changes in cell shape and reorganization of the actin cytoskeleton. (From Denker
and Nigam [19]; with permission)
Calcium switch (NC)
FIGURE 16-8
Protein kinase C (PKC) is important for
tight junction assembly. Immunofluorescent
localization of the tight junction protein
zonula occludens 1 (ZO-1) during the
Madin-Darby canine kidney (MDCK) cell
calcium switch. In low-calcium media
MDCK cells are round and have little cellcell contact. Under these conditions, ZO-1
is found in the cell interior and has little, if
any, membrane staining, A. After 2 hours
incubation in normal calcium media,
MDCK cells undergo significant changes in
cell shape and make extensive cell-cell contact along the lateral portions of the plasma
membrane. B, Here, ZO-1 has redistributed
to areas of cell-cell contact with little
apparent intracellular staining. This process
is blocked by treatment with either 500
nM calphostin C, C, or 25M H7, D,
inhibitors of PKC. These results suggest
that PKC plays a role in regulating tight
junction assembly. Similar studies have
demonstrated roles for a number of other
signaling molecules, including calcium and
G proteins, in the assembly of tight junctions [12, 13, 1619, 37, 4446]. An
analogous set of signaling events is likely
responsible for tight junction reassembly
after ischemia. (From Stuart and Nigam
16.6
Acute Renal Failure

FIGURE 16-9
Signalling molecules that may be involved in tight junction assembly. Model of the potential signaling events involved in tight junction assembly. Tight junction assembly probably
depends on a complex interplay of several signaling molecules, including protein kinase C
(PKC), calcium (Ca2+), heterotrimeric G proteins, small guanodine triphosphatases
(Rab/Rho), and tyrosine kinases [1316, 18, 37, 4453]. Although it is not clear how this
process is initiated, it depends on cell-cell contact and involves wide-scale changes in levels
of intracellular free calcium. Receptor/CAMcell adhesion molecule; DAGdiacylglycerol; ERendoplasmic reticulum; Galpha subunit of GTP-binding protein; IP3inositol trisphosphate. (From Denker and Nigam [19]; with permission.)
PKC
P-Tyr
P-Ser
P
G
Effector
Tyr-kinases
?TP
DAG 2+
Ca
+
IP3
Rab/Rho
?Receptor/CAM
ER
The Endoplasmic Reticulum Stress Response in Ischemia

mRNA
Ribosome
Free chaperones
Secretioncompetent
reutilization
protein
Dissociation of
chaperones
ATP
ADP
Protein folding
Peptidyl-prolyl isomerization
N-linked glycosylation
Disulfide bond formation
n
ein
ot
tio
Pr
iza
r
e
m
go
oli
Misassembled
protein
Degradation
Misfolded
protein
Resident ER
proteolytic pathway?
To proteasome?
To
Golgi
FIGURE 16-10
Protein processing in the endoplasmic reticulum (ER). To recover from serious injury,
cells must synthesize and assemble new membrane (tight junction proteins) and secreted
(growth factors) proteins. The ER is the initial site of synthesis of all membrane and
secreted proteins. As a protein is translocated
into the lumen of the ER it begins to interact
with a group of resident ER proteins called
molecular chaperones [20, 5457]. Molecular
chaperones bind transiently to and interact
with these nascent polypeptides as they fold,
assemble, and oligomerize [20, 54, 58]. Upon
successful completion of folding or assembly,
the molecular chaperones and the secretioncompetent protein part company via a reaction that requires ATP hydrolysis, and the
chaperones are ready for another round of
protein folding [20, 5961]. If a protein is
recognized as being misfolded or misassembled it is retained within the ER via stable
association with the molecular chaperones
and is ultimately targeted for degradation
[62]. Interestingly, some of the more characteristic features of epithelial ischemia include
loss of cellular functions mediated by proteins that are folded and assembled in the ER
(ie, cell adhesion molecules, integrins, tight
junctional proteins, transporters). This suggests that proper functioning of the proteinfolding machinery of the ER could be critically important to the ability of epithelial cells
to withstand and recover from ischemic
insult. ADPadenosine diphosphate.
45' Ischemia
GAPDH
BiP
BiP
grp94
grp94
ERp72
ERp72
FIGURE 16-11
Ischemia upregulates endoplasmic reticulum
(ER) molecular chaperones. Molecular
chaperones of the ER are believed to function normally to prevent inappropriate
intra- or intermolecular interactions during
the folding and assembly of proteins [20,
54]. However, ER molecular chaperones are
also part of the quality control apparatus
involved in the recognition, retention, and
degradation of proteins that fail to fold or
assemble properly as they transit the ER
[20, 54]. In fact, the messages encoding the
ER molecular chaperones are known to
increase in response to intraorganelle accumulation of such malfolded proteins [11,
20, 54, 55]. Here, Northern blot analysis of
total RNA from either whole kidney or cultured epithelial cells demonstrates that
ischemia or ATP depletion induces the
mRNAs that encode the ER molecular
chaperones, including immunoglobulin
binding protein (BiP), 94 kDa glucose regulated protein (grp94), and 72 kDa endoplasmic reticulum protein (Erp72) [11].
This suggests not only that ischemia or ATP
depletion causes the accumulation of malfolded proteins in the ER but that a major
effect of ischemia and ATP depletion could
be perturbation of the folding environment of the ER and disruption of protein
processing. GAPDHglyceraldehyde-3phosphate dehydrogenase; Hsp7070 kDa
heat-shock protein. (From Kuznetsov et al.
15' Ischemia
GAPDH
A
B
Thyroid Cell Line
Kidney Cell Line

28 S
rRNA
GAPDH
BiP
BiP
grp94
grp94
ERp72
ERp72
Hsp70
Hsp70
D
C
MED
PBS
1M
5M
10M
Antimycin A
Tg
16.7
FIGURE 16-12
ATP depletion perturbs normal endoplasmic reticulum (ER) function. Because ATP
and a proper redox environment are necessary for folding and assembly [20, 54, 63,
64] and ATP depletion alters ATP levels
and the redox environment, the secretion
of proteins is perturbed under these conditions. Here, Western blot analysis of the
culture media from thyroid epithelial cells
subjected to ATP depletion (ie, treatment
with antimycin A, an inhibitor of oxidative
phosphorylation) illustrates this point.
A, Treatment with as little as 1M antimycin
A for 1 hour completely blocks the secretion
of thyroglobulin (Tg) from these cells.
16.8
Acute Renal Failure

BD, Moreover, indirect immunofluorescence with antithyroglobulin antibody
demonstrates that the nonsecreted protein is
trapped almost entirely in the ER. Together
with data from Northern blot analysis, this
suggests that perturbation of ER function
and disruption of the secretory pathway is
likely to be a key cellular lesion in ischemia
[11]. MEDcontrol media; PBSphosphate-buffered saline. (From Kuznetsov et
al. [11]; with permission.)
C
Antimycin A
MED
PBS
10
Tg
grp94
BiP
ERp72
1
FIGURE 16-13
ATP depletion increases the stability of chaperone-folding
polypeptide interactions in the endoplasmic reticulum (ER).
Immunoglobulin binding protein (BiP), and perhaps other ER
molecular chaperones, associate with nascent polypeptides as they
are folded and assembled in ER [20, 54, 56, 57, 6573]. The dissociation of these proteins requires hydrolysis of ATP [69]. Thus,
when levels of ATP drop, BiP should not dissociate from the
secretory proteins and the normally transient interaction should
become more stable. Here, the associations of ER molecular chaperones with a model ER secretory protein is examined by Western
blot analysis of thyroglobulin (Tg) immunoprecipitates from thyroid cells subjected to ATP depletion. After treatment with
antimycin A, there is an increase in the amounts of ER molecular
chaperones (BiP, grp94 and ERP72) which co-immunoprecipitate
with antithyroglobulin antibody [11], suggesting that ATP depletion causes stabilization of the interactions between molecular
chaperones and secretory proteins folded and assembled in the
ER. Moreover, because a number of proteins critical to the proper
functioning of polarized epithelial cells (ie, occludin, E-cadherin,
Na-K-ATPase) are folded and assembled in the ER, this suggests
that recovery from ischemic injury is likely to depend, at least in
part, on the ability of the cell to rescue the protein-folding and assembly apparatus of the ER. Control media (MED) and phosphate buffered saline (PBS)no ATP depletion; 1, 5, 10M
antimycin AATP-depleting conditions. (From Kuznetsov et al.
16.9
Growth Factors and Morphogenesis

Basement membrane
degrading proteinases
Cytoskeletal
rearrangement
Integrin receptors for

interstitial matrix
Terminal
nephron
Proteinases
Cell-surface receptors
for proteinases
(uPA-R, ? for MMPs)
Arcade
Lack of integrin-mediated
basement membrane
initiated signaling
FIGURE 16-14
Kidney morphogenesis. Schematics demonstrate the development of the ureteric bud and
metanephric mesenchyme during kidney organogenesis. During embryogenesis, mutual inductive
events between the metanephric mesenchyme and the ureteric bud give rise to primordial structures that differentiate and fuse to form functional nephrons [74-76]. Although the process has
been described morphologically, the nature and identity of molecules involved in the signaling and
regulation of these events remain unclear. A, Diagram of branching tubulogenesis of the ureteric
bud during kidney organogenesis. The ureteric bud is induced by the metanephric mesenchyme to
branch and elongate to form the urinary collecting system [74-76]. B, Model of cellular events
involved in ureteric bud branching. To branch and elongate, the ureteric bud must digest its way
through its own basement membrane, a highly complicated complex of extracellular matrix proteins. It is believed that this is accomplished by cellular projections, invadopodia, which allow
for localized sites of proteolytic activity at their tips [77-81]. C, Mesenchymal cell compaction.
The metanephric mesenchyme not only induces ureteric bud branching but is also induced by the
ureteric bud to epithelialize and differentiate into the proximal through distal tubule [7476].
(From Stuart and Nigam [80] and Stuart et al. [81]; with permission.)
Uninduced mesenchyme
Condensing cells
S-shaped body
Tubulogenesis in vitro
Basic research
Applied research
Renal development
Renal diseases
Renal injury and repair
Renal cystic diseases
Urogenital abnormalities
Hypertension
Artificial kidneys
FIGURE 16-15
Potential of in vitro tubulogenesis research. Flow chart indicates
relevance of in vitro models of kidney epithelial cell branching
tubulogenesis to basic and applied areas of kidney research. While
results from such studies provide critical insight into kidney development, this model system might also contribute to the elucidation
of mechanisms involved in kidney injury and repair for a number
of diseases, including tubular epithelial cell regeneration secondary
to acute renal failure. Moreover, these models of branching tubulogenesis could lead to therapies that utilize tubular engineering as
artificial renal replacement therapy [82].
16.10
Acute Renal Failure
Mitogenesis
Motogenesis
Growth
factor
Cell proliferation
Cell movement
Cell organization
Morphogenesis
Antiapoptosis
Cell survival
FIGURE 16-16
Cellular response to growth factors. Schematic representation of
the pleiotrophic effects of growth factors, which share several
properties and are believed to be important in the development and
morphogenesis of organs and tissues, such as those of the kidney.
Among these properties are the ability to regulate or activate
numerous cellular signaling responses, including proliferation
(mitogenesis), motility (motogenesis), and differentiation (morphogenesis). These characteristics allow growth factors to play critical
roles in a number of complex biological functions, including
embryogenesis, angiogenesis, tissue regeneration, and malignant
transformation [83].
DD
Remodeling of cell substratum
FIGURE 16-17
Motogenic effect of growth factorshepatocyte growth factor
(HGF) induces cell scattering. During development or regeneration the recruitment of cells to areas of new growth is vital.
Growth factors have the ability to induce cell movement. Here,
subconfluent monolayers of either Madin-Darby canine kidney
(MDCK) C, D, or murine inner medullary collecting duct
(mIMCD) A, B, cells were grown for 24 hours in the absence,
A, C, or presence B, D, of 20 ng/mL HGF. Treatment of either
type of cultured renal epithelial cell with HGF induced the dissociation of islands of cells into individual cells. This phenomenon is
referred to as scattering. HGF was originally identified as scatter
factor, based on its ability to induce the scattering of MDCK cells
[83]. Now, it is known that HGF and its receptor, the transmembrane tyrosine kinase c-met, play important roles in development,
regeneration, and carcinogenesis [83]. (From Cantley et al. [84];
with permission.)
Growth
factors
FIGURE 16-18
Three-dimensional extracellular matrix gel tubulogenesis model.
Model of the three-dimensional gel culture system used to study
the branching and tubulogenesis of renal epithelial cells. Analyzing

the role of single factors (ie, extracellular matrix, growth factors,
cell-signaling processes) involved in ureteric bud branching tubulogenesis in the context of the developing embryonic kidney is an
extremely daunting task, but a number of model systems have been
devised that allow for such investigation [77, 79, 85]. The simplest
model exploits the ability of isolated kidney epithelial cells suspended in gels composed of extracellular matrix proteins to form
branching tubular structures in response to growth factors. For
example, Madin-Darby canine kidney (MDCK) cells suspended in
gels of type I collagen undergo branching tubulogenesis reminiscent
of ureteric bud branching morphogenesis in vivo [77, 79].
Although the results obtained from such studies in vitro might not
correlate directly with events in vivo, this simple, straightforward
system allows one to easily manipulate individual components (eg,
growth factors, extracellular matrix components) involved in the
generation of branching epithelial tubules and has provided crucial
insights into the potential roles that these various factors play in
epithelial cell branching morphogenesis [77, 79, 8487].
FIGURE 16-19
An example of the branching tubulogenesis of renal epithelial cells cultured in threedimensional extracellular matrix gels. Microdissected mouse embryonic kidneys
(11.5 to 12.5 days) were cocultured with A, murine inner medullary collecting duct
Pregnant SV40transgenic mouse
Isolate embryos
Dissect out embryonic kidney
Isolate metanephric mesenchyme
Isolate ureteric bud
Culture to obtain immortalized cells
16.11
(mIMCD) or, B, Madin-Darby canine

kidney (MDCK) cells suspended in gels
of rat-tail collagen (type I). Embryonic
kidneys (EK) induced the formation of
branching tubular structures in both
mIMCD and MDCK cells after 48 hours
of incubation at 37oC. EKs produce a
number of growth factors, including
hepatocyte growth factor, transforming
growth factor-alpha, insulin-like growth
factor, and transforming growth factor,
which have been shown to effect tubulogenic activity [8693]. Interestingly, many
of these same growth factors have been
shown to be effective in the recovery of
renal function after acute ischemic insult
[2130]. (From Barros et al. [87]; with
permission.)
FIGURE 16-20
Development of cell lines derived from embryonic kidney. Flow
chart of the establishment of ureteric bud and metanephric mesenchymal cell lines from day 11.5 mouse embryo. Although the
results obtained from the analysis of kidney epithelial cells
Madin-Darby canine kidney (MDCK) or murine inner medullary
collecting duct (mIMCD) seeded in three-dimensional extracellular
matrix gels has been invaluable in furthering our understanding of
the mechanisms of epithelial cell branching tubulogenesis, questions can be raised about the applicability to embryonic development of results using cells derived from terminally differentiated
adult kidney epithelial cells [94]. Therefore, kidney epithelial cell
lines have been established that appear to be derived from the
ureteric bud and metanephric mesenchyme of the developing
embryonic kidney of SV-40 transgenic mice [94, 95]. These mice
have been used to establish a variety of immortal cell lines.
16.12
Acute Renal Failure
FIGURE 16-21
Ureteric bud cells undergo branching tubulogenesis in threedimensional extracellular matrix gels. Cell line derived from
ureteric bud (UB) and metanephric mesenchyme from day 11.5
mouse embryonic kidney undergo branching tubulogenesis in
three-dimensional extracellular matrix gels. Here, UB cells have
been induced to form branching tubular structures in response to
conditioned media collected from the culture of metanephric
mesenchymal cells. During normal kidney morphogenesis, these
two embryonic cell types undergo a mutually inductive process
that ultimately leads to the formation of functional nephrons
[7476]. This model system illustrates this process, ureteric bud
cells being induced by factors secreted from metanephric mesenchymal cells. Thus, this system could represent the simplest in
Free HGF and empty

c-Met receptor
HGF binding to
c-Met receptor
CMet
CMet
HGF
HGF
HGF
Plasma
membrane
Gab-1
Gab-1
Dimerization of c-Met
receptor and activation
of Gab 1
HGF
HGF
HGF
CMet
Gab-1
Growth factor
binding
HGF
HGF HGF
Plasma
membrane
Gab-1
vitro model with the greatest relevance to early kidney development [94]. A, UB cells grown for 1 week in the presence of conditioned media collected from cells cultured from the metanephric
mesenchyme. Note the formation of multicellular cords. B, After
2 weeks growth under the same conditions, UB cells have formed
more substantial tubules, now with clear lumens. C, Interestingly,
after 2 weeks of culture in a three-dimensional gel composed
entirely of growth factorreduced Matrigel, ureteric bud cells have
not formed cords or tubules, only multicellular cysts. Thus, changing the matrix composition can alter the morphology from tubules
to cysts, indicating that this model might also be relevant to renal
cystic disease, much of which is of developmental origin. (From
Sakurai et al. [94]; with permission.)
Plasma
membrane
Gab-1
Gab-1
Transduction of Gab-1
signal leading to
branching tubulogenesis
FIGURE 16-22
Signalling pathway of hepatocyte growth factor action. Diagram of
the proposed intracellular signaling pathway involved in hepatocyte
growth factor (HGF)mediated tubulogenesis. Although HGF is perhaps the best-characterized of the growth factors involved in epithelial cell-branching tubulogenesis, very little of its mechanism of
action is understood. However, recent evidence has shown that the
HGF receptor (c-Met) is associated with Gab-1, a docking protein
believed to be involved in signal transduction [96]. Thus, on binding
to c-Met, HGF activates Gab-1mediated signal transduction, which,
by an unknown mechanism, affects changes in cell shape and cell
movement or cell-cellcell-matrix interactions. Ultimately, these alterations lead to epithelial cellbranching tubulogenesis.
Branching morphogenesis
Up-regulation of proteases
Mitogenic response
Motogenic response
Alteration of cytoskeleton
Other responses
FIGURE 16-23
Mechanism of growth factor action. Proposed model for the generalized response of epithelial cells to growth factors, which the
depends on their environment. Epithelial cells constantly monitor
their surrounding environment via extracellular receptors (ie, integrin receptors) and respond accordingly to growth factor stimulation. If the cells are in the appropriate environment, growth factor
binding induces cellular responses necessary for branching tubulogenesis. There are increases in the levels of extracellular proteinases
and of structural and functional changes in the cytoarchitecture
that enable the cells to form branching tubule structures.
16.13
GROWTH FACTORS IN DEVELOPMENTAL AND RENAL RECOVERY

Growth Factor
Expression Following Renal Ischemia
Effect of Exogenous Administration
Branching/Tubulogenic Activity
HGF
EGF
HB-EGF
TGF-
IGF
KGF
bFGF
GDNF
TGF-
PDGF
Increased [97]
Unclear [98,99]
Increased [100]
Unclear
Increased [101]
Increased [102]
Undetermined
Undetermined
Increased [98]
Increased [98]
Enhanced recovery [103]

Enhanced recovery [104,105]
Undetermined
Enhanced recovery [106]
Enhanced recovery [107,108]
Undetermined
Undetermined
Undetermined
Undetermined
Undetermined
Facilatory [109,110]
Facilatory [111]
Facilatory [111]
Facilatory [111]
Facilatory [112,113]
Undetermined
Facilatory [112]
Facilatory [114]
Inhibitory for branching [115]
No effect [112]
*Increase in endogenous biologically active EGF probably from preformed sources; increase in EGF-receptor mRNA
Chemoattractants for macrophages and monocytes (important source of growth promoting factors)
FIGURE 16-24
Growth factors in development and renal recovery. This table
describes the roles of different growth factors in renal injury or in
branching tubulogenesis. A large variety of growth factors have
been tested for their ability either to mediate ureteric branching
tubulogenesis or to affect recovery of kidney tubules after ischemic

or other injury. Interestingly, growth factors that facilitate branching tubulogenesis in vitro also enhance the recovery of injured
renal tubules.
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16.15
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embryonic kidney. Am J Physiol 1997, 273:F463F472.
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Molecular Responses
and Growth Factors
Steven B. Miller
Babu J. Padanilam
he kidney possesses a remarkable capacity for restoring its

structure and functional ability following an ischemic or toxic
insult. It is unique as a solid organ in its ability to suffer an
injury of such magnitude that the organ can fail for weeks and yet
recover full function. Studying the natural regenerative process after
an acute renal insult has provided new insights into the pathogenesis
of acute renal failure (ARF) and possible new therapies. These therapies may limit the extent of injury or even accelerate the regenerative
process and improve outcomes for patients suffering with ARF. In this
chapter we illustrate some of the molecular responses of the kidney to
an acute insult and demonstrate the effects of therapy with growth
factors in the setting of experimental models of ARF. We conclude by
demonstrating strategies that will provide future insights into the molecular response of the kidney to injury.
The regions of the nephron most susceptible to ischemic injury are
the distal segment (S3) of the proximal tubule and the medullary thick
ascending limb of the loop of Henle. Following injury, there is loss of
the epithelial lining as epithelial cells lose their integrin-mediated
attachment to basement membranes and are sloughed into the lumen.
An intense regenerative process follows. Normally quiescent renal
tubule cells increase their nucleic acid synthesis and undergo mitosis.
It is theorized that surviving cells situated close to or within the
denuded area dedifferentiate and enter mitotic cycles. These cells then
redifferentiate until nephron segment integrity is restored. The molecular basis that regulates this process is poorly-understood. After an
injury, there is a spectrum of cell damage that is dependent on the type
and severity of the insult. If the intensity of the insult is limited, cells
become dysfunctional but survive. More severe injury results in
detachment of cells from the tubule basement membranes, resulting in
necrosis. Still other cells have no apparent damage and may proliferate to reepithelialize the damaged nephron segments. Thus, several
CHAPTER
17
17.2
Acute Renal Failure
different processes are required to achieve structural and functional integrity of the kidney after a toxic or ischemic insult:
1) uninjured cells must proliferate and reepithelialize damaged
nephron segments; 2) nonlethally damaged cells must recover;
Subcellular
Organelles
Cytosol
Cellular
Plasma
membrane
Noninjured
cells
Insult
ATP
Ca2+
ER blebbing
Mitochondrial
switching
Brush
border
sloughing
Loss of
membrane
protein
orientation
Nonlethally
injured cells
Nephron/Kidney
1 Growth factors
Dysfunction
morphological
changes
2
Cell death
FIGURE 17-1
Schematic representation of some of the events pursuant to a
renal insult and epithelial cell repair. Subcellular; Initial events
include a decrease in cellular ATP and an increase in intracellular free calcium. There is blebbing of the endoplasmic reticulum
with mitochondrial swelling and dysfunction. The brush border
of the proximal tubules is sloughed into the tubule lumen, and
there is redistribution of membrane proteins with the loss of cellular polarity. Cellular; At a cellular level this results in three
populations of tubule cells, depending on the severity of the
insult. Some cells are intact and are poised to participate in the
proliferative process (Pathway 1). Growth factors participate by
Basement membrane
and 3) some damaged cells may actually dienot as a result of

the initial insult but through a process of programmed cell death
known as apoptosis. Figure 17-1 provides a schematic representation of the renal response to an ischemic or toxic injury.
Cell
proliferation
Reepithelialization
of nephron
Cellular
recovery
Recovery of
nephron structure
and function
stimulating cells to undergo mitosis. Nonlethally injured cells

have the potential to follow one of two pathways. In the appropriate setting, perhaps stimulated by growth factors, these cells
may recover with restoration of cellular integrity and function
(Pathway 2); however, if the injury is significant the cell may still
die, but through a process of programmed cell death or apoptosis. The third population of cells are those with severe injury
that undergo necrotic cell death. Nephron/Kidney; With the
reepithelialization of damaged nephron segments and cellular
recovery of structural and functional integrity, renal function is
restored. (Modified from Toback [1]; with permission.)
FIGURE 17-2
Growth regulation after an acute insult in regenerating renal tubule
epithelial cells. Under the influence of growth-stimulating factors
the damaged renal tubule epithelium is capable of regenerating
with restoration of tubule integrity and function. The growth factors may be 1) produced by the tubule epithelium itself and act
locally in an autocrine, juxtacrine or paracrine manner; 2) produced by surrounding cells to work in a paracrine manner; or 3)
presented to the regenerating area via the circulation mediated by
an endocrine mechanism. Cells at the edge of an injured nephron
segment are illustrated on the left. These cells proliferate in
response to the growth-stimulating factors. The middle cell is in the
process of dividing and the cell on the right is migrating into the
area of injury. (Adapted from Toback [1]; with permission.)
Molecular Responses and Growth Factors
17.3
Growth Factors in Acute Renal Failure

FIGURE 17-3
At least three growth factors have now been demonstrated to be
useful as therapeutic agents in animal models of acute renal failure
(ARF). These include epidermal growth factor (EGF), insulin-like
growth factor I (IGF-I) and hepatocyte growth factor (HGF). All
have efficacy in ischemia models and in a variety of toxic models
of ARF. In addition, both IGF-I and HGF are beneficial when therapy is delayed and ARF is established after an ischemic insult.
IGF-I has the additional advantage in that it also ameliorates the
course of renal failure when given prophylactically before an acute
ischemic insult.
GROWTH FACTORS IN ACUTE RENAL FAILURE
EGF
Ischemic and toxic
IGF-I
Ischemic and toxic
Pretreatment and established ARF
HGF
Ischemic and toxic
Established ARF
ARFacute renal failure; EGFepidermal growth factor; HGFhepatocyte growth

factor; IGF-Iinsulin-like growth factor.
DCT
Prepro-EGF
mRNA
PCT
CTAL
OMCD
MTAL
IMCD
FIGURE 17-4
Expression of messenger RNA (mRNA) for preproepidermal
growth factor (EGF) in kidney. This schematic depicts the localization of mRNA for prepro-EGF under basal states in kidney.
Prepro-EGF mRNA is localized to the medullary thick ascending
limbs (MTAL) and distal convoluted tubules (DCT).
Immunohistochemical studies demonstrate that under basal conditions the peptide is located on the luminal membrane with the
active peptide actually residing within the tubule lumen. It is speculated that, during pathologic states, preformed EGF is either transported or routed to the basolateral membrane or can enter the
interstitium via backleak. After a toxic or ischemic insult, expression of EGF is rapidly suppressed and can remain low for a long
time. Likewise, total renal content and renal excretion of EGF
decreases. CTALcortical thick ascending limb; IMCDinner
medullary collecting duct; OMCDouter medullary collecting
duct; and PCTproximal convoluted tubule.
17.4
Acute Renal Failure

FIGURE 17-5
Production of epidermal growth factor (EGF), insulin-like growth
factor (IGF-I), and hepatocyte growth factor (HGF) by various tissues. EGF, IGF-I, and HGF have all been demonstrated to improve
outcomes in various animal models of acute renal failure (ARF).
All three growth-promoting factors are produced in the kidneys
and in a variety of other organs. The local production is probably
most important for recovery from an acute renal insult. The influence of production in other organs in the setting of ARF has yet to
be determined. This chapter deals primarily with local production
and actions of EGF, IGF-I, and HGF.
GROWTH FACTOR PRODUCTION
EGF
Submandibular salivary glands
Kidney
Others
IGF-I
Liver
Lung
Kidney
Heart
Muscle
Other organs
HGF
Liver
Spleen
Kidney
Lung
Other organs
DCT
EGF-receptor
binding
PCT
CTAL
GLOM
OMCD
MTAL
IMCD
FIGURE 17-6
Receptor binding for epidermal growth factor (EGF). EGF binding
in kidney under basal conditions is extensive. The most significant
specific binding occurs in the proximal convoluted (PCT) and
proximal straight tubules. There is also significant EGF binding in
the glomeruli (GLOM), distal convoluted tubules (DCT), and the
entire collecting duct (OMCD, IMCD). After an ischemic renal
insult, EGF receptor numbers increase. This change in the renal
EGF system may be responsible for the beneficial effect of exogenously administered EGF is the setting of acute renal failure.
CTALcortical thick ascending loop.
EGF
GAP
PKC
SHC
PI3K
Grb2
PLC
DAG + IP3
Ca2+
CamK
PIP
SOS
PI-3,4 P2
PIP2
Signal
transduction
RasGDP
RasGTP
RAF
MAPKK
ERK1/ ERK2
Gene transcription
Growth differentiation
FIGURE 17-7
Epidermal growth factor (EGF)mediated signal transduction pathways. The EGF receptor
triggers the phospholipase C-gamma (PLC-gamma), phosphatidylinositol-3 kinase (PI3K),
and mitogen-activated protein kinase (MAPK) signal transduction pathways described in
the text that follows.
Growth factors exert their downstream effects through their plasma membranebound
protein tyrosine kinase (PTK) receptors. All known PTK receptors are found to have four
major domains: 1) a glycosylated extracellular ligand-binding domain; 2) a transmembrane
domain that anchors the receptor to the plasma membrane; 3) an intracellular tyrosine
kinase domain; and 4) regulatory domains for the PTK activity. Upon ligand binding, the
receptors dimerize and autophosphorylate, which leads to a cascade of intracellular events
resulting in cellular proliferation, differentiation, and survival.
The tyrosine phosphorylated residues in the cytoplasmic domain of PTK are of utmost
importance for its interactions with cytoplasmic proteins involved in EGFmediated signal
transduction pathways. The interactions of cytoplasmic proteins are governed by specific
domains termed Src homology type 2 (SH2) and type 3 (SH3) domains. The SH2 domain
is a conserved 100amino acid sequence initially characterized in the PTK-Src and binds to
tyrosine phosphorylated motifs in proteins; the SH3 domain binds to their targets through
proline-rich sequences. SH2 domains have been found in a multitude of signal transducers
and docking proteins such as growth factor receptorbound protein 2 (Grb2), phophatidylinositol-3 kinase (p85-PI3K), phospholipase C-gamma (PLC-gamma), guanosine triphosphatase (GTPase)activating protein of ras (ras-GAP), and signal transducer and activator
of transcription 3 (STAT-3).
Upon ligand binding and phosphorylation of PTKs, SH2domain containing proteins
interact with the receptor kinase domain. PLC-gamma on interaction with the PTK,
becomes phosphorylated and catalyzes the turnover of phosphatidylinositol (PIP2) to
two other second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG).
17.5
DAG activates protein kinase C; IP3 raises

the intracellular calcium (Ca2+) levels by
inducing its release from intracellular
stores. Ca2+ is involved in the activation of
the calmodulin-dependent CAM-kinase,
which is a serine/threonine kinase.
A more important signal transduction
pathway activated by PTKs concerns the
ras pathway. The ras cycle is connected to
activated receptors via the adapter protein
Grb2 and the guanosine diphosphateguanosine triphosphate exchange factor Sos
(son of sevenless). GDP-ras, upon phosphorylation, is converted to its activated form,
GTP-ras. The activated ras activates another Ser/Thr kinase called raf-1, which in turn
activates another kinase, the mitogen activated protein kinase kinase (MAPKK).
MAPKK activates the serine/threonine
kinases, and extracellular signal-regulated
kinases Erk1 and 2. Activation of Erk1/2
leads to translocation into the nucleus,
where it phosphorylates key transcription
factors such as Elk-1, and c-myc.
Phosphorylated Elk-1 associates with serum
response factor (SRF) and activates transcription of c-fos. The protein products of
c-fos and c-jun function cooperatively as
components of the mammalian transcription factor AP-1. AP-1 binds to specific
DNA sequences in putative promoter
sequences of target genes and regulates gene
transcription. Similarly, c-myc forms a heterodimer with another immediate early
gene max and regulates transcription.
The expression of c-fos, c-jun, and Egr-1 is
found to be upregulated after ischemic renal
injury. Immunohistochemical analysis showed
the spatial expression of c-fos and Egr-1 to be
in thick ascending limbs, where cells are
undergoing minimal proliferation as compared with the S3 segments of the proximal
tubules. This may suggest that the expression
of immediate early genes after ischemic injury
is not associated with cell proliferation.
Several mechanisms control the specificity
of RTK signaling: 1) the specific ligandreceptor interaction; 2) the repertoire of
substrates and signaling molecules associated with the activated RTK; 3) the existence
of tissue-specific signaling molecules; and 4)
the apparent strength and persistence of the
biochemical signal. Interplay of these factors can determine whether a given ligandreceptor interaction lead to events such as
growth, differentiation, scatter or survival.
17.6
Acute Renal Failure

DCT
IGF-1
mRNA
DCT
IGF-receptor
binding
PCT
CTAL
PCT
CTAL
GLOM
OMCD
MTAL
IMCD
FIGURE 17-8
Expression of mRNA for insulin-like growth factor I (IGF-I).
Under basal conditions, a variety of nephron segments can produce
IGF-I. Glomeruli (GLOM), medullary and cortical thick ascending
limbs (MTAL/CTAL), and collecting ducts (OMCD, IMCD) are all
reported to produce IGF-I. Within hours of an acute ischemic renal
insult, the expression of IGF-I decreases; however, 2 to 3 days after
the insult, when there is intense regeneration, there is an increase in
the expression of IGF-I in the regenerative cells. In addition,
extratubule cells, predominantly macrophages, express IGF-I in the
regenerative period. This suggests that IGF-I works by both
autocrine and paracrine mechanisms during the regenerative
process. DCT/PCTdistal/proximal convoluted tubule.
GLOM
OMCD
MTAL
IMCD
FIGURE 17-9
Receptor binding for insulin-like growth factor I (IGF-I).
IGF-I binding sites are conspicuous throughout the normal
kidney. Binding is higher in the structures of the inner medulla
than in the cortex. After an acute ischemic insult, there is a
marked increase in IGF-I binding throughout the kidney. The
increase appears to be greatest in the regenerative zones, which
include structures of the cortex and outer medulla. These findings suggest an important trophic effect of IGF-I in the setting
of acute renal injury. CTAL/MTALcortical/medullary thick
ascending loop; DCT/PCTdistal/proximal convoluted tubule;
GLOMglomerulus; OMCD/IMCDouter/inner medullary collecting duct.
IGF-I
IGF-IR
Other
substrates
SHC
Grb2
P110
p85
SOS
PI3-kinase
signaling
Crk II
IRS-1/IRS-2
C3G
Akt
SYP
nck
Grb2
BAD
SOS
Cell survival
Phosphotyrosine
dephosphorylation
Ras
Growth,
differentiation
Raf-1
MEKs
ERKs
EGF-R
MBP
S6-kinase
TF
Gene
expression
17.7
FIGURE 17-10
Diagram of intracellular signaling pathways
mediated by the insulin-like growth factor I
(IGF-IR) receptor. IGF-IR when bound to
IGF-I undergoes autophosphorylation on its
tyrosine residues. This enhances its intrinsic
tyrosine kinase activity and phosphorylates
multiple substrates, including insulin receptor substrate 1 (IRS-1), IRS-2, and Src
homology/collagen (SHC). IRS-1 upon
phosphorylation associates with the p85
subunit of the PI3-kinase (PI3K) and phosphorylates PI3-kinase. PI3K upon phosphorylation converts phosphoinositide-3 phosphate (PI-3P) into PI-3,4-P2, which in turn
activates a serine-thronine kinase Akt (protein kinase B). Activated Akt kinase phosphorylates the proapoptotic factor Bad on a
serine residue, resulting in its dissociation
from B-cell lymphoma-X (Bcl-XL) . The
released Bcl-XL is then capable of suppressing cell death pathways that involve the
activity of apoptosis protease activating factor (Apaf-1), cytochrome C, and caspases.
A number of growth factors, including
platelet-derived growth factor (PDGF) and
IGF 1 promotes cell survival. Activation of
the PI3K cascade is one of the mechanisms
by which growth factors mediate cell survival. Phosphorylated IRS-1 also associates
with growth factor receptor bound protein
2 (Grb2), which bind son of sevenless (Sos)
and activates the ras-raf-mitogen activated
protein (ras/raf-MAP) kinase cascade. SHC
also binds Grb2/Sos and activates the
ras/raf-MAP kinase cascade. Other substrates for IGF-I are phosphotyrosine phosphatases and SH2 domain containing tyrosine phosphatase (Syp). Figure 17-7 has
details on the other signaling pathways in
this figure. MBPmyelin basic protein;
nckan adaptor protein composed of SH2
and SH3 domains; TFtranscription factor.
17.8
Acute Renal Failure
DCT
HGF mRNA
HGF receptor
mRNA
PCT
CTAL
OMCD
MTAL
IMCD
FIGURE 17-11
Expression of hepatocyte growth factor (HGF) mRNA and HGF
receptor mRNA in kidney. While the liver is the major source of
circulating HGF, the kidney also produces this growth-promoting
peptide. Experiments utilizing in situ hybridization, immunohistochemistry, and reverse transcriptionpolymerase chain reaction
(RT-PCR) have demonstrated HGF production by interstitial cells
but not by any nephron segment. Presumably, these interstitial
cells are macrophages and endothelial cells. Importantly, HGF
expression in kidney actually increases within hours of an
ischemic or toxic insult. This expression peaks within 6 to 12
hours and is followed a short time later by an increase in HGF
bioactivity. HGF thus seems to act as a renotrophic factor, participating in regeneration via a paracrine mechanism; however, its
expression is also rapidly induced in spleen and lung in animal
models of acute renal injury. Reported levels of circulating HGF
in patients with acute renal failure suggest that an endocrine
mechanism may also be operational.
The receptor for HGF is the c-met proto-oncogene product.
Receptor binding has been demonstrated in kidney in a variety of
sites, including the proximal convoluted (PCT) and straight
tubules, medullary and cortical thick ascending limbs (MTAL,
CTAL), and in the outer and inner medullary collecting ducts
(OMCD, IMCD). As with HGF peptide production, expression of
c-met mRNA is induced by acute renal injury.

Pro-HGF
convertase
Mature
HGF
Membrane bound
Pro-HGF
Matrix soluble
pro-HGF
uPa
GTP-as
Raf-1
HGFR
Urokinase
receptor
Extracellular
Antiapoptosis
BAG-1
Y
Y
SHC
Y
Y
PIP2
PLC-
DAG
mSos1
P
Grb2
IP3
Gab 1
p85
MAP kinases
kinases (MEK S)
PI3K
C-SC
STAT3
Focal
adhesion
MAP kinases
(ERK5)
TF
Scatter
SRE
TF
Nuclear
membrane
Growth
TF
DETERMINANT MECHANISMS FOR

OUTCOMES OF ACUTE RENAL FAILURE
Mitogenic
Morphogenic
Cell migration
Hemodynamic
Cytoprotective
Cytosol
Anabolic
Alter leukocyte function
Alter inflammatory process
Apoptosis
Others
Transcription
Gene
PKC , ,
activation
17.9
FIGURE 17-12
Model of hepatocyte growth factor
(HGF)/c-met signal transduction. In the
extracellular space, single-chain precursors
of HGF bound to the proteoglycans at the
cell surface are converted to the active form
by urokinase plasminogen activator (uPA),
while the matrix soluble precursor is
processed by a serum derived pro-HGF
convertase. HGF, upon binding to its receptor c-met, induces its dimerization as well
as autophosphorylation of tyrosine
residues. The phosphorylated residue binds
to various adaptors and signal transducers
such as growth factor receptor bound protein-2 (Grb2), p85-PI3 kinase, phospholipase C-gamma (PLC-gamma), signal transducer and activator of transcription-3
(STAT-3) and Src homology/collagen (SHC)
via Src homology 2 (SH2) domains and
triggers various signal transduction pathways. A common theme among tyrosine
kinase receptors is that phosphorylation of
different specific tyrosine residues determines which intracellular transducer will
bind the receptor and be activated. In the
case of HGF receptor, phosphorylation of a
single multifunctional site triggers a
pleiotropic response involving multiple signal transducers. The synchronous activation
of several signaling pathways is essential to
conferring the distinct invasive growth ability of the HGF receptor. HGF functions as
a scattering (dissociation/motility) factor for
epithelial cells, and this ability seems to be
mediated through the activation of STAT-3.
Phosphorylation of adhesion complex
regulatory proteins such as ZO-1, betacatenin, and focal adhesion kinase (FAK)
may occur via activation of c-src. Another
Bcl2 interacting protein termed BAG-1
mediates the antiapoptotic signal of HGF
receptor by a mechanism of receptor association independent from tyrosine residues.
FIGURE 17-13
Mechanisms by which growth factors may possibly alter outcomes
of acute renal failure (ARF). Epidermal growth factor, insulin-like
growth factor, and hepatocyte growth factor (HGF) have all been
demonstrated to improve outcomes when administered in the setting of experimental ARF. While the results are the same, the
respective mechanisms of actions of each of these growth factors
are probably quite different. Many investigators have examined
individual growth factors for a variety of properties that may be
beneficial in the setting of ARF. This table lists several of the properties examined to date. Suffice it to say that the mechanisms by
which the individual growth factors alter the course of experimental ARF is still unknown.
17.10
Acute Renal Failure
ACTIONS OF GROWTH FACTORS

Actions
IGF-I
EGF
Protein
mRNA
Receptiors
Vascular
Anabolic
Mitogenic
Apoptosis
/
/
FIGURE 17-14
Selected actions of growth factors in the setting of acute renal failure
(ARF). After an acute renal injury, a spectrum of molecular responses occur involving the local expression of growth factors and their
receptors. In addition, there is considerable variation in the mechanisms by which the growth factors are beneficial for ARF. After an
acute renal insult there is an initial decrease in both insulin-like

growth factor (IGF-I) peptide and mRNA, which recovers over several days but only after the regenerative process is under way. The
pattern with epidermal growth factor (EGF) is different in that a
transient increase in available mature peptide from cleavage of preformed EGF is followed by a pronounced and prolonged decrease in
both peptide and message. Both peptide and message for hepatocyte
growth factor (HGF) are transiently increased in kidney after a toxic
or an ischemic insult. The receptors for all three growth factors are
increased after injury, which may be crucial to the response to exogenous administration.
The mechanism by which the different growth factors act in the setting of acute renal injury is quite variable. IGF-I is known to increase
renal blood flow and glomerular filtration rate in both normal animals and those with acute renal injury. To the other extreme, EGF is
a vasoconstrictor and HGF is vasoneutral. IGF-I has an additional
advantage in that it has anabolic properties, and ARF is an extremely
catabolic state. Neither EGF nor HGF seems to affect nutritional
parameters. Finally, both EGF and HGF are potent mitogens for renal
proximal tubule cells, the nephron segment is most often damaged by
ischemic acute renal injury, whereas IGF-I is only a modest mitogen.
Likewise, both EGF and HGF appear to be more effective than IGF-I
at inhibiting apoptosis in the setting of acute renal injury, but it is not
clear whether this is an advantage or a disadvantage.
Clinical Use of Growth Factors in Acute Renal Failure

HGF
Serum creatinine, mg/dL
+Vehicle
+IGF-I
*
*
*
*
*
0
0
FIGURE 17-15
Rationale for the use of insulin-like growth factor IGF-I in the setting of acute renal failure (ARF). Of the growth factors that have
been demonstrated to improve outcomes after acute renal injury,
the most progress has been made with IGF-I. From this table, it is
evident that IGF-I has a broad spectrum of activities, which makes
it a logical choice for treatment of ARF. An agent that increased
renal plasma flow and glomerular filtration rate and was mitogenic for proximal tubule cells and anabolic would address several
features of ARF.
2
4
Time after ischemia, d
FIGURE 17-16
Serial serum creatinine values in rats with ischemic acute renal failure
(ARF) treated with insulin-like growth factor (IGF-I) or vehicle. This is
the original animal experiment that demonstrated a benefit from IGF-I
in the setting of ARF. In this study, IGF-I was administered beginning
30 minutes after the ischemic insult (arrow). Data are expressed as
mean standard error. Significant differences between groups are indicated by asterisks.
This experiment has been reproduced, with variations, by several
groups, with similar findings. IGF-I has now been demonstrated to be
beneficial when administered prophylactically before an ischemic injury
and when started as late as 24 hours after reperfusion when injury is
established. It has also been reported to improve outcomes for a variety
of toxic injuries and is beneficial in a model of renal transplantation
with delayed graft function and in cyclosporine-induced acute renal
insufficiency. (From Miller et al. [2]; with permission.)

280
+ Vehicle
+ IGF-I
Body weight, g
*
*
220
17.11
FIGURE 17-17
Body weights of rats with ischemic acute renal failure (ARF) treated with insulin-like growth factor (IGF-I) or vehicle. Unlike epidermal growth factor or hepatocyte growth factor (HGF), IGF-I is
anabolic even in the setting of acute renal injury. These data are
from the experiment described in Figure 17-16. As the data in this
figure demonstrate, ARF is a highly catabolic state: vehicle-treated
animals experience 15% weight reduction. Animals that received
IGF-I experienced only a 5% reduction in body weight and were
back to baseline by 7 days. Data are expressed as mean standard
error. Significant differences between groups are indicated by asterisks. (From Miller et al. [2]; with permission.)
160
0
2
4
Time after ischemia, d
A
FIGURE 17-18
Photomicrograph of kidneys from rats with acute renal failure
(ARF) treated with insulin-like growth factor (IGF-I) or vehicle.
These photomicrographs are of histologic sections stained with
hematoxylin and eosin originating from kidneys of rats that
received vehicle or IGF 1 after ischemic renal injury. Kidneys
were obtained 7 days after the insult. There is evidence of considerable residual injury in the kidney from the vehicle-treated
rat (A): dilation and simplification of tubules, interstitial calcifi-
B
cations, and papillary proliferations the tubule lumen of proximal tubules. The kidney obtained from the IGF-Itreated rat (B)
appears almost normal, showing evidence of regeneration and
restoration of normal renal architecture. In this experiment the
histologic appearance of kidneys from the IGF-Itreated animals
was statistically better than that of the vehicle-treated controls,
as determined by a pathologist blinded to therapy. (From Miller
17.12
Acute Renal Failure
RATIONALE FOR INSULIN-LIKE GROWTH

FACTOR I (IGF-I) IN ACUTE RENAL FAILURE
Renal dysfunction, %
FIGURE 17-19
Reported therapeutic trials of insulin-like growth factor (IGF-I)
in humans. Based on the compelling animal data and the fact
that there are clearly identified disease states involving both
35
30
25
20
15
10
5
0
*P<0.05 Chi square
over- and underexpression of IGF-I, this is the first growth factor that has been used in clinical trials for kidney disease. Listed
above are a variety of studies of the effects of IGF-I in humans.
This peptide has now been examined in several published studies
of both acute and chronic renal failure. Additional studies are
currently in progress.
In the area of acute renal failure there are now two reported trials of IGF-I. In the initial study IGF-I or placebo was administered
to patients undergoing surgery involving the suprarenal aorta or
the renal arteries. This group was selected as it best simulated the
work that had been reported in animal trials of ischemic acute
renal injury. Fifty-four patients were randomized in a double-blind,
placebo-controlled trial of IGF-I to prevent the acute decline in
renal function frequently associated with this type of surgery. The
primary end-point in this study was the incidence of renal dysfunction, defined as a reduction of the glomerular filtration rate as
compared with a preoperative baseline, at each of three measurements obtained during the 3 postoperative days. Modern surgical
techniques have decreased the incidence of acute renal failure to
such a low level, even in this high-risk group, so as to make it
impractical to perform a single center trial with enough power to
obtain differences in clinically important end-points. Thus, this
trial was intended only to offer proof of concept that IGF-I is
useful for patients with acute renal injuries.
Receptors are present on proximal tubules

Regulates proximal tubule metabolism and transport
*
Increases renal plasma flow and glomerular filtration rates
Mitogenic for proximal tubule cells
Enhanced expression after acute renal injury
Anabolic
Placebo
IGF-I
Treatment groups
FIGURE 17-20
Incidence of postoperative renal dysfunction treated with insulin
(IGF-I) or placebo. IGF-I significantly reduced the incidence of postoperative renal dysfunction in these high-risk patients. Renal dysfunction occurred in 33% of those who received placebo but in only
22% of patients treated with IGF-I. The groups were well-matched
with respect to age, sex, type of operation, ischemia time, and baseline renal function as defined by serum creatinine or glomerular filtration rate. The IGF-I was tolerated well: no side effects were
attributed to the drug. Secondary end-points such as discharge,
serum creatinine, length of hospitalization, length of stay in the
intensive care unit, or duration of intubation were not significantly
different between the two groups. (Adapted from Franklin, et al.
THERAPEUTIC TRIALS OF INSULIN-LIKE

GROWTH FACTOR I IN HUMANS
FIGURE 17-21
Summary of an abstract describing the trial of insulin-like growth
factor (IGF-I) in the treatment of patients with established acute
renal failure (ARF). Based on the accumulated animal and human
data, a multicenter, double-blind, randomized, placebo-controlled
trial was performed to examine the effects of IGF-I in patients with
established ARF. Enrolled patients had ARF of a wide variety of
causes, including surgery, trauma, hypertension, sepsis, and nephrotoxic injury. Approximately 75 patients were enrolled, treatment
being initiated within 6 days of the renal insult. Renal function was
evaluated by iodothalimate clearance. Unfortunately, at an interim
analysis (the study was originally designed to enroll 150 patients)
there was no difference in renal function or survival between the
groups. The investigators recognized several potential problems with
the trial, including the severity of many patients illnesses, the variety
of causes of the renal injury, and delay in initiating therapy [4].
Growth hormoneresistant short stature
17.13
Corticosteroid therapy
Postoperative state
Laron-type dwarfism
Insulin-dependent and noninsulin-dependent diabetes mellitus
Acute renal failure
Anabolic agent in catabolic states

AIDS (Protein wasting malnutrition)
Burns
FIGURE 17-22
Advantages of insulin-like growth factor (IGF-I) in the treatment of
acute renal failure. The limited data obtained to date on the use of
IGF-I for acute renal failure demonstrate that the peptide is welltolerated and may be useful in selected patient populations.
Additional human trials are ongoing including use in the settings of
renal transplantation and chronic renal failure.
LACK OF EFFECT OF RECOMBINANT

FIGURE 17-23
Limitations in the use of growth factors to treat acute renal failure
(ARF). The disappointing results of several recent clinical trials of
ARF therapy reflect the fact that our understanding of its pathophysiology is still limited. Screening compounds using animal models may
be irrelevant. Most laboratories use relatively young animals, even
though ARF frequently affects older humans, whose organ regenerative capacity may be limited. In addition, our laboratory models are
usually based on a single insult, whereas many of our patients suffer
repeated or multiple insults. Until we gain a better understanding of
the basic pathogenic mechanisms of ARF, studies in human patients
are likely to be frustrating.
Future Directions
HUMAN IGF-I IN PATIENTS WITH ARF*
Multicenter, doubleblind, randomized,
placebo-controlled
ARF secondary to
surgery, trauma,
hypertensive
nephropathy, sepsis, or drugs
Treated within the
first 6 days for 14
days
Evaluated renal function and mortality
*No difference between the groups were observed in final values or changes in values for glomerular filtration
1 Hour
1 Day
2 Days
(6 h)
(6 h)
5 Days
References
Bardella et al. [5]
Ouellette et al. [6]
Bonventre et al. [7]
Witzgall et al. [8]
Safirstein et al. [9]
Goes et al. [10]
Singh et al. [11]
Soifer et al. [12]

Firth and Ratcliffe [13]
(Table continued on next page)
FIGURE 17-24
A list of genes
whose expression
is induced at
various time points
by ischemic renal
injury. The molecular response of
the kidney to an
ischemic insult is
complex and is
the subject of
investigations by
several laboratories.
(Continued on
next page)
17.14
Acute Renal Failure
Well-tolerated
Safe in short-term studies

Experience with diseases of
overexpression and underexpression
Did not worsen outcomes
IGF-Iinsulin-like growth
factor.
GROWTH
I
FACTOR LIMITATIONS

Several genes have already been identified to be
induced or down-regulated after ischemia and reperfusion. This table lists genes whose expression is
N ACUTE
RENAL
FAILURE
Lack of basic knowledge
of the pathophysiology
of ARF
No screening system for
compounds to treat
ARF
Animal models may not
be relevant
Animal studies have not
predicted results in
human trials
Difficulty of identifying
appropriate target populations
altered as a result of ischemic injury. It is not clear at

present if the varied expression of these genes plays a
role in cell injury, survival, or proliferation.
FIGURE 17-25
Schematic representation of differential display. In a complex
organ like the kidney, ischemic renal injury triggers altered
expression of various cell factors and vascular components.
Depending on the severity of the insult, expression of these genes
can vary in individual cells, leading to their death, survival, or
proliferation. A better understanding of the various factors and
the signal transduction pathways transduced by them that contribute to cell death can lead to development of therapeutic
strategies to interfere with the process of cell death. Similarly,
identification of factors that are involved in initiating cell migration, dedifferentiation, and proliferation may lead to therapy
aimed at accelerating the regeneration program. To identify the
various factors involved in cell injury and regeneration, powerful
methods for identification and cloning of differentially expressed
genes are critical. One such method that has been used extensively by several laboratories is the differential display polymerase chain reaction (DD-PCR).
In this schematic, mRNA is derived from kidneys of shamoperated (controls) and ischemia-injured rats, some pretreated
with insulin-like growth factor (IGF-I). The mRNAs are reverse
transcribed using an anchored deoxy thymidine-oligonucleotide
(oligo-dT) primer (Example: dT[12]-MX, where M represent G,
A, or C, and X represents one of the four nucleotides). An
anchored primer limits the reverse transcription to a subset of
mRNAs. The first strand cDNA is then PCR amplified using an
arbitrary 10 nucleotide-oligomer primer and the anchored
primer. The PCR reaction is performed in the presence of
radioactive or fluorescence-labeled nucleotides, so that the
amplified fragments can be displayed on a sequencing gel. Bands
of interest can be excised from the gel and used for further characterization. ARFacute renal failure.
ARFacute renal failure.
MOLECULAR RESPONSE TO RENAL

ISCHEMIC/REPERFUSION INJURY
Genes
Transcription factors
c-jun
c-fos
Egr-1
Kid 1
Cytokines
JE
KC
IL-2
IL-10
IFN-
GM-CSF
MIP-2
IL-6
IL-11
LIF
PTHrP
Endothelin 1
Endothelin 3
Sham
Sham
+IGF-1
ARF
17.15
ARF
+ IGF-1
1
2
3
FIGURE 17-26
Schematic representation of a differential display gel in which
mRNA from kidneys is reverse-transcribed and polymerase chain
reaction (PCR) amplified (see Figure 17-25). The PCR amplification is conducted in the presence of radioactive nucleotides. The
cDNA fragments corresponding to the 3 end of the mRNA species
are displayed by running them on a sequencing gel, followed by
autoradiography. The arrows show bands corresponding to mRNA
transcripts that are expressed differentially 1) in response to
insulin-like growth factor (IGF-I) treatment and induction of
ischemic injury; 2) in an IGF-Idependent manner; 3) in response
to induction of ischemic injury; and 4) to genes that are down-regulated after induction of ischemic injury. ARFacute renal failure.
17.16
Acute Renal Failure
References
1. Toback GF: Regeneration after acute tubular necrosis. Kidney Int
1992, 41:226246.
2. Miller SB, Martin DR, Kissane J, Hammerman, MR: Insulin-like
3. Franklin SC, Moulton M, Sicard GA, et al.: Insulin-like growth factor
I preserves renal function postoperatively. Am J Physiol 1997,
272:F257F259.
4. Kopple JD, Hirschberg R, Guler H-P, et al.: Lack of effect of recombinant human insulin-like growth factor I (IGF-I) in patients with acute
renal failure (ARF). J Amer Soc Nephro 1996, 7:1375.
5. Bardella L, Comolli R: Differential expression of c-jun, c-fos and hsp
70 mRNAs after folic acid and ischemia reperfusion injury: effect of
antioxidant treatment. Exp Nephrol 1994, 2:158165.
6. Ouellette AJ, et al.: Expression of two immediate early genes, Egr-1
and c-fos, in response to renal ischemia and during compensatory
renal hypertrophy in mice. J Clin Invest 1990, 85:766771.
7. Bonventre JV, et al.: Localization of the protein product of the immediate early growth response gene, Egr-1, in the kidney after ischemia
and reperfusion. Cell Regulation 1991, 2:25160.
8. Witzgall R, et al.: Kid-1, a putative renal transcription factor: regulation during ontogeny and in response to ischemia and toxic injury.
Mol Cell Biol 1993, 13:19331942.
9. Safirstein R, et al.: Expression of cytokine-like genes JE and KC is
increased during renal ischemia. Amer J Physiol 1991, 261:F1095F1101.
10. Goes N, et al.: Ischemic acute tubular necrosis induces an extensive
local cytokine response. Evidence for induction of interferon-gamma,
transforming growth factor-beta 1, granulocyte-macrophage
colonystimulating factor, interleukin-2, and interleukin-10.
Transplantation 1995, 59:565572.
11. Singh AK, et al.: Prominent and sustained upregulation of MIP-2 and
gp130 signaling cytokines in murine renal ischemic-reperfusion injury.
J Am Soc Nephrol 1997, 8:595A.
12. Soifer NE, et al.: Expression of parathyroid hormonerelated protein
in the rat glomerulus and tubule during recovery from renal ischemia.
J Clin Invest 1993, 92:28502857.
13. Firth JD, Ratcliffe PJ: Organ distribution of the three rat endothelin
messenger RNAs and the effects of ischemia on renal gene expression.
J Clin Invest 1992, 90:10231031.
14. Witzgall R, et al.: Localization of proliferating cell nuclear antigen,
vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for
a heterogeneous genetic response among nephron segments, and a
large pool of mitotically active and dedifferentiated cells. J Clin Invest
1994, 93:21752188.
15. Basile DP, Liapis H, Hammerman MR: Expression of bcl-2 and bax in
regenerating rat renal tubules following ischemic injury. Am J Physiol
1997, 272:F640F647.
16. Matejka GL, Jennische E: IGF-I binding and IGF-1 mRNA expression
in the post-ischemic regenerating rat kidney. Kidney Int 1992,
42(5):11131123.
17. Ishibashi K, et al.: Expressions of receptor for hepatocyte growth

factor in kidney after unilateral nephrectomy and renal injury.
Biochem Biophys Res Commun 1993, 187:14541459.
18. Safirstein R, et al.: Changes in gene expression after temporary renal
ischemia. Kidney Int 1990, 37:15151521.
19. Basile DP, et al.: Increased transforming growth factor-beta 1 expression in regenerating rat renal tubules following ischemic injury. Amer
J Physiol 1996, 270:F500F509.
20. Padanilam BJ, Hammerman MR: Ischemia-induced receptor for activated C kinase (RACK1) expression in rat kidneys. Amer J Physiol
1997, 272:F160F166.
21. Pombo CM, et al.: The stress-activated protein kinases are major
c-Jun amino-terminal kinases activated by ischemia and reperfusion.
J Biol Chem 1994, 269:2654626551.
22. Safirstein R: Gene expression in nephrotoxic and ischemic acute renal
failure [editorial]. J Am Soc Nephrol 1994, 4:13871395.
23. Safirstein R, Zelent AZ, Price PM: Reduced renal prepro-epidermal
growth factor mRNA and decreased EGF excretion in ARF. Kid Int
1989, 36:810815.
24. Raju VS, Maines, MD: Renal ischemia/reperfusion up-regulates heme
oxygenase-1 (HSP32) expression and increases cGMP in rat heart.
J Pharmacol Exp Ther 1996, 277:18141822.
25. Van Why SK, et al.: Induction and intracellular localization of HSP-72
after renal ischemia. Am J Physiol 1992, 263:F769F775.
26. Padanilam BJ, Martin DR, Hammerman MR: Insulin-like growth
factor Ienhanced renal expression of osteopontin after acute
ischemic injury in rats. Endocrinology 1996, 137:21332140.
27. Walker PD: Alterations in renal tubular extracellular matrix components after ischemia-reperfusion injury to the kidney. Lab Invest 1994,
70:339345.
28. Van Why SK, et al.: Expression and molecular regulation of Na+-K+ATPase after renal ischemia. Am J Physiol 1994, 267:F75F85.
29. Wang Z, et al.: Ischemic-reperfusion injury in the kidney: overexpression of colonic H+-K+-ATPase and suppression of NHE-3. Kidney Int
1997, 51:11061115.
30. McKanna JA, et al.: Localization of p35 (annexin I, lipocortin I) in
normal adult rat kidney and during recovery from ischemia. J Cell
Physiol 1992, 153:46776.
31. Nakamura H, et al.: Subcellular characteristics of phospholipase A2
activity in the rat kidney. Enhanced cytosolic, mitochondrial, and
microsomal phospholipase A2 enzymatic activity after renal ischemia
and reperfusion. J Clin Invest 1991, 87:18101818.
32. Lewington AJP, Padanilam BJ, Hammerman MR: Induction of calcyclin after ischemic injury to rat kidney. Am J Physiol 1997,
273(42):F380F385.
Nutrition and Metabolism

in Acute Renal Failure
Wilfred Druml
dequate nutritional support is necessary to maintain protein

stores and to correct pre-existing or disease-related deficits in
lean body mass. The objectives for nutritional support for
patients with acute renal failure (ARF) are not much different from
those with other catabolic conditions. The principles of nutritional support for ARF, however, differ from those for patients with chronic renal
failure (CRF), because diets or infusions that satisfy minimal requirements in CRF are not necessarily sufficient for patients with ARF.
In patients with ARF modern nutritional therapy must include a
tailored regimen designed to provide substrate requirements with various degrees of stress and hypercatabolism. If nutrition is provided to
a patient with ARF the composition of the dietary program must be
specifically designed because there are complex metabolic abnormalities that affect not only water, electrolyte, and acid-base-balance but
also carbohydrate, lipid, and protein and amino acid utilization.
In patients with ARF the main determinants of nutrient requirements (and outcome) are not renal dysfunction per se but the degree of
hypercatabolism caused by the disease associated with ARF, the nutritional state, and the type and frequency of dialysis therapy. Pre-existing or hospital-acquired malnutrition has been identified as an important contributor to the persisting high mortality in critically ill persons.
Thus, with modern nutritional support requirements must be met for
all nutrients necessary for preservation of lean body mass, immunocompetence, and wound healing for a patient who has acquired ARFin
may instances among other complications. At the same time the specific metabolic alterations and demands in ARF and the impaired
excretory renal function must be respected to limit uremic toxicity.
In this chapter the multiple metabolic alterations associated with
ARF are reviewed, methods for estimating nutrient requirements are
discussed and, current concepts for the type and composition of nutritional programs are summarized. This information is relevant for
designing nutritional support in an individual patient with ARF.
CHAPTER
18
18.2
Acute Renal Failure
NUTRITION IN ACUTE RENAL FAILURE

Goals
Preservation of lean body mass
Stimulation of wound healing and reparatory functions
Stimulation of immunocompetence
Acceleration of renal recovery (?)
But not (in contrast to stable CRF)
Minimization of uremic toxicity (perform hemodialysis and CRRT as required)
Retardation of progression of renal failure
Thus, provision of optimal but not minimal amounts of substrates
METABOLIC PERTURBATIONS
Determined by
Plus
Renal dysfunction (acute uremic state)

Underlying illness
The acute disease state, such as
systemic inflammatory response
syndrome (SIRS)
Associated complications (such as
infections)
Specific effects of renal

replacement therapy
Nonspecific effects of extracorporeal
circulation (bioincompatibility)
FIGURE 18-1
Nutritional goals in patients with acute renal failure (ARF). The
goals of nutritional intervention in ARF differ from those in
patients with chronic renal failure (CRF): One should not provide
a minimal intake of nutrients (to minimize uremic toxicity or to
retard progression of renal failure, as recommended for CRF) but
rather an optimal amount of nutrients should be provided for correction and prevention of nutrient deficiencies and for stimulation
of immunocompetence and wound healing in the mostly hypercatabolic patients with ARF [1].
FIGURE 18-2
Metabolic perturbations in acute renal failure (ARF). In most
instances ARF is a complication of sepsis, trauma, or multiple
organ failure, so it is difficult to ascribe specific metabolic alterations to ARF. Metabolic derangements will be determined by the
acute uremic state plus the underlying disease process or by complications such as severe infections and organ dysfunctions and,
last but not least by the type and frequency of renal replacement
therapy [1, 2].
Nevertheless, ARF does not affect only water, electrolyte, and acid
base metabolism: it induces a global change of the metabolic environment with specific alterations in protein and amino acid, carbohydrate, and lipid metabolism [2].
Metabolic Alterations in Acute Renal Failure

Energy metabolism
FIGURE 18-3
Energy metabolism in acute renal failure (ARF). In experimental animals ARF decreases oxygen consumption even when hypothermia
and acidosis are corrected (uremic hypometabolism) [3]. In contrast,
in the clinical setting oxygen consumption of patients with various
form of renal failure is remarkably little changed [4]. In subjects
with chronic renal failure (CRF), advanced uremia (UA), patients
on regular hemodialysis therapy (HD) but also in patients with uncomplicated ARF (ARFNS) resting energy expenditure (REE) was
comparable to that seen in controls (N). However, in patients with
ARF and sepsis (ARFS) REE is increased by approximately 20%.
Thus, energy expenditure of patients with ARF is more determined by the underlying disease than acute uremic state and taken
together these data indicate that when uremia is well-controlled by
hemodialysis or hemofiltration there is little if any change in energy
metabolism in ARF. In contrast to many other acute disease processes ARF might rather decrease than increase REE because in multiple
organ dysfunction syndrome oxygen consumption was significantly
higher in patients without impairment of renal function than in
those with ARF [5]. (From Schneeweiss [4]; with permission.)
Nutrition and Metabolism in Acute Renal Failure
ESTIMATION OF ENERGY REQUIREMENTS

Calculation of resting energy expenditure (REE) (Harris Benedict equation):
Males: 66.47 (13.75 BW) (5 height) (6.76 age)
Females: 655.1 (9.56 BW) (1.85 height) (4.67 age)
The average REE is approximately 25 kcal/kg BW/day
Stress factors to correct calculated energy requirement for hypermetabolism:
Postoperative (no complications) 1.0
Long bone fracture 1.151.30
Cancer 1.101.30
Peritonitis/sepsis 1.201.30
Severe infection/polytrauma 1.201.40
Burns ( approxim. REE % burned body surface area) 1.202.00
Corrected energy requirements (kcal/d) REE stress factor
18.3
FIGURE 18-4
Estimation of energy requirements. Energy requirements of
patients with acute renal failure (ARF) have been grossly overestimated in the past and energy intakes of more than 50 kcal/kg
of body weight (BW) per day (ie, about 100% above resting
energy expenditure (REE) haven been advocated [6]. Adverse
effects of overfeeding have been extensively documented during
the last decades, and it should be noted that energy intake must
not exceed the actual energy consumption. Energy requirements
can be calculated with sufficient accuracy by standard formulas
such as the Harris Benedict equation. Calculated REE should be
multiplied with a stress factor to correct for hypermetabolic
disease; however, even in hypercatabolic conditions such as sepsis
or multiple organ dysfunction syndrome, energy requirements
rarely exceed 1.3 times calculated REE [1].
Protein metabolism
FIGURE 18-5
Protein metabolism in acute renal failure (ARF): activation of
protein catabolism. Protein synthesis and degradation rates in
acutely uremic and sham-operated rats. The hallmark of metabolic alterations in ARF is activation of protein catabolism with
excessive release of amino acids from skeletal muscle and sustained negative nitrogen balance [7, 8]. Not only is protein breakdown accelerated, but there also is defective muscle utilization of
amino acids for protein synthesis. In muscle, the maximal rate of
insulin-stimulated protein synthesis is depressed by ARF and protein degradation is increased, even in the presence of insulin [9].
(From [8]; with permission.)
18.4
Acute Renal Failure
FIGURE 18-6
Protein metabolism in acute renal failure (ARF): impairment of
cellular amino acid transport. A, Amino acid transport into skeletal muscle is impaired in ARF [10]. Transmembranous uptake of
the amino acid analogue methyl-amino-isobutyrate (MAIB) is
reduced in uremic tissue in response to insulin (muscle tissue
from uremic animals, black circles, and from sham-operated animals, open circles, respectively). Thus, insulin responsiveness is
reduced in ARF tissue, but, as can be seen from the parallel shift
of the curves, insulin sensitivity is maintained (see also Fig. 18-14).

This abnormality can be linked both to insulin resistance and to
a generalized defect in ion transport in uremia; both the activity
and receptor density of the sodium pump are abnormal in adipose cells and muscle tissue [11]. B, The impairment of rubidium
uptake (Rb) as a measure of Na-K-ATPase activity is tightly correlated to the reduction in amino acid transport. (From [10,11];
with permission.)
FIGURE 18-7
Protein catabolism in acute renal failure (ARF). Amino acids are
redistributed from muscle tissue to the liver. Hepatic extraction of
amino acids from the circulationhepatic gluconeogenesis, A, and
ureagenesis, B, from amino acids all are increased in ARF [12].
The dominant mediator of protein catabolism in ARF is this accel-
erated hepatic gluconeogenesis, which cannot be suppressed by

exogenous substrate infusions (see Fig. 18-15). In the liver, protein
synthesis and secretion of acute phase proteins are also stimulated.
Circleslivers from acutely uremic rats; squareslivers from sham
operated rats. (From Frhlich [12]; with permission.).
18.5
FIGURE 18-8
Protein catabolism in acute renal failure (ARF): contributing factors.
The causes of hypercatabolism in ARF are complex and multifold
and present a combination of nonspecific mechanisms induced by
the acute disease process and underlying illness and associated complications, specific effects induced by the acute loss of renal function,
and, finally, the type and intensity of renal replacement therapy.
A major stimulus of muscle protein catabolism in ARF is insulin

resistance. In muscle, the maximal rate of insulin-stimulated
protein synthesis is depressed by ARF and protein degradation is
increased even in the presence of insulin [9].
Acidosis was identified as an important factor in muscle protein
breakdown. Metabolic acidosis activates the catabolism of protein
and oxidation of amino acids independently of azotemia, and
nitrogen balance can be improved by correcting the metabolic
acidosis [13]. These findings were not uniformly confirmed for
ARF in animal experiments [14].
Several additional catabolic factors are operative in ARF. The
secretion of catabolic hormones (catecholamines, glucagon,
glucocorticoids), hyperparathyroidism which is also present in ARF
(see Fig. 18-22), suppression of or decreased sensitivity to growth
factors, the release of proteases from activated leukocytesall can
stimulate protein breakdown. Moreover, the release of inflammatory mediators such as tumor necrosis factor and interleukins have
been shown to mediate hypercatabolism in acute disease [1, 2].
The type and frequency of renal replacement therapy can also
affect protein balance. Aggravation of protein catabolism, certainly,
is mediated in part by the loss of nutritional substrates, but some
findings suggest that, in addition, both activation of protein
breakdown and inhibition of muscular protein synthesis are
induced by hemodialysis [15].
Last (but not least), of major relevance for the clinical situation
is the fact that inadequate nutrition contributes to the loss of lean
body mass in ARF. In experimental animals, starvation potentiates
the catabolic response of ARF [7].
FIGURE 18-9
Amino acid pools and amino acid utilization in acute renal failure
(ARF). As a consequence of these metabolic alterations, imbalances in amino acid pools in plasma and in the intracellular compartment occur in ARF. A typical plasma amino acid pattern is
seen [16]. Plasma concentrations of cysteine (CYS), taurine (TAU),
methionine (MET), and phenylalanine (PHE) are elevated, whereas plasma levels of valine (VAL) and leucine (LEU) are decreased.
Moreover, elimination of amino acids from the intravascular
space is altered. As expected from the stimulation of hepatic
extraction of amino acids observed in animal experiments,

overall amino acid clearance and clearance of most glucoplastic
amino acids is enhanced. In contrast, clearances of PHE, proline
(PRO), and, remarkably, VAL are decreased [16, 17]. ALA
alanine; ARGarginine; ASNasparagine; ASPaspartate;
CITcitrulline; GLNglutamine; GLUglutamate; GLY
glycine; HIShistidine; ORNornithine; PROproline; SER
serine; THRthreonine; TRPtryptophan; TYRtyrosine.
(From Druml et al. [16]; with permission.)
CONTRIBUTING FACTORS TO PROTEIN

CATABOLISM IN ACUTE RENAL FAILURE
Impairment of metabolic functions by uremia toxins
Endocrine factors
Insulin resistance
Increased secretion of catabolic hormones (catecholamines,
glucagon, glucocorticoids)
Hyperparathyroidism
Suppression of release or resistance to growth factors
Acidosis
Systemic inflammatory response syndrome (activation of cytokine network)
Release of proteases
Inadequate supply of nutritional substrates
Loss of nutritional substrates (renal replacement therapy)
18.6
Acute Renal Failure
FIGURE 18-10
Metabolic functions of the kidney and protein and amino acid
metabolism in acute renal failure (ARF). Protein and amino acid
metabolism in ARF are also affected by impairment of the metabolic functions of the kidney itself. Various amino acids are synthe-
sized or converted by the kidneys and released into the circulation:

cysteine, methionine (from homocysteine), tyrosine, arginine, and
serine [18]. Thus, loss of renal function can contribute to the
altered amino acid pools in ARF and to the fact that several amino
acids, such as arginine or tyrosine, which conventionally are
termed nonessential, might become conditionally indispensable in
ARF (see Fig. 18-11) [19].
In addition, the kidney is an important organ of protein degradation. Multiple peptides are filtered and catabolized at the tubular
brush border, with the constituent amino acids being reabsorbed
and recycled into the metabolic pool. In renal failure, catabolism of
peptides such as peptide hormones is retarded. This is also true for
acute uremia: insulin requirements decrease in diabetic patients
who develop of ARF [20].
With the increased use of dipeptides in artificial nutrition as a
source of amino acids (such as tyrosine and glutamine) which are
not soluble or stable in aqueous solutions, this metabolic function
of the kidney may also gain importance for utilization of these
novel nutritional substrates. In the case of glycyl-tyrosine, metabolic clearance progressively decreases with falling creatinine clearance
(open circles, 7 healthy subjects and a patient with unilateral
nephrectomy*) but extrarenal clearance in the absence of renal
function (black circles) is sufficient for rapid utilization of the
dipeptide and release of tyrosine [21]. (From Druml et al. [21];
with permission.)
FIGURE 18-11
Amino acids in nutrition of acute renal failure (ARF): Conditionally
essential amino acids. Because of the altered metabolic environment
of uremic patients certain amino acids designated as nonessential
for healthy subjects may become conditionally indispensable to ARF
patients: histidine, arginine, tyrosine, serine, cysteine [19]. Infusion

of arginine-free amino acid solutions can cause life-threatening complications such as hyperammonemia, coma, and acidosis.
Healthy subjects readily form tyrosine from phenylalanine in
the liver: During infusion of amino acid solutions containing
phenylalanine, plasma tyrosine concentration rises (circles) [22].
In contrast, in patients with ARF (triangles) and chronic renal
failure (CRF, squares) phenylalanine infusion does not increase
plasma tyrosine, indicating inadequate interconversion.
Recently, it was suggested that glutamine, an amino acid that
traditionally was designated non-essential exerts important metabolic functions in regulating nitrogen metabolism, supporting
immune functions, and preserving the gastrointestinal barrier.
Thus, it can become conditionally indispensable in catabolic illness [23]. Because free glutamine is not stable in aqueous solutions, dipeptides containing glutamine are used as a glutamine
source in parenteral nutrition. The utilization of dipeptides in
part depends on intact renal function, and renal failure can impair
hydrolysis (see Fig. 18-10) [24]. No systematic studies have been
published on the use of glutamine in patients with ARF, and it
must be noted that glutamine supplementation increases nitrogen
intake considerably.
18.7
Protein requirements
ESTIMATING THE EXTENT OF PROTEIN CATABOLISM
Urea nitrogen appearance (UNA) (g/d)
Urinary urea nitrogen (UUN) excretion
Change in urea nitrogen pool
(UUN V) (BUN2 BUN1) 0.006 BW
(BW2 BW1) BUN2/100
If there are substantial gastrointestinal losses, add urea nitrogen in secretions:
volume of secretions BUN2
Net protein breakdown (g/d) UNA 6.25
Muscle loss (g/d) UNA 6.25 5
V is urine volume; BUN1 and BUN2 are BUN in mg/dL on days 1 and 2
BW1 and BW2 are body weights in kg on days 1 and 2
FIGURE 18-13
Amino acid and protein requirements of patients with acute renal
failure (ARF). The optimal intake of protein or amino acids is
affected more by the nature of the underlying cause of ARF and
the extent of protein catabolism and type and frequency of dialysis
than by kidney dysfunction per se. Unfortunately, only a few studies have attempted to define the optimal requirements for protein
or amino acids in ARF:
In nonhypercatabolic patients, during the polyuric phase of ARF
protein intake of 0.97 g/kg body weight per day was required to
achieve a positive nitrogen balance [25]. A similar number (1.03g/kg
FIGURE 18-12
Estimation of protein catabolism and nitrogen balance. The extent
of protein catabolism can be assessed by calculating the urea nitrogen appearance rate (UNA), because virtually all nitrogen arising
from amino acids liberated during protein degradation is converted
to urea. Besides urea in urine (UUN), nitrogen losses in other body
fluids (eg, gastrointestinal, choledochal) must be added to any
change in the urea pool. When the UNA rate is multiplied by 6.25,
it can be converted to protein equivalents. With known nitrogen
intake from the parenteral or enteral nutrition, nitrogen balance
can be estimated from the UNA calculation.
body weight per day) was derived from a study in which, unfortunately, energy intake was not kept constant [6]. In the polyuric
recovery phase in patients with sepsis-induced ARF, a nitrogen intake
of 15 g/day (averaging an amino acid intake of 1.3 g/kg body weight
per day) as compared to 4.4 g/kg per day (about 0.3 g/kg amino
acids) was superior in ameliorating nitrogen balance [26].
Several recent studies have tried to evaluate protein and amino
acid requirements of critically ill patients with ARF. Kierdorf and
associates found that, in these hypercatabolic patients receiving
continuous hemofiltration therapy, the provision of amino acids 1.5
g /kg body weight per day was more effective in reducing nitrogen
loss than infusion of 0.7 g (3.4 versus 8.1 g nitrogen per day)
[27]. An increase of amino acid intake to 1. 74 g/kg per day did not
further ameliorate nitrogen balance.
Chima and coworkers measured a mean PCR of 1.7 g kg body
weight per day in 19 critically ill ARF patients and concluded that
protein needs in these patients range between 1.4 and 1.7 g/kg per
day [28]. Similarly, Marcias and coworkers have obtained a protein
catabolic rate (PCR) of 1.4 g/kg per day and found an inverse
relationship between protein and energy provision and PCR and
again recommended protein intake of 1.5 to 1.8 g/kg per day [29].
Similar conclusions were drawn by Ikitzler in evaluating ARF
patients on intermittent hemodialysis therapy [30]. (From Kierdorf
18.8
Acute Renal Failure
Glucose metabolism
FIGURE 18-14
Glucose metabolism in acute renal failure (ARF): Peripheral insulin
resistance. ARF is commonly associated with hyperglycemia. The
major cause of elevated blood glucose concentrations is insulin
resistance [31]. Plasma insulin concentration is elevated. Maximal
insulin-stimulated glucose uptake by skeletal muscle is decreased by
50 %, A, and muscular glycogen synthesis is impaired, B. However,
insulin concentrations that cause half-maximal stimulation of glucose uptake are normal, pointing to a postreceptor defect rather
than impaired insulin sensitivity as the cause of defective glucose

metabolism. The factors contributing to insulin resistance are more
or less identical to those involved in the stimulation of protein
breakdown (see Fig. 18-8). Results from experimental animals suggest a common defect in protein and glucose metabolism: tyrosine
release from muscle (as a measure of protein catabolism) is closely
correlated with the ratio of lactate release to glucose uptake [9].
(From May et al. [31]; with permission.)
FIGURE 18-15
Glucose metabolism in acute renal failure (ARF): Stimulation of
hepatic gluconeogenesis. A second feature of glucose metabolism
(and at the same time the dominating mechanism of accelerated protein breakdown) in ARF is accelerated hepatic gluconeogenesis, mainly from conversion of amino acids released during protein catabolism.
Hepatic extraction of amino acids, their conversion to glucose, and
urea production are all increased in ARF (see Fig. 18-7) [12].
In healthy subjects, but also in patients with chronic renal failure,
hepatic gluconeogenesis from amino acids is readily and completely
suppressed by exogenous glucose infusion. In contrast, in ARF hepatic glucose formation can only be decreased, but not halted, by substrate supply. As can be seen from this experimental study, even during glucose infusion there is persistent gluconeogenesis from amino
acids in acutely uremic dogs () as compared with controls dogs (o)
whose livers switch from glucose release to glucose uptake [32].
These findings have important implications for nutrition support
for patients with ARF: 1) It is impossible to achieve positive nitrogen
balance; 2) Protein catabolism cannot be suppressed by providing
conventional nutritional substrates alone. Thus, for future advances
alternative means must be found to effectively suppress protein catabolism and preserve lean body mass. (From Cianciaruso et al. [32];
with permission.)
18.9
Lipid metabolism
FIGURE 18-16
Lipid metabolism in acute renal failure (ARF). Profound alterations
of lipid metabolism occur in patients with ARF. The triglyceride content of plasma lipoproteins, especially very low-density (VLDL) and
low-density ones (LDL) is increased, while total cholesterol and in
particular high-density lipoprotein (HDL) cholesterol are decreased
[33,34]. The major cause of lipid abnormalities in ARF is impairment of lipolysis. The activities of both lipolytic systems, peripheral
lipoprotein lipase and hepatic triglyceride lipase are decreased in
patients with ARF to less than 50% of normal [35].
Maximal postheparin lipolytic activity (PHLA), hepatic triglyceride
lipase (HTGL), and peripheral lipoprotein lipase (LPL) in 10 controls
(open bars) and eight subjects with ARF (black bars). However, in
contrast to this impairment of lipolysis, oxidation of fatty acids is
not affected by ARF. During infusion of labeled long-chain fatty
acids, carbon dioxide production from lipid was comparable
between healthy subjects and patients with ARF [36]. FFAfree
fatty acids. (Adapted from Druml et al. [35]; with permission.)
FIGURE 18-17
Impairment of lipolysis and elimination of artificial lipid emulsions
in acute renal failure (ARF). Fat particles of artificial fat emulsions
for parenteral nutrition are degraded as endogenous very low-density lipoprotein is. Thus, the nutritional consequence of the
impaired lipolysis in ARF is delayed elimination of intravenously
infused lipid emulsions [33, 34]. The increase in plasma triglycerides during infusion of a lipid emulsion is doubled in patients
with ARF (N=7) as compared with healthy subjects (N=6). The
clearance of fat emulsions is reduced by more than 50% in ARF.
The impairment of lipolysis in ARF cannot be bypassed by using
medium-chain triglycerides (MCT); the elimination of fat emulsions containing long chain triglycerides (LCT) or MCT is equally
retarded in ARF [34]. Nevertheless, the oxydation of free fatty acid
released from triglycerides is not inpaired in patients with ARF
[36]. (From Druml et al. [34]; with permission.)
18.10
Acute Renal Failure
Electrolytes and micronutrients

CAUSES OF ELECTROLYTE DERANGEMENTS
Hyperkalemia
Hyperphosphatemia
Decreased renal elimination

Increased release during catabolism
2.38 mEq/g nitrogen
0.36 mEq/g glycogen
Decreased cellular uptake/
increased release
Metabolic acidosis: 0.6 mmol/L rise/0.1
decrease in pH
Decreased renal elimination

Increased release from bone
Increased release during catabolism:
2 mmol/g nitrogen
Decreased cellular uptake/utilization
and/or increased release from cells
FIGURE 18-19
Electrolytes in acute renal failure (ARF): hypophosphatemia and
hypokalemia. It must be noted that a considerable number of
patients with ARF do not present with hyperkalemia or hyperphosphatemia, but at least 5% have low serum potassium and more
than 12% have decreased plasma phosphate on admission [38].
Nutritional support, especially parenteral nutrition with low electrolyte content, can cause hypophosphatemia and hypokalemia in
as many as 50% and 19% of patients respectively [39,40].
In the case of phosphate, phosphate-free artificial nutrition causes
hypophosphatemia within a few days, even if the patient was hyperphosphatemic on admission (black circles) [41]. Supplementation of
5 mmol per day was effective in maintaining normal plasma phosphate concentrations (open squares), whereas infusion of more than
10 mmol per day resulted in hyperphosphatemia, even if the patients
had decreased phosphate levels on admission (open circles).
Potassium or phosphate depletion increases the risk of developing
ARF and retards recovery of renal function. With modern nutritional support, hyperkalemia is the leading indication for initiation of
extracorporeal therapy in fewer than 5% of patients [38]. (Adapted
from Kleinberger et al. [41]; with permission.)
FIGURE 18-18
Electrolytes in acute renal failure (ARF): causes of hyperkalemia
and hyperphosphatemia. ARF frequently is associated with hyperkalemia and hyperphosphatemia. Causes are not only impaired
renal excretion of electrolytes but release during catabolism, altered
distribution in intracellular and extracellular spaces, impaired
cellular uptake, and acidosis. Thus, the type of underlying disease
and degree of hypercatabolism also determine the occurrence and
severity of electrolyte abnormalities. Either hypophosphatemia or
hyperphosphatemia can predispose to the development and
maintenance of ARF [37].
FIGURE 18-20
Micronutrients in acute renal failure (ARF): water-soluble vitamins.
Balance studies on micronutrients (vitamins, trace elements) are not
available for ARF. Because of losses associated with renal replacement therapy, requirements for water-soluble vitamins are expected
to be increased also in patients with ARF. Malnutrition with depletion of vitamin body stores and associated hypercatabolic underlying disease in ARF can further increase the need for vitamins.
Depletion of thiamine (vitamin B1) during continuous hemofiltration and inadequate intake can result in lactic acidosis and heart
failure [42]. This figure depicts the evolution of plasma lactate concentration before and after administration of 600 mg thiamine in
two patients. Infusion of 600 mg of thiamine reversed the metabolic abnormality within a few hours. An exception to this approach
to treatment is ascorbic acid (vitamin C); as a precursor of oxalic
acid the intake should be kept below 200 mg per day because any
excessive supply may precipitate secondary oxalosis [43]. (From
Madl et al. [42]; with permission.)
FIGURE 18-21
Micronutrients in acute renal failure (ARF): fat-soluble vitamins
(A, E, K). Despite the fact that fat-soluble vitamins are not lost during hemodialysis and hemofiltration, plasma concentrations of vitamins A and E are depressed in patients with ARF and requirements
are increased [44]. Plasma concentrations of vitamin K (with broad
variations of individual values) are normal in ARF. Most commercial multivitamin preparations for parenteral infusions contain the
recommended daily allowances of vitamins and can safely be used
in ARF patients. (From Druml et al. [44]; with permission.)
18.11
FIGURE 18-22
Hypocalcemia and the vitamin Dparathyroid hormone (PTH) axis
in acute renal failure (ARF). ARF is also frequently associated with
hypocalcemia secondary to hypoalbuminemia, elevated serum phosphate, plus skeletal resistance to calcemic effect of PTH and impairment of vitamin-D activation. Plasma concentration of PTH is
increased. Plasma concentrations of vitamin D metabolites, 25-OH
vitamin D3 and 1,25-(OH)2 vitamin D3, are decreased [44]. In ARF
caused by rhabdomyolysis rebound hypercalcemia may develop during
the diuretic phase. (Adapted from Druml et al. [44]; with permission.)
FIGURE 18-23
Micronutrients in acute renal failure (ARF): antioxidative factors.
Micronutrients are part of the organisms defense mechanisms
against oxygen free radical induced injury to cellular components.
In experimental ARF, antioxidant deficiency of the organism
(decreased vitamin E or selenium status) exacerbates ischemic renal
injury, worsens the course, and increases mortality, whereas repletion of antioxidant status exerts the opposite effect [45]. These
data argue for a crucial role of reactive oxygen species and peroxidation of lipid membrane components in initiating and mediating
ischemia or reperfusion injury.
In patients with multiple organ dysfunction syndrome and associated ARF (lightly shaded bars) various factors of the oxygen radical scavenger system are profoundly depressed as compared with
healthy subjects (black bars): plasma concentrations of vitamin C,
of -carotene, vitamin E, selenium, and glutathione all are profoundly depressed, whereas the end-product of lipid peroxidation,
malondialdehyde, is increased (double asterisk, P < 0.01; triple
asterisk, P < 0.001). This underlines the importance of supplementation of antioxidant micronutrients for patients with ARF.
(Adapted from Druml et al. [46]; with permission.)
18.12
Acute Renal Failure
Metabolic Impact of Renal Replacement Therapy

METABOLIC EFFECTS OF CONTINUOUS
RENAL REPLACEMENT THERAPY
Amelioration of uremia intoxication (renal replacement)
Plus
Heat loss
Excessive load of substrates (eg, lactate, glucose)
Loss of nutrients (eg, amino acids, vitamins)
Elimination of short-chain proteins (hormones, mediators?)
Induction or activation of mediator cascades
Stimulation of protein catabolism?
FIGURE 18-24
Metabolic impact of extracorporeal therapy. The impact of hemodialysis therapy on metabolism is multifactorial. Amino acid and protein
metabolism are altered not only by substrate losses but also by activation of protein breakdown mediated by release of leukocyte-derived
proteases, of inflammatory mediators (interleukins and tumor necrosis factor) induced by blood-membrane interactions or endotoxin.
Dialysis can also induce inhibition of muscle protein synthesis [15].
In the management of patients with acute renal failure (ARF), continuous renal replacement therapies (CRRT), such as continuous
(arteriovenous) hemofiltration (CHF) and continuous hemodialysis

have gained wide popularity. CRRTs are associated with multiple
metabolic effects in addition to renal replacement [47].
By cooling of the extracorporeal circuit and infusion of cooled
substitution fluids, CHF may induce considerable heat loss (350 to
700 kcal per day). On the other hand, hemofiltration fluids contain
lactate as anions, oxidation of which in part compensates for the
heat loss. This lactate load can result in hyperlactemia in the presence of liver dysfunction or increased endogenous lactate formation
such as in circulatory shock.
Several nutrients with low protein binding and small molecular
weight (sieving coefficient 0.8 to 1.0), such as vitamins or amino
acids are eliminated during therapy. Amino acid losses can be estimated from the volume of the filtrate and average plasma concentration, and usually this accounts for a loss of approximately 0.2
g/L of filtrate and, depending on the filtered volume, 5 to 10 g of
amino acid per day, respectively, representing about 10 % of amino
acid input, but it can be even higher during continuous hemodiafiltration [48].
With the large molecular size cut-off of membranes used in hemofiltration, small proteins such as peptide hormones are filtered. In view
of their short plasma half-life hormone losses are minimal and probably not of pathophysiologic importance. Quantitatively relevant elimination of mediators by CRRT has not yet been proven. On the other
hand, prolonged blood-membrane interactions can induce consequences of bioincompatibility and activation of various endogenous
cascade systems.
Nutrition, Renal Function, and Recovery
FIGURE 18-25
A, B, Impact of nutritional interventions on renal function and
course of acute renal failure (ARF). Starvation accelerates protein
breakdown and impairs protein synthesis in the kidney, whereas
refeeding exerts the opposite effects [49]. In experimental animals,
provision of amino acids or total parenteral nutrition accelerates
tissue repair and recovery of renal function [50]. In patients,
however, this has been much more difficult to prove, and only one
study has reported on a positive effect of TPN on the resolution
of ARF [51].
Infusion of amino acids raised renal cortical protein synthesis as

evaluated by 14C-leucine incorporation and depressed protein breakdown
in rats with mercuric chlorideinduced ARF [49]. On the other hand, in a
similar model of ARF, infusions of varying quantities of essential amino
acids (EAA) and nonessential amino acids (NEAA) did not provide any
protection of renal function and in fact increased mortality [52]. However,
in balance available evidence suggests that provision of substrates may
enhance tissue regeneration and wound healing, and potentially, also
renal tubular repair [49]. (From Toback et al. [50]; with permission.)
18.13
FIGURE 18-26
Impact of nutritional interventions on renal function in acute renal
failure (ARF). Amino acid infused before or during ischemia or
nephrotoxicity may enhance tubule damage and accelerate loss of
renal function in rat models of ARF. In part, this therapeutic paradox [53] from amino acid alimentation in ARF is related to the
increase in metabolic work for transport processes when oxygen
supply is limited, which may aggravate ischemic injury [54].
Similar observations have been made with excess glucose infusion
during renal ischemia. Amino acids may as well exert a protective
effect on renal function. Glycine, and to a lesser degree alanine,
limit tubular injury in ischemic and nephrotoxic models of ARF
[55]. Arginine (possibly by producing nitric oxide) reportedly acts
to preserve renal perfusion and tubular function in both nephrotoxic and ischemic models of ARF, whereas inhibitors of nitric
oxide synthase exert an opposite effect [56,57]. In myoglobininduced ARF the drop in renal blood flow (black circles, ARF controls) is prevented by L-arginine infusion (black triangles) [57].
(From Wakabayashi et al. [57]; with permission.)
FIGURE 18-27
Impact of endocrine-metabolic interventions on renal function and
course of acute renal failure (ARF). Various other endocrine-metabolic interventions (eg, thyroxine, human growth hormone [HGH],
epidermal growth factor, insulin-like growth factor 1 [IGF-1]) have
been shown to accelerate regeneration after experimental ARF
[51]. In a rat model of postischemic ARF, treatment with IGF-1
starting 5 hours after induction of ARF accelerates recovery from
ischemic ARF, A, but also reduces the increase in BUN and

improves nitrogen balance, B, [58]. (open circles) ARF plus vehicle; (black circles, sham-operated rats plus vehicle; open squares,
ARF plus rhIGF-I; black squares, sham operated rats plus rhIGFI.) Unfortunately, efficacy of these interventions was not uniformly confirmed in clinical studies [59, 60]. (From Ding et al. [58];
with permission.)
18.14
Acute Renal Failure
Decision Making, Patient Classification,

and Nutritional Requirements
DECISIONS FOR NUTRITION IN PATIENTS
WITH ACUTE RENAL FAILURE
Decisions dependent on
Patients ability to resume oral diet (within 5 days?)
Nutritional status
Underlying illness/degree of associated hypercatabolism
1. What patient with acute renal failure needs nutritional support?
2. When should nutritional support be initiated?
3. At what degree of impairment in renal function should the nutritional regimen
be adapted for renal failure?
4. In a patient with multiple organ dysfunction, which organ determines the type of
nutritional support?
5. Is enteral or parenteral nutrition the most appropriate method for providing
nutritional support?
FIGURE 18-28
Nutrition in patients with acute renal failure (ARF): decision making. Not every patient with ARF requires nutritional support. It is
important to identify those who will benefit and to define the optimal time to initiate therapy [1].
The decision to initiate nutritional support is influenced by the
patients ability to cover nutritional requirements by eating, in addition to the nutritional status of the patient as well as the type of
underlying illness involved. In any patient with evidence of malnourishment, nutritional therapy should be instituted regardless of
whether the patient will be likely to eat. If a well-nourished patient
can resume a normal diet within 5 days, no specific nutritional support is necessary. The degree of accompanying catabolism is also a
factor. For patients with underlying diseases associated with excess
protein catabolism, nutritional support should be initiated early.
If there is evidence of malnourishment or hypercatabolism, nutritional therapy should be initiated early, even if the patient is likely to
eat before 5 days. Modern nutritional strategies should be aimed at
avoiding the development of deficiency states and of hospitalacquired malnutrition. During the acute phase of ARF (the first
24 hours after trauma or surgery) nutritional support should be
withheld because nutrients infused during this ebb phase are not
utilized, could increase oxygen requirements, and aggravate tissue
injury and renal dysfunction.
The nutritional regimen should be adapted for renal failure when
renal function is impaired. The multiple metabolic alterations characteristic of ARF occur when kidney function is below 30% of
normal. Thus, when creatinine clearance falls below 50 to 30 mL
per minute/1.73 m2 (or serum creatinine rises above 2.5 to 3.0
mg/dL) the nutritional regimen should be adapted to ARF.
With the exception of severe hepatic failure and massively deranged
amino acid metabolism (hyperammonemia) or protein synthesis (depletion of coagulation factors) renal failure is the major determinant of the
nutritional regimen in patients with multiple organ dysfunction.
Enteral feeding is preferred for all patients, including those with ARF.
Nevertheless, for a large portion of patients, parenteral nutritiontotal
or partialwill be necessary to meet nutritional requirements.
PATIENT CLASSIFICATION AND SUBSTRATE REQUIREMENTS

IN PATIENTS WITH ACUTE RENAL FAILURE
Extent of Catabolism
Mild
Moderate
Severe
Excess urea appearance

(above nitrogen intake)
Clinical setting (examples)
>6 g
612 g
>12 g
Drug toxicity
Elective surgery
infection
Severe injury or
sepsis
Mortality
Dialysis or hemofiltration frequency
Route of nutrient
administration
Energy recommendations
(kcal/kg BW/d)
Energy substrates
Glucose (g/kg BW/d)
Fat (g/kg BW/d)
Amino acids/protein (g/kg/d)
20 %
Rare
Oral
60%
As needed
Enteral or parenteral
>80%
Frequent
Enteral or parenteral
25
2530
2535
Glucose
3.05.0
Glucose + fat
3.05.0
0.51.0
0.81.2
EAA NEAA
Enteral formulas
Glucose 50%70%
fat emulsions 10%
or 20%
Glucose fat
3.05.0 (max. 7.0)
0.81.5
1.01.5
EAA NEAA
Enteral formulas
Glucose 50%70% +
fat emulsions 10%
or 20%
Nutrients used
0.61.0
EAA (NEAA)
Foods
EAA + specific NEAA solutions (general or nephro)

Multivitamin and multitrace element preparations
BWbody weight; EAAessential amino acids; NEAAnonessential amino acids.
FIGURE 18-29
Patient classification: substrate requirements. Ideally, a nutritional program should be
designed for each individual acute renal failure (ARF) patient. In clinical practice, it has
proved useful to distinguish three groups of patients based on the extent of protein catabolism associated with the underlying disease and resulting levels of dietary requirements.
Group I includes patients without excess catabolism and a UNA of less than 6 g of
nitrogen above nitrogen intake per day. ARF is usually caused by nephrotoxins (aminoglycosides, contrast media, mismatched blood transfusion). In most cases, these patients are
fed orally and the prognosis for recovery of renal function and survival is excellent.
Group II consists of patients with moderate hypercatabolism and a UNA exceeding
nitrogen intake 6 to 12 g of nitrogen per day. Affected patients frequently suffer from
complicating infections, peritonitis, or moderate injury in association with ARF. Tube feeding or intravenous nutritional support is generally required, and dialysis or hemofiltration
often becomes necessary to limit waste product accumulation.
Group III are patients who develop ARF in association with severe trauma, burns, or
overwhelming infection. UNA is markedly elevated (more than 12 g of nitrogen above
nitrogen intake). Treatment strategies are usually complex and include parenteral nutrition, hemodialysis or continuous hemofiltration plus blood pressure and ventilatory support. To reduce catabolism and avoid protein depletion nutrient requirements are high and
dialysis is used to maintain fluid balance and blood urea nitrogen below 100 mg/dL.
Mortality in this group of patients exceeds 60% to 80%, but it is not the loss of renal
function that accounts for the poor prognosis. It is superimposed hypercatabolism and the
severity of the underlying illness. (Adapted from Druml [1]; with permission.)
18.15
18.16
Acute Renal Failure
Enteral Nutrition
FIGURE 18-30
Enteral nutrition (tube feeding). The gastrointestinal tract should be used whenever
possible because enteral nutrients may help to maintain gastrointestinal function and the
mucosal barrier and thus prevent translocation of bacteria and systemic infection [61].
Even small amounts of enteral diets exert a protective effect on the intestinal mucosa.
Recent animal experiments suggest that enteral feeds may exert additional advantages in
acute renal failure (ARF) patients [63]: in glycerol-induced ARF in rats enteral feeding
improved renal perfusion, A, and preserved renal function, B. For patients with ARF who
are unable to eat because of cerebral impairment, anorexia, or nausea, enteral nutrition
should be provided through small, soft feeding tubes with the tip positioned in the stomach or jejunum [61]. Feeding solutions can be administered by pump intermittently or continuously. If given continuously, the stomach should be aspirated every 2 to 4 hours until
adequate gastric emptying and intestinal peristalsis are established. To avoid diarrhea, the
amount and concentration of the solution should be increased gradually over several days
until nutritional requirements are met. Undesired, but potentially treatable side effects
include nausea, vomiting, abdominal distension and cramping and diarrhea. (From
Roberts et al. [62]; with permission.)
18.17
SPECIFIC ENTERAL FORMULAS FOR NUTRITIONAL SUPPORT OF PATIENTS WITH RENAL FAILURE
Amin-Aid
Volume (mL)
Calories (kcal)
(cal/mL)
Energy distribution
Protein:fat:carbohydrates (%)
kcal/g N
Proteins (g)
EAA (%)
NEAA (%)
Hydrolysate (%)
Full protein (%)
Nitrogen (g)
Carbohydrates (g)
Monodisaccharides (%)
Oligosaccharides (%)
Polysaccharides (%)
Fat (g)
LCT (%)
Essential GA (%)
MCT (%)
Nonprotein (cal/g N)
Osmol (mOsm/kg)
Sodium (mmol/L)
Potassium (mmol/L)
Phosphate (mmol)
Vitamins
Minerals
Travasorb
renal*
Salvipeptide
nephro
Survimed
renal
Suplena
Nepro
750
1467
1.96
1050
1400
1.35
500
1000
2.00
1000
1320
1.32
500
1000
2.00
500
1000
2.00
4:21:75
832:1
14.6
100
1.76
274
100
34.6
7:12:81
389:1
24.0
60
30
3.6
284
100
18.6
30
18
70
363
590
16.1
a
b
8:22:70
313:1
20.0
23
20
23
34
3.2
175
3
28
69
24
50
31
50
288
507
7.2
1.5
6.13
a
a
6:10:84
398:1
20.8
6:43:51
418:1
15.0
14:43:43
179:1
35
100
2.4
128
10
100
5.6
108
12
502
1095
11
b
b
100
3.32
276
88
15.2
52
30
374
600
15.2
8
6.4
a
a
48
100
22
0
393
635
32
27.0
11.0
a
a
90
47.8
100
0
154
615
34.0
28.5
11.0
a
a
* 3 bags 810 mL 1050 mL

component I component II 350 mL = 500 mL
4 bags 800 mL 1000 mL
Liquid formula, cans 8 fl oz (237.5 mL), supplemented with carnitine, taurine with a low-protein (Suplena) or moderate-protein content (Nepro)
a 2000 kcal/d meets RDA for most vitamins/trace elements
b Must be added
EAAessential amino acids; FAfatty acids; LCTlong-chain triglycerides; MCTmedium-chain triglycerides; Nnitrogen; NEAAnon-essential amino acids.
FIGURE 18-31
Enteral feeding formulas. There are standardized tube feeding formulas designed for subjects with normal renal function that can
also be given to patients with acute renal failure (ARF).
Unfortunately, the fixed composition of nutrients, including proteins and high content of electrolytes (especially potassium and
phosphate) often limits their use for ARF.
Alternatively, enteral feeding formulas designed for nutritional
therapy of patients with chronic renal failure (CRF) can be used.
The preparations listed here may have advantages also for patients
with ARF. The protein content is lower and is confined to highquality proteins (in part as oligopeptides and free amino acids), the
electrolyte concentrations are restricted. Most formulations contain
recommended allowances of vitamins and minerals.
In part, these enteral formulas are made up of components that
increase the flexibility in nutritional prescription and enable adaptation to individual needs. The diets can be supplemented with additional electrolytes, protein, and lipids as required. Recently, ready-touse liquid diets have also become available for renal failure patients.
18.18
Acute Renal Failure
Parenteral Nutrition
RENAL FAILURE FLUIDALL-IN-ONE SOLUTION
Component
Quantity
Glucose 40%70%
500 mL
Fat emulsion 10%20%
500 mL
Amino acids 6.5%10%
500 mL
Water-soluble vitamins
Fat-soluble vitamins*
Trace elements*
Electrolytes
Daily
Daily
Twice weekly
As required
Insulin
As required
Remarks
In the presence of severe insulin resistance
switch to D30W
Start with 10%, switch to 20% if triglycerides
are < 350 mg/dL
General or special nephro amino acid
solutions, including EAA and NEAA
Limit vitamin C intake < 200 mg/d
Caveats: toxic effects
Caveats: hypophosphatemia or hypokalemia
after initiation of TPN
Added directly to the solution or given separately
* Combination products containing the recommended daily allowances.
FIGURE 18-32
Parenteral solutions. Standard solutions are available with amino acids, glucose, and
lipids plus added vitamins, trace elements, and electrolytes contained in a single bag
(total admixture solutions, all-in-one solutions). The stability of fat emulsions in
such mixtures should be tested. If hyperglycemia is present, insulin can be added to the
solution or administered separately.
To ensure maximal nutrient utilization and avoid metabolic derangements as mineral
imbalance, hyperglycemia or blood urea nitrogen rise, the infusion should be started at a
slow rate (providing about 50% of requirements) and gradually increased over several days.
Optimally, the solution should be infused continuously over 24 hours to avoid marked
derangements in substrate concentrations in the presence of impaired utilization for several
nutritional substrates in patients with acute renal failure. EAA, NEAAessential and
nonessential amino acids; TPNtotal parenteral nutrition.
18.19
AMINO ACID SOLUTIONS FOR THE TREATMENT OF ACUTE RENAL FAILURE (NEPHRO SOLUTIONS)
Rose-Requirements
Amino acids (g/L)
( g/%)
Volume (mL)
(mOsm/L)
Nitrogen (g/L)
Essential amino acids (g/L)
Isoleucine
Leucine
Lysine acetate/HCl
Methionine
Phenylalanine
Threonine
Tryptophan
Valine
1.40
2.20
1.60
2.20
2.20
1.00
0.50
1.60
Nonessential amino acids (g/L)

Alanine
Arginine
Glycine
Histidine
Proline
Serine
Tyrosine
Cysteine
RenAmin (Clintec)
Aminess
(Clintec)
Aminosyn
RF (Abbott)
65
6.5
500
600
10
52
5.2
400
416
8.3
52
5.2
1000
475
8.3
5.00
6.00
4.50
5.00
4.90
3.80
1.60
8.20
5.60
6.30
3.00
4.20
3.50
3.00
0.40
5.25
8.25
6.00
8.25
8.25
3.75
1.88
4.62
7.26
5.35
7.26
7.26
3.30
1.60
5.20
6.00
6.00
4.12
4.29
NephrAmine
(McGaw)
54
5.4
1000
435
6.5
5.60
8.80
6.40
8.80
8.80
4.00
2.00
6.40
2.50
0.20
Nephrotect
(Fresenius)
100
10
500
908
16.3
5.80
12.80
12.00
2.00
3.50
8.20
3.00
8.70
6.20
8.20
6.30*
9.80
3.00
7.60
3.00
0.40
* Glycine is a componenet of the dipeptide.

Tyrosine is included as dipeptide (glycyl-L-tyrosine).
FIGURE 18-33
Amino acid (AA) solutions for parenteral nutrition in acute renal
failure (ARF). The most controversial choice regards the type of
amino acid solution to be used: either essential amino acids (EAAs)
exclusively, solutions of EAA plus nonessential amino acids
(NEAAs), or specially designed nephro solutions of different
proportions of EAA and specific NEAA that might become conditionally essential for ARF (see Fig. 18-11).
Use of solutions of EAA alone is based on principles established for
treating chronic renal failure (CRF) with a low-protein diet and an
EAA supplement. This may be inappropriate as the metabolic adaptations to low-protein diets in response to CRF may not have occurred
in patients with ARF. Plus, there are fundamental differences in the
goals of nutritional therapy in the two groups of patients, and consequently, infusion solutions of EAA may be sub-optimal.
Thus, a solution should be chosen that includes both essential
and nonessential amino acids (EAA, NEAA) in standard propor-
tions or in special proportions designed to counteract the

metabolic changes of renal failure (nephro solutions), including the amino acids that might become conditionally essential
in ARF.
Because of the relative insolubility of tyrosine in water, dipeptides containing tyrosine (such as glycyl-tyrosine) are contained in
modern nephro solutions as the tyrosine source [22, 23]. One
should be aware of the fact that the amino acid analogue N-acetyl
tyrosine, which previously was used frequently as a tyrosine
source, cannot be converted into tyrosine in humans and might
even stimulate protein catabolism [21].
Despite considerable investigation, there is no persuasive evidence that amino acid solutions enriched in branched-chain amino
acids exert a clinically significant anticatabolic effect. Systematic
studies using glutamine supplementation for patients with ARF are
lacking (see Fig. 18-11).
18.20
Acute Renal Failure

FIGURE 18-34
Energy substrates in total parenteral nutrition (TPN) in acute
renal failure (ARF): glucose and lipids. Because of the well-documented effects of overfeeding, energy intake of patients with ARF
must not exceed their actual energy expenditure (ie, in most cases
100% to 130% of resting energy expenditure [REE]; see Figs. 18-3
and 18-4) [2].
Glucose should be the principal energy substrate because it can be
utilized by all organs, even under hypoxic conditions, and has the
potential for nitrogen sparing. Since ARF impairs glucose tolerance,
insulin is frequently necessary to maintain normoglycemia. Any
hyperglycemia must be avoided because of the untoward associated
side effectssuch as aggravation of tissue injury, glycation of proteins, activation of protein catabolism, among others [2]. When
intake is increased above 5 g/kg of body weight per day infused glucose will not be oxidized but will promote lipogenesis with fatty
infiltration of the liver and excessive carbon dioxide production and
hypercarbia. Often, energy requirements cannot be met by glucose
infusion without adding large amounts of insulin, so a portion of
the energy should be supplied by lipid emulsions [2].
The most suitable means of providing the energy substrates for
parenteral nutrition for patients with ARF is not glucose or lipids,
but glucose and lipids [2]. In experimental uremia in rats, TPN
with 30% of nonprotein energy as fat promoted weight gain and
ameliorated the uremic state and survival [63]. (From Wennberg
FIGURE 18-35
Energy substrates in parenteral nutrition: lipid emulsions. Advantages of intravenous lipids
include high specific energy content, low osmolality, provision of essential fatty acids and
phospholipids to prevent deficiency syndromes, fewer hepatic side effects (such as steatosis, hyperbilirubinemia), and reduced carbon dioxide production, especially relevant for
patients with respiratory failure.
Changes in lipid metabolism associated with acute renal failure (ARF) should not prevent the use of lipid emulsions. Instead, the amount infused should be adjusted to meet the
patients capacity to utilize lipids. Usually, 1 g/kg of body weight per day of fat will not
increase plasma triglycerides substantially, so about 20% to 25% of energy requirements
can be met [1]. Lipids should not be administered to patients with hyperlipidemia (ie, plasma triglycerides above 350 mg/dL) activated intravascular coagulation, acidosis (pH below
7.25), impaired circulation or hypoxemia.
Parenteral lipid emulsions usually contain long-chain triglycerides (LCT), most derived
from soybean oil. Recently, fat emulsions containing a mixture of LCT and medium-chain
triglycerides (MCT) have been introduced for intravenous use. Proposed advantages
include faster elimination from the plasma owing to higher affinity to the lipoprotein
lipase enzyme, complete, rapid, and carnitine-independent metabolism, and a triglyceridelowering effect; however, use of MCT does not promote lipolysis, and elimination of
triglycerides of both types of fat emulsions is equally retarded in ARF [34]. (Adapted from
SUGGESTED SCHEDULE FOR MINIMAL

MONITORING OF PARENTERAL NUTRITION
Metabolic Status
Variables
Unstable
Stable
Blood glucose
Osmolality
Electrolytes (Na+, K+, Cl+)
Calcium, phosphate, magnesium
Daily BUN increment
Urea nitrogen appearance rate
Triglycerides
Blood gas analysis, pH
Ammonia
Transaminases bilirubin
16 daily
Daily
Daily
Daily
Daily
Daily
Daily
Daily
2 weekly
2 weekly
Daily
2 weekly
Daily
3 weekly
Daily
2 weekly
2 weekly
1 weekly
1 weekly
1 weekly
18.21
FIGURE 18-36
Complications and monitoring of nutritional support in acute renal
failure (ARF).
Complications: Technical problems and infectious complications originating from the central venous catheter, chemical
incompatibilities, and metabolic complications of parenteral
nutrition are similar in ARF patients and in nonuremic subjects.
However, tolerance to volume load is limited, electrolyte derangements can develop rapidly, exaggerated protein or amino acid
intake stimulates excessive blood urea nitrogen (BUN) and waste
product accumulation and glucose intolerance, and decreased fat
clearance can cause hyperglycemia and hypertriglyceridemia.
Thus, nutritional therapy for ARF patients requires more frequent monitoring than it does for other patient groups, to avoid
metabolic complications.
Monitoring: This table summarizes laboratory tests that monitor parenteral nutrition and avoid metabolic complications.
The frequency of testing depends on the metabolic stability of
the patient. In particular, plasma glucose, potassium, and phosphate should be monitored repeatedly after the start of parenteral nutrition.
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Supportive Therapies:
Intermittent Hemodialysis,
Continuous Renal
Replacement Therapies,
and Peritoneal Dialysis
Ravindra L. Mehta
ver the last decade, significant advances have been made in the
availability of different dialysis methods for replacement of
renal function. Although the majority of these have been
developed for patients with end-stage renal disease, more and more
they are being applied for the treatment of acute renal failure (ARF).
The treatment of ARF, with renal replacement therapy (RRT), has the
following goals: 1) to maintain fluid and electrolyte, acid-base, and
solute homeostasis; 2) to prevent further insults to the kidney; 3) to
promote healing and renal recovery; and 4) to permit other support
measures such as nutrition to proceed without limitation. Ideally, therapeutic interventions should be designed to achieve these goals, taking
into consideration the clinical course. Some of the issues that need
consideration are the choice of dialysis modality, the indications for
and timing of dialysis intervention, and the effect of dialysis on outcomes from ARF. This chapter outlines current concepts in the use of
dialysis techniques for ARF.
CHAPTER
19
19.2
Acute Renal Failure
Dialysis Methods
DIALYSIS MODALITIES FOR ACUTE RENAL FAILURE
Intermittent therapies
Hemodialysis (HD)
Single-pass
Sorbent-based
Peritoneal (IPD)
Hemofiltration (IHF)
Ultrafiltration (UF)
Continuous therapies
Peritoneal (CAPD, CCPD)
Ultrafiltration (SCUF)
Hemofiltration (CAVH, CVVH)
Hemodialysis (CAVHD, CVVHD)
Hemodiafiltration (CAVHDF, CVVHDF)
CVVHDF
FIGURE 19-1
Several methods of dialysis are available for renal replacement therapy. While most of these have been adapted from dialysis procedures
developed for end-stage renal disease several variations are available
specifically for ARF patients [1] .
Of the intermittent procedures, intermittent hemodialysis (IHD) is
currently the standard form of therapy worldwide for treatment of
ARF in both intensive care unit (ICU) and non-ICU settings. The vast
majority of IHD is performed using single-pass systems with moderate blood flow rates (200 to 250 mL/min) and countercurrent
dialysate flow rates of 500 mL/min. Although this method is very efficient, it is also associated with hemodynamic instability resulting from
the large shifts of solutes and fluid over a short time. Sorbent system
IHD that regenerates small volumes of dialysate with an in-line
Sorbent cartridge have not been very popular; however, they are a
useful adjunct if large amounts of water are not available or in disasters [2]. These systems depend on a sorbent cartridge with multiple
layers of different chemicals to regenerate the dialysate. In addition to
the advantage of needing a small amount of water (6 L for a typical
run) that does not need to be pretreated, the unique characteristics of

the regeneration process allow greater flexibility in custom tailoring
the dialysate. In contrast to IHD, intermittent hemodiafiltration
(IHF), which uses convective clearance for solute removal, has not
been used extensively in the United States, mainly because of the high
cost of the sterile replacement fluid [3]. Several modifications have
been made in this therapy, including the provision of on-line preparation of sterile replacement solutions. Proponents of this modality
claim a greater degree of hemodynamic stability and improved middle
molecule clearance, which may have an impact on outcomes.
As a more continuous technique, peritoneal dialysis (PD) is an
alternative for some patients. In ARF patients two forms of PD have
been used. Most commonly, dialysate is infused and drained from
the peritoneal cavity by gravity. More commonly a variation of the
procedure for continuous ambulatory PD termed continuous equilibrated PD is utilized [4]. Dialysate is instilled and drained manually
and continuously every 3 to six hours, and fluid removal is achieved
by varying the concentration of dextrose in the solutions.
Alternatively, the process can be automated with a cycling device
programmed to deliver a predetermined volume of dialysate and
drain the peritoneal cavity at fixed intervals. The cycler makes the
process less labor intensive, but the utility of PD in treating ARF in
the ICU is limited because of: 1) its impact on respiratory status
owing to interference with diaphragmatic excursion; 2) technical difficulty of using it in patients with abdominal sepsis or after abdominal surgery; 3) relative inefficiency in removing waste products in
catabolic patients; and 4) a high incidence of associated peritonitis. Several continuous renal replacement therapies (CRRT) have
evolved that differ only in the access utilized (arteriovenous [nonpumped: SCUF, CAVH, CAVHD, CAVHDF] versus venovenous
[pumped: CVVH, CVVHD, CVVHDF]), and, in the principal
method of solute clearance (convection alone [UF and H], diffusion
alone [hemodialyis (HD)], and combined convection and diffusion
[hemodiafiltration (HDF)]).
CRRT techniques: SCUF

A
AV SCUF
V
V
UFC Uf
Qb = 50200 mL/min
Qf = 28 mL/min
No
Low
Low
A
FIGURE 19-2
Schematics of different CRRT techniques. A, Schematic representation of SCUF therapy. B, Schematic representation of
Uf
Qb = 50200 mL/min
Qf = 1020 mL/min
TMP=50mmHg
Highflux
out
Mechanisms of function
Pressure profile Membrane Reinfusion Diffusion Convection
CAVHCVVH
Highflux
in
Treatment
CVVH
Uf
Qb = 50100 mL/min
Qf = 812 mL/min
TMP=30mmHg
R
V
SCUF
CAVH
Uf
Qb = 50100 mL/min
Qf = 26 mL/min
Treatment
CRRT techniques: CAVH CVVH

VV SCUF
in
Yes
Low
High
out
continuous arteriovenous or venovenous hemofiltration

(CAVH/CVVH) therapy.
19.3
Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis
CRRT techniques: CAVHD CVVHD

A
CAVHD
P
V
Dial. Out
Dial. in
V
Dial. Out
Qb = 50100 mL/min Qf=15 mL/min

Qd=1030 mL/min
TMP=50mmHg
No
High
Dial. Out
Dial. In
+Uf
Qb = 100200 Qd=2040 mL/min
Qf = 1020 mL/min
Treatment
Low
CVVHDF
V P
TMP=50mmHg
CAVHDFCVVHDF
Lowflux
Dial. Out
Dial. In
+Uf
Qb = 50100 Qd=1020 mL/min
Qf = 812 mL/min
Dial. in
CAVHDCVVHD
CAVHDF
Qb = 50100 mL/min Qf=13 mL/min

Qd= 1020 mL/min
Treatment
CRRT techniques: CAVHDF CVVHDF
CVVHD
Highflux
Yes
High
High

C, Schematic representation of continuous arteriovenous/
venovenous hemodialysis (CAVHD-CVVHD) therapy.
D, Schematic representation of continuous arteriovenous/
venovenous hemodiafiltration (CAVHDF/CVVHDF) therapy.
Aartery; Vvein; Ufultrafiltrate; Rreplacement fluid;
Pperistaltic pump; Qbblood flow; Qfultrafiltration

rate; TMPtransmembrane pressure; indilyzer inlet; out
dialyzer outlet; UFCultrafiltration control system; Dial
dialysate; Qddialysate flow rate. (From Bellomo et al. [5];
with permission.)
CONTINUOUS RENAL REPLACEMENT THERAPY: COMPARISON OF TECHNIQUES
Access
Pump
Filtrate (mL/h)
Filtrate (L/d)
Dialysate flow (L/h)
Replacement fluid (L/d)
Urea clearance (mL/min)
Simplicity*
Cost*
SCUF
CAVH
CVVH
AV
No
100
2.4
0
0
1.7
1
1
AV
No
600
14.4
0
12
10
2
2
VV
Yes
1000
24
0
21.6
16.7
3
4
CAVHD
AV
No
300
7.2
1.0
4.8
21.7
2
3
CAVHDF
AV
No
600
14.4
1.0
12
26.7
2
3
CVVHD
VV
Yes
300
7.2
1.0
4.8
21.7
3
4
CVVHDF
VV
Yes
800
19.2
1.0
16.8
30
3
4
PD
Perit. Cath.
No
100
2.4
0.4
0
8.5
2
3
* 1 = most simple and least expensive; 4 = most difficult and expensive

cycler can be used to automate exchanges, but they add to the cost and complexity
FIGURE 19-3
In contrast to intermittent techniques, until recently, the terminology for continuous renal replacement therapy (CRRT) techniques
has been subject to individual interpretation. Recognizing this lack
of standardization an international group of experts have proposed
standardized terms for these therapies [5]. The basic premise in the
development of these terms is to link the nomenclature to the operational characteristics of the different techniques. In general all
these techniques use highly permeable synthetic membranes and
differ in the driving force for solute removal. When arteriovenous
(AV) circuits are used, the mean arterial pressure provides the
pumping mechanism. Alternatively, external pumps generally utilize
a venovenous (VV) circuit and permit better control of blood flow
rates. The letters AV or VV in the terminology serve to identify the
driving force in the technique. Solute removal in these techniques is
achieved by convection, diffusion, or a combination of these two.
Convective techniques include ultrafiltration (UF) and hemofiltration (H) and depend on solute removal by solvent drag [6].
Diffusion-based techniques similar to intermittent hemodialysis

(HD) are based on the principle of a solute gradient between the
blood and the dialysate. If both diffusion and convection are used
in the same technique the process is termed hemodiafiltration
(HDF). In this instance, both dialysate and a replacement solution
are used, and small and middle molecules can both be removed
easily. The letters UF, H, HD, and HDF identify the operational
characteristics in the terminology. Based on these principles, the
terminology for these techniques is easier to understand. As shown
in Figure 19-1 the letter C in all the terms describes the continuous
nature of the methods, the next two letters [AV or VV] depict the
driving force and the remaining letters [UF, H, HD, HDF] represent
the operational characteristics. The only exception to this is the
acronym SCUF (slow continuous ultrafiltration), which remains as
a reminder of the initiation of these therapies as simple techniques
harnessing the power of AV circuits. (Modified from Mehta [7];
with permission.)
19.4
Acute Renal Failure
Operational Characteristics
Anticoagulation
Anticoagulation in Dialysis for ARF
Surface
Platelet
activation
FIXa
Dialyzer Membrane
Geometry
Manufacture
Dialysis
technique
Patient
Propagation
Initiation
Contact
activation
Procoagulant
surface
Uremia
Drug therapy
Dialyzer preparation
Anticoagulation
Blood flow access
Thrombin
Fibrin
FIGURE 19-4
Pathways of thrombogenesis in extracorporeal circuits. (Modified
from Lindhout [8]; with permission.)
Heparin CRRT
Anticoagulant
heparin
(~400/h)
Replacement
Dialysate
solutions
1.5% dianeal
(A & B alternating) (1000mL/h)
Arterial
Venous
Filter
catheter
(a)
3way
stop cock
(b)
Anticoagulant
4%% trisodium citrate
(~170 mL/h)
(c)
Ultrafiltrate
(effluent dialysate
plus net ultrafiltrate)
Citrate CRRT
(d)
catheter
Dialysate
Calcium
NA 117, K4, Mg 1., 1 mEq/10 mL
Cl 122.5 mEq/L; (~40 mL/h)
dextrose 0.1%2.5%
Replacement
zero alkali
Central
solution
zero calcium
line
0.9%% saline
(1000 mL/h)
Arterial
Venous
Filter
catheter
(a)
3way
stop cock
(b)
(d)
Ultrafiltrate
(effluent dialysate
plus net ultrafiltrate)
catheter
(c)
FIGURE 19-5
Factors influencing dialysis-related thrombogenicity. One of the
major determinants of the efficacy of any dialysis procedure in acute
renal failure (ARF) is the ability to maintain a functioning extracorporeal circuit. Anticoagulation becomes a key component in this
regard and requires a balance between an appropriate level of anticoagulation to maintain patency of the circuit and prevention of
complications. Figures 19-4 and 19-5 show the mechanisms of
thrombus formation in an extracorporeal circuit and the interaction
of various factors in this process. (From Ward [9]; with permission.)
FIGURE 19-6
Modalities for anticoagulation for continuous renal replacement
therapy. While systemic heparin is the anticoagulant most commonly used for dialysis, other modalities are available. The utilization of these modalities is largely influenced by prevailing local
experience. Schematic diagrams for heparin, A, and citrate, B, anticoagulation techniques for continuous renal replacement therapy
(CRRT). A schematic of heparin and regional citrate anticoagulation for CRRT techniques. Regional citrate anticoagulation minimizes the major complication of bleeding associated with heparin,
but it requires monitoring of ionized calcium. It is now well-recognized that the longevity of pumped or nonpumped CRRT circuits
is influenced by maintaining the filtration fraction at less than
20%. Nonpumped circuits (CAVH/HD/HDF) have a decrease in
efficacy over time related to a decrease in blood flow (BFR),
whereas in pumped circuits (CVVH/HD/HDF) blood flow is maintained; however, the constant pressure across the membrane results
in a layer of protein forming over the membrance reducing its efficacy. This process is termed concentration repolarization [10].
CAVH/CVVHcontinuous arteriovenous/venovenous hemofiltration. (From Mehta RL, et al. [11]; with permission.)
19.5
Solute Removal
Membrane
Blood
Dialysate
Blood
Membrane
Dialysate
Middle
molecules
Small
molecules
Diffusion
Convection
Concentration gradient based transfer.

Small molecular weight substances (<500 Daltons)
are transferred more rapidly.
Blood
Membrane
Dialysate
Adsorption
Several solutes are removed from circulation by

adsorption to the membrane. This process is
influenced by the membrane structure and charge.
Movement of water across the membrane

carries solute across the membrane.
Middle molecules are removed more efficiently.
FIGURE 19-7
Mechanisms of solute removal in dialysis. The success of any dialysis
procedure depends on an understanding of the operational characteristics that are unique to these techniques and on appropriate use of
specific components to deliver the therapy. Solute removal is achieved
by diffusion (hemodialysis), A, convection (hemofiltration), B, or a
combination of diffusion and convection (hemodiafiltration), C.
19.6
Acute Renal Failure
DETERMINANTS OF SOLUTE REMOVAL IN DIALYSIS

TECHNIQUES FOR ACUTE RENAL FAILURE
Small solutes (MW <300)
Middle molecules (MW 5005000)
LMW proteins (MW 500050,000)
Large proteins (MW >50,000)
IHD
CRRT
PD
Diffusion:
Qb
Membrane width
Qd
Diffusion
Convection:
Qf
SC
Convection
Diffusion
Adsorption
Convection
Diffusion:
Qd
Convection:
Qf
Diffusion:
Qd
Convection:
Qf
Convection:
Qf
SC
Convection
Adsorption
Convection:
Qf
SC
Convection
Convection
Convection
FIGURE 19-8
Determinants of solute removal in dialysis techniques for acute renal failure. Solute removal
in these techniques is achieved by convection, diffusion, or a combination of these two.
Convective techniques include ultrafiltration (UF) and hemofiltration (H) and they depend
on solute removal by solvent drag [6]. As solute removal is solely dependent on convective
clearance it can be enhanced only by increasing the volume of ultrafiltrate produced. While
ultrafiltration requires fluid removal only, to prevent significant volume loss and resulting
hemodynamic compromise, hemofiltration necessitates partial or total replacement of the
fluid removed. Larger molecules are removed more efficiently by this process and, thus,
middle molecular clearances are superior. In intermittent hemodialysis (IHD) ultrafiltration
is achieved by modifying the transmembrane pressure and generally does not contribute significantly to solute removal. In peritoneal dialysis (PD) the UF depends on the osmotic gradient achieved by the concentration of dextrose solution (1.55% to 4.25%) utilized the
Dialyste flow, L/h

1.5
1
Dialysis time
4 h/d 4 h qod
352
268
Ultrafiltrate volume, Cycling Manual

treatment time, hrs
L/d
40
48
20
15
Dialysate inflow, L/wk
160
96
302
140
84
CAVHDF/CVVHDF
IHD
CAVH
72
PD
number of exchanges and the dwell time of

each exchange. In continuous arteriovenous
and venovenous hemodialysis in most situations ulrafiltration rates of 1 to 3 L/hour are
utilized; however recently high-volume
hemofiltration with 6 L of ultrafiltrate produced every hour has been utilized to
remove middle and largemolecular weight
cytokines in sepsis [12]. Fluid balance is
achieved by replacing the ultrafiltrate
removed by a replacement solution. The
composition of the replacement fluid can be
varied and the solution can be infused
before or after the filter.
Diffusion-based techniques (hemodialysis)
are based on the principle of a solute gradient between the blood and the dialysate. In
IHD, typically dialysate flow rates far exceed
blood flow rates (200 to 400 mL/min,
dialysate flow rates 500 to 800 mL/min) and
dialysate flow is single pass. However, unlike
IHD, the dialysate flow rates are significantly slower than the blood flow rates (typically, rates are 100 to 200 mL/min, dialysate
flow rates are 1 to 2 L/hr [17 to 34mL/min]),
resulting in complete saturation of the
dialysate. As a consequence, dialysate flow
rates become the limiting factor for solute
removal and provide an opportunity for
clearance enhancement. Small molecules are
preferentially removed by these methods. If
both diffusion and convection are used in
the same technique (hemodiafiltration, HDF)
both dialysate and a replacement solution
are used and small and middle molecules can
both be easily removed.
FIGURE 19-9
Comparison of weekly urea clearances with different dialysis techniques. Although continuous therapies are less efficient than intermittent techniques, overall clearances are higher as they are utilized
continuously. It is also possible to increase clearances in continuous
techniques by adjustment of the ultrafiltration rate and dialysate
flow rate. In contrast, as intermittent dialysis techniques are operational at maximum capability, it is difficult to enhance clearances
except by increasing the size of the membrane or the duration of
therapy. CAV/CVVHDFcontinuous arteriovenous/venovenous
hemodiafiltration; IHDintermittent hemodialysis; CAVHcontinuous arteriovenous hemodialysis; PDperitoneal dialysis.
19.7
COMPARISON OF DIALYSIS PRESCRIPTION

AND DOSE DELIVERED IN CRRT AND IHD
DRUG DOSING IN CRRT*

Drug
Dialysis Prescription
IHD
Membrane characteristics
Anticoagulation
Blood flow rate
Dialysate flow
Duration
Clearance
Variable permeability
Short duration
200 mL/min
500 mL/min
34 hrs
High
CRRT
High permeability
Prolonged
<200 mL/min
1734 mL/min
Days
Low
Dialysis Dose Delivered

Patient factors
Hemodynamic stability
Recirculation
Infusions
Technique factors
Blood flow
Concentration repolarization
Membrane clotting
Duration
Other factors
Nursing errors
Interference
IHD
CRRT
+++
+++
++
+
+
+
+++
+
+
+++
++
+++
+++
+
+
+
+++
++++
FIGURE 19-10
Comparison of dialysis prescription and dose delivered in continuous renal replacement (CRRT) and intermittent hemodialysis (IHD).
The ability of each modality to achieve a particular clearance is
influenced by the dialysis prescription and the operational characteristics; however, it must be recognized that there may be a significant difference between the dialysis dose prescribed and that delivered. In general, IHD techniques are limited by available time, and
in catabolic patients it may not be possible to achieve a desired level
of solute control even by maximizing the operational characteristics.
Amikacin
Netilmycin
Tobramycin
Vancomycin
Ceftazidime
Cefotaxime
Ceftriaxone
Ciprofloxacin
Imipenem
Metronidazole
Piperacillin
Digoxin
Phenobarbital
Phenytoin
Theophylline
Normal Dose (mg/d)
Dose in CRRT (mg)
1050
420
350
2000
6000
12,000
4000
400
4000
2100
24,000
0.29
233
524
720
250 qdbid
100150 qd
100 qd
500 qdbid
1000 bid
2000 bid
2000 qd
200 qd
500 tidqid
500 tidqid
4000 tid
0.10 qd
100 bidqid
250 qdbid
600900 qd
* Reflects doses for continuous venovenous hemofiltration with ultrafiltration rate of

20 to 30 mL/min.
FIGURE 19-11
Drug dosing in continuous renal replacement (CRRT) techniques.
Drug removal in CRRT techniques is dependent upon the molecular
weight of the drug and the degree of protein binding. Drugs with
significant protein binding are removed minimally. Aditionally,
some drugs may be removed by adsorption to the membrane. Most
of the commonly used drugs require adjustments in dose to reflect
the continuous removal in CRRT. (Modified from Kroh et al. [13];
with permission.)
19.8
Acute Renal Failure
NUTRITIONAL ASSESSMENT AND SUPPORT WITH RENAL REPLACEMENT TECHNIQUES

Parameters: Initial Assessment
IHD
CAVH/CVVH
CAVHD/CVVHDF
Energy assessment
Dialysate dextrose absorption
HBE x AF x SF, or indirect calorimetry

Negligible
Same
Not applicable
Same
43% uptake 1.5% dextrose dialysate (525 calories/D)
45% uptake 2.5% dextrose dialysate (920 calories/D)
Negligible absorption with dextrose free or dialysate
0.10.15% dextrose
Serum prealbumin
Nitrogen in: protein in TPN +/enteral
solutions/6.25
Nitrogen out: urea nitrogen appearance
Same
Nitrogen in: same
Same
Nitrogen in: same
UUN
Insensible losses
Dialysis amino acid losses
(1.01.5 N2/dialysis therapy)
Nitrogen out: ultrafiltrate urea

nitrogen losses
UUN
Insensible losses
Ultrafiltrate amino acid losses
(1.52.0 N2/D)
Nitrogen out: ultrafiltrate/dialysate urea

nitrogen losses
UUN
Insensible losses
Ultrafiltrate/dialysate amino acid losses
(1.52.0 N2/D)
Renal formulas with limited fluid, potassium, phosphorus, and magnesium
Standard TPN/enteral formulations.

No fluid or electrolyte restrictions.
Standard TPN/enteral formulations when 0.10.15%

dextrose dialysate used
Modified formulations when 1.52.5% dextrose
dialysate used
TPN: Low-dextrose solutions to prevent carbohydrate overfeeding; amino acid concentration
may be increased to meet protein requirements.
Enteral: Standard formulas. May require modular
protein to meet protein requirements without
carbohydrate overfeeding.
Weekly HBE x AF x SF*, or

indirect calorimetry
Weekly
Weekly
Same
Same
Same
Same
Same
Same
Protein assessment
Visceral proteins
Nitrogen balance: N2 inN2 out
Nutrition support prescription:

TPN/enteral nutrition
Reassessment of requirements and

efficacy of nutrition support
Energy assessment
Serum prealbumin
Nitrogen balance
* Harris Benedict equation multiplied by acimity and stress factors

Collect 24-hour urine for UUN if UOP 400 ml/d
FIGURE 19-12
Nutritional assessment and support with renal replacement techniques. A key feature of dialysis support in acute renal failure is to
permit an adequate amount of nutrition to be delivered to the
patient. The modality of dialysis and operational characteristics
affect the nutritional support that can be provided. Dextrose
absorption occurs form the dialysate in hemodialysis and hemodiafiltration modalities and can result in hyperglycemia. Intermittent
dialysis techniques are limited by time in their ability to allow
unlimited nutritional support. (From Monson and Mehta [14];
with permission.)
19.9
Fluid Control
OPERATING CHARACTERISTICS OF CRRT:
FLUID REMOVAL VERSUS FLUID REGULATION
Ultrafiltration rate (UFR)

Fluid management
Fluid balance
Volume removed
Application
Fluid Removal
Fluid Regulation
To meet anticipated needs

Adjust UFR
Zero or negative balance
Based on physician estimate
Easy, similar to intermittent hemodialysis
Greater than anticipated needs

Adjust amount of replacement fluid
Positive, negative, or zero balance
Driven by patient characteristics
Requires specific tools and training
FIGURE 19-13
Operating characteristics of continuous renal replacement (CRRT): fluid removal versus
fluid regulation. Fluid management is an integral component in the management of
APPROACHES FOR FLUID MANAGEMENT IN CRRT

Approaches
Level 1
Level 2
Level 3
UF volume
Replacement
Limited
Minimal
Fluid balance
8h
Increase intake
Adjusted to achieve
fluid balance
Hourly
UF pump
Examples
Yes
SCUF/CAVHD
CVVHD
Yes/No
CAVH/CVVH
CAVHDF/CVVHDF
Increase intake
Adjusted to achieve
fluid balance
Hourly
Targeted
Yes/No
CAVHDF/CVVHDF
CVVH
+++
+
+
+
++
+++
++
++
+
+++
+++
+++
+
+++
++
+++
++
++
++
+
+++
+
+
+
Advantages
Simplicity
Achieve fluid balance
Regulate volume changes
CRRT as support
Disadvantages
Nursing effort
Errors in fluid balance
Fluid overload
FIGURE 19-14
Approaches for fluid management in continuous renal replacement therapy (CRRT).
CRRT techniques are uniquely situated in providing fluid regulation, as fluid management can be achieved with three levels of intervention [16]. In Level 1, the ultrafiltrate
(UF) volume obtained is limited to match the anticipated needs for fluid balance. This
calls for an estimate of the amount of fluid to be removed over 8 to 24 hours and subsequent calculation of the ultrafiltration rate. This strategy is similar to that commonly
used for intermittent hemodialysis and differs only in that the time to remove fluid is 24
patients with acute renal failure in the

intensive care setting. In the presence of a
failing kidney, fluid removal is often a challenge that requires large doses of diuretics
with a variable response. It is often necessary in this setting to institute dialysis for
volume control rather than metabolic control. CRRT techniques offer a significant
advantage over intermittent dialysis for
fluid control [14,15]; however, if not carried out appropriately they can result in
major complications. To utilize these therapies for their maximum potential it is necessary to recognize the factors that influence
fluid balance and have an understanding of
the principles of fluid management with
these techniques. In general it is helpful to
consider dialysis as a method for fluid
removal and fluid regulation.
hours instead of 3 to 4 hours. In Level 2
the ultrafiltrate volume every hour is deliberately set to be greater than the hourly
intake, and net fluid balance is achieved by
hourly replacement fluid administration. In
this method a greater degree of control is
possible and fluid balance can be set to
achieve any desired outcome. The success
of this method depends on the ability to
achieve ultrafiltration rates that always
exceed the anticipated intake. This allows
flexibility in manipulation of the fluid balance, so that for any given hour the fluid
status could be net negative, positive, or
balanced. A key advantage of this technique is that the net fluid balance achieved
at the end of every hour is truly a reflection of the desired outcome. Level 3
extends the concept of the Level 2 intervention to target the desired net balance
every hour to achieve a specific hemodynamic parameter (eg, central venous pressure, pulmonary artery wedge pressure, or
mean arterial pressure). Once a desired
value for the hemodynamic parameter is
determined, fluid balance can be linked to
that value. Each level has advantages and
disadvantages; in general greater control
calls for more effort and consequently
results in improved outcomes. SCUF
ultrafiltration; CAVHD/CVVHDcontinuous arteriovenous/venovenous hemodialysis; CAVH/CVVHcontinuous arteriovenous/venovenous hemofiltration;
CAVHDF/CVVHDFcontinuous arteriovenous/venovenous hemodiafiltration.
19.10
Acute Renal Failure
COMPOSITION OF REPLACEMENT FLUID AND DIALYSATE FOR CRRT

Replacement Fluid
Investigator
Na+
ClHCO3K+
Ca2+
Mg2+
Glucose
Acetate
Golper [19]
147
115
36
0
1.2
0.7
6.7
Kierdorf [20]
140
110
34
0
1.75
0.5
5.6
Lauer [21]
140
2
3.5
1.5
41
Paganini [22]
140
120
6
2
4
2
10
40
Mehta [11]
140.5
115.5
25
0
4
Mehta [11]
154
154
FIGURE 19-15
Composition of dialysate and replacement
fluids used for continuous renal replacement therapy (CRRT). One of the key features of any dialysis method is the manipulation of metabolic balance. In general, this
is achieved by altering composition of
dialysate or replacement fluid . Most commercially available dialysate and replacement solutions have lactate as the base;
however, bicarbonate-based solutions are
being utilized more and more [17,18].
Dialysate
Component (mEq/L)
Sodium
Potassium
Chloride
Lactate
Acetate
Calcium
Magnesium
Dextrose (g/dL)
1.5% Dianeal
132
96
35
3.5
1.5
1.5
Hemosol AG 4D
140
4
119
30
3.5
1.5
0.8
Hemosol LG 4D
140
4
109.5
40
4
1.5
.11
Replacement 17 mL/min
Prefilter
Prefilter
Prepump
Prepump
BFR 83 mL/min
BFR 117 mL/min
Postfilter
BFR 100 mL/min
Filter
Blood pump
BFR 100 mL/min
Baxter
140
2
117
30
3.5
1.5
0.1
Citrate
117
4
121
1.5
0.12.5
FIGURE 19-16
Effect of site of delivery of replacement fluid: pre- versus postfilter
continuous venovenous hemofiltration with ultrafiltration rate of 1
L/hour. Replacement fluids may be administered pre- or postfilter,
depending on the circuit involved . It is important to recognize that
the site of delivery can influence the overall efficacy of the procedure. There is a significant effect of fluid delivered prepump or
postpump, as the amount of blood delivered to the filter is reduced
in prepump dilution. BFRblood flow rate.
Ultrafiltrate
50
40
Prefilter prepump
Prefilter postpump
Postfilter
30
20
22.6
19.5
23.9
47.6
41.6
35.7
32.2
32.2
26.3
10
0
CVVH 1L/h
CVVH 3L/h
CVVH 6L/h
FIGURE 19-17
Pre- versus postfilter replacement fluid: effect on filtration fraction.
Prefilter replacement tends to dilute the blood entering the circuit
and enhances filter longevity by reducing the filtration fraction;
however, in continuous venovenous hemofiltration (CVVH) circuits
the overall clearance may be reduced as the amount of solute delivered to the filter is reduced.
19.11
Applications and Indications for Dialytic Intervention

INDICATIONS AND TIMING OF DIALYSIS FOR ACUTE RENAL FAILURE:
RENAL REPLACEMENT VERSUS RENAL SUPPORT
Renal Replacement
Renal Support
Purpose
Replace renal function
Support other organs
Timing of intervention
Indications for dialysis
Based on level of biochemical markers

Narrow
Based on individualized need

Broad
Dialysis dose
Extrapolated from ESRD
Targeted for overall support
FIGURE 19-18
Dialysis intervention in acute renal failure (ARF): renal replacement versus renal support. An important consideration in the management of ARF is defining the goals of
therapy. Several issues must be considered, including the timing of the intervention, the
amount and frequency of dialysis, and the duration of therapy. In practice, these issues
are based on individual preferences and experience, and no immutable criteria are followed [7,23]. Dialysis intervention in ARF is usually considered when there is clinical
evidence of uremia symptoms or biochemical evidence of solute and fluid imbalance. An
POTENTIAL APPLICATIONS FOR CONTINUOUS

RENAL REPLACEMENT THERAPY
Renal Replacement
Renal Support
Extrarenal Applications
Acute renal failure

Fluid management
Solute control
Acid-base adjustments
Nutrition
Burn management
Cytokine removal ? sepsis

Heart failure
Cancer chemotherapy
Liver support
Inherited metabolic disorders
important consideration in this regard is to

recognize that the patient with ARF is
somewhat different than the one with endstage renal disease (ESRD). The rapid
decline of renal function associated with
multiorgan failure does not permit much
of an adaptive response which characterizes the course of the patient with ESRD.
As a consequence, the traditional indications for renal replacement may need to be
redefined. For instance, excessive volume
resuscitation, a common strategy for multiorgan failure, may be an indication for
dialysis, even in the absence of significant
elevations in blood urea nitrogen. In this
respect, it may be more appropriate to
consider dialysis intervention in the intensive care patient as a form of renal support
rather than renal replacement. This terminology serves to distinguish between the
strategy for replacing individual organ
function and one to provide support for
all organs.
FIGURE 19-19
Potential applications for continuous renal
replacement therapy (CRRT). CRRT techniques are increasingly being utilized as support modalities in the intensive care setting
and are particularly suited for this function.
The freedom to provide continuous fluid
management permits the application of
unlimited nutrition, adjustments in hemodynamic parameters, and achievement of
steady-state solute control, which is difficult
with intermittent therapies. It is thus possible to widen the indications for renal intervention and provide a customized approach
for the management of each patient.
19.12
Acute Renal Failure
RELATIVE ADVANTAGES () AND DISADVANTAGES () OF CRRT, IHD, AND PD

Variable
Continuous renal replacement
Hemodynamic stability
Fluid balance achievement
Unlimited nutrition
Superior metabolic control
Continuous removal of toxins
Simple to perform
Stable intracranial pressure
Rapid removal of poisons
Limited anticoagulation
Need for intensive care nursing support
Need for hemodialysis nursing support
Patient mobility
CRRT
IHD
PD

DETERMINANTS OF THE CHOICE OF TREATMENT

MODALITY FOR ACUTE RENAL FAILURE
Patient
Indication for dialysis
Presence of multiorgan failure
Access
Mobility and location of patient
Anticipated duration of therapy
Dialysis process
Components (eg, membrane, anticoagulation)
Type (intermittent or continuous)
Efficacy for solute and fluid balance
Complications
Outcome
Nursing and other support
Availability of machines
Nursing support
FIGURE 19-20
Advantages () and disadvantages () of
dialysis techniques. CRRTcontinuous
renal replacement therapy; IHDintermittent hemodialysis; PDperitoneal dialysis.
FIGURE 19-21
Determinants of the choice of treatment modality for acute renal
failure. The primary indication for dialysis intervention can be a
major determinant of the therapy chosen because different therapies vary in their efficacy for solute and fluid removal. Each technique has its advantages and limitations, and the choice depends
on several factors. Patient selection for each technique ideally
should be based on a careful consideration of multiple factors [1].
The general principle is to provide adequate renal support without
adversely affecting the patient. The presence of multiple organ failure may limit the choice of therapies; for example, patients who
have had abdominal surgery may not be suitable for peritoneal
dialysis because it increases the risk of wound dehiscence and infection. Patients who are hemodynamically unstable may not tolerate
intermittent hemodialysis (IHD). Additionally, the impact of the
chosen therapy on compromised organ systems is an important
consideration. Rapid removal of solutes and fluid, as in IHD, can
result in a disequilibrium syndrome and worsen neurologic status.
Peritoneal dialysis may be attractive in acute renal failure that complicates acute pancreatitis, but it would contribute to additional
protein losses in the hypoalbuminemic patient with liver failure.
RECOMMENDATION FOR INITIAL DIALYSIS

MODALITY FOR ACUTE RENAL FAILURE (ARF)
Indication
Clinical Condition
Preferred Therapy
Uncomplicated ARF
Fluid removal
Uremia
Increased intracranial pressure
Antibiotic nephrotoxicity
Cardiogenic shock, CP bypass
Complicated ARF in ICU
Subarachnoid hemorrhage,
hepatorenal syndrome
Sepsis, ARDS
Burns
Theophylline, barbiturates
Marked hyperkalemia
Uremia in 2nd, 3rd trimester
IHD, PD
SCUF, CAVH
CVVHDF, CAVHDF, IHD
CVVHD, CAVHD
Shock
Nutrition
Poisons
Electrolyte abnormalities
ARF in pregnancy
CVVH, CVVHDF, CAVHDF

CVVHDF, CAVHDF, CVVH
Hemoperfusion, IHD, CVVHDF
IHD, CVVHDF
PD
19.13
FIGURE 19-22
Recommendation for initial dialysis modality
for acute renal failure (ARF). Patients with
multiple organ failure (MOF) and ARF can
be treated with various continuous therapies
or IHD. Continuous therapies provide better
hemodynamic stability; however, if not monitored carefully they can lead to significant
volume depletion. In general, hemodynamically unstable, catabolic, and fluid-overloaded patients are best treated with continuous therapies, whereas IHD is better suited
for patients who require early mobilization
and are more stable. It is likely that the mix
of modalities used will change as evidence
linking the choice of modality to outcome
becomes available. For now, it is probably
appropriate to consider all these techniques
as viable options that can be used collectively.
Ideally, each patient should have an individualized approach for management of ARF.
CRRT
IHD
100
S Creat, mg/dL
BUN, mg/dL
Outcomes
80
60
40
0 1 2
Urea, mmol/L
3 4 5
Days
6 7
50
40
30
20
0
3
Days
0 1 2
Survivors
Non-survivors
6
5
4
3
2
1
FIGURE 19-23
Efficacy of continuous renal replacement
therapy (CRRT) versus intermittent
hemodialysis (IHD): effect on blood urea
nitrogen, A, and creatinine levels, B, in
acute renal failure.
CRRT
IHD
3 4 5 6
Days
7 8
FIGURE 19-24
Blood urea nitrogen (BUN) levels in survivors and non-survivors in acute renal failure
treated with continuous renal replacement therapy (CRRT). It is apparent that CRRT techniques offer improved solute control and fluid management with hemodynamic stability,
however a relationship to outcome has not been demonstrated. In a recent retrospective
analysis van Bommel [24] found no difference in BUN levels among survivors and nonsurvivors with ARF While it is clear that lower solute concentrations can be achieved with
CRRT whether this is an important criteria impacting on various outcomes from ARF still
needs to be determined. A recent study form the Cleveland Clinic suggests that the dose of
dialysis may be an important determinant of outcome allowing for underlying severity of
illness [25]. In this study the authors found that in patients with ARF, 65.4% of all IHD
treatments resulted in lower Kt/V than prescribed. There appeared to be an influence of
dose of dialysis on outcome in patients with intermediate levels of severity of illness as
judged by the Cleveland Clinic Foundation acuity score for ARF (see Fig. 19-25). Patients
receiving a higher Kt/V had a lower mortality than predicted. These data illustrate the
importance of the underlying severity of illness, which is likely to be a major determinant
of outcome and should be considered in the analysis of any studies.
Acute Renal Failure
Low Kt/V
High Kt/V
CCF score
Survival, %
19.14
0.8
0.6
BIOCOMPATIBLE MEMBRANES IN INTERMITTENT HEMODIALYSIS (IHD)

AND ACUTE RENAL FAILURE (ARF): EFFECT ON OUTCOMES
0.4
0.2
0
0
5
10
15
Cleveland clinic ICU ARF score
Patients, n
All patients recover of renal function
Survival
Patients nonoliguric before hemodialysis
Development of oliguria with dialysis
Recovery of renal function
Survival
Patients oliguric before hemodialysis
Recovery of renal function
Survival
20
FIGURE 19-25
Effect of dose of dialysis in acute renal failure (ARF) on outcome from ARF.
BCM Group
BICM Group
72
46 (64%)
41 (57%)
39
17 (44%)
31 (79%)
28 (74%)
33
15 (45%)
12 (36%)
81
35 (43%)
37 (46%)
46
32 (70%)
21 (46%)
22 (48%)
35
14 (40%)
15 (43%)
Probability
0.001
0.03
0.03
0.0004
0.003
ns
ns
FIGURE 19-26
Biocompatible membranes in intermittent hemodialysis (IHD) and acute renal failure (ARF):
effect on outcomes. The choice of dialysis membrane and its influence on survival from ARF
has been of major interest to investigators over the last few years. While the evidence tends to
support a survival advantage for biocompatible membranes, most of the studies were not well
controlled. The most recent multicenter study showed an improvement in mortality and recovery of renal function with biocompatible membranes; however, this effect was not significant
in oliguric patients. Further investigations are required in this area. NSnot significant.
MORTALITY IN ACUTE RENAL FAILURE: COMPARISON OF CRRT VERSUS IHD

IHD
CRRT
Investigator
Type of Study
No
Mortality, %
No
Mortality, %
Change, %
P Value
Mauritz [32]
Alarabi [33]
Mehta [34]
Kierdorf [20]
Bellomo [35]
Bellomo [36]
Kruczynski [37]
Simpson [38]
Kierdorf [39]
Mehta [40]
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Prospective
Prospective
Prospective
31
40
24
73
167
84
23
58
47
82
90
55
85
93
70
70
82
82
65
41.5
27
40
18
73
84
76
12
65
48
84
70
45
72
77
59
45
33
70
60
59.5
20
10
13
16
11
25
49
12
4.5
18
ns
ns
ns
< 0.05
ns
< 0.01
< 0.01
ns
ns
ns
FIGURE 19-27
Continuous renal replacement therapy (CRRT) versus intermittent
hemodialysis (IHD): effect on mortality. Despite significant advances
in the management of acute renal failure (ARF) over the last four
decades, the perception is that the associated mortality has not
changed significantly [26]. Recent publications suggest that there
may have been some improvement during the last decade [27]. Both
IHD and peritoneal dialysis (PD) were the major therapies until a
decade ago, and they improved the outcome from the 100% mortality of ARF to its current level. The effect of continuous renal replacement therapy on overall patient outcome is still unclear [28] . The
major studies done in this area do not show a survival advantage for
CRRT [29,30]. Although several investigators have not been able to
demonstrate an advantage of these therapies in influencing mortality,
we believe this may represent the difficulty in changing a global outcome which is impacted by several other factors [31]. It is probably
more relevant to focus on other outcomes such as renal functional
recovery rather than mortality. We believe that continued research is
required in this area; however, there appears to be enough evidence
to support the use of CRRT techniques as an alternative that may be
preferable to IHD in treating ARF in an intensive care setting.
19.15
Future Directions
1 Blood delivered
to lumen of fibers
in filter device (only one fiber shown)
4 Postfiltered blood
delivered to extracapillary
space of RAD
Filter unit
Reabsorber unit
2 Filtrate conveyed
to tubule lumens
3 Filtrate delivered
to interiors of
fibers in RAD
6 Transported and synthesized

elements added to postfiltered
blood, returned to general
circulation
7 Concentrated metabolic
wastes (urine) voided
5 Renal tubule cells
lining fibers provide
transport and metabolic
function
FIGURE 19-28
Schematic for the bioartificial kidney. As experience with these techniques grows, innovations in technology
will likely keep pace. Over the last 3 years, most of the major manufacturers of dialysis equipment have developed new pumps dedicated for continuous renal replacement therapy (CRRT). Membrane technology is also
evolving, and antithrombogenic membranes are on the horizon [41]. Finally the application of these therapies
is likely to expand to other arenas, including the treatment of sepsis, congestive heart failure [42], and multiorgan failure [43]. An exciting area of innovative research is the development of a bioartificial tubule utilizing
porcine tubular epithelial cells grown in a hollow fiber to add tubular function to the filtrative function provided by dialysis [44]. These devices are likely to be utilized in combination with CRRT to truly provide complete RRT in the near future. (From Humes HD [44]; with permission.)
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
Mehta RL: Therapeutic alternatives to renal replacement therapy for

critically ill patients in acute renal failure. Semin Nephro 1994,
14:6482.
Shapiro WB: The current status of Sorbent hemodialysis. Semin Dial
1990, 3:4045.
Botella J, Ghezzi P, Sanz-Moreno C, et al.: Multicentric study on
paired filtration dialysis as a short, highly efficient dialysis technique.
Nephrol Dial Transplant 1991, 6:715721.
Steiner RW: Continuous equilibration peritoneal dialysis in acute renal
failure. Perit Dial Intensive 1989, 9:57.
Bellomo R, Ronco C, Mehta RL: Nomenclature for continuous renal
replacement therapies. Am J Kidney Dis 1996, 28(5)S3:27.
Henderson LW: Hemofiltration: From the origin to the new wave. Am
J Kidney Dis 1996, 28(5)S3:100104.
Mehta RL: Renal replacement therapy for acute renal failure:
Matching the method to the patient. Semin Dial 1993, 6:253259.
Lindhout T: Biocompatability of extracorporeal blood treatment.
Selection of hemostatic parameters. Nephrol Dial Transplant 1994,
9(Suppl. 2):8389.
Ward RA: Effects of hemodialysis on corpulation and platelets: Are
we measureing membrane biocompatability? Nephrol Dial Transplant
1995, 10(Suppl. 10):1217.
10. Ronco C, Brendolan A, Crepaldi C, et al.: Importance of hollow fiber

geometry in CAVH. Contrib Nephrol 1991, 15:175178.
11. Mehta RL, McDonald BR, Aguilar MM, Ward DM: Regional citrate
anticoagulation for continuous arteriovenous hemodialysis in critically
ill patients. Kidney Int 1990, 38:976981.
12. Grootendorst AF, Bouman C, Hoeben K, et al.: The role of continuous renal replacement therapy in sepsis multiorgan failure. Am J
Kidney Dis 1996, 28(5) S3:S50S57.
13. Kroh UF, Holl TJ, Steinhausser W: Management of drug dosing in
continuous renal replacement therapy. Semin Dial 1996, 9:161165.
14. Monson P, Mehta RL: Nutritional considerations in continuous renal
replacement therapies. Semin Dial 1996, 9:152160.
15. Golper TA: Indications, technical considerations, and strategies for
renal replacement therapy in the intensive care unit. J Intensiv Care
Med 1992, 7:310317.
16. Mehta RL: Fluid management in continuous renal replacement therapy. Semin Dial 1996, 9:140144.
17. Palevsky PM: Continuous renal replacement therapy component selection: replacement fluid and dialysate. Semin Dial 1996, 9:107111.
18. Thomas AN, Guy JM, Kishen R, et al.: Comparison of lactate and
bicarbonate buffered haemofiltration fluids: Use in critically ill
patients. Nephrol Dial Transplant 1997, 12(6):12121217.
19.16
Acute Renal Failure
19. Golper TA: Continuous arteriovenous hemofiltration in acute renal

failure. Am J Kidney Dis 1985, 6:373386.
20. Kierdorf H: Continuous versus intermittent treatment: clinical results
21. Lauer
22. Paganini EP: Slow continuous hemofiltration and slow continuous
ultrafiltration. Trans Am Soc Artif Intern Organs 1988, 34:6366.
23. Schrier RW, Abraham HJ: Strategies in management of acute renal
failure in the intensive therapy unit. In Current Concepts in Critical
Care: Acute Renal Failure in the Intensive Therapy Unit. Edited by
Bihari D, Neild G. Berlin:Springer-Verlag, 1990:193214.
24. Van Bommel EFH, Bouvy ND, So KL, et al.: High risk surgical acute
renal failure treated by continuous arterio venous hemodiafiltration:
Metabolic control and outcomes in sixty patients. Nephron 1995,
70:185196.
25. Paganini EP, Tapolyai M, Goormastic M, et al.: Establishing a dialysis
therapy/patient outcome link in intensive care unit acute dialysis for
patients with acute renal failure. Am J Kidney Dis 1996,
28(5)S3:8190.
26. Wilkins RG, Faragher EB: Acute renal failure in an intensive care unit:
Incidence, prediction and outcome. Anesthesiology 1983, 38:638.
27. Firth JD: Renal replacement therapy on the intensive care unit. Q J
Med 1993, 86:7577.
28. Bosworth C, Paganini EP, Cosentino F, et al.: Long term experience
with continuous renal replacement therapy in intensive care unit acute
renal failure. Contrib Nephrol 1991, 93:1316.
29. Kierdorf H: Continuous versus intermittent treatment: Clinical results
30. Jakob SM, Frey FJ, Uhlinger DE: Does continuous renal replacement
therapy favorably influence the outcome of patients? Nephrol Dial
Transplant 1996, 11:12501235.
31. Mehta RL: Acute renal failure in the intensive care unit: Which outcomes should we measure? Am J Kidney Dis 1996, 28(5)S3:7479.
32. Mauritz W, Sporn P, Schindler I, et al.: Acute renal failure in abdominal infection: comparison of hemodialysis and continuous arteriovenous hemofiltration. Anasth Intensivther Notfallmed 1986,
21:212217.
33. Alarabi AA, Danielson BG, Wikstrom B, Wahlberg J: Outcome of

continuous arteriovenous hemofiltration (CAVH) in one centre. Ups J
Med Sci 1989, 94:299303.
34. McDonald BR, Mehta RL: Decreased mortality in patients with acute
renal failure undergoing continuous arteriovenous hemodialysis.
Contrib Nephrol 1991, 93:5156.
35. Bellomo R, Mansfield D, Rumble S, et al.: Acute renal failure in critical illness. Conventional dialysis versus acute continuous hemodiafiltration. Am Soc Artif Intern Organs J 1992, 38:654657.
36. Bellomo R, Boyce N: Continuous venovenous hemodiafiltration compared with conventional dialysis in critically ill patients with acute
renal failure. Am Soc Artif Intern Organs J 1993, 39:794797.
37. Kruczynski K, Irvine-Bird K, Toffelmire EB, Morton AR: A comparison of continuous arteriovenous hemofiltration and intermittent
hemodialysis in acute renal failure patients in the intensive care unit.
Am Soc Artif Intern Organs J 1993, 39:778781.
38. Simpson K, Allison MEM: Dialysis and acute renal failure: can mortality be improved? Nephrol Dial Transplant 1993, 8:946.
39. Kierdorf H: Einfuss der kontinuierlichen Hamofiltration auf
Proteinkatabolismus, Mediatorsubstanzen und Prognose des akuten
Nierenversagens [Habilitation-Thesis], Medical Faculty Technical
University of Aachen, 1994.
40. Mehta RL, McDonald B, Pahl M, et al.: Continuous vs. intermittent
dialysis for acute renal failure (ARF) in the ICU: Results from a randomized multicenter trial. Abstract A1044. JASN 1996, 7(9):1456.
41. Yang VC, Fu Y, Kim JS: A potential thrombogenic hemodialysis membranes with impaired blood compatibility. ASAIO Trans 1991,
37:M229M232.
42. Canaud B, Leray-Moragues H, Garred LJ, et al.: Slow isolated ultrafiltration for the treatment of congestive heart failure. Am J Kidney
Dis 1996, 28(5)S3:6773.
43. Druml W: Prophylactic use of continuous renal replacement therapies
in patients with normal renal function. Am J Kidney Dis 1996,
28(5)S3:114120.
44. Humes HD, Mackay SM, Funke AJ, Buffington DA: The bioartificial
renal tuble assist device to enhance CRRT in acute renal failure. Am J
Kidney Dis 1997, 30(Suppl. 4):S28S30.
Normal Vascular and

Glomerular Anatomy
Arthur H. Cohen
Richard J. Glassock
he topic of normal vascular and glomerular anatomy is introduced here to serve as a reference point for later illustrations of
disease-specific alterations in morphology.
CHAPTER
1.2
Glomerulonephritis and Vasculitis
Interlobar
artery
Arcuate
artery
Renal
artery
Pelvis
Pyramid
Interlobular
artery
FIGURE 1-1
A, The major renal circulation. The renal artery divides into the interlobar arteries (usually
4 or 5 divisions) that then branch into arcuate arteries encompassing the corticomedullary
junction of each renal pyramid. The interlobular arteries (multiple) originate from the
arcuate arteries. B, The renal microcirculation. The afferent arterioles branch from the
interlobular arteries and form the glomerular capillaries (hemi-arterioles). Efferent arterioles then reform and collect to form the post-glomerular circulation (peritubular capillaries, venules and renal veins [not shown]). The efferent arterioles at the corticomedullary
junction dip deep into the medulla to form the vasa recta, which embrace the collecting
tubules and form hairpin loops. (Courtesy of Arthur Cohen, MD.)
Ureter
Afferent
arteriole
Interlobular
artery
Glomerulus
Arcuate
artery
Efferent
arteriole
Collecting
tubule
Interlobar
artery
Normal Vascular and Glomerular Anatomy
aa
ILA
1.3

Microscopic view of the normal vascular and glomerular anatomy.
The largest intrarenal arteries (interlobar) enter the kidneys
between adjacent lobes and extend toward the cortex on the side
of a pyramid. These arteries branch dichotomously at the corticomedullary junction, forming arcuate arteries that course between
the cortex and medulla. The arcuate arteries branch into a series of
interlobular arteries that course at roughly right angles through the
cortex toward the capsule. Blood reaches glomeruli through afferent arterioles, most of which are branches of interlobular arteries,
although some arise from arcuate arteries. ILAinterlobular
artery; aaafferent arteriole.
FIGURE 1-3
Microscopic view of the juxtaglomerular apparatus. The juxtaglomerular apparatus (arrow) located immediately adjacent to the
glomerular hilus, is a complex structure with vascular and tubular
components. The vascular component includes the afferent and
efferent arterioles, and the region between them is known as the
lacis. The tubular component consists of the macula densa (arrowhead). The juxtaglomerular apparatus is an integral component of
the renin-angiotensin system.
FIGURE 1-4
Electron micrograph of the arterioles. Modified smooth muscle
cells of the arterioles of the juxtaglomerular apparatus produce and
secrete renin. Renin is packaged in characteristic amorphous
mature granules (arrow) derived from smaller rhomboid-shaped
immature protogranules (arrowhead).
1.4
FP
A
Microscopic view of the glomeruli. Glomeruli are spherical
bags of capillaries emanating from afferent arterioles and confined within the urinary space, which is continuous with the
proximal tubule. The capillaries are partially attached to the
mesangium, a continuation of the arteriolar wall consisting of
B
mesangial cells (A, arrow) and the matrix (B, arrow). The free
wall of glomerular capillaries, across which filtration takes place,
consists of a basement membrane (arrowheads) covered by visceral epithelial cells with individual foot processes (FP) and lined by
endothelial cells.
FIGURE 1-6
Schematic illustration of a glomerulus and adjacent hilar structure.
Note the relationship of mesangial cells to the juxtaglomerular
apparatus and distal tubule (macula densa). Redmesangial cells;
bluemesangial matrix; blackbasement membrane; greenvisceral and parietal epithelial cells; yellowendothelial cells. (From
Churg and coworkers [1]; with permission.)
FIGURE 1-7
Electron photomicrograph illustrating a portion of the ultrastructure of the glomerular capillary wall. The normal width of
the lamina rara externa (LRE) plus the lamina densa (LD) plus
the lamina rara interna (LRI) equals about 250 to 300 nm. The
spaces between the foot processes (FP), having diameters of 20
to 60 nm, are called filtration slit pores. It is believed they are
the path by which filtered fluid reaches the urinary space (U).
The endothelial cells on the luminal aspect of the basement
membrane (BM) are fenestrated, having diameters from 70 to
100 nm (see Fig. 1-9). The BM (LRE plus LD plus LRI) is composed of Type IV collagen and negativity charged proteoglycans
(heparan sulfate). Llumen. (From Churg and coworkers [1];
with permission.)
Normal Vascular and Glomerular Anatomy
1.5
FIGURE 1-8
Scanning electron microscopy of the glomerulus. The surface
anatomy of the interdigitating foot processes of normal visceral
epithelial cells (podocytes) is demonstrated. These cells and their
processes cover the capillary, and ultrafiltration occurs between
the fine branches of the cells. (From Churg and coworkers [1];
with permission.)
FIGURE 1-9
Scanning electron microscopy of the glomerulus. The surface
anatomy of endothelial cells of a normal glomerulus is demonstrated. Note the fenestrated appearance. (From Churg and coworkers
Reference
1.
Churg J, Bernstein J, Glassock RJ: Renal Disease. Classification and

Atlas of Glomerular Diseases, edn 2. New York: Igaku-Shoin; 1995.
The Primary
Glomerulopathies
Arthur H. Cohen
Richard J. Glassock
he primary glomerulopathies are those disorders that affect

glomerular structure, function, or both in the absence of a multisystem disorder. The clinical manifestations are predominately the consequence of the glomerular lesion (such as proteinuria,
hematuria, and reduced glomerular filtration rate). The combination
of clinical manifestations leads to a variety of clinical syndromes.
These syndromes include acute glomerulomphritis; rapidly progressive glomerulonephritis; chronic renal failure; the nephrotic syndrome
or asymptomatic hematuria, proteinuria, or both.
CHAPTER
2.2

FIGURE 2-1
Each of these syndromes arises as a consequence of disturbances of
glomerular structure and function. Acute glomerulonephritis consists
of the abrupt onset of hematuria, proteinuria, edema, and hypertension. Rapidly progressive glomerulonephritis is characterized by
features of nephritis and progressive renal insufficiency. Chronic
glomerulonephritis features proteinuria and hematuria with indolent
progressive renal failure. Nephrotic syndrome consists of massive
proteinuria (>3.5 g/d in adults), hypoalbuminemia with edema,
lipiduria, and hyperlipidemia. Asymptomatic hematuria, proteinuria, or both is not associated initially with renal failure or edema.
Each of these syndromes may be complicated by hypertension.
CLINICAL SYNDROMES OF GLOMERULAR DISEASE

Rapidly progressive glomerulonephritis
Chronic glomerulonephritis
Nephrotic syndrome
Asymptomatic hematuria, proteinuria, or both
%
100
5
4
2
5
1
7
%
Others
Lupus
90
10.8
Amyloid
5.9
1.6
Diabetes
80
Other
proliferative
70
16.0
25.8
60
MCGN
9.8
Membranous
19.7
50
76
40
30
11.8
FSGS
20
Minimal
changes
10
22
0
All
children
5 10 15 20
30
40
50
Age at onset of NS
PRIMARY GLOMERULAR LESIONS

Minimal change disease
Focal segmental glomerulosclerosis with hyalinosis
Membranous glomerulonephritis
Membranoproliferative glomerulonephritis
Mesangial proliferative glomerulonephritis
Crescentic glomerulonephritis
Immunoglobulin A nephropathy
Fibrillary and immunotactoid glomerulonephritis
Collagenofibrotic glomerulopathy
Lipoprotein glomerulopathy
60
70
80
All
adults
FIGURE 2-2
Age-associated prevalence of various
glomerular lesions in nephrotic syndrome.
This schematic illustrates the age-associated prevalence of various diseases and
glomerular lesions among children and
adults undergoing renal biopsy for evaluation of nephrotic syndrome (Guys
Hospital and the International Study of
Kidney Disease in Children) [1]. Both the
systemic and primary causes of nephrotic
syndrome are included. (Diabetes mellitus
with nephropathy is underrepresented
because renal biopsy is seldom needed for
diagnosis.) The bar on the left summarizes
the prevalence of various lesions in children aged 0 to 16 years; the bar on the
right summarizes the prevalence of various lesions in adults aged 16 to 80 years.
Note the high prevalence of minimal
change disease in children and the increasing prevalence of membranous glomerulonephritis in the age group of 16 to 60
years. FSGSfocal segmental glomeruosclerosis; MCGNmesangiocapillary
glomerulonephritis. (From Cameron [1];
with permission.)
FIGURE 2-3
The primary glomerular lesions.
The Primary Glomerulopathies
2.3
Minimal Change Disease
FIGURE 2-4
Light and electron microscopy in minimal change disease (lipoid
nephrosis). A, This glomerulopathy, one of many associated with
nephrotic syndrome, has a normal appearance on light microscopy.
No evidence of antibody (immune) deposits is seen on immunofluorescence. B, Effacement (loss) of foot processes of visceral epithelial cells is observed on electron microscopy. This last feature is the
major morphologic lesion indicative of massive proteinuria.
Minimal change disease is considered to be the result of glomerular

capillary wall damage by lymphokines produced by abnormal T
cells. This glomerulopathy is the most common cause of nephrotic
syndrome in children (>70%) and also accounts for approximately
20% of adult patients with nephrotic syndrome. This glomerulopathy typically is a corticosteroid-responsive lesion, and usually has a
benign outcome with respect to renal failure.
100
80
60
40
ISKDC children
Prednisone + Cyclophosphamide (11)
Prednisone (75)
Cyclophosphamide (25)
20
0
Cumulative percentage sustained

remission
Complete remission, cumulative %
100
12 weeks
8 weeks
80
60
40
20
0
16
Weeks from starting treatment
28
FIGURE 2-5
Therapeutic response in minimal change disease. This graph
illustrates the cumulative complete response rate (absence of
abnormal proteinuria) in patients of varying ages in relation to
type and duration of therapy [1]. Note that most children with
minimal change disease respond to treatment within 8 weeks.
Adults require prolonged therapy to reach equivalent response
rates. Number of patients are indicated in parentheses. (From
Cameron [2]; with permission.)
200
400
600
Days
FIGURE 2-6
Cyclophosphamide in minimal change disease. One of several
controlled trials of cyclophosphamide therapy in pediatric patients
that pursued a relapsing steroid-dependent course is illustrated.
Note the relative freedom from relapse when children were given
a 12-week course of oral cyclophosphamide. An 8-week course
of chlorambucil (0.150.2 mg/kg/d) may be equally effective.
(From Arbeitsgemeinschaft fr pediatrische nephrologie [3];
with permission.)
2.4

100
Cyclosporine
Cyclophosphamide
Overall probability
80
60
FIGURE 2-7
Cyclosporine in minimal change disease. One of several controlled
trials of cyclosporine therapy in this disease is illustrated. Note the
relapses that occur after discontinuing cyclosporine therapy (arrow).
Cyclophosphamide was given for 2 months, and cyclosporine for 9
months. Probabilityactuarial probability of remaining relapse-free.
(From Ponticelli and coworkers [4]; with permission.)
40
20
0
0
90
Number of patients
Cyclosporine 36
Cyclophosphamide 30
180
270
36
29
360 450
Time, d
36
28
540
630
720
31
26
Focal Segmental Glomerulosclerosis
A
FIGURE 2-8
Light and immunofluorescent microscopy in focal segmental
glomerulosclerosis (FSGS). Patients with FSGS exhibit massive
proteinuria (usually nonselective), hypertension, hematuria, and
renal functional impairment. Patients with nephrotic syndrome
often are not responsive to corticosteroid therapy. Progression to
chronic renal failure occurs over many years, although in some
patients renal failure may occur in only a few years. A, This
glomerulopathy is defined primarily by its appearance on light
microscopy. Only a portion of the glomerular population, initially
B
in the deep cortex, is affected. The abnormal glomeruli exhibit
segmental obliteration of capillaries by increased extracellular
matrixbasement membrane material, collapsed capillary walls,
or large insudative lesions. These lesions are called hyalinosis
(arrow) and are composed of immunoglobulin M and complement C3 (B, IgM immunofluorescence). The other glomeruli
usually are enlarged but may be of normal size. In some patients,
mesangial hypercellularity may be a feature. Focal tubular
atrophy with interstitial fibrosis invariably is present.
2.5
FIGURE 2-9
Electron microscopy of focal segmental glomerulosclerosis. The electron microscopic findings in the involved glomeruli mirror the light
microscopic features, with capillary obliteration by dense hyaline
deposits (arrow) and lipids. The other glomeruli exhibit primarily
foot process effacement, occasionally in a patchy distribution.
CLASSIFICATION OF FOCAL SEGMENTAL

GLOMERULOSCLEROSIS WITH HYALINOSIS
Primary (Idiopathic)
Classic
Tip lesion
Collapsing
Secondary
Human immunodeficiency virusassociated
Heroin abuse
Vesicoureteric reflux nephropathy
Oligonephronia (congenital absence or hypoplasia of one kidney)
Obesity
Analgesic nephropathy
Hypertensive nephrosclerosis
Sickle cell disease
Transplantation rejection (chronic)
Vasculitis (scarring)
Immunoglobulin A nephropathy (scarring)
FIGURE 2-10
Note that a variety of disease processes can lead to the lesion of
focal segmental glomerulosclerosis. Some of these are the result of
infections, whereas others are due to loss of nephron population.
Focal sclerosis may also complicate other primary glomerular diseases (eg, Immunoglobulin A nephropathy).
CLASSIFICATION OF MEMBRANOUS
GLOMERULONEPHRITIS
Secondary
Neoplasia (carcinoma, lymphoma)
Autoimmune disease (systemic lupus erythematosus thyroiditis)
Infectious diseases (hepatitis B, hepatitis C, schistosomiasis)
Drugs (gold, mercury, nonsteroidal anti-inflammatory drugs, probenecid, captopril)
Other causes (kidney transplantation, sickle cell disease, sarcoidosis)
FIGURE 2-11
Most adult patients (75%) have primary or idiopathic disease. Most
children have some underlying disease, especially viral infection. It
is not uncommon for adults over the age of 60 years to have an
underlying carcinoma (especially lung, colon, stomach, or breast).
2.6
FIGURE 2-12
Histologic variations of focal segmental glomerulosclerosis (FSGS).
Two important variants of FSGS exist. In contrast to the histologic
appearance of the involved glomeruli, with the sclerotic segment in
any location in the glomerulus, the glomerular tip lesion (A) is
characterized by segmental sclerosis at an early stage of evolution,
at the tubular pole (tip) of all affected glomeruli (arrow).
Capillaries contain monocytes with abundant cytoplasmic lipids
(foam cells), and the overlying visceral epithelial cells are enlarged
and adherent to cells of the most proximal portion of the proximal
100
tubule. Some investigators have described a more favorable

response to steroids and a more benign clinical course.
The other variant, known as collapsing glomerulopathy, most
likely represents a virulent form of FSGS. In this form of FSGS,
most visceral epithelial cells are enlarged and coarsely vacuolated
and most capillary walls are wrinkled or collapsed (B). These
features indicate a severe lesion, with a corresponding rapidly progressing clinical course of the disease. Integral and concomitant acute
abnormalities of tubular epithelia and interstitial edema occur.
<15 y (138)
1559 y (68)
60
<15 y (62)
40
20

FSGS
0
0
>60 y (20)
>15 y (60)
10
15
Years from onset
20
Survival, %
Survival, %
80
100
90
80
70
60
50
40
30
20
10
0
Without nephrotic
syndrome
With nephrotic
syndrome
FIGURE 2-13
Evolution of focal segmental glomerulosclerosis (FSGS). This graph
compares the renal functional survival rate of patients with FSGS
to that seen in patients with minimal change disease (in adults and
children). Note the poor prognosis, with about a 50% rate of renal
survival at 10 years. (From Cameron [2]; with permission.)
10
15
Years from onset
20
FIGURE 2-14
The outcome of focal segmental glomerulosclerosis according to the
degree of proteinuria at presentation is shown. Note the favorable
prognosis in the absence of nephrotic syndrome. Spontaneous or
therapeutically induced remissions have a similar beneficial effect on
long-term outcome. (From Ponticelli, et al. [5]; with permission.)
2.7
Membranous Glomerulonephritis
E
Light, immunofluorescent, and electron microscopy in membranous glomerulonephritis. Membranous glomerulonephritis is an
immune complexmediated glomerulonephritis, with the immune
deposits localized to subepithelial aspects of almost all glomerular
capillary walls. Membranous glomerulonephritis is the most common cause of nephrotic syndrome in adults in developed countries.
In most instances (75%), the disease is idiopathic and the
antigen(s) of the immune complexes are unknown. In the remainder, membranous glomerulonephritis is associated with welldefined diseases that often have an immunologic basis (eg, systemic
lupus erythematosus and hepatitis B or C virus infection); some
solid malignancies (especially carcinomas); or drug therapy, such as
gold, penicillamine, captopril, and some nonsteroidal anti-inflammatory reagents. Treatment is controversial.
The changes by light and electron microscopy mirror one another quite well and represent morphologic progression that is likely
dependent on duration of the disease. A, At all stages immunofluorescence discloses the presence of uniform granular capillary
wall deposits of immunoglobulin G and complement C3. B, In the
early stage the deposits are small and without other capillary wall
changes; hence, on light microscopy, glomeruli often are normal in
appearance. C, On electron microscopy, small electron-dense
deposits (arrows) are observed in the subepithelial aspects of capillary
walls. D, In the intermediate stage the deposits are partially encircled
by basement membrane material. E, When viewed with periodic
acid-methenamine stained sections, this abnormality appears as
spikes of basement membrane perpendicular to the basement
membrane, with adjacent nonstaining deposits. Similar features
are evident on electron microscopy, with dense deposits and intervening basement membrane (D). Late in the disease the deposits
are completely surrounded by basement membranes and are undergoing resorption.
2.8

FIGURE 2-16
Evolution of deposits in membranous glomerulonephritis. This
schematic illustrates the sequence of immune deposits in red; basement membrane (BM) alterations in blue; and visceral epithelial cell
changes in yellow. Small subepithelial deposits in membranous
glomerulonephritis (predominately immunoglobulin G) initially
form (A) then coalesce. BM expansion results first in spikes (B) and
later in domes (C) that are associated with foot process effacement,
as shown in gray. In later stages the deposits begin to resorb (dotted
and crosshatched areas) and are accompanied by thickening of the
capillary wall (D). (From Churg, et al. [6]; with permission.)
FIGURE 2-17
Natural history of membranous glomerulonephritis. This schematic illustrates the clinical
evolution of idiopathic membranous glomerulonephritis over time. Almost half of all patients
undergo spontaneous or therapy-related remissions of proteinuria. Another group of patients
(2540%), however, eventually develop chronic renal failure, usually in association with persistent proteinuria in the nephrotic range. (From Cameron [2]; with permission.)
100
Dead/ESRD
80
Nephrotic syndrome
60
Proteinuria
40
20
Remission
0
0
5
10
Years of known disease
15
2.9
Membranoproliferative Glomerulonephritis
1
2
3
4
5
C
Light, immunofluorescence, and electron microscopy in membranoproliferative glomerulonephritis type I. In these types of
immune complexmediated glomerulonephritis, patients often
exhibit nephrotic syndrome accompanied by hematuria and
depressed levels of serum complement C3. The morphology is varied, with at least three pathologic subtypes, only two of which are
at all common. The first, known as membranoproliferative

(mesangiocapillary) glomerulonephritis type I, is a primary
glomerulopathy most common in children and adolescents. The
same pattern of injury may be observed during the course of many
diseases with chronic antigenemic states; these include systemic
lupus erythematosus and hepatitis C virus and other infections. In
membranoproliferative glomerulonephritis type I, the glomeruli
are enlarged and have increased mesangial cellularity and variably
increased matrix, resulting in lobular architecture. The capillary
walls often are thickened with double contours, an abnormality
resulting from peripheral migration and interposition of
mesangium (A). Immunofluorescence discloses granular to confluent granular deposits of C3 (B), immunoglobulin G, and
immunoglobulin M in the peripheral capillary walls and mesangial
regions. The characteristic finding on electron microscopy is in the
capillary walls. C, Between the basement membrane and endothelial cells are, in order inwardly: (1) epithelial cell, (2) basement
membrane, (3) electron-dense deposits, (4) mesangial cell cytoplasm, (5) mesangial matrix, and (6) endothelial cell. Electrondense deposits also are in the central mesangial regions.
Subepithelial deposits may be present, albeit typically in small
numbers. The electron-dense deposits may contain an organized
(fibrillar) substructure, especially in association with hepatitis C
virus infection and cryoglobulemia.
2.10
C
Light, immunofluorescence, and electron microscopy in membranoproliferative glomerulonephritis type II. In this disease, also
A
B
known as dense deposit disease, the glomeruli may be lobular
or may manifest only mild widening of mesangium. A, The capillary walls are thickened, and the basement membranes are
stained intensely positive periodic acidSchiff reaction, with a
refractile appearance. B, On immunofluorescence, complement
C3 is seen in all glomerular capillary basement membranes in
a coarse linear pattern. With the use of thin sections, it can be
appreciated that the linear deposits actually consist of two thin
parallel lines. Round granular deposits are in the mesangium.
Coarse linear deposits also are in Bowmans capsule and the
tubular basement membranes. C, Ultrastructurally, the glomerular capillary basement membranes are thickened and darkly
stained; there may be segmental or extensive involvement of
the basement membrane. Similar findings are seen in Bowmans
capsule and tubular basement membranes; however, in the latter,
the dense staining is usually on the interstitial aspect of that
structure. Patients with dense deposit disease frequently show
isolated C3 depression and may have concomitant lipodystrophy.
These patients also have autoantibodies to the C3 convertase
enzyme C3Nef.
2.11
SERUM COMPLEMENT CONCENTRATIONS IN GLOMERULAR LESIONS

Serum Concentration
Lesion
C3
C4
CH50
Other

Focal sclerosis
Membranous glomerulonephritis (idiopathic)
Membranoproliferative glomerulonephritis:
Type I
Type II
Acute poststreptococcal glomerulonephritis
Lupus nephritis:
(World Health Organization Class IV)
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Moderate decrease
Severe decrease
Moderate decrease
Mild decrease
Normal
Normal
Mild decrease
Mild decrease
Mild decrease
C3 nephritic factor+
Antistreptolysin 0 titer increased
Moderate to severe
decrease
Normal or mild decrease
Normal
Normal or increased
Moderate to severe
decrease
Severe decrease
Normal
Normal or increased
Mild decrease
antidouble-stranded DNA antibody+

Moderate decrease
Normal
Normal
antidouble-stranded DNA antibody+

Cryoglobulins; hepatitis C ab
Antineutrophil cytoplasmic antibody+
(World Health Organization Class V)

Cryoglobulinemia (hepatitis C)
Amyloid
Vasculitis
CH50serum hemolytic complement activity.
FIGURE 2-20
The serum complement component concentration (C3 and C4) and
serum hemolytic complement activity (CH50) in various primary
CLASSIFICATION OF MEMBRANOPROLIFERATIVE
GLOMERULONEPHRITIS TYPE I
Secondary
Hepatitis C (with or without cryoglobulinemia)
Hepatitis B
Light or heavy chain nephropathy
Sickle cell disease
Sjgrens syndrome
Sarcoidosis
Shunt nephritis
Antitrypsin deficiency
Quartan malaria
Chronic thrombotic microangiopathy
Buckleys syndrome
and secondary glomerular lesions are depicted. Note the limited

number of disorders associated with a low C3 or C4 level.
FIGURE 2-21
Note that although there is the wide variety of underlying causes for
the lesion of membranoproliferative glomerulonephritis hepatitis C,
with or without cryoglobulinemia, accounts for most cases.
2.12
Mesangial Proliferative Glomerulonephritis
C
Light, immunofluorescence, and electron microscopy in mesangial
proliferative glomerulonephritis. This heterogeneous group of disorders is characterized by increased mesangial cellularity in most of
the glomeruli associated with granular immune deposits in the
B
mesangial regions. Little if any increased cellularity is seen, despite
the presence of deposits. In this latter instance, the term mesangial
injury glomerulonephritis is more properly applied. The disorders
are defined on the basis of the immunofluorescence findings, rather
than on the presence or absence of mesangial hypercellularity. There
are numerous disorders with this appearance; some have specific
immunopathologic or clinical features (such as immunoglobulin A
nephropathy, Henoch-Schonlein purpura, and systemic lupus erythematosus). Patients with primary mesangial proliferative glomerulonephritis typically exhibit the disorder in one of four ways:
asymptomatic proteinuria, massive proteinuria often in the nephrotic range, microscopic hematuria, or proteinuria with hematuria. A,
On light microscopy, widening of the mesangial regions is observed,
often with diffuse increase in mesangial cellularity commonly of a
mild degree. No other alterations are present. B, Depending on the
specific entity or lesion, the immunofluorescence is of granular
mesangial deposits. In the most common of these disorders,
immunoglobulin M is the dominant or sole deposit. Other disorders
are characterized primarily or exclusively by complement C3,
immunoglobulin G, or C1q deposits. C, On electron microscopy the
major finding is of small electron-dense deposits in the mesangial
regions (arrow). Foot process effacement is variable, depending on
the clinical syndrome (eg, whether massive proteinuria is present).
2.13
Crescentic Glomerulonephritis

Crescentic glomerulonephritis. A crescent is the accumulation of
cells and extracellular material in the urinary space of a glomerulus.
The cells are parietal and visceral epithelia as well as monocytes and
other blood cells. The extracellular material is fibrin, collagen, and
basement membrane material. In the early stages of the disease, the
crescents consist of cells and fibrin. In the later stages the crescents
undergo organization, with disappearance of fibrin and replacement
by collagen. Crescents represent morphologic consequences of
severe capillary wall damage. A, In most instances, small or large
areas of destruction of capillary walls (cells and basement membranes) are observed (arrow), thereby allowing fibrin, other high
molecular weight substances, and blood cells to pass readily from
capillary lumina into the urinary space. B, Immunofluorescence frequently discloses fibrin in the urinary space. C, The proliferating
cells in Bowmans space ultimately give rise to the typical crescent
shape. Whereas crescents may complicate many forms of glomerulonephritis, they are most commonly associated with either
antiglomerular basement membrane (AGBM) antibodies or antineu-
trophil cytoplasmic antibodies (ANCAs). The clinical manifestations

are typically of rapidly progressive glomerulonephritis with moderate proteinuria, hematuria, oliguria, and uremia. The immunomorphologic features depend on the basic disease process. On light
microscopy in both AGBM antibodyinduced disease and
ANCAassociated crescentic glomerulonephritis, the glomeruli without crescents often have a normal appearance. It is the remaining
glomeruli that are involved with crescents. D, Anti-GBM disease is
characterized by linear deposits of immunoglobulin G and often
complement C3 in all capillary basement membranes, and in
approximately two thirds of affected patients in tubular basement
membranes. The ANCA-associated lesion typically has little or no
immune deposits on immunofluorescence; hence the term pauciimmune crescentic glomerulonephritis is used. By electron
microscopy, as on light microscopy, defects in capillary wall continuity are easily identified. Both AGBM- and ANCA-associated crescentic glomerulonephritis can be complicated by pulmonary hemorrhage (see Fig. 2-25).
2.14
CLASSIFICATION OF CRESCENTIC GLOMERULONEPHRITIS

Type
Serologic Pattern
Primary
Secondary
I
II
Anti-GBM+ ANCAAnti-GBM- ANCA-
III
IV
Anti-GBM- ANCA+
Anti-GBM+ANCA+
Anti-GBM antibodymediated crescentic glomerular nephritis

Idiopathic crescentic glomerular nephritis (with or without immune
complex deposits)
Pauci-immune crescentic glomerular nephritis (microscopic polyangiitis)
Anti-GBM antibodymediated crescentic glomerular nephritis with ANCA
Goodpastures disease
Systemic lupus erythematosus, immunoglobulin A, MPGN
cryoimmunoglobulin (with immune complex deposits
Drug-induced crescentic glomerulonephritis
Goodpastures syndrome with ANCA
ANCAantineutrophil cytoplasmic antibody; anti-GBMglomerular basement membrane antibody;

MPGN membranoproliferative glomerulonephritis.
FIGURE 2-24
Note that the serologic findings allow for a differentiation of the various forms of
primary and secondary (eg, multisystem disease) forms of crescentic glomerulonephritis.
FIGURE 2-25
Chest radiograph of alveolar hemorrhage. This patient has antiglomerular basement membranemediated glomerulonephritis complicated by pulmonary hemorrhage (Goodpastures
disease). Note the butterfly appearance of the alveolar infiltrates characteristic of intrapulmonary (alveolar) hemorrhage. Such lesions can also occur in patients with antineutrophil
cytoplasmic autoantibodyassociated vasculitis and glomerulonephritis, lupus nephritis
(SLE), cryoglobulinemia, and rarely in Henoch-Schonlein purpura (HSP).
FIGURE 2-26
Evaluation of rapidly progressive glomerulonephritis. This algorithm schematically
illustrates a diagnostic approach to the
various causes of rapidly progressive
glomerulonephritis (Figure 2-24), Serologic
studies, especially measurement of circulating antiglomerular basement membrane
antibodies, antineutrophil cytoplasmic
antibodies, antinuclear antibodies, and
serum complement component concentrations, are used for diagnosis. Serologic
patterns (A through D)permit categorization of probable disease entities.
Serum creatinine
Proteinuria
"Nephritic" sediment
Renal ultrasonography
Small kidneys
Normal or enlarged
kidneys; no obstruction
Obstruction
Serology*
Pattern type (A)
aGBMA*
+
ANCA
(B)
(C)
(D)
+
+
Goodpasture's disease Type II IC-mediated

Type I primary CrGN CGN SLE, HSP, and
MPGN CryoIg, type V
primary CrGN
(idiopathic)
2.15
Microscopic
Combined
polyangiitis; type III
form; type IV
primary crescentic
primary CrGN
CrGN; Wegener's GN;
drug-induced CrGN
*Antiglomerular basement membrane autoantibody by radioimmunoassay or enzyme-linked

immunosorbent assay
Antineutrophil cytoplasmic autoantibody by indirect immunofluorescence, confirmed by antigen-specific
assay (anti-MPO, anti-PR3, or both).
C-ANCA
P-ANCA

Antineutrophil cytoplasmic autoantibodies
(ANCA). Frequently, ANCA are found in
crescentic glomerulonephritis, particularly
type III (Figure 2-24). Two varieties are
seen (on alcohol-fixed slides). A, C-ANCA
are due to antibodies reacting with cytoplasmic granule antigens (mainly proteinase-3). B, P-ANCA are due to antibodies reacting with other antigens (mainly
myeloperoxidase).
2.16
Immunoglobulin A Nephropathy

Light, immunofluorescence, and electron microscopy in immunoglobulin A (IgA) nephropathy. IgA nephropathy is a chronic
glomerular disease in which IgA is the dominant or sole component
of deposits that localize in the mesangial regions of all glomeruli.
In severe or acute cases, these deposits also are observed in the
capillary walls. This disorder may have a variety of clinical presentations. Typically, the presenting features are recurrent macroscopic
hematuria, often coincident with or immediately after an upper respiratory infection, along with persistent microscopic hematuria and
low-grade proteinuria between episodes of gross hematuria.
Approximately 20% to 25% of patients develop end-stage renal
disease over the 20 years after onset. A, On light microscopy,
widening and often an increase in cellularity in the mesangial
regions are observed, a process that affects the lobules of some
glomeruli to a greater degree than others. This feature gives rise
to the term focal proliferative glomerulonephritis. In advanced

cases, segmental sclerosis often is present and associated with massive proteinuria. During acute episodes, crescents may be present.
B, Large round paramesangial fuchsinophilic deposits often are
identified with Massons trichrome or other similar stains (arrows).
C, Immunofluorescence defines the disease; granular mesangial
deposits of IgA are seen with associated complement C3, and IgG
or IgM, or both. IgG and IgM often are seen in lesser degrees of
intensity than is IgA. D, On electron microscopy the abnormalities
typically are those of large rounded electron-dense deposits
(arrows) in paramesangial zones of most if not all lobules.
Capillary wall deposits (subepithelial, subendothelial, or both) may
be present, especially in association with acute episodes. In addition, capillary basement membranes may show segmental thinning
and rarefaction.
2.17
FIGURE 2-29
Natural history of immunoglobulin A (IgA) nephropathy. The evolution of IgA nephropathy over time with respect to the occurrence of end-stage renal failure (ESRF) is illustrated.
The percentage of renal survival (freedom from ESRF) is plotted versus the time in years
from the apparent onset of the disease. Note that on average about 1.5% of patients enter
ESRF each year over the first 20 years of this nephropathy. Factors indicating an unfavorable outcome include elevated serum creatinine, tubulointerstitial lesions or glomerulosclerosis, and moderate proteinuria (>1.0 g/d). (Modified from Cameron [2].)
Fibrillary and Immunotactoid Glomerulonephritis
C
Light, immunofluorescent, and electron microscopy in nonamyloid
fibrillary glomerulonephritis. Fibrillary glomerulonephritis is an
B
entity in which abnormal extracellular fibrils, typically ranging
from 10- to 20-nm thick, permeate the glomerular mesangial
matrix and capillary basement membranes. The fibrils are defined
only on electron microscopy and have an appearance, at first
glance, similar to amyloid. Congo red stain, however, is negative.
Patients with fibrillary glomerulonephritis usually exhibit proteinuria often in the nephrotic range, with variable hematuria, hypertension, and renal insufficiency. A, On light microscopy the
glomeruli display widened mesangial regions, with variable
increase in cellularity and thickened capillary walls and often with
irregularly thickened basement membranes, double contours, or
both. B, On immunofluorescence, there is coarse linear or confluent granular staining of capillary walls for immunoglobulin G and
complement C3 and similar staining in the mesangial regions.
Occasionally, monoclonal immunoglobulin G k deposits are identified; in most instances, however, both light chains are equally represented. The nature of the deposits is unknown. C, On electron
microscopy the fibrils are roughly 20-nm thick, of indefinite length,
and haphazardly arranged. The fibrils permeate the mesangial
matrix and basement membranes (arrow). The fibrils have been
infrequently described in organs other than the kidneys.
2.18
B
Light, immunofluorescent, and electron microscopy in immunotactoid glomerulopathy. Immunotactoid glomerulopathy appears to be
an immune-mediated glomerulonephritis. On electron microscopy
the deposits are composed of multiple microtubular structures in
subepithelial or subendothelial locations, or both, with lesser
involvement of the mesangium. Patients with this disorder typically
exhibit massive proteinuria or nephrotic syndrome. This glomerulopathy frequently is associated with lymphoplasmacytic disorders.
A, On light microscopy the glomerular capillary walls often are
thickened and the mesangial regions widened, with increased cellularity. B, On immunofluorescence, granular capillary wall and
mesangial immunoglobulin G and complement C3 deposits are present. The ultrastructural findings are of aggregates of microtubular
structures in capillary wall locations corresponding to granular
deposits by immunofluorescence. C, The microtubular structures
are large, ranging from 30- to 50-nm thick, or more (arrows).
2.19
Collagenofibrotic Glomerulopathy

Collagenofibrotic glomerulopathy (collagen III glomerulopathy).
The collagens normally found in glomerular basement membranes and the mesangial matrix are of types IV (which is dominant) and V. In collagenofibrotic glomerulopathy, accumulation
of type III collagen occurs largely in capillary walls in a subendothelial location. It is likely that this disease is hereditary; however, because it is very rare, precise information regarding transmission is not known. Collagenofibrotic glomerulopathy originally was thought to be a variant of nail-patella syndrome.
Current evidence suggests little relationship exists between the
two disorders. Patients with collagen III glomerulopathy often
exhibit proteinuria and mild progressive renal insufficiency.

For reasons that are not clear, hemolytic-uremic syndrome has
evolved in a small number of pediatric patients. A, On light
microscopy the capillary walls are thickened and mesangial
regions widened by pale staining material. These features are in
sharp contrast to the normal staining of the capillary basement
membranes, as evidenced by the positive period acidSchiff reaction. With this stain, collagen type III is not stained and therefore is much paler. Amyloid stains (Congo red) are negative.
B, On electron microscopy, banded collagen fibrils are evident
in the subendothelial aspect of the capillary wall.
References
1.
2.
3.
Cameron JS, Glassock RJ: The natural history and outcome of the
nephrotic syndrome. In The Nephrotic Syndrome. Edited by Cameron
JS and Glassock RJ. New York: Marcel Dekker, 1987.
Cameron JS: The long-term outcome of glomerular diseases. In
Diseases of the Kidney Vol II, edn 6. Edited by Schrier RW,
Gottschalk CW. Boston: Little Brown; 1996.
4.
Arbeitsgemeinschaft fr pediatrische nephrologie. Cyclophosphamide

treatment of steroid-dependent nephrotic syndrome: comparison of an
eight-week with a 12-week course. Arch Dis Child 1987, 62:11021106.
6.
5.
Ponticelli C: Cyclosporine versus cyclophosphamide for patients with

steroid-dependent and frequently relapsing idiopathic nephrotic syndrome. A multi-center randomized trial. Nephrol Dial Transplant
1993, 8:13261332.
Ponticelli C, Glassock RJ: Treatment of Segmental Glomerulonephritis.
Oxford: Oxford Medical Publishers, 1996:110.
Churg J, Bernstein J, Glassock RJ: Renal Disease. Classification and
Atlas of Glomerular Disease, edn 2. New York: Igaku-Shoin; 1995.
Heredofamilial
and Congenital
Glomerular Disorders
Arthur H. Cohen
Richard J. Glassock
he principal characteristics of some of the more common heredofamilial and congenital glomerular disorders are described and
illustrated. Diabetes mellitus, the most common heredofamilial
glomerular disease, is illustrated in Volume IV, Chapter 1. These disorders are inherited in a variety of patterns (X-linked, autosomal dominant, or autosomal recessive). Many of these disorders appear to be
caused by defective synthesis or assembly of critical glycoprotein
(collagen) components of the glomerular basement membrane.
CHAPTER
3.2
FIGURE 3-1
Alports syndrome. Alports syndrome (hereditary nephritis) is a
hereditary disorder in which glomerular and other basement membrane collagen is abnormal. This disorder is characterized clinically
by hematuria with progressive renal insufficiency and proteinuria.
Many patients have neurosensory hearing loss and abnormalities of
NC1
7S
100nm
the eyes. The disease is inherited as an X-linked trait; in some families, however, autosomal recessive and perhaps autosomal dominant
forms exist. Clinically, the disease is more severe in males than in
females. End-stage renal disease develops in persons 20 to 40 years
of age. In some families, ocular manifestations, thrombocytopenia
with giant platelets, esophageal leiomyomata, or all of these also
occur. In the X-linked form of Alports syndrome, mutations occur in
genes encoding the -5 chain of type IV collagen (COL4A5). In the
autosomal recessive form of this syndrome, mutations of either -3
or -4 chain genes have been described. On light microscopy, in the
early stages of the disease the glomeruli appear normal. With progression of the disease, however, an increase in the mesangial matrix
and segmental sclerosis develop. Interstitial foam cells are common
but are not used to make a diagnosis. Results of immunofluorescence
typically are negative, except in glomeruli with segmental sclerosis in
which segmental immunoglobulin M and complement (C3) are in
the sclerotic lesions. Ultrastructural findings are diagnostic and consist of profound abnormalities of glomerular basement membranes.
These abnormalities range from extremely thin and attenuated to
considerably thickened membranes. The thickened glomerular basement membranes have multiple layers of alternating medium and
pale staining strata of basement membrane material, often with
incorporated dense granules. The subepithelial contour of the basement membrane typically is scalloped.
FIGURE 3-2
Schematic of basement membrane collagen type IV. The postulated
arrangement of type IV collagen chains in a normal glomerular basement membrane is illustrated. The joining of noncollagen (NC-1)
and 75 domains creates a lattice (chicken wire) arrangement (A). In
the glomerular basement membrane, 1 and 2 chains predominate
in the triple helix (B), but 3, 4, 5, and 6 chains are also found (not
shown). Disruption of synthesis of any of these chains may lead to
anatomic and pathologic alternations, such as those seen in Alports
syndrome. Arrows indicate fibrils. (From Abrahamson and coworkers
-S--S1 -S--S- 1
2 -S--S- 2
-S--S1 -S--S- 1
-S--S-
Hearing loss, dB
FIGURE 3-3
Neurosensory hearing defect in Alports syndrome. In patients with adult onset Alports
syndrome, classic X-linked sensorineural hearing defects occur. These defects often begin
with an auditory loss of high-frequency tone, as shown in this audiogram. The shaded
area represents normal ranges. (Modified from Gregory and Atkin [2]; with permission.)
20
40
60
80
100
500 2K 4K 8K 10K 12K 14K 16K 18K
Frequency
Heredofamilial and Congenital Glomerular Disorders
3.3
FIGURE 3-4
Thin basement membrane nephropathy. Glomeruli with abnormally thin basement membranes may be a manifestation of benign
familial hematuria. Glomeruli with thin basement membranes
many also occur in persons who do not have a family history of
renal disease but who have hematuria, low-grade proteinuria, or
both. Although the ultrastructural abnormalities have some similarities in common with the capillary basement membranes of
Alports syndrome, these two glomerulopathies are not directly
related. Clinically, persistent microscopic hematuria or occasional
episodic gross hematuria are important features. Nonrenal abnormalities are absent. On light microscopy, the glomeruli are normal;
no deposits are seen on immunofluorescence. Here, the electron
microscopic abnormalities are diagnostic; all or virtually all
glomerular basement membranes are markedly thin (<200 nm in
adults) without other features such as splitting, layering, or abnormal subepithelial contours.
C
Fabrys disease. Fabrys disease, also known as angiokeratoma corporis diffusum or Anderson-Fabrys disease, is the result of deficiency
B
of the enzyme -galactosidase with accumulation of sphingolipids in
many cells. In the kidney, accumulation of sphingolipids especially
affects glomerular visceral epithelial cells. Deposition of sphingolipids in the vascular tree may lead to premature coronary artery
occlusion (angina or myocardial infarction) or cerebrovascular insufficiency (stroke). Involvement of nerves leads to painful acroparesthesias and decreased perspiration (anhidrosis). The most common
renal manifestation is that of proteinuria with progressive renal
insufficiency. On light microscopy, the morphologic abnormalities of
the glomeruli primarily consist of enlargement of visceral epithelial
cells and accumulation of multiple uniform small vacuoles in the
cytoplasm (arrow in Panel A). Ultrastructurally, the inclusions are
those of whorled concentric layers appearing as zebra bodies or
myeloid bodies representing sphingolipids (B). These structures also
may be observed in mesangial and endothelial cells and in arterial
and arteriolar smooth muscle cells and tubular epithelia. At considerably higher magnification, the inclusions are observed to consist of
multiple concentric alternating clear and dark layers, with a periodicity ranging from 3.9 to 9.8 nm. This fine structural appearance (best
appreciated at the arrow) is characteristic of stored glycolipids (C).
3.4

FIGURE 3-6
Electron microscopy of nail-patella syndrome. This disorder having
skeletal and renal manifestations affects the glomeruli, with accumulation of banded collagen fibrils within the substance of the capillary basement membrane. This accumulation appears as empty
lacunae when the usual stains with electron microscopy (lead citrate and uranyl acetate) are used. However, as here, the fibrils easily can be identified with the use of phosphotungstic acid stain in
conjunction with or instead of typical stains. Note that this disorder differs structurally from collagen type III glomerulopathy in
which the collagen fibrils are subendothelial and not intramembranous in location. Patients with nail-patella syndrome may develop
proteinuria, sometimes in the nephrotic range, with variable progression to end-stage renal failure. No distinguishing abnormalities
are seen on light microscopy.
FIGURE 3-7
Radiography of nail-patella syndrome. The
skeletal manifestations of nail-patella syndrome are characteristic and consist of
absent patella and absent and dystrophic
nails. These photographs illustrate absent
patella (A) and the characteristic nail
changes (B) that occur in patients with the
disorder. (From Gregory and Atkin [2];
with permission.)
A
Lecithin-cholesterol acyl transferase deficiency. Lipid accumulation occurs in this hereditary metabolic disorder, especially in
extracellular sites throughout glomerular basement membranes
and the mesangial matrix. A, On electron microscopy the lipid
appears as multiple small lacunae, often with small round dense
granular or membranous structures (arrows). Lipid-containing
monocytes may be in the capillary lumina. B, The mesangial
regions are widened on light microscopy, usually with expansion
of the matrix that stains less intensely than normal. Basement
A
Lipoprotein glomerulopathy. Patients with this rare disease, which
often is sporadic (although some cases occur in the same family),
exhibit massive proteinuria. Lipid profiles are characterized by
increased plasma levels of cholesterol, triglycerides, and very low
density lipoproteins. Most patients have heterozygosity for
apolipoprotein E2/3 or E2/4. A, The glomeruli are the sites of massive intracapillary accumulation of lipoproteins, which appear as
slightly tan masses (thrombi) dilating capillaries (arrows). Segmental
3.5
B
membranes are irregularly thickened. Some capillary lumina may
contain foam cells. Although quite rare, this autosomal recessive
disease has been described in most parts of the world; however,
it occurs most commonly in Norway. Patients exhibit proteinuria,
often with microscopic hematuria usually noted in childhood.
Renal insufficiency may develop in the fourth or fifth decade of
life and may progress rapidly. Nonrenal manifestations include
corneal opacification, hemolytic anemia, early atherosclerosis,
and sea-blue histocytes in the bone marrow and spleen.
B
mesangial hypercellularity or mesangiolysis may be present. With
immunostaining for -lipoprotein, apolipoproteins E and B are
identified in the luminal masses. B, Electron microscopic findings
indicate the thrombi consist of finely granular material with numerous vacuoles (lipoprotein). Lipoprotein glomerulopathy may
progress to renal insufficiency over a long period of time.
Recurrence of the lesions in a transplanted organ has been reported
infrequently. Lipid-lowering agents are mostly ineffective.
3.6
A
Nephropathic cystinosis. In older children and young adults,
compared with young children, patients with cystinosis commonly
exhibit glomerular involvement rather than tubulointerstitial disease.
Proteinuria and renal insufficiency are the typical initial manifestations.
A, As the most constant abnormality on light microscopy, glomeruli
A
Finnish type of congenital nephrotic syndrome. Several disorders
are responsible for nephrotic syndrome within the first few
months to first year of life. The most common and important of
these is known as congenital nephrotic syndrome of Finnish type
because the initial descriptions emphasized the more common
occurrence in Finnish families. This nephrotic syndrome is an
inherited disorder in which infants exhibit massive proteinuria
shortly after birth; typically, the placenta is enlarged. This disorder
can be diagnosed in utero; increased -fetoprotein levels in amniotic fluid is a common feature. A, The microscopic appearance of
B
have occasionally enlarged and multinucleated visceral epithelial cells
(arrow). As the disease progresses, segmental sclerosis becomes evident
as in the photomicrograph. B, Crystalline inclusions are identified on
electron microscopy. The crystals of cysteine are usually dissolved in
processing, leaving an empty space as shown here by the arrows.
B
the kidneys is varied. Some glomeruli are small and infantile without other alterations, whereas others are enlarged, more mature,
and have diffuse mesangial hypercellularity. Because of the massive proteinuria, some tubules are microcystically dilated, a finding responsible for the older term for this disorder, microcystic
disease. Because this syndrome is primarily a glomerulopathy,
the tubular abnormalities are a secondary process and should
not be used to designate the name of the disease. B, On electron
microscopy, complete effacement of the foot processes of visceral
epithelial cells is observed.
FIGURE 3-12
Diffuse mesangial sclerosis. This disorder is exhibited within the
first few months of life with massive proteinuria, often with
3.7
hematuria and progressive renal insufficiency. Currently, no evidence exists that this disorder is an inherited process with genetic
linkage. The glomeruli characteristically are small compact masses of extracellular matrix with numerous or all capillary lumina
being obliterated. As here, the visceral epithelial cells typically are
arranged as a corona or crown overlying the contracted capillary
tufts. Earlier stages of glomerular involvement are characterized
by variable increase in mesangial cellularity. Immunofluorescence
is typically negative for immunoglobulin deposits because this
disorder is not immune mediated. In some patients, diffuse
mesangial sclerosis may be part of the triad of the Drash syndrome characterized by ambiguous genitalia, Wilms tumor, and
diffuse mesangial sclerosis. In some patients, only two of the
three components may be present; however, some investigators
consider all patients with diffuse mesangial sclerosis to be at risk
for the development of Wilms tumor even in the absence of genital abnormalities. Thus, close observation or bilateral nephrectomy as prophylaxis against the development of Wilms tumor is
employed occasionally.
References
1.
Abrahamson D, Van der Heurel GB, Clapp WL, et al.: Nephritogenic

antigens in the glomerular basement membrane. In Immunologic
Renal Diseases. Edited by Nielson EG, Couser, WG. Philadelphia:
Lippincott-Raven, 1997.
2.
Gregory M, Atkin C: Alports syndrome, Fabry disease and nail-patella syndrome. In Diseases of the Kidney, Vol. I. edn 6. Edited by
Schrier RW, Gottschalk CW. Boston: Little Brown, 1995.
Infection-Associated
Glomerulopathies
Arthur H. Cohen
Richard J. Glassock
any glomerular diseases may be associated with acute and

chronic infectious diseases of bacterial, viral, fungal, or
parasitic origin. In many instances, the glomerular activators are transient and of little clinical consequence. In other
instances, distinct clinical syndromes such as acute nephritis or
nephrotic syndrome may be provoked. Some of the more important
infection-related glomerular diseases are illustrated here. Others diseases, including human immunodeficiency virus and hepatitis, are
also discussed in Volume IV.
CHAPTER
4.2
C
Light, immunofluorescent, and electron microscopy of poststreptococcal (postinfectious) glomerulonephritis. Glomerulonephritis may
follow in the wake of cutaneous or pharyngeal infection with a limited number of nephritogenic serotypes of group A -hemolytic
B
streptococcus. Typically, patients with glomerulonephritis exhibit
hematuria, edema, proteinuria, and hypertension. Renal function
frequently is depressed, sometimes severely. Most patients recover
spontaneously, and a few go on to rapidly progressive or chronic
indolent disease. A, On light microscopy the glomeruli are enlarged
and hypercellular, with numerous leukocytes in the capillary lumina
and a variable increase in mesangial cellularity. The leukocytes are
neutrophils and monocytes. The capillary walls are single-contoured, and crescents may be present. B, On immunofluorescence,
granular capillary wall and mesangial deposits of immunoglobulin
G and complement C3 are observed (starry-sky pattern). Three predominant patterns occur depending on the location of the deposits;
these include garlandlike, mesangial, and starry-sky patterns.
C, The ultrastructural findings are those of electron-dense deposits,
characteristically but not solely in the subepithelial aspects of the
capillary walls, in the form of large gumdrop or hump-shaped
deposits (arrow). However, electron-dense deposits also are found
in the mesangial regions and occasionally subendothelial locations.
Endothelial cells often are swollen, and leukocytes are not only
found in the capillary lumina but occasionally in direct contact
with basement membranes in capillary walls with deposits. Similar
findings may be observed in glomerulonephritis after infectious
diseases other than certain strains of Streptococci.
Infection-Associated Glomerulopathies
4.3
FIGURE 4-2
Infective endocarditis and shunt nephritis. The glomerulonephritis
accompanying infective endocarditis or infected ventriculoatrial
shunts or other indwelling devices is that of a postinfectious
glomerulonephritis or membranoproliferative glomerulonephritis
type I pattern, or both (see Fig. 2-18). In reality, the changes often
are a combination of both. As shown here, this glomerulopathy is
characterized by increased mesangial cellularity, with slight lobular
architecture; occasionally thickened capillary walls, with double
contours (arrow); and leukocytes in some capillary lumina. This
glomerulus also has a small crescent.
C
Human immunodeficiency virus (HIV) infection. Many forms of
renal disease have been described in patients infected with HIV.
Various immune complexmediated glomerulonephritides associated with complicating infections are known; however, several disorders appear to be directly or indirectly related to HIV itself.
Perhaps the more common of these is known as HIV-associated
nephropathy (HIVAN). This disease is a form of the collapsing
B
(focal segmental) glomerulosclerosis with significant tubular and
interstitial abnormalities. A, In HIVAN, many visceral epithelial
cells are enlarged, coarsely vacuolated, contain protein reabsorption droplets, and overlay capillaries with varying degrees of wrinkling and collapse of the walls (arrows). B, In HIVAN, the tubules
are dilated and filled with a precipitate of plasma protein, and the
tubular epithelial cells display various degenerative features
(arrow). Ultrastructural findings are a combination of those expected for the glomerulopathy as well as those common to HIV infection. Thus, the foot processes of visceral epithelial cells are effaced
and often detached from the capillary basement membranes. C,
Common in HIV infection are tubuloreticular structures, modifications of the cytoplasm of endothelial cells in which clusters of
microtubular arrays are in many cells (arrow). Some evidence suggests that HIV or viral proteins localize in renal epithelial cells and
perhaps are directly or indirectly responsible for the cellular and
functional damage. HIVAN often has a rapidly progressive downhill course, culminating in end-stage renal disease in as few as 4
months. HIVAN has a striking racial predilection; over 90% of
patients are black.
The other glomerulopathy that may be an integral feature of HIV
infection is immunoglobulin A nephropathy. In this setting, HIV
antigen may be part of the glomerular immune complexes and circulating immune complexes. The morphology and clinical course
generally are the same as in immunoglobulin A nephropathy occurring in the non-HIV setting.
4.4
HT
C
Hepatitis C virus infection. The most common glomerulonephritis in patients infected with the hepatitis C virus is membranoproliferative glomerulonephritis with, in some instances,
cryoglobulinemia and cryoglobulin precipitates in glomerular
capillaries. Thus, the morphology is basically the same as in
membranoproliferative glomerulonephritis type I (Fig. 2-18AC).
A, With cryoglobulins, precipitates of protein representing cryoglobulin in the capillary lumina and appearing as hyaline thrombi (HT)are observed (arrows), often with numerous monocytes
in most capillaries. B, Immunofluorescence microscopy discloses
D
peripheral granular to confluent granular capillary wall deposits
of immunoglobulin M (IgM) and complement C3; the same
immune proteins are in the luminal masses corresponding to
hyaline thrombi (arrow). C, Electron microscopy indicates the
luminal masses (HT). D, On electron microscopy the deposits
also appear to be composed of curvilinear or annular structures
(arrows). Hepatitis C viral antigen has been documented in the
circulating cryoglobulins. Membranous glomerulonephritis with
a mesangial component also has been infrequently described in
patients infected with the hepatitis C virus.
Infection-Associated Glomerulopathies
C
Hepatitis B virus infection. Several glomerulopathies have been
described in association with hepatitis B viral infection. Until
4.5
B
the isolation of the hepatitis C virus and its separation from the
hepatitis B virus, membranoproliferative glomerulonephritis was
considered a common immune complexmediated manifestation
of hepatitis B virus infection. However, more recent data indicate that this form of glomerulonephritis is a feature of hepatitis
C virus infection rather than hepatitis B virus infection. In contrast, membranous glomerulonephritis, often with mesangial
deposits and variable mesangial hypercellularity, is the glomerulopathy that is a common accompaniment of hepatitis B virus
infection. Hepatitis B virus surface, core, or e antigens have
been identified in the glomerular deposits. The morphology of
the glomerular capillary walls is similar to the idiopathic form
of membranous glomerulonephritis. A, Some degree of mesangial widening with increased cellularity occurs in most affected
patients. B, Similarly, on immunofluorescence, uniform granular
capillary wall deposits of immunoglobulin G (IgG), complement
C3, and both light chains are disclosed (IgG). It sometimes is
very difficult to identify mesangial deposits in this setting. C, In
addition to the expected capillary wall changes, electron microscopy discloses deposits in mesangial regions of many lobules
(the arrow indicates mesangial deposits; the arrowheads indicate
subepithelial deposits).
Vascular Disorders
Arthur H. Cohen
Richard J. Glassock
ascular disorders of the kidney comprise a very heterogeneous

array of lesions and abnormalities, depending on the site of the
lesion and underlying pathogenesis. Here, three common disorders are the focus: thrombotic microangiopathies, benign and
malignant nephrosclerosis, and vascular occlusive disease (atheroembolism). Vasculitis and renovascular hypertension are discussed in
other chapters.
CHAPTER
5.2
E
FIGURE 5-1
Light microscopy of thrombotic microangiopathies. This group
of disorders includes hemolytic-uremic syndrome and thrombotic
D
thrombocytopenic purpura, malignant hypertension, and renal
disease in progressive systemic sclerosis (scleroderma renal crises).
A, These lesions are characterized primarily by fibrin deposition in
the walls of the glomeruli (fibrin). B, This fibrin deposition is associated with endothelial cell swelling (arrow) and thickened capillary
walls, sometimes with a double contour. Variable capillary wall
wrinkling and luminal narrowing occur. Mesangiolysis (dissolution
of the mesangial matrix and cells) is not uncommon and may be
associated with microaneurysm formation. With further endothelial
cell damage, capillary thrombi ensue. C, Arteriolar thrombi also
may be present. In arterioles, fibrin deposits in the walls and lumina
are known as thrombonecrotic lesions, with extension of this
process into the glomeruli on occasion (arrow). The arterial walls
are thickened, with loose concentric intimal proliferation. D, On
electron microscopy, the subendothelial zones of the glomerular
capillary wall are widened (arrows). Flocculent material accumulates, corresponding to mural fibrin, with associated endothelial cell
swelling. E, With widespread arterial thrombosis, cortical necrosis is
a common complicating feature. The necrotic cortex consists
of pale confluent multifocal zones throughout the cortex.
Vascular Disorders

Microangiopathic hemolytic anemia. Bizarrely shaped and
fragmented erythrocytes are commonly seen in Wrights stained
peripheral blood smears from patients with active lesions of
thrombotic microangiopathy. These abnormally shaped erythrocytes presumably arise when the fibrin strands within small
blood vessels shear the cell membrane, with imperfect resolution
of the biconcave disk shape. The resultant intravascular hemolysis causes anemia, reticulocytosis, and reduced plasma haptoglobin level.
A
FIGURE 5-4
Benign and malignant nephrosclerosis. In benign nephrosclerosis
the artery walls are thickened with intimal fibrosis and luminal
narrowing. Arteriolar walls are thickened with insudative lesions,
a process affecting afferent arterioles almost exclusively. Both
of these processes, which can be quite patchy, result in chronic
ischemia. A, In glomeruli, chronic ischemia is manifested by gradual capillary wall wrinkling, luminal narrowing, and shrinkage
and solidification of the tufts. B, As these processes progress, collagen forms internal to Bowmans capsule, beginning at the vascu-
5.3

Disseminated intravascular coagulation. In disseminated intravascular coagulation, fibrin thrombi are typically found in many
glomerular capillary lumina. In contrast to the thrombotic
microangiopathies, in disseminated intravascular coagulation, fibrin is not primarily in vessel walls but in the lumina. Consequently,
the capillary wall thickening, endothelial cell swelling, and fibrin
accumulation in subendothelial locations are not features of this
lesion. In the glomerulus illustrated, the fibrin is in many capillary
lumina and appears as bright fuchsin positive (red) masses.
B
lar pole and growing as a collar around the wrinkled ischemic
tufts. This collagen formation ultimately is associated with tubular
atrophy and interstitial fibrosis.
In malignant nephrosclerosis the changes are virtually identical
to those of thrombotic microangiopathies (Fig. 5-1 C). Malignant
nephrosclerosis may be seen in essential hypertension, scleroderma, unilateral renovascular hypertension (with a contralateral or
unprotected kidney), and as a complicating event in many
chronic renal parenchymal diseases.
5.4
C
FIGURE 5-5
Vascular occlusive disease and thrombosis. Atheroemboli (cholesterol emboli) are most commonly associated with intravascular
B
instrumentation of patients with severe arteriosclerosis. Most
commonly, aortic plaques are complicated with ulceration and
often adherent fibrin, A. Portions of plaques are dislodged and
travel distally in the aorta. Because the kidneys receive a disproportionately large share of the cardiac output, they are a favored
site of emboli. Typically, the emboli are in small arteries and
arterioles, although glomerular involvement with a few cholesterol crystals in capillaries is not uncommon. Because of the
size of the crystals, it is sometimes difficult if not impossible
to identify them in glomerular capillaries in paraffin-embedded
sections. In plastic-embedded sections prepared for electron
microscopy, however, the crystals are quite easy to detect. On
light microscopy, cholesterol is represented by empty crystalline
spaces. In the early stages of the disease the crystals lie free in the
vascular lumina. In time, the crystals are engulfed by multinucleated foreign body giant cells. B, In this light microscopic photograph, a few crystals are evident in the glomerular capillary lumina and in an arteriole (arrows). C, In the electron micrograph the
elongated empty space represents dissolved cholesterol. Note that
no cellular reaction is evident.
Renal Interstitium and

Major Features of Chronic
Tubulointerstitial Nephritis
Garabed Eknoyan
Luan D. Truong
s a rule, diseases of the kidney primarily affect the glomeruli, vasculature, or remainder of the renal parenchyma that consists of
the tubules and interstitium. Although the interstitium and the
tubules represent separate functional and structural compartments, they
are intimately related. Injury initially involving either one of them
inevitably results in damage to the other. Hence the term tubulointerstitial diseases is used. Because inflammatory cellular infiltrates of variable
severity are a constant feature of this entity, the terms tubulointerstitial
diseases and tubulointerstitial nephritis have come to be used interchangeably. The clinicopathologic syndrome that results from these
lesions, commonly termed tubulointerstitial nephropathy, may pursue
an acute or chronic course. The chronic course is discussed here. The
abbreviation TIN is used to refer synonymously to chronic tubulointerstitial nephritis and tubulointerstitial nephropathy.
TIN may be classified as primary or secondary in origin. Primary
TIN is defined as primary tubulointerstitial injury without significant
involvement of the glomeruli or vasculature, at least in the early stages
of the disease. Secondary TIN is defined as secondary tubulointerstitial
injury, which is consequent to lesions initially involving either the
glomeruli or renal vasculature. The presence of secondary TIN is especially important because the magnitude of impairment in renal function
and the rate of its progression to renal failure correlate better with the
extent of TIN than with that of glomerular or vascular damage.
Renal insufficiency is a common feature of chronic TIN, and its diagnosis must be considered in any patient who exhibits renal insufficiency. In most cases, however, chronic TIN is insidious in onset, renal insufficiency is slow to develop, and earliest manifestations of the disease are
those of tubular dysfunction. As such, it is important to maintain a high
CHAPTER
6.2
Tubulointerstitial Disease
index of suspicion of this entity whenever any evidence of tubular dysfunction is detected clinically. At this early stage, removal
of a toxic cause of injury or correction of the underlying systemic
or renal disease can result in preservation of residual renal function. Of special relevance in patients who exhibit renal insufficiency caused by primary TIN is the absence or modest degree of
the two principal hallmarks of glomerular and vascular diseases

of the kidney: salt retention, manifested by edema and hypertension; and proteinuria, which usually is modest and less than 1 to
2 g/d in TIN. These clinical considerations notwithstanding, a
definite diagnosis of TIN can be established only by morphologic
examination of kidney tissue.
Structure of the Interstitium

FIGURE 6-1
Diagram of the approximate relative volume composition of tissue compartments at different segments of the kidney in rats. The interstitium of the kidney consists of peritubular and
periarterial spaces. The relative contribution of each of these two spaces to interstitial volume varies, reflecting in part the arbitrary boundaries used in assessing them, but increases
in size from the cortex to the papilla. In the cortex there is little interstitium because the
peritubular capillaries occupy most of the space between the tubules. The cortical interstitial
cells are scattered and relatively inconspicuous. In fact, a loss of the normally very close
approximation of the cortical tubules is the first evidence of TIN. In the medulla there is a
noticeable increase in interstitial space. The interstitial cells, which are in greater evidence,
have characteristic structural features and an organized arrangement. The ground substance
of the renal interstitium contains different types of fibrils and basementlike material embedded in a glycosaminoglycan-rich substance. (From Bohman [1]; with permission.)
CCortex
ISInner stripe of outer medulla
OSOuter stripe of outer medulla
IZInner zone of medulla
C
OS
IS
IZ
10
50
100%
Extracellular space
Interstitial cells
Vessels
Tubules
Cortex
FIGURE 6-2
A, Electron micrograph of a rat kidney cortex, where C is the cortex. B, Schematic rendering, where the narrow interstitium is shown in black and the wide interstitium is shown by
dots. The relative volume of the interstitium of the cortex is approximately 7%, consisting of
about 3% interstitial cells and 4% extracellular space. The vasculature occupies another
6%; the remainder (ie, some 85% or more) is occupied by the tubules. The cortical interstitial space is unevenly distributed and has been divided into narrow and wide structural
components. The tubules and peritubular capillaries either are closely apposed at several
points, sometimes to the point of sharing a common basement membrane, or are separated
by a very narrow space.
This space, the so-called narrow interstitium, has been estimated to occupy 0.6% of cortical volume in rats. The narrow interstitium occupies about one-half to two-thirds of the
cortical peritubular capillary surface area. The remainder of the cortical interstitium consists of irregularly shaped clearly discernible larger areas, the so-called wide interstitium.
The wide interstitium has been estimated to occupy 3.4% of cortical volume in rats. The
capillary wall facing the narrow interstitium is significantly more fenestrated than is that
facing the wide interstitium. Functional heterogeneity of these interstitial spaces has been
proposed but remains to be clearly defined. (From Bohman [1]; with permission.)
Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis
6.3
Medulla
FIGURE 6-3
Scanning electron micrograph of the inner medulla, showing a
prominent collecting duct, thin wall vessels, and abundant interstitium. A gradual increase in interstitial volume from the outer
medullary stripe to the tip of the papilla occurs. In the outer stripe
of the outer medulla, the relative volume of the interstitium is
slightly less than is that of the cortex. This volume has been
estimated to be approximately 5% in rats. It is in the inner stripe
of the outer medulla that the interstitium begins to increase significantly in volume, in increments that gradually become larger
toward the papillary tip.
The inner stripe of the outer medulla consists of the vascular bundles and the interbundle regions, which are occupied principally by
tubules. Within the vascular bundles the interstitial spaces are meager,
whereas in the interbundle region the interstitial spaces occupy
some 10% to 20% of the volume. In the inner medulla the differentiation into vascular bundles and interbundle regions becomes
gradually less obvious until the two regions merge. A gradual increase
in the relative volume of the interstitial space from the base of the
inner medulla to the tip of the papilla also occurs. In rats, the
increment in interstitial space is from 10% to 15% at the base to
about 30% at the tip. In rabbits, the increment is from 20% to
25% at the base to more than 40% at the tip.
Cell types
B. RENAL INTERSTITIAL CELLS
A
FIGURE 6-4
A, High-power view of the medulla showing the wide interstitium
and interstitial cells, which are abundant, varied in shape, and
arranged as are the rungs of a ladder. B, Renal interstitial cells.
The interstitium contains two main cell types, whose numbers
increase from the cortex to the papilla. Type I interstitial cells are
fibroblastic cells that are active in the deposition and degradation
of the interstitial matrix. Type I cells contribute to fibrosis in response
to chronic irritation. Type II cells are macrophage-derived mononuclear cells with phagocytic and immunologic properties. Type II
Cortex
Outer medulla
Inner medulla
Fibroblastic cells
Mononuclear cells
Fibroblastic cells
Mononuclear cells
Pericytes
Lipid-laden cells
Mononuclear cells
cells are important in antigen presentation. Their cytokines contribute to recruitment of infiltrating cells, progression of injury,
and sustenance of fibrogenesis.
In the cortex and outer zone of the outer medulla, type I cells are
more common than are type II cells. In the inner zone of the medulla,
some type I cells form pericytes whereas others evolve into specialized lipid-laden interstitial cells. These specialized cells increase
in number toward the papillary tip and are a possible source of
medullary prostaglandins and of production of matriceal glycosaminoglycans. A characteristic feature of these medullary cells is
their connection to each other in a characteristic arrangement,
similar to the rungs of a ladder. These cells have a distinct close
and regular transverse apposition to their surrounding structures,
specifically the limbs of the loop of Henle and capillaries, but not
to the collecting duct cells.
6.4
Matrix
FIGURE 6-5
Peritubular interstitium in the cortex at the interface of a tubule (T) on the left and a capillary
(C) on the right. The inset shows the same space in cross section, including the basement
membrane (BM) of the two compartments. The extracellular loose matrix is a hydrated
gelatinous substance consisting of glycoproteins and glycosaminoglycans (hyaluronic acid,
heparan sulfate, dermatan sulfate, and chondroitin sulfate) that are embedded within a
fibrillar reticulum. This reticulum consists of collagen fibers (types I, III, and VI) and
unbanded microfilaments. Collagen types IV and V are the principal components of the
basement membrane lining the tubules. Glycoprotein components (fibronectin and laminin)
of the basement membrane connect it to the interstitial cell membranes and to the fibrillar
structures of the interstitial matrix. The relative increase in the interstitial matrix of the
medulla may be important for providing support to the delicate tubular and vascular
structures in this region. (From Lemley and Kriz [2]; with permission.)
Pathologic Features of Chronic TIN

FIGURE 6-6
Primary chronic TIN. The arrow indicates a normal glomerulus.
Apart from providing structural support, the interstitium serves as a
conduit for solute transport and is the site of production of several
cytokines and hormones (erythropoietin and prostaglandins). For the
exchange processes to occur between the tubules and vascular compartment, the absorbed or secreted substances must traverse the interstitial space. The structure, composition, and permeability characteristics of the interstitial space must, of necessity, exert an effect on any
such exchange. Although the normal structural and functional correlates of the interstitial space are poorly defined, changes in its composition and structure in chronic TIN are closely linked to changes in
tubular function. In addition, replacement of the normal delicate
interstitial structures by fibrosclerotic changes of chronic TIN would
affect the vascular perfusion of the adjacent tubule, thereby contributing to tubular dysfunction and progressive ischemic injury.
FIGURE 6-7
Secondary chronic TIN. The arrow indicates a glomerulus with a
cellular crescent. The diagnosis of TIN can be established only by
morphologic examination of kidney tissue. The extent of the lesions
of TIN, whether focal or diffuse, correlates with the degree of
impairment in renal function.
6.5
Tubular atrophy and dilation comprise a principal feature of

TIN. The changes are patchy in distribution, with areas of atrophic
chronically damaged tubules adjacent to dilated tubules displaying
compensatory hypertrophy. In atrophic tubules the epithelial cells
show simplification, decreased cell height, loss of brush border,
and varying degrees of thickened basement membrane. In dilated
tubules the epithelial cells are hypertrophic and the lumen may
contain hyalinized casts, giving them the appearance of thyroid
follicles. Hence the term thyroidization is used.
The interstitium is expanded by fibrous tissue, in which are interspersed proliferating fibroblasts and inflammatory cells comprised
mostly of activated T lymphocytes and macrophages. Rarely, B
lymphocytes, plasma cells, neutrophils, and even eosinophils may
be present.
The glomeruli, which may appear crowded in some areas owing
to tubulointerstitial loss, usually are normal in the early stages of
the disease. Ultimately, the glomeruli become sclerosed and develop
periglomerular fibrosis.
The large blood vessels are unremarkable in the early phases of
the disease. Ultimately, these vessels develop intimal fibrosis, medial
hypertrophy, and arteriolosclerosis. These vascular changes, which
also are associated with hypertension, can be present even in the
absence of elevated blood pressure in cases of chronic TIN.
CONDITIONS ASSOCIATED WITH PRIMARY CHRONIC TIN
Immunologic diseases
Urinary tract
obstructions
Hematologic diseases
Miscellaneous
Hereditary diseases
Endemic diseases
Systemic lupus
erythematosus
Sjgren syndrome
Transplanted kidney
Cryoglobulinemia
Goodpastures syndrome
Immunoglobulin A
nephropathy
Amyloidosis
Pyelonephritis
Vesicoureteral reflux
Mechanical
Sickle hemoglobinopathies
Multiple myeloma
Lymphoproliferative
disorders
Aplastic anemia
Vascular diseases
Nephrosclerosis
Radiation nephritis
Diabetes mellitus
Sickle hemoglobinopathies
Vasculitis

Hereditary nephritis
Polycystic kidney disease
Balkan nephropathy
Nephropathia epidemica
Infections
Drugs
Heavy metals
Metabolic disorders
Granulomatous disease
Idiopathic TIN
Systemic
Renal
Bacterial
Viral
Fungal
Mycobacterial
Analgesics
Cyclosporine
Nitrosourea
Cisplatin
Lithium
Miscellaneous
Lead
Cadmium
Hyperuricemiahyperuricosuria
Hypercalcemiahypercalciuria
Hyperoxaluria
Potassium depletion
Cystinosis
Sarcoidosis
Tuberculosis
FIGURE 6-8
Tubulointerstitial nephropathy occurs in a motley group of diseases
of varied and diverse causes. These diseases are arbitrarily grouped
together because of the unifying structural changes associated with

TIN noted on morphologic examination of the kidneys.
6.6
Pathogenesis of Chronic TIN

Glomerular disease
Vascular damage
Altered filtration
Tubular ischemia
Reabsorption
of noxious
macromolecules
NH3C3bC5
b-9
Chronic tubular cell injury
Release of cytokines, proteinases

adhesion molecules, growth factors
Cell balance
Recruitment of
antigenically
activated cells
Fibroblast proliferation
Matrix deposition
Tubular
atrophy
Interstitial
fibrosis
Interstitial
infiltrates
Tubular dysfunction
Capillary perfusion
FIGURE 6-9
Schematic presentation of the potential pathways incriminated in
the pathogenesis of chronic TIN caused by primary tubular injury
(dark boxes) or secondary to glomerular disease (light boxes). The
mechanism by which TIN is mediated remains to be elucidated.
Chronic tubular epithelial cell injury appears to be pivotal in the
process. The injury may be direct through cytotoxicity or indirect
by the induction of an inflammatory or immunologic reaction.
Studies in experimental models and humans provide compelling
evidence for a role of immune mechanisms. The infiltrating lymphocytes have been shown to be activated immunologically. It is the
inappropriate release of cytokines by the infiltrating cells and loss
of regulatory balance of normal cellular regeneration that results in
increased fibrous tissue deposition and tubular atrophy. Another
potential mechanism of injury is that of increased tubular ammoniagenesis by the residual functioning but hypertrophic tubules. Increased
tubular ammoniagenesis contributes to the immunologic injury by
activating the alternate complement pathway.
Altered glomerular permeability with consequent proteinuria
appears to be important in the development of TIN in primary
glomerular diseases. By the same token, the proteinuria that
develops late in the course of primary TIN may contribute to
the tubular cell injury and aggravate the course of the disease.
In primary vascular diseases TIN has been attributed to ischemic
injury. In fact, hypertension is probably the most common cause of
TIN. The vascular lesions that develop late in the course of primary
TIN, in turn, can contribute to the progression of TIN. (From
Eknoyan [3]; with permission.)
Progressive loss of renal function
ROLE OF TUBULAR EPITHELIAL CELLS

Chemoattractant
cytokines
Pro-inflammatory
cytokines
Monocyte chemoattractant peptide-1
Interleukin-6 (IL-6), IL-8
Osteopontin
Platelet-derived growth
factor-
Chemoattractant
lipids
Granulocyte -macrophage
colony-stimulating factor
Endothelin-1
Transforming growth
factor-1
RANTES
Tumor necrosis factor-

From Palmer [4]; with permission.
Cell surface markers
Matrix proteins
Human leukocyte antigen

class II
Collagen I, III, IV
Intercellular adhesion
molecule-1
Vascular cell adhesion
molecule-1
Laminin, fibronectin
FIGURE 6-10
The infiltrating interstitial cells contribute
to the course TIN. However, increasing
evidence exists for a primary role of the
tubular epithelial cells in the recruitment
of interstitial infiltrating cells and in perpetuation of the process. Injured epithelial
cells secrete a variety of cytokines that
have both chemoattractant and pro-inflammatory properties. These cells express a
number of cell surface markers that enable
them to interact with infiltrating cells.
Injured epithelial cells also participate in
the deposition of increased interstitial
matrix and fibrous tissue. Listed are
cytokines, cell surface markers, and matrix
components secreted by the renal tubular
cell that may play a role in the development of tubulointerstitial disease.
6.7
Role of Infiltrating Cells
FIGURE 6-11
TIN showing early phase with focal (A) and more severe and diffuse
(B) interstitial inflammatory cell infiltrates. Late phase showing
thickened tubular basement membrane, distorted tubular shape,
and cellular infiltration of the tubules, called tubulitis (C). The
extent and severity of interstitial cellular infiltrates show a direct
correlation with the severity of tubular atrophy and interstitial
fibrosis. Experimental studies show the sequential accumulation of
T cells and monocytes after the initial insult. Accumulation of these
cells implicates their important role both in the early inflammatory
stage of the disease and in the progression of subsequent injury.
Immunohistologic examination utilizing monoclonal antibodies,
coupled with conventional and electron microscopy, indicates that
most of the mononuclear inflammatory cells comprising renal
interstitial infiltrates are T cells. These T cells are immunologically
activated in the absence of any evidence of tubulointerstitial immune
deposits, even in classic examples of immune complexmediated
diseases such as systemic lupus erythematosus. The profile of
immunocompetent cells suggests a major role for cell-mediated
immunity in the tubulointerstitial lesions. The infiltrating cells
may be of the helper-inducer subset or the cyotoxic-suppressor
subset, although generally there seems to be a selective prevalence
for the former variety. Lymphocytes that are peritubular and are
seen invading the tubular epithelial cells, so-called tubulitis, are
generally of the cytotoxic (CD8+) variety.
The interstitial accumulation of monocytes and macrophages
involves osteopontin (uropontin). Osteopontin is a secreted cell
attachment glycoprotein whose messenger RNA expression becomes
upregulated, and its levels are increased at the sites of tubular injury
in proportion to the severity of tubular damage. The expression of
other cell adhesion molecules (intercellular adhesion molecule-1,
vascular cellular adhesion molecule-1, and E-selectin) also is increased
at the sites of tubular injury. This increased expression may contribute
to the recruitment of mononuclear cells and increase the susceptibility
of renal cells to cell-mediated injury.
Fibroblastic (type I) interstitial cells, which normally produce and
maintain the extracellular matrix, begin to proliferate in response
to injury. They increase their well-developed rough endoplasmic
reticulum and acquire smooth muscle phenotype (myofibroblast).
Growth kinetic studies of these cells reveal a significant increase in
their proliferating capacity and generation time, indicating hyperproliferative growth.
6.8
Mechanisms Involved in Renal Interstitial Fibrosis
Macrophage
Virus
TNF4
IL 1
TGF3
PDGF
GMCSF
Protein
Sig
na
l
Lymphocyte
IL 2
IFN
l
na
Sig
DO
HLA DR
DP
IL 4
Proliferating TH-Cell
Proliferating B-cell
Epithelial cell
IL 1
ICAM1
Proximal
tubulus
PDGF
IL1
IL6
IL7
IL8
IIFN
GM-CSF
G-CSF
M-CSF
Factor x
P (30/7.3)
Proliferation
Fibroblast
Differentiation
MF I MF III
PMF IV PMF VI
Synthesis and Secretion

of collagen
Fibrosin
P 53/6.1
FIGURE 6-12
Expression of human leukocyte antigen class II and adhesion
molecules released by injured tubular epithelial cells, as well
as by infiltrating cells, modulate and magnify the process to
repair the injury (Figure 6-10). When the process becomes unresponsive to controlling feedback mechanisms, fibroblasts proliferate and increase fibrotic matrix deposition. The precise mechanism of TIN remains to be identified. A number of pathogenetic
pathways have been proposed to operate at different stages of the

disease process. Each of these individual pathways usually is part
of a recuperative process that works in concert in response to
injury. However, it is the loss of their controlling feedback in
chronic TIN that seems to account for the altered balance and
results in persistent cellular infiltrates, progressive fibrosis, and
tubular degeneration.
6.9
Patterns of Tubular Dysfunction

PATTERNS OF TUBULAR DYSFUNCTION IN CHRONIC TIN
Site of injury
Cause
Tubular dysfunction
Proximal tubule
Heavy metals
Multiple myeloma
Cystinosis
Decreased reabsorption of sodium, bicarbonate, glucose,

uric acid, phosphate, amino acids
Distal tubule
Granulomatous diseases
Hereditary diseases
Hypercalcemia
Sickle hemoglobinopathy
Amyloidosis
Decreased secretion of hydrogen, potassium

Decreased reabsorption of sodium
Medulla
Uric acid disorders
Hypercalcemia
Infection
Hereditary disorders
Granulomatous diseases
Decreased ability to concentrate urine

Papilla
Diabetes mellitus
Infection
Transplanted kidney
Decreased ability to concentrate urine

Cortex
FIGURE 6-13
The principal manifestations of TIN are those of tubular dysfunction. Because of the focal
nature of the lesions that occur and the segmental nature of normal tubular function, the
pattern of tubular dysfunction that results varies, depending on the major site of injury.
The extent of damage determines the severity of tubular dysfunction. The hallmarks of
glomerular disease (such as salt retention, edema, hypertension, proteinuria, and hematuria) are characteristically absent in the early phases of chronic TIN. The type of insult
determines the segmental location of injury. For example, agents secreted by the organic
pathway in the pars recta (heavy metals) or reabsorbed in the proximal tubule (light chain
proteins) cause predominantly proximal tubular lesions. Depositional disorders (amyloidosis
and hyperglobulinemic states) cause predominantly distal tubular lesions. Insulting agents
that are affected by the urine concentrating mechanism (analgesics and uric acid) or
medullary tonicity (sickle hemoglobinopathy) cause medullary injury.
The tubulointerstitial lesions are localized

either to the cortex or medulla. Cortical
lesions mainly affect either the proximal or
distal tubule. Medullary lesions affect the
loop of Henle and the collecting duct. The
change in the normal function of each of
these affected segments then determines the
manifestations of tubular dysfunction.
Essentially, the proximal nephron segment
reabsorbs the bulk of bicarbonate, glucose,
amino acids, phosphate, and uric acid.
Changes in proximal tubular function,
therefore, result in bicarbonaturia (proximal
renal acidosis), 2-microglobinuria, glucosuria (renal glucosuria), aminoaciduria,
phosphaturia, and uricosuria.
The distal nephron segment secretes
hydrogen and potassium and regulates the
final amount of sodium chloride excreted.
Lesions primarily affecting this segment,
therefore, result in the distal form of renal
tubular acidosis, hyperkalemia, and salt
wasting. Lesions that primarily involve the
medulla and papilla disproportionately
affect the loops of Henle, collecting ducts,
and the other medullary structures essential
to attaining and maintaining medullary
hypertonicity. Disruption of these structures, therefore, results in different degrees
of nephrogenic diabetes insipidus and clinically manifests as polyuria and nocturia.
Although this general framework is useful in localizing the site of injury, considerable overlap may be encountered clinically,
with different degrees of proximal, distal,
and medullary dysfunction present in the
same individual. Additionally, the ultimate
development of renal failure complicates
the issue further because of the added
effect of urea-induced osmotic diuresis
on tubular function in the remaining
nephrons. In this later stage of TIN, the
absence of glomerular proteinuria and the
more common occurrence of hypertension
in glomerular diseases can be helpful in
the differential diagnosis.
6.10
Correlates of Tubular Dysfunction

with Severity of Chronic TIN
1200
160
Chronic GN
Acute GN
PTIN
Nephrosclerosis
140
1000
900
Maximal osmolality, mOs/kg
120
Inulin clearance, mL/min
Chronic GN
Acute GN
PTIN
Nephrosclerosis
1100
100
80
60
800
700
600
500
400
300
40
200
20
100
0
0
0
4 5
6 7
8 9
Interstitial disease (total score)
10
11
Chronic GN
Acute GN
PTIN
Nephrosclerosis
100
Ammonium excretion, Eq/min
90
80
70
60
50
40
30
20
10
0
0
4 5
6 7
8 9
10
11
10
11
12
FIGURE 6-14
Relationship of inulin clearance (A), maximum urine concentration
(B), and ammonium excretion in response to an acute acid load (C)
to the severity of tubulointerstitial nephritis. A close correlation
exists between the severity of chronic TIN and impaired renal
tubular and glomerular function. Repeated evaluations of kidney
biopsy for the extent of tubulointerstitial lesions have shown a
close correlation with renal function test results in tests performed
before biopsy. These tests include those for inulin clearance, maximal
ability to concentrate the urine, and ability to acidify the urine. This
correlation has been validated in a variety of renal diseases, including
primary and secondary forms of chronic TIN. (From Shainuck and
coworkers [5]; with permission.)
1200
110
12
12
6.11
Probability of maintaining renal function, %
Correlates of Chronic TIN with Progressive Renal Failure

FIGURE 6-15
Effect on long-term prognosis of the presence of cortical chronic
tubulointerstitial nephritis in patients with mesangioproliferative
glomerulonephritis (n = 455), membranous nephropathy (n = 334),
and membranoproliferative glomerulonephritis (n = 220). The
extent of tubulointerstitial nephritis correlates not only with altered
glomerular and tubular dysfunction at the time of kidney biopsy
but also provides a prognostic index of the progression rate to endstage renal disease. As shown, the presence of interstitial fibrosis
on the initial biopsy exerts a significant detrimental effect on the
progression rate of renal failure in a variety of glomerular diseases.
(From Eknoyan [3]; with permission.)
100
80
Normal interstitium
60
40
20
0
0
10
12
14
16
Follow-up, y
Drugs
Analgesic Nephropathy
Acetaminophen Metabolism
nOHpacetophenetidine
pphenetidine
Methhemoglobin
Sulfhemoglobin
Cytochrome
P450
Reactive toxic
metabolites
Phenactin
pacetophenetidine
Glucoronide
sulfate
Paracetamol
nacetylpaminophenol
Glutathione
Covalent binding to
cellular sulfhydryl
Glutathione
conjugate
Cell death
Mercapturic
acid
FIGURE 6-16
Metabolism of acetaminophen and its excretion by the kidney. Prolonged exposure to drugs
can cause chronic TIN. Although a number of drugs (eg, lithium, cyclosporine, cisplatin,
and nitrosoureas) have been implicated, the more commonly responsible agents are analgesics. As a rule, the lesions of analgesic nephropathy develop in persons who abuse analgesic combinations (phenacetin, or its main metabolite acetaminophen, plus aspirin, with or
without caffeine). Experimental evidence indicates that phenacetin, or acetaminophen, plus
aspirin taken alone are only moderately nephrotoxic and only at massive doses, but that the
lesions can be more readily induced when these drugs are taken together. In all experimental
studies the extent of renal injury has been dose-dependent and, when examined, water
diuresis has provided protection from analgesic-induced renal injury. Relative to plasma
levels, both acetaminophen (paracetamol)
and its excretory conjugate attain significant
(fourfold to fivefold) concentrations in the
medulla and papilla, depending on the state
of hydration of the animal studied. The
toxic effect of these drugs apparently is
related to their intrarenal oxidation to reactive intermediates that, in the absence of
reducing substances such as glutathione,
become cytotoxic by virtue of their capacity
to induce oxidative injury. Salicylates also
are significantly (sixfold to thirteenfold
above plasma levels) concentrated in the
medulla and papilla, where they attain a
level sufficient to uncouple oxidative phosphorylation and compromise the ability of
cells to generate reducing substances. Thus,
both agents attain sufficient renal medullary
concentration to individually exert a detrimental and injurious effect on cell function,
which is magnified when they are present
together. By reducing the medullary tonicity, and therefore the medullary concentration of drug attained, water diuresis protects from analgesic-induced cell injury. A
direct role of analgesic-induced injury can
be adduced from the improvement of renal
function that can occur after cessation of
analgesic abuse.
6.12
Pathogenesis of renal lesion associated

with analgesic abuse
Cortex normal
Outer medula patchy tubular damage
a. tubular dilatation
b. increased interstitial tissue
c. casts: pigment
Stage I
Papilla possible microscopic changes
Cortex normal
Outer medula increase in changes
Papilla necrosis and atrophy
attached or separated
Stage II
Cortex
a. atrophy area overlying
necrotic papilla
b. hypertrophy
Papilla atrophic, necrotic
Stage III
FIGURE 6-17
Course of the renal lesions in analgesic nephropathy. The intrarenal
distribution of analgesics provides an explanation for the medullary
location of the pathologic lesions of analgesic nephropathy. The initial
lesions are patchy and consist of necrosis of the interstitial cells, thin
limbs of the loops of Henle, and vasa recta of the papilla. The collecting ducts are spared. The quantities of tubular and vascular
basement membrane and ground substance are increased. At this
stage the kidneys are normal in size and no abnormalities have
occurred in the renal cortex. With persistent drug exposure the
changes extend to the outer medulla. Again, the lesions are initially
patchy, involving the interstitial cells, loops of Henle, and vascular
bundles. With continued analgesic abuse, the severity of the inner
medullary lesions increases with sclerosis and obliteration of the
capillaries, atrophy and degeneration of the loops of Henle and
collecting ducts, and the beginning of calcification of the necrotic
foci. Ultimately, the papillae become entirely necrotic, with sequestration and demarcation of the necrotic tissue. The necrotic papillae
may then slough and are excreted into the urine or remain in situ,
where they atrophy further and become calcified. Cortical scarring,
characterized by interstitial fibrosis, tubular atrophy, and periglomerular fibrosis, develops over the necrotic medullary segments.
The medullary rays traversing the cortex are usually spared and
become hypertrophic, thereby imparting a characteristic cortical
nodularity to the now shrunken kidneys. Visual observation of these
configurational changes by computed tomography scan can be
extremely useful in the diagnosis of analgesic nephropathy.
Size
Right kidney
RV
RA
Left kidney
RA
Spine
Appearance
Bumpy contours
Papillary calcifications
0
B
12
35
Number of indentations
>5
D
FIGURE 6-18
Computed tomography (CT) imaging criteria for diagnosing analgesic nephropathy. Renal
size (A) is considered decreased if the sum of a and b (panels A and B) is less than 103 mm
in men and 96 mm in women. Bumpy contours are considered to be present if at least

three indentations are evident (panels B and
C). The scan can reveal papillary calcifications (panels B and D). Visual observation
of the configurational changes illustrated
in Figure 6-18 can be extremely useful in
diagnosing the scarred kidney in analgesic
nephropathy. A series of careful studies
using CT scans without contrast material
have provided imaging criteria for the diagnosis of analgesic nephropathy. Validation
of these criteria currently is underway by a
study at the National Institutes of Health.
From studies comparing analgesic abusers
to persons in control groups, it has been
shown that a decrease in kidney size and
bumpy contours of both kidneys provide a
diagnostic sensitivity of 90% and a specificity
of 95%. The additional finding of evidence of
renal papillary necrosis provides a diagnostic
sensitivity of 72% and specificity of 97%, giving a positive predictive value of 92%. RA
renal artery; RV renal vein. (From DeBroe
and Elseviers [6]; with permission.)
6.13
CLINICAL FEATURES
a
b
3
a
b
b
c
Female predominance, 6085%

Age, >30 y
Personality disorders: introvert, dependent, anxiety, neurosis, family instability
acortical nephron
Addictive habits: smoking, alcohol, laxatives, psychotropics, sedatives

Causes of analgesic dependency: headache, 4060%; mood, 630%; musculoskeletal
pain, 2030%
FIGURE 6-19
Certain personality features and clinical findings characterize patients
prone to analgesic abuse. These patients tend to deny analgesic use
on direct questioning; however, their history can be revealing. In all
cases, a relationship exists between renal function and the duration, intensity, and quantity of analgesic consumed. The magnitude
of injury is related to the quantity of analgesic ingested chronically
over years. In persons with significant renal impairment, the average dose ingested has been estimated at about 10 kg over a mean
period of 13 years. The minimum amount of drug consumption
that results in significant renal damage is unknown. It has been
estimated that a cumulative dose of 3 kg of the index compound,
or a daily ingestion of 1 g/d over 3 years or more, is a minimum
that can result in detectable renal impairment.
bjuxta medullary nephron
cmidcortical nephron
FIGURE 6-20
Diagram of cortical and juxtamedullary nephrons in the normal kidney (1). Papillary necrosis (2) and sloughing (3) result in loss of
juxtamedullary nephrons. Cortical nephrons are spared, thereby
preserving normal renal function in the early stages of the disease.
The course of analgesic nephropathy is slowly progressive, and
deterioration of renal function is insidious. One reason for these
characteristics of the disease is that lesions beginning in the papillary tip affect only the juxtamedullary nephrons, sparing the cortical nephrons. It is only when the lesions are advanced enough to
affect the whole medulla that the number of nephrons lost is sufficient to result in a reduction in filtration rate. However, renal
injury can be detected by testing for sterile pyuria, reduced concentrating ability, and a distal acidifying defect. These features may be
evident at levels of mild renal insufficiency and become more pronounced and prevalent as renal function deteriorates. Proximal
tubular function is preserved in patients with mild renal insufficiency
but can be abnormal in those with more advanced renal failure.
Cyclosporine
A
FIGURE 6-21
A, Chronic TIN caused by cyclosporine. The arrow indicates the
characteristic hyaline-type arteriolopathy of cyclosporine nephrotoxicity. B, Patchy nature of chronic TIN caused by cyclosporine.
Note the severe TIN on the right adjacent to an otherwise intact
area on the left. Tubulointerstitial nephritis has emerged as the
most serious side effect of cyclosporine. Cyclosporine-mediated
vasoconstriction of the cortical microvasculature has been implicated
in the development of an occlusive arteriolopathy and tubular
B
epithelial cell injury. Whereas these early lesions tend to be
reversible with cessation of therapy, an irreversible interstitial
fibrosis and mononuclear cellular infiltrates develop with prolonged use of cyclosporine, especially at high doses. The irreversible nature of TIN associated with the use of cyclosporine
and its attendant reduction in renal function have raised concerns
regarding the long-term use of this otherwise efficient immunosuppressive agent.
6.14
Heavy Metals
Lead Nephropathy
FIGURE 6-22
Lead nephropathy. Arrows indicate the characteristic intranuclear
inclusions. Exposure to a variety of heavy metals results in development of chronic TIN. Of these metals, the more common and
clinically important implicated agent is lead. Major sources of
exposure to lead are lead-based paints; lead leaked into food during storage or processing, particularly in illegal alcoholic beverages
(moonshine); and increasingly, through environmental exposure
(gasoline and industrial fumes). This insidious accumulation of lead
in the body has been implicated in the causation of hyperuricemia,
hypertension, and progressive renal failure. Gout occurs in over
half of cases. Blood levels of lead usually are normal. The diagnosis
is established by demonstrating increased levels of urinary lead
after infusion of 1 g of the chelating agent erthylenediamine
tetraacetic acid (EDTA).
The renal lesions of lead nephropathy are those of chronic TIN.
Cases examined early, before the onset of end-stage renal disease,
show primarily focal lesions of TIN with relatively little interstitial
cellular infiltrates. In more advanced cases the kidneys are fibrotic
and shrunken. On microscopy, the kidneys show diffuse lesions of
TIN. As expected from the clinical features, hypertensive vascular
changes are prominent.
Other heavy metals associated with TIN are cadmium, silicon,
copper, bismuth, and barium. Sufficient experimental evidence and
some weak epidemiologic evidence suggest a possible role of organic
solvents in the development of chronic TIN.
Ischemic Vascular Disease

Hypertensive Nephrosclerosis
FIGURE 6-23
Chronic TIN associated with hypertension. The arrows indicate
arterioles and small arteries with thickened walls. Tubular degeneration, interstitial fibrosis, and mononuclear inflammatory cell infiltration are part of the degenerative process that affects the kidneys
in all vascular diseases involving the intrarenal vasculature with
any degree of severity as to cause ischemic injury. Rarely, if the
insult is sudden and massive (such as in fulminant vasculitis), the
lesions are those of infarction and acute deterioration of renal
function. More commonly, the vascular lesions develop gradually
and go undetected until renal insufficiency supervenes. This chronic
form of TIN accounts for the tubulointerstitial lesions of arteriolar
nephrosclerosis in persons with hypertension. Ischemic vascular
changes also contribute to the lesions of TIN in patients with diabetes, sickle cell hemoglobinopathy, cyclosporine nephrotoxicity,
and radiation nephritis.
6.15
FIGURE 6-24
Gross appearance of the kidney as a result of arteriolonephrosclerosis, showing the granular and scarified cortex.
Obstruction
Chronic TIN secondary to vesicoureteral reflux (VUR). Clearly
demonstrated is an area that is fairly intact (lower left corner) adjacent to one that shows marked damage. Urinary tract obstruction,
whether congenital or acquired, is a common cause of chronic TIN.
Clinically, superimposed infection plays a secondary, adjunctive, and
definitely aggravating role in the progressive changes of TIN. However, the entire process can occur in the absence of infection.
As clearly demonstrated in experimental models of obstruction,
mononuclear inflammatory cell infiltration is one of the earliest
responses of the kidney to ureteral obstruction. The infiltrating
cells consist of macrophages and suppressor-cytotoxic lymphocytes.
The release of various cytokines by the infiltrating cells of the
hydronephrotic kidney appears to exert a significant modulating
role in the transport processes and hemodynamic changes seen
early in the course of obstruction. With persistent obstruction,
changes of chronic TIN set in within weeks. Fibrosis gradually
becomes prominent.
FIGURE 6-26
Gross appearance of a hydronephrotic kidney caused by
vesicoureteral reflux.
6.16
Obstructive Nephropathy
FIGURE 6-27
Glomerular lesion of advanced chronic TIN secondary to vesicoureteral
reflux in a patient with massive proteinuria. Note the segmental
sclerosis of the glomerulus and the reactive proliferation of the
visceral epithelial cells. In persons with obstructive nephropathy,
the onset of significant proteinuria (>2g/d) is an ominous sign of
progressive renal failure. As a rule, most of these patients will have
coexistent hypertension, and the renal vasculature will show changes
of hypertensive arteriolosclerosis. The glomerular changes are ischemic
in nature. In those with significant proteinuria, the lesions are those
of focal and segmental glomerulosclerosis and hyalinosis. The
affected glomeruli commonly contain immunoglobulin M and C3
complement on immunofluorescent microscopy. The role of an
immune mechanism remains unclear. Autologous (Tamm-Horsfall
protein and brush-border antigen) or bacterial antigen derivatives
have been incriminated. Adaptive hemodynamic changes (hyperfiltration) in response to a reduction in renal mass, by the glomeruli
of remaining intact nephrons of the hydronephrotic kidney, also
have been implicated.
Hematopoietic Diseases
Sickle Hemoglobinopathy
FIGURE 6-28
The kidney in sickle cell disease. Note the tubular deposition of
hemosiderin. The principal renal lesion of hemoglobinopathy S is
that of chronic TIN. By far more prevalent and severe in patients

with sickle cell disease, variable degrees of TIN also are common
in those with the sickle cell trait, sickle cellhemoglobin C disease,
or sickle cellthalassemia disease. The predisposing factors that lead
to a propensity of renal involvement are the physicochemical properties of hemoglobin S that predispose its polymerization in an
environment of low oxygen tension, hypertonicity, and low pH.
These conditions are characteristic of the renal medulla and therefore
are conducive to the intraerythrocyte polymerization of hemoglobin S.
The consequent erythrocyte sickling accounts for development of
the typical vascular occlusive lesions. Although some of these changes
occur in the cortex, the lesions begin and are predominantly located
in the inner medulla, where they are at the core of the focal scarring
and interstitial fibrosis. These lesions account for the common
occurrence of papillary necrosis.
Examples of tubular functional abnormalities common and detectable
early in the course of the disease are the following: impaired concentrating ability, depressed distal potassium and hydrogen secretion,
tubular proteinuria, and decreased proximal reabsorption of phosphate, and increased secretion of uric acid and creatinine.
6.17
Hematologic Diseases
Plasma Cell Dyscrasias

A, Myeloma cast nephropathy. The arrow indicates a multinucleated
giant cell. B, Light chain deposition disease. Note the changes indicative of chronic TIN and light chain deposition along the tubular
basement membrane (dark purple). C, Immunofluorescent stain
for light chain deposition along the tubular basement membrane.
The renal complications of multiple myeloma are a major risk factor
in the morbidity and mortality of this neoplastic disorder. Whereas
the pathogenesis of renal involvement is multifactorial (hypercalcemia and hyperuricemia), it is the lesions that result from the
excessive production of light chains that cause chronic TIN. These
lesions are initiated by the precipitation of the light chain dimers in
the distal tubules and result in what has been termed myeloma cast
nephropathy. The affected tubules are surrounded by multinucleated
giant cells. Adjoining tubules show varying degrees of atrophy. The
propensity of light chains to lead to myeloma cast nephropathy
appears to be related to their concentration in the tubular fluid,
the tubular fluid pH, and their structural configuration. This
propensity accounts for the observation that increasing the flow
rate of urine or its alkalinization will prevent or reverse the casts
in their early stages of formation.
Direct tubular toxicity of light chains also may contribute to
tubular injury. Light chains appear to be more injurious than are
light chains. Binding of human and light chains to human
and rat proximal tubule epithelial cell brush-border membrane has
been demonstrated. Epithelial cell injury associated with the
absorption of these light chains in the proximal tubules has been
implicated in the pathogenesis of cortical TIN. Another mechanism
relates to the perivascular deposition of paraproteins, either as
amyloid fibrils that are derived from chains or as fragments of
light chains that are derived from kappa chains, and produce the
so-called light chain deposition disease.
Of the various lesions, myeloma cast nephropathy appears to be
the most common, being observed at autopsy in one third of cases,
followed by amyloid deposition, which is present in 10% of cases.
Light chain deposition is relatively rare, being present in less than
5% of cases.
6.18
Metabolic Disorders
Hyperuricemia
A
FIGURE 6-30
A, Intratubular deposits of uric acid. B, Gouty tophus in the renal
medulla. The kidney is the major organ of urate excretion and a
primary target organ affected in disorders of its metabolism. Renal
lesions result from crystallization of urate in the urinary outflow
tract or the renal parenchyma. Depending on the load of urate,
one of three lesions result: acute urate nephropathy, uric acid
nephrothiasis, or chronic urate nephropathy. Whereas any of these
lesions produce tubulointerstitial lesions, it is those of chronic
urate nephropathy that account for most cases of chronic TIN.
The principal lesion of chronic urate nephropathy is due to
deposition of microtophi of amorphous urate crystals in the interstitium, with a surrounding giant-cell reaction. An earlier change,
however, probably is due to the precipitation of birefringent uric
acid crystals in the collecting tubules, with consequent tubular
obstruction, dilatation, atrophy, and interstitial fibrosis. The renal
injury in persons who develop lesions has been attributed to
B
hyperacidity of their urine caused by an inherent abnormality in
the ability to produce ammonia. The acidity of urine is important
because uric acid is 17 times less soluble than is urate. Therefore,
uric acid facilitates precipitation in the distal nephron of persons
who do not overproduce uric acid but who have a persistently
acidic urine.
The previous notion that chronic renal disease was common in
patients with hyperuricemia is now considered doubtful in light of
prolonged follow-up studies of renal function in persons with
hyperuricemia. Renal dysfunction could be documented only when
the serum urate concentration was more than 10 mg/dL in women
and more than 13 mg/dL in men for prolonged periods. The deterioration of renal function in persons with hyperuricemia of a lower
magnitude has been attributed to the higher than expected occurrence of concurrent hypertension, diabetes mellitus, abnormal lipid
metabolism, and nephrosclerosis.
6.19
Hyperoxaluria

A, Calcium oxalate crystals (arrow) seen on light microscopy. B, Dark
field microscopy. When hyperoxaluria is sudden and massive (such as
after ethylene glycol ingestion) acute renal failure develops. Otherwise, in most cases of hyperoxaluria the overload is insidious and
chronic. As a result, interstitial fibrosis, tubular atrophy, and dilation

result in chronic TIN with progressive renal failure. The propensity
for recurrent calcium oxalate nephrolithiasis and consequent obstructive uropathy contribute to the tubulointerstitial lesions.
Granulomatous Diseases
Malacoplakia
3
FIGURE 6-32
Schematic representation of the forms and course of renal involvement by malacoplakia:
1, normal kidney; 2, enlarged kidney resulting from interstitial nephritis without nodularity;
3, unifocal nodular involvement; 4, multifocal nodular involvement; 5, abscess formation
with perinephric spread of malacoplakia; 6, cystic lesions; and 7, atrophic multinodular
kidney after treatment. Interstitial granulomatous reactions are a rare but characteristic
hallmark of certain forms of tubulointerstitial

disease. The best-known form is that of
sarcoidosis. Interstitial granulomatous reactions also have been noted in renal tuberculosis, xanthogranulomatous pyelonephritis,
renal malacoplakia, Wegeners granulomatosis, renal candidiasis, heroin abuse,
hyperoxaluria after jejunoileal bypass
surgery, and an idiopathic form in association with anterior uveitis.
The inflammatory lesions of malacoplakia
principally affect the urinary bladder but
may involve other organs, most notably the
kidneys. The kidney lesions may be limited
to one focus or may be multifocal. In three
fourths of cases the renal involvement is
multifocal, and in one third of cases both
kidneys are involved. The lesions are nodular,
well-demarcated, and variable in size. They
may coalesce, developing foci of suppuration that may become cystic or calcified.
The lesions usually are located in the cortex
but may be medullary and result in papillary
necrosis. (From Dobyan and coworkers [7];
with permission.)
6.20
Endemic Diseases
FIGURE 6-33
Hemorrhagic TIN associated with Hantavirus infection. Two
endemic diseases in which tubulointerstitial lesions are a predominant component are Balkan nephropathy and nephropathia epidemica. Endemic Balkan nephropathy is a progressive chronic
tubulointerstitial nephritis whose occurrence is mostly clustered
in a geographic area bordering the Danube River as it traverses

Romania, Bulgaria, and the former Yugoslavia. The cause of
Balkan nephropathy is unknown; however, it has been attributed
to genetic factors, heavy metals, trace elements, and infectious
agents. The disease evolves in emigrants from endemic regions,
suggesting a role for inheritance or the perpetuation of injury
sustained before emigration.
Initially thought to be restricted to Scandinavian countries, and
thus termed Scandinavian acute hemorrhagic interstitial nephritis,
Nephropathia epidemica has been shown to have a more universal
occurrence. It therefore has been more appropriately renamed hemorrhagic fever with renal syndrome. As a rule the disease presents
as a reversible acute tubulointerstitial nephritis but can progress to
a chronic form. It is caused by a rodent-transmitted virus of the
Hantavirus genus of the Bunyaviridae family, the so-called Hantaan
virus. Humans appear to be infected by respiratory aerosols contaminated by rodent excreta. Antibodies to the virus are detected in
the serum, and viruslike structures have been demonstrated in the
kidneys of persons infected with the virus.
Tubulointerstitial nephropathy caused by viral infection also has
been reported in polyomavirus, cytomegalovirus, herpes simplex
virus, human immunodeficiency virus, infectious mononucleosis,
and Epstein-Barr virus.
Hereditary Diseases
Hereditary Nephritis
A
FIGURE 6-34
A, Interstitial foam cells in Alports syndrome. B, Late phase Alports
syndrome showing chronic TIN and glomerular changes in a patient
with massive proteinuria. Tubulointerstitial lesions are a prominent
component of the renal pathology of a variety of hereditary diseases
of the kidney, such as medullary cystic disease, familial juvenile
nephronophthisis, medullary sponge kidney, and polycystic kidney
disease. The primary disorder of these conditions is a tubular defect
that results in the cystic dilation of the affected segment in some
patients. Altered tubular basement membrane composition and
B
associated epithelial cell proliferation account for cyst formation. It
is the continuous growth of cysts and their progressive dilation that
cause pressure-induced ischemic injury, with consequent TIN of the
adjacent renal parenchyma.
Tubulointerstitial lesions also are a salient feature of inherited
diseases of the glomerular basement membrane. Notable among
them are those of hereditary nephritis or Alports syndrome, in
which a mutation in the encoding gene localized to the X chromosome results in a defect in the -5 chain of type IV collagen.
Papillary Necrosis
A
FIGURE 6-35
A, Renal papillary necrosis. The arrow points to the
region of a sloughed necrotic papilla. B, Whole mount of
a necrotic papilla. Arrows delineate focal necrosis principally affecting the medullary inner stripe. Renal papillary
necrosis (RPN) develops in a variety of diseases that
cause chronic tubulointerstitial nephropathy in which the
lesion is more severe in the inner medulla. The basic
lesion affects the vasculature with consequent focal or
diffuse ischemic necrosis of the distal segments of one or
more renal pyramids. In the affected papilla, the sharp
demarcation of the lesion and coagulative necrosis seen
in the early stages of the disease closely resemble those of
infarction. The fact that the necrosis is anatomically limited to the papillary tips can be attributed to a variety of
features unique to this site, especially those affecting the
vasculature. The renal papilla receives its blood supply
from the vasa recta. Measurements of medullary blood
flow notwithstanding, it should be noted that much of
the blood flow in the vasa recta serves the countercurrent exchange mechanism. Nutrient blood supply is provided by small capillary vessels that originate in each
given region. The net effect is that the blood supply to
the papillary tip is less than that to the rest of the medulla, hence its predisposition to ischemic necrosis.
The necrotic lesions may be limited to only a few of
the papillae or may involve several of the papillae in
B
either one or both kidneys. The lesions are bilateral in
most patients. In patients with involvement of one kidney at the time of initial presentation, RPN will develop in the other kidney within 4 years, which is not
unexpected because of the systemic nature of the diseases associated with RPN. RPN may be unilateral in
patients in whom predisposing factors (such as infection and obstruction) are limited to one kidney.
Azotemia may be absent even in bilateral papillary
necrosis, because it is the total number of papillae
involved that ultimately determines the level of renal
insufficiency that develops. Each human kidney has an
average of eight pyramids, such that even with bilateral
RPN affecting one papilla or two papillae in each kidney, sufficient unaffected renal lobules remain to maintain an adequate level of renal function.
As a rule, RPN is a disease of an older age group,
the average age of patients being 53 years. Nearly half
of cases occur in persons over 60 years of age. More
than 90% of cases occur in persons over 40 years of
age, except for those caused by sickle cell hemoglobinopathy. RPN is much less common in children, in
whom the chronic conditions associated with papillary necrosis are rare. However, RPN does occur in
children in association with hypoxia, dehydration,
and septicemia.
6.21
6.22
Total Papillary Necrosis

Renal Papillary Necrosis Papillary Form
Normal
Lesion
Pyelogram
Early necrosis, mucosa

normal, papilla swollen.
Normal calyx
Progressive necrosis,
swelling, mucosal loss.
Irregular or
fuzzy calyx
Sequestrian of necrotic
area.
Sinus or
"Arc Shadow"
Sinus formation begins.

Sinus surrounds
sequestrum.
"Ring Shadow"
Sequestrum extruded
or resorbed.
"Clubbing"
"Clubbed calyx"
"Caliectasis"
Sequestrum calcifies.
"Ring Shadow"
Obstruction
Extruded sequestrum
FIGURE 6-36
Schematic of the progressive stages of the papillary form of renal papillary necrosis and
their associated radiologic changes seen on intravenous pyelography. Papillary necrosis
occurs in one of two forms. In the medullary form, also termed partial papillary necrosis,
the inner medulla is affected; however, the papillary tip and fornices remain intact. In the
papillary form, also termed total papillary necrosis, the calyceal fornices and entire papillary
tip are necrotic. In total papillary necrosis shown here, the lesion is characterized from the
outset by necrosis, demarcation, and sequestration of the papillae, which ultimately slough
Renal Papillary Necrosis Medullary Form

Normal
Lesion
Pyelogram
Early focal, necrosis

of medullary inner
stripe.
Normal calyx
Progressive necrosis,
coalescence of necrotic
areas. Swelling. Mucosa
normal.
Normal calyx
Mucosal break.
Sequestration
and sinus formation.
Sinus
Progressive sequestration,
extrusion, or resorption
of necrotic tissue.
Irregular sinus
Healing. Irregular
medullary cavity with
communicating
sinus tract.
Irregular
medullary
cavity
into the pelvis and may be recovered in the

urine. In most of these cases, however, the
necrotic papillae are not sloughed but are
either resorbed or remain in situ, where
they becomes calcified or form the nidus of
a calculus. In these patients, excretory radiologic examination and computed tomography scanning are diagnostic. Unfortunately,
these changes may not be evident until the
late stages of RPN, when the papillae
already are shrunken and sequestered. In
fact, even when the papillae are sloughed
out, excretory radiography can be negative.
The passage of sloughed papillae is
associated with lumbar pain, which is
indistinguishable from ureteral colic of
any cause and is present in about half of
patients. Oliguria occurs in less than 10%
of patients. A definitive diagnosis of RPN
can be made by finding portions of necrotic
papillae in the urine. A deliberate search
should be made for papillary fragments in
urine collected during or after attacks of
colicky pain of all suspected cases, by
straining the urine through filter paper or a
piece of gauze. The separation and passage
of papillary tissue may be associated with
hematuria, which is microscopic in some
40% to 45% of patients and gross in 20%.
The hematuria can be massive, and occasionally, instances of exsanguinating hemorrhage requiring nephrectomy have been
reported. (From Eknoyan and coworkers
FIGURE 6-37
Schematic of the progressive stages of the
medullary form of renal papillary necrosis
and their associated radiologic appearance
seen on intravenous pyelography. In partial papillary necrosis the lesion begins as
focal necrosis within the substance of the
medullary inner stripe. The lesion progresses by coagulative necrosis to form a
sinus to the papillary tip, with subsequent
extrusion or resorption of the sequestered
necrotic tissue. The medullary form of
papillary necrosis is commonly encountered in persons with sickle cell hemoglobinopathy. The incidence of radiographically demonstrative papillary necrosis is
as high as 33% to 65% in such persons.
CONDITIONS ASSOCIATED WITH

RENAL PAPILLARY NECROSIS
Diabetes mellitus
Pyelonephritis
Rejection of transplanted kidney
Vasculitis
Miscellaneous
FIGURE 6-38
Diabetes mellitus is the most common condition associated with
papillary necrosis. The occurrence of capillary necrosis is likely
more common than is generally appreciated, because pyelography
(the best diagnostic tool for detection of papillary necrosis) is
Spectrum of Renal Papillary Necrosis
Obstruction
Diabetes
Infection
Analgesic
abuse
Sickle
Hgb
6.23
avoided in these patients because of dye-induced nephrotoxicity.

When sought, papillary necrosis has been reported in as many as
25% of cases. Analgesic nephropathy accounts for 15% to 25%
of papillary necrosis in the United States but accounts for as much
as 70% of cases in countries in which analgesic abuse is common.
Papillary necrosis also has been reported in patients receiving nonsteroidal anti-inflammatory drugs.
Sickle hemoglobinopathy is another common cause of papillary
necrosis, which, when sought by intravenous pyelography, is detected
in well over half of cases.
Infection is usually but not invariably a concomitant finding in
most cases of RPN. In fact, with few exceptions, most patients
with RPN ultimately develop a urinary tract infection, which
represents a complication of papillary necrosis: that is, the infection develops after the primary underlying disease has initiated
local injury to the renal medulla, with foci of impaired blood flow
and poor tubular drainage. Infection contributes significantly to
the symptomatology of RPN, because fever and chills are the presenting symptoms in two thirds of patients and a positive urine
culture is obtained in 70%. However, RPN is not an extension of
severe pyelonephritis. In most patients with florid acute
pyelonephritis, RPN does not occur.
FIGURE 6-39
Spectrum and overlap of diseases principally associated with renal papillary necrosis
(RPN). Although each disease can cause RPN, it is their coexistence (darkly shaded areas)
that increases the risk, which is even greater after the onset of infection (lightly shaded
areas). In most cases of RPN, more than one of the conditions associated with RPN is present. Thus, in most cases, the lesion seems to be multifactorial in origin. The pathogenesis
of the lesion may be considered the result of an overlapping phenomenon, in which a combination of detrimental factors appear to operate in concert to cause RPN. As such,
whereas each of the conditions alone can cause RPN, the coexistence of more than one
predisposing factor in any one person significantly increases the risk for RPN. The contribution of any one of these factors to RPN would be expected to differ among individuals
and at various periods during the course of the disease. To the extent that the natural
course of RPN itself predisposes patients to development of infection of necrotic foci and
obstruction by sloughed papillae, it may be difficult to assign a primary role for any of
these processes in an individual patient. Furthermore, the occurrence of any of these factors (necrosis, obstruction, or infection) may itself initiate a vicious cycle that can lead to
another of these factors and culminate in RPN.
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Hematologic Diseases
Allon M: Renal abnormalities in sickle cell disease. Arch Intern Med 1990,
150:501504.
Falk RJ, Scheinmann JI, Phillips G et al.: Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of
angiotensin converting enzyme. N Engl J Med 1992, 326:910915.
Ivanyi B: Frequency of light chain deposition nephropathy relative to renal
amyloidosis and Bence Jones cast nephropathy in a necropsy study of
patients with myeloma. Arch Pathol Lab Med 1990, 114:986987.
Rota S, Mougenot B, Baudouin M: Multiple myeloma and severe renal
failure: a clinicopathologic study of outcome and prognosis in 34
patients. Medicine 1987, 66:126137.
Sanders PW, Herrera GA, Kirk KA: Spectrum of glomerular and tubulointerstitial renal lesions associated with monotypical immunoglobulin light
chain deposition. Lab Invest 1991, 64:527537.
6.25
Metabolic Disorders
Viral Infections
Chaplin AJ: Histopathological occurrence and characterization of calcium

oxalate. A review. J Clin Pathol 1977, 30:800811.
Ito M, Hirabayashi N, Uno Y: Necrotizing tubulointerstitial nephritis associated with adenovirus infection. Human Pathol 1991, 22:12251231.
Papadimitriou M.: Hantavirus nephropathy. Kidney Int 1995, 48:887902.
Foley RJ, Weinman EJ: Urate nephropathy. Am J Med Sci 1984,

288:208211.
Hanif M, Mobarak MR, Ronan A: Fatal renal failure caused by diethylene
glycol in paracetamol elixir: the Bangladesh epidemic. Br Med J 1995,
311:8891.
Hereditary Diseases
Zawada ET, Johnson VH, Bergstein J: Chronic interstitial nephritis. Its

occurrence with oxalosis and antitubular basement membrane antibodies after jejunal bypass. Arch Pathol Ub Med 1981, 105:379383.
Fick GM, Gabow PA: Hereditary and acquired cystic disease of the kidney.
Kidney Int 1994, 46:951964.
Gabow PA, Johnson AM, Kaehny VM: Factors affecting the progression
of renal disease in autosomal-dominant polycystic kidney disease.
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Gregory MC, Atkin CL: Alports syndrome, Fabrys disease and nail patella
syndrome. In Diseases of the Kidney, edn 6. Edited by Schrier RW,
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Granulomatous Diseases
Papillary Necrosis
Schneider JA, Lovell H, Calhoun F: Update on nephropathic cystinosis.

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Viero RM, Cavallo T: Granulomatous interstitial nephritis. Hum Pathol
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Griffin MD, Bergstralk EJ, Larson TS: Renal papillary necrosis. A sixteen
year clinical experience. J Am Soc Nephrol 1995, 6:248256.
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1984, 4:1106.
Urinary Tract Infection

Alain Meyrier
he concern of renal specialists for urinary tract infections

(UTIs) had declined with the passage of time. This trend is now
being reversed, owing to new imaging techniques and to substantial progress in the understanding of host-parasite relationships,
of mechanisms of bacterial uropathogenicity, and of the inflammatory
reaction that contributes to renal lesions and scarring.
UTIs account for more than 7 million visits to physicians offices and
well over 1 million hospital admissions in the United States annually
[1]. French epidemiologic studies evaluated its annual incidence at
53,000 diagnoses per million persons per year, which represents
1.05% to 2.10% of the activity of general practitioners. In the United
States, the annual number of diagnoses of pyelonephritis in females
was estimated to be 250,000 [2].
The incidence of UTI is higher among females, in whom it commonly
occurs in an anatomically normal urinary tract. Conversely, in males
and children, UTI generally reveals a urinary tract lesion that must be
identified by imaging and must be treated to suppress the cause of
infection and prevent recurrence. UTI can be restricted to the bladder
(essentially in females) with only superficial mucosal involvement, or
it can involve a solid organ (the kidneys in both genders, the prostate
in males). Clinical signs and symptoms, hazards, imaging, and treatment
of various types of UTIs differ. In addition, the patients background
helps to further categorize UTIs according to age, type of urinary tract
lesion(s), and occurrence in immunocompromised patients, especially
with diabetes or pregnancy. Such various forms of UTI explain the
wide spectrum of treatment modalities, which range from ambulatory,
single-dose antibiotic treatment of simple cystitis in young females, to
rescue nephrectomy for pyonephrosis in a diabetic with septic shock.
This chapter categorizes the various forms of UTI, describes progress
in diagnostic imaging and treatment, and discusses recent data on
bacteriology and immunology.
CHAPTER
7.2
Diagnosis
FIGURE 7-1
Urine test strips. Normal urine is sterile, but suprapubic aspiration of the bladder, which is by no means a routine procedure,
Schematic set up of
a dip-slide container
would be the only way of proving it. Urinary tract infection

(UTI) cannot be identified simply by the presence of bacteria in
a voided specimen, as micturition flushes saprophytic urethral
organisms along with the urine. Thus a certain number of colonyforming units of uropathogens are to be expected in the urine
sample. Midstream collection is the most common method of
urine sampling used in adults. When urine cannot be studied
without delay, it must be stored at 4C until it is sent to the
bacteriology laboratory. The urine test strip is the easiest means
of diagnosing UTI qualitatively. This test detects leukocytes and
nitrites. Simultaneous detection of the two is highly suggestive of
UTI. This test is 95% sensitive and 75% specific, and its negative
predictive value is close to 96% [3]. The test does not, however,
detect such bacteria as Staphyloccocus saprophyticus, a strain
responsible for some 3% to 7% of UTIs. Thus, treating UTI solely on the basis of test strip risks failure in about 15% of simple
community-acquired infections and a much larger proportion of
UTIs acquired in a hospital.
Interpretation after 24-hour incubation at 37C
Paddle-holding Nonsignificant
stopper
Significant
Agar
Moist sponge
103
104
105
106
107
FIGURE 7-2
Culture interpretation. Urinalysis must examine bacterial and leukocyte counts
(per milliliter). An approximate way of estimating bacterial counts in the urine uses
a dip-slide method: a plastic paddle covered on both sides with culture medium is
immersed in the urine, shaken, and incubated overnight.

The most specific results, however, are
provided by laboratory analysis, which
allows precise counting of bacteria and
leukocytes. Normal values for a midstream
specimen are less than or equal to 105
Escherichia coli organisms and 104 leukocytes per milliliter. These classical Kass criteria, however, are not always reliable. In
some cases of incipient cystitis the number
of E. coli per milliliter can be lower, on the
order of 102 to 104 [4]. When fecal contamination has been ruled out, growth of
bacteria that are not normally urethral
saprophytes indicates infection. This is the
case for Pseudomonas, Klebsiella,
Enterobacter, Serratia, and Moraxella,
among others, especially in a hospital setting or after urologic procedures.
CAUSES OF ASEPTIC LEUKOCYTURIA

Self-medication before urine culture
Sample contamination by cleansing solution
Vaginal discharge
Urinary stone
Urinary tract tumor
Chronic interstitial nephritis (especially due to analgesics)
Fastidious microorganisms requiring special culture medium (Ureaplasma urealyticum,
Chlamydia, Candida)
7.3
FIGURE 7-3
Leukocyturia. A significant number of leukocytes (more than 10,000
per milliliter) is also required for the diagnosis of urinary tract infection, as it indicates urothelial inflammation. Abundant leukocyturia
can originate from the vagina and thus does not necessarily indicate
aseptic urinary leukocyturia [1]. Bacterial growth without leukocyturia indicates contamination at sampling. Significant leukocyturia
without bacterial growth (aseptic leukocyturia) can develop from
various causes, among which self-medication before urinalysis is the
most common.
Bacteriology
A. MAIN MICROBIAL STRAINS RESPONSIBLE
FOR URINARY TRACT INFECTION
Microbial Strain
Escherichia coli
Proteus mirabilis
Klebsiella
Enterobacter
Enterococcus
Staphylococcus saprophyticus
Other species
Percent
100
First Episode or
Delayed Relapse
Relapse Due to
Early Reinfection
71%79%
1.1%9.7%
1.0%9.2%
1.0%3.2%
3%7%
2%6%
60%
15%
20%
5%
FIGURE 7-4
Principal pathogens of urinary tract infection (UTI). A and B, Most
pathogens responsible for UTI are enterobacteriaceae with a high predominance of Escherichia coli. This is especially true of spontaneous
UTI in females (cystitis and pyelonephritis). Other strains are less
common, including Proteus mirabilis and more rarely gram-positive
microbes. Among the latter, Staphylococcus saprophyticus deserves
special mention, as this gram-positive pathogen is responsible for 5%
to 15% of such primary infections, is not detected by the leukocyte
esterase dipstick, and is resistant to antimicrobial agents that are
active on gram-negative rods.
C, Acute simple pyelonephritis is a common form of upper UTI
in females and results from the encounter of a parasite and a host.
In the absence of urologic abnormality, this renal infection is mostly due to uropathogenic strains of bacteria [5,6], a majority of
cases to community-acquired E. coli. The clinical picture consists
of fever, chills, renal pain, and a general discomfort. Tissue invasion is associated with a high erythrocyte sedimentation rate and
C-reactive protein level well above 2 mg/dL.
Minimum
Maximum
E. coli
60%
Other
5%
50
P. mirabilis
15%
Klebsiella
20%
0
E. coli P. mirabilis Klebsiella Enterococcus S. saprophyticus Other

Enterobacter
7.4
Virulence Factors of Uropathogenic Strains

Escherichia coli
P
Fimbriae
S Type 1
Flagella
Hemolysin
Aerobactin
+
Na+ Na
Fe3+
Erythrocyte
FIGURE 7-5
Bacterial uropathogenicity plays a major role in host-pathogen interactions that lead to urinary tract infection (UTI). For Escherichia
coli, these factors include flagella necessary for motility, aerobactin
necessary for iron acquisition in the iron-poor environment of the
urinary tract, a pore-forming hemolysin, and, above all, presence of
adhesins on the bacterial fimbriae, as well as on the bacterial cell
surface. (From Mobley et al. [7]; with permission.)
Proteus mirabilis
Fimbriae MR/P PMF ATF NAF
Deaminase
Urease
Flagella
Ni
Urea
2+
[Keto acid]3Fe3+
Amino acid
NH3+CO2
IgA protease Hemolysin
Na+
Renal epithelial cell
FIGURE 7-7
Proteus mirabilis is endowed with other nonfimbrial virulence factors,
including the property of secreting urease, which splits urea into NH3
and CO2.
FIGURE 7-6
An electron microscopic view of an Escherichia coli organism
showing the fimbriae (or pili) bristling from the bacterial cell.
FIGURE 7-8
Staghorn calculi.
Ammonium generation alkalinizes the
urine, creating
conditions favorable
for build-up of
voluminous struvite
stones, which can
progressively invade
the entire pyelocalyceal system, forming staghorn calculi.
These stones are an
endless source of
microbes, and the
urinary tract
obstruction perpetuates infection.

Fimbrial adhesive structures
Type 1 Fimbriae
Type P Fimbriae
Adhesin
Fibrillum
7.5
Nonfimbrial
adhesive structure
PapG
FimH
PapF
FimH, FimG
PapE
FimF, FimG
PapK
FimA
~100
FimA
Rigid fiber
PapA
Adhesins
PapH
Pilin
Minor subunits
Adhesin
FIGURE 7-9
Schematic representation of morphology and composition of type P
and type 1 adhesive structures. Bacterial adhesins are paramount in
fostering attachment of the bacteria to the mucous membranes of the
perineum and of the urothelium. There are several molecular forms
of adhesins. The most studied is the pap G adhesin, which is located
at the tip of the bacterial fimbriae (or pili). This lectin recognizes
binding site conformations provided by oligosaccharide sequences
present on the mucosal surface [8].
FIGURE 7-10
Uropathogenic strains of Escherichia coli readily adhere to epithelial
cells. This figure shows two epithelial cells incubated in urine infected
with E. colicarrying pap adhesins. Numerous bacteria are scattered
on the epithelial cell membranes. About half of all cases of cystitis are
due to uropathogenic strains of E. colicarrying adhesins. Females
with primary pyelonephritis and no urologic abnormality harbor a
uropathogenic strain in almost 100% of cases [5].
APPROPRIATE ANTIBIOTICS FOR URINARY TRACT INFECTIONS
Antibiotics
Aminoglycosides
Aminopenicillins
Carboxypenicillins
Ureidopenicillins
Quinolones
Fluoroquinolones
Cephalosporins
First generation
Second generation
Third generation
Monobactams
Carbapenem
Cotrimoxazole
Fosfomycin trometamole
Nitroturantoin
General Indications
Pregnancy
Prophylaxis
+
+
+
+
+
+
+*
+
+
+
-
+
+
+
+
+
+
+
+
+**
+
+
+
+
+
+
-
+
+
+
* Aminoglycosides should not be prescribed during pregnancy except for very severe infection and for the shortest
possible duration.
With the exception of amoxicillin plus clavulanic acid, aminopenicillins should not be prescribed as first-line treatment,
owing to the frequency of primary resistance to this class of antibiotics.
According to antibiotic sensitivity tests.
Fluoroquinolones carry a risk of tendon rupture (especially Achilles tendon).
Oral administration only.
** Single-dose treatment of cystitis.
Simple cystitis; not pyelonephritis or prostatitis.
FIGURE 7-11
Appropriate antibiotics for urinary tract
infections (UTI). An appropriate antibiotic
for treating UTI must be bactericidal and
conform to the following general specifications: 1) its pharmacology must include, in
case of oral administration, rapid absorption and attainment of peak serum concentrations; 2) its excretion must be predominantly renal; 3) it must achieve high concentrations in the renal or prostate tissue;
4) it must cover the usual spectrum of
enterobacteria with reasonable chance of
being effective on an empirical basis.
Excluding special considerations for childhood and pregnancy, several classes of
antibiotics fulfill these specifications and
can be used alone or in combination. The
choice also depends on market availability,
cost, patient tolerance, and potential for
inducing emergence of resistant strains.
7.6
Classification of Urinary Tract Infection

Upper versus lower urinary tract infection
FIGURE 7-12
Cystitis in a female patient. In case of urinary tract infection (UTI), distinguishing between
lower and upper tract infection is classical, but the distinction is also beside the point. The real
point is to determine whether infection is confined to the bladder mucosa, which is the case in
simple cystitis in females, or whether it involves solid organs (ie, prostatitis or pyelonephritis).
The dots in this figure symbolize the presence of bacteria and leukocytes (ie, infection) in the
relevant organ. Here, infection is confined to the bladder mucosa, which can be severely
inflamed and edematous. This could be reflected radiographically by mucosal wrinkling on
the cystogram. In some cases inflammation is severe enough to be accompanied by bladder
purpura, which induces macroscopic hematuria but is not a particular grave sign.
FIGURE 7-13
Prostatitis. Anatomically, prostatitis involves
the lower urinary tract, but invasion of
prostate tissue affords easy passage of
pathogens to the prostatic venous system
and, usually, poor penetration by antibiotics. Presence of bacteria in the bladder is
also symbolized in this picture, but owing to
free communication between bladder urine
and prostate tissue, it can be accepted that
pure cystitis does not exist in males.
FIGURE 7-14
Acute prostatitis can be complicated by
ascending infection, that is, pyelonephritis.
FIGURE 7-15
Pyelonephritis in females. Essentially, this is
an ascending infection caused by uropathogens. From the perineum the bacteria gain
access to the bladder, ascending to the renal
pelvocalyceal system and thence to the renal
medulla, from which they spread toward the
cortex. It has been shown that pyelitis cannot be considered a pathologic entity, as renal
pelvis infection is invariably associated with
nearby contamination of the renal medulla.
7.7
CRITERIA FOR TISSUE INVASION

Clinical
Kidney or prostate infection is marked by fever over 38C, chills, and pain. The patient appears acutely ill.
Laboratory
Tissue invasion is invariably accompanied by an erythrocyte sedimentation rate over 20 mm/h and serum C-reactive protein
levels over 2.0 mg/dL. Blood cultures grow in 30%50% of cases, which in an immunocompetent host indicates simply bacteremia, not septicemia. This reflects easy permeability between the urinary and the venous compartments of the kidney.
Imaging
When indicated, ultrasound imaging, tomodensitometry, and scintigraphy provide objective evidence of pyelonephritis.
In case of vesicoureteral reflux, urinary tract infection necessarily involves the upper urinary tract.
FIGURE 7-17
Criteria for tissue invasion.
FIGURE 7-16
Renal abscess formation. As specified elsewhere, renal abscess due to enterobacteriaceae (as opposed to hematogenous renal
abscess, often of staphylococcal origin) can
be considered a severe form of pyelonephritis
with renal tissue liquefaction, ending in a
walled-off cavity.
Primary versus secondary urinary tract infection

FIGURE 7-19
Cystogram of a
65-year-old woman.
A voluminous bladder tumor (arrows)
infiltrates the bladder floor and the
initial segment of
the urethra.
FIGURE 7-18
An episode of urinary tract infection (UTI) should prompt consideration of whether it involves a normal urinary tract or, alternatively, if
it is a complication of an anatomic malformation. This is especially
true of relapsing UTI in both genders, and this hypothesis should be
systematically raised in males and in children.
Recurrent cystitis in females can be explained by hymeneal scars
that pull open the urethral outlet during intercourse. Although
rarely, other malformations that promote recurrent female cystitis
are occasionally discovered, such as urethral diverticula (arrows).
Finally, it should be recalled that recurrent or chronic cystitis in an
older woman can also reveal an unsuspected bladder tumor.
7.8
FIGURE 7-20
Urethrocystogram of a man following acute prostatitis. In males,
acute prostatitis may reveal urethral stenosis. Urethral stenosis is a
good explanation for acute prostatitis. The beaded appearance of the
stenosis (arrow) suggests an earlier episode of gonorrheal urethritis.
II
III
IV
FIGURE 7-21
The severity of vesicoureteral reflux (VUR) as graded in 1981 by
the International Reflux Study Committee. When children have
A
FIGURE 7-22
Cystogram demonstrating left ureteral reflux (A). The consequences on the left kidney (B) consist of calyceal distension and a
clubbed appearance due to the destruction of the papillae and of
pyelonephritis, the possibility of VUR should always be considered.

Childhood vesicoureteral reflux is five times more common in girls
than in boys. It has a genetic background: several cases occasionally
occur in the same family. Unless detected and corrected early, especially the most severe forms of this class and when urine is infected
(one episode of pyelonephritis suffices), childhood VUR is a major
cause of cortical scarring, renal atrophy, and in bilateral cases chronic
renal insufficiency. The International Reflux Study classifies reflux
grades as follows: I) ureter only; II) ureter, pelvis, and calyces, no
dilation, and normal calyceal fornices; III) mild or moderate dilation
or tortuosity of ureter and mild or moderate dilation of renal pelvis
but no or slight blunting of fornices; IV) moderate dilation or tortuosity of ureter and moderate dilation of renal pelvis and calyces,
complete obliteration of sharp angle of fornices but maintenance of
papillary impressions in majority of calyces; V) gross dilation and
tortuosity of ureter, gross dilation of renal pelvis and calyces. Papillary
impressions are no longer visible in the majority of calyces. (From
International Reflux Study Committee [9]; with permission.)
B
the adjacent renal tissue. The calyceal cavities are very close to the
renal capsule, indicating complete cortical atrophy. This picture is
typical of chronic pyelonephritis secondary to vesicoureteral reflux.
FIGURE 7-23
In case of bilateral, neglected vesicoureteral reflux, chronic pyelonephritis is bilateral and asymmetric. Here, the right kidney is globally
atrophic. A typical cortical scar is seen on the outer aspect of the left
kidney. The lower pole, however, is fairly well-preserved with nearly
normal parenchymal thickness.
FIGURE 7-25
(see Color Plate)
In children, isotopic
cystography allows
a diagnosis of vesicoureteral reflux
with much less radiation than if cystography were carried
out with iodinated
contrast medium.
7.9
FIGURE 7-24
When intravenous pyelography discloses two ureters, the one draining
the lower pyelocalyceal system crosses the upper ureter and opens
into the bladder less obliquely than normally, allowing reflux of urine
and explaining repeated attacks of pyelonephritis followed by atrophy
of the lower pole of the kidney. Retrograde cystography is indicated
for repeated episodes of pyelonephritis and when intravenous pyelography or computed tomography renal examination discovers cortical
scars. In adults, retrograde cystography is obtained by direct catheterization of the bladder.
FIGURE 7-26
In the paraplegic,
and more generally
in patients with
spinal disease,
neurogenic bladder
is responsible for
stasis, bladder
distension, and
diverticula. These
functional and
anatomic factors
explain the frequency
of chronic urinary
tract infection
complicated with
bladder and upper
urinary tract
infectious stones.
7.10
Imaging
FIGURE 7-27
When acute pyelonephritis occurs in a sound, immunocompetent
female with no history of urologic disease, imaging can be limited
to a plain abdominal film (to rule out renal and ureteral stones) and
renal ultrasonography. Ultrasonography typically discloses a swollen
kidney with loss of corticomedullary differentiation, denoting renal
inflammatory edema. Images corresponding to the infected zones
are more dense than normal renal tissue (arrows).
A
FIGURE 7-29
Computed tomodensitometry. Simple pyelonephritis does not
require much imaging; however, it should be remembered that there
is no correlation between the severity of the clinical picture and the
renal lesions. Therefore, a diagnosis of simple pyelonephritis at
first contact can be questioned when response to treatment is not
clear after 3 or 4 days. This is an indication for uroradiologic imaging, such as renal tomodensitometry followed by radiography of the
urinary tract while it is still opacified by the contrast medium.
The typical picture of acute pyelonephritis observed after contrast medium injection [10] consists of hypodensities of the infected
FIGURE 7-28
The ultrasound procedure occasionally discloses the cavity of a small
renal abscess, a common complication of acute pyelonephritis, even
in simple forms.
B
areas in an edematous, swollen kidney. The pathophysiology of
hypodense images has been elucidated by animal experiments in
the primates [11] which have shown that renal infection with
uropathogenic Escherichia coli induces intense vasoconstriction.
Computed tomodensitometric images of acute pyelonephritis can
take various appearances. The most common findings consist of
one or several wedge-shaped or streaky zones of low attenuation
extending from papilla to cortex, A. Hypodense images can be
round, B. On this figure, the infected zone reaches the renal cortex
and is accompanied with adjacent perirenal edema. Several such
7.11
D
images can coexist in the same kidney, C.
Marked juxtacortical, circumscribed hypodense zones, bulging under the renal capsule, D, usually correspond to lesions close
to liquefaction and should be closely followed, as they can lead to abscess formation and opening into the perinephric space,
E and F. (E and F from Talner et al. [10];
with permission.)
FIGURE 7-30
Comparative sensitivity of four diagnostic imaging techniques for
acute pyelonephritis. Renal cortical scintigraphy using 99mTc-dimethyl
succinic acid (DMSA) or 99mTc-gluconoheptonate (GH) is very sensitive for diagnosing acute pyelonephritis. It entails very little irradiation
as compared with conventional radiography using contrast medium.
Some nephrologists consider 99mTc-DMSA cortical scintigraphy as the
first-line diagnostic imaging method for renal infection in children. It is
interesting to compare its sensitivity with that of more conventional
imaging methods. (From Meyrier and Guibert [5]; with permission.)
100
86
Percent
75
50
42
24
0
Renal
scintigraphy
CT scan Ultrasonography
IVP
(intravenous
pyelography)
7.12
cortical imaging of simple pyelonephritis in a female.
The clinical signs implicated the right kidney. (Contrary to conventional radiology, the right kidney appears on the right of the image.)
The false colors indicate cortical renal blood supply from red (normal) to blue (ischemia). The right kidney is obviously involved
with pyelonephritis, especially its poles. However, contrary to
the results of computed tomography, which indicated right-sided
pyelonephritis only, a focus of infection also occupies the lower pole
of the right kidney. This picture illustrates the greater sensitivity of
renal scintigraphy for diagnosing renal infection. It also indicates
that clinically unilateral acute pyelonephritis can, in fact, be bilateral.
99mTc-DMSA
A
FIGURE 7-32
Renal pathology in acute pyelonephritis. Renal pathology of human
acute pyelonephritis is quite comparable to what is observed in
experimental pyelonephritis in primates [11]. However, our knowledge of renal pathology in this condition in humans is based mainly
on the most catastrophic cases, which required nephrectomy, like
A
FIGURE 7-33
Histologic appearance of pyelonephritic kidney. A, The renal tissue
is severely edematous and interspersed with inflammatory cells and
hemorrhagic streaks. B, On another section, severe inflammation,
B
the diabetes patient whose kidney is shown here. A, The surgically
removed kidney is swollen, and its surface shows whitish zones.
B, A section of the same organ shows white suppurative areas (scattered with small abscesses) extending eccentrically from the medulla
to the cortex. There also were sloughed papillae (see Fig. 7-37).
B
comprising a majority of polymorphonuclear leukocytes, induces
tubular destruction and is accompanied by a typical infectious cast
in a tubular lumen (arrow).
Clinical picture compatible

with acute pyelonephritis (APN)
Urine culture and cytology
ESR
CRP
Renal
scintigraphy
and/or CT scan
Negative.
Reconsider
diagnosis of APN
No renal lesion.
Seek other
infection
Renal lesions.
Maintain
diagnosis of APN
Abnormal.
Call urologist
Positive
Initial
work-up
Previous
history of
upper UTI
Yes
IVP
Secondary APN
Treat
Treat
cause
infection
Possible urinary
tract obstruction
or stone?
No
No previous
history of
upper UTI
Plain abdominal
radiograph
Ultrasonography
Primary APN
Drug therapy only
Normal
Day
1
Start treatment with first-line antibiotics

Good clinical
response and
lab. Confirmation of
appropriate initial
antibiotic choice
Atypical clinical
response or
Wrong initial
antibiotic choice
Continue
same
treatment
Adapt
antibiotic
treatment
Further
imaging
(IVP, CT)
Normal.
Consider drug
intolerance
Days
2 to
4 or 5
Abnormal.
Call
urologist
Days
5 to 15
Day
15
End treatment
Recurrence
of bacteriuria
Radiourological work-up.
New treatment
Verify
urine sterility
Sterile
Between
days
30 and 45
No further
investigations or treatment
7.13
FIGURE 7-34
A general algorithm for the investigation
and treatment of acute pyelonephritis.
Treatment of acute pyelonephritis is based
on antibiotics selected from the list in
Figure 7-11. Preferably, initial treatment is
based on parenteral administration. It is
debatable whether common forms of simple pyelonephritis initially require both an
aminoglycoside and another antibiotic.
Initial parenteral treatment for an average
of 4 days should be followed by about 10
days of oral therapy based on bacterial
sensitivity tests. It is strongly recommended
that urine culture be carried out some 30
to 45 days after the end of treatment, to
verify that bacteriuria has not recurred.
APNacute pyelonephritis; ESRerythrocyte sedimentation rate; CRPC-reactive
protein; UTIurinary tract infection;
IVPintravenous pyelography. (From
Meyrier and Guibert [5]; with permission.)
7.14
Renal abscess. Like acute pyelonephritis, one third of cases of renal abscess occur in a normal urinary tract; in the others it is a complication of a urologic abnormality. The clinical
picture is that of severe pyelonephritis. In fact, it can be conceptualized as an unfavorably
developing form of acute pyelonephritis that progresses from presuppurative to suppurative
renal lesions, leading to liquefaction and formation of a walled-off cavity. The diagnosis of
renal abscess is suspected when, despite adequate treatment of pyelonephritis (described in
Fig. 7-34), the patient remains febrile after day 4. Here, necrotic renal tissue is visible close
to the abscess wall. The tubules are destroyed, and the rest of the preparation shows innumerable polymorphonuclear leukocytes within purulent material.
A
FIGURE 7-36
Renal computed tomography (CT). In addition to ultrasound
examination, CT is the best way of detecting and localizing a
renal abscess. The abscess cavity can be contained entirely within
B
the renal parenchyma, A, or bulge outward under the renal capsule,
risking rupture into Gerotas space, B.
7.15
FIGURE 7-37
Urinary tract infection (UTI) in the immunocompromised host. UTI
results from the encounter of a pathogen and a host. Natural defenses
against UTI rest on both cellular and humoral defense mechanisms.
These defense mechanisms are compromised by diabetes, pregnancy,
and advanced age. Diabetic patients often harbor asymptomatic bacteriuria and are prone to severe forms of pyelonephritis requiring
immediate hospitalization and aggressive treatment in an intensive
care unit.
A particular complication of upper renal infection in diabetes is
papillary necrosis (see Fig. 7-32). The pathologic appearance of a
sloughing renal papilla, A. The sloughed papilla is eliminated and can
be recovered by sieving the urine, B. In other cases, the necrotic papilla obstructs the ureter, causing retention of infected urine and severely
aggravating the pyelonephritis. C, It can lead to pyonephrosis (ie,
complete destruction of the kidney), as shown on CT.
Nonpregnant
Pregnant
500
IgG
Antibody activity, % of control
0
1000
IgA
500
0
1000
IgM
500
0
2
Time of sampling, wks
FIGURE 7-38
Urinary tract infection (UTI) in an immunocompromised host.
Pregnancy is associated with suppression of the hosts immune
response, in the form of reduced cytotoxic T-cell activity and
reduced circulating immunoglobulin G (IgG) levels. Asymptomatic
bacteriuria is common during pregnancy and represents a major
risk of ascending infection complicated by acute pyelonephritis.
7.16
Nonpregnant
Pregnant
>250
IgG
1000
250
200
0
1000
IgA
Levels of IL-6, units/mL
Antibody activity, Abs 405 nm
500
150
100
50
20
500
20
0
0
0
0
2
0
Time of sampling, wks

Petersson and coworkers [12] recently demonstrated that the susceptibility of the pregnant woman to acute UTI is accompanied by reduced
serum antibody activity (IgG, IgA, IgM), reduced urine antibody activity (IgG, IgA), and low interleukin 6 (IL-6) response, AC, respectively.
Nonpregnant
Pregnant
Serum
Nonpregnant
Pregnant
Urine
The last may indicate that pregnant women have a generally reduced
level of mucosal inflammation. These factors may be crucial for
explaining the frequency and the severity of acute pyelonephritis
during pregnancy. (From Petersson et al. [12]; with permission.)
FIGURE 7-39
Acute prostatitis as visualized sonographically. Acute prostatitis
is common after urethral or bladder infection (usually by
Escherichia coli or Proteus organisms). Another cause is prostate
hematogenous contamination, especially by Staphylococcus.
Signs and symptoms of acute prostatitis, in addition to fever,
chills, and more generally the signs and symptoms of tissue invasion by infection described above, are accompanied by dysuria,
pelvic pain, and septic urine. Acute prostatitis is an indication
for direct ultrasound (US) examination of the prostate by
endorectal probe. In this case of acute prostatitis in a young
male, US examination disclosed a prostatic abscess (1) complicating acute prostatitis in the right lobe (2). Acute prostatitis is
an indication for thorough radiologic imaging of the whole urinary tract, giving special attention to the urethra. Urethral stricture may favor prostate infection (see Fig. 7-20).
7.17
Special Forms of Renal Infection

Xanthogranulomatous pyelonephritis (XPN). XPN is a special
form of chronic renal inflammation caused by an abnormal
immune response to infected obstruction [13]. This case in a
middle-aged woman with a long history of renal stones is typical.
For several months she complained of flank pain, fever, fatigue,
anorexia and weight loss. Laboratory workup found inflammatory
anemia and increased erythrocyte sedimentation rate and C-reactive
protein levels. Urinalysis showed pyuria and culture grew Escherichia
coli. CT scan of the right kidney showed replacement of the renal
tissue by several rounded, low-density areas and detected an
obstructive renal stone. Nephrectomy was performed. A, The

obstructive renal stone is shown by an arrowhead. The renal
cavities are dilated. The xanthogranulomatous tissue (arrows)
consists of several round, pseudotumoral masses with a typical
yellowish color due to presence of lipids. In some instances such
xanthogranulomatous tissue extends across the capsule into the
perirenal fat and fistulizes into nearby viscera such as the colon
or duodenum. B, Microscopic view of the xanthogranulomatous
tissue. This part of the lesion is made of lipid structures composed
of innumerable clear droplets.
Spectrum of renal malakoplakia

Inflammation
Mononuclear
cells
(nonspecific)
Interstitial
nephritis
Persistent
inflammation
von Hansemann
cells
(prediagnostic)
Megalocytic
interstitial
nephritis
Ca2+
Defective
cell function
Michaelis-Gutmann
(MG) bodies
(diagnostic)
Malakoplakia
Destuctive
granulomas
xanthogranulomatous
pyelonephritis
Fibrosis
"pseudosarcoma"
FIGURE 7-41
Malakoplakia. Malakoplakia (or malacoplakia), like xanthogranulomatous pyelonephritis, is also a consequence of abnormal macrophage
response to gram-negative bacteria, A. Malakoplakia occurs in association with chronic UTI [14]. In more than 20% of cases, affected persons have some evidence of immunosuppression, especially corticos-
teroid therapy for autoimmune disease. In 13% of the published cases,

malakoplakia involved a transplanted kidney. The female-male ratio is
3:1. Lesions can involve the kidney, the bladder, or the ureter and form
pseudotumors. B, Histologically, malakoplakia is distinguished by
large, pale, periodic acidSchiffpositive macrophages (von Hansemann cells) containing calcific inclusions (Michaelis-Gutmann bodies).
The larger ones are often free in the interstitium. Malakoplakia, an
unusual form of chronic tubulointerstitial nephritis, must be recognized by early renal biopsy and can resolve, provided treatment
consisting of antibiotics with intracellular penetration is applied for
several weeks. (B, Courtesy of Gary S. Hill, MD.)
7.18
References
1. Stamm WE, Hooton TM: Management of urinary tract infections in
adults. N Engl J Med 1993, 329:13281334.
2. Pinson AG, Philbrick JT, Lindbeck GH, Schorling JB: ED management
of acute pyelonephritis in women: A cohort study. Am J Emerg Med
1994, 12:271278.
3. Pappas PG: Laboratory in the diagnosis and management of urinary
tract infections. Med Clin North Am 1991, 75:313325.
4. Kunin CM, VanArsdale White L, Tong HH: A reassessment of the
importance of low-count bacteriuria in young women with acute
urinary symptoms. Ann Intern Med 1993, 119:454460.
5. Meyrier A, Guibert J: Diagnosis and drug treatment of acute
pyelonephritis. Drugs 1992, 44:356367.
6. Meyrier A: Diagnosis and management of renal infections. Curr Opin
Nephrol Hypertens 1996, 5:151157.
7. Mobley HLT, Island MD, Massad G: Virulence determinants of
uropathogenic Escherichia coli and Proteus mirabilis. Kidney Int
1994, 46(Suppl. 47):S129S136.
8. Roberts JA, Marklund BI, Ilver D, et al.: The Gal( 1-4)Gal

specific tip adhesin of Escherichia coli P-fimbriae is needed for
pyelonephritis to occur in the normal urinary tract. Proc Natl Acad
Sci USA 1994, 91:1188911893.
9. International Reflux Study Committee: Medical versus surgical
treatment of primary vesicoureteral reflux. J Urol 1981, 125:277.
10. Talner LB, Davidson AJ, Lebowitz RL, et al.: Acute pyelonephritis:
Can we agree on terminology? Radiology 1994, 192:297306.
11. Roberts JA: Etiology and pathophysiology of pyelonephritis.
Am J Kidney Dis 1991, 17:19.
12. Petersson C, Hedges S, Stenqvist K, et al.: Suppressed antibody and
interleukin-6 responses to acute pyelonephritis in pregnancy. Kidney
Int 1994, 45:571577.
13. Case records of the Massachusetts General Hospital. N Engl J Med
1995, 332:174179.
14. Dobyan DC, Truong LD, Eknoyan G: Renal malacoplakia
reappraised. Am J Kidney Dis 1993, 22:243252.
Reflux and Obstructive

Nephropathy
James M. Gloor
Vicente E. Torres
eflux nephropathy, or renal parenchymal scarring associated

with vesicoureteral reflux (VUR), is an important cause of
renal failure. Some studies have shown that in up to 10% of
adults and 30% of children requiring renal replacement therapy for
end-stage renal disease, reflux nephropathy is the cause of the renal
failure. Reflux nephropathy is thought to result from the combination
of VUR of infected urine into the kidney by way of an incompetent
ureterovesical junction valve mechanism and intrarenal reflux. Acute
inflammatory responses to the infection result in renal parenchymal
damage and subsequent renal scarring. Loss of functioning renal mass
prompt compensatory changes in renal hemodynamics that, over time,
are maladaptive and result in glomerular injury and sclerosis.
Clinically, reflux nephropathy may cause hypertension, proteinuria,
and decreased renal function when the scarring is extensive. The identification of VUR raises the theoretic possibility of preventing reflux
nephropathy. The inheritance pattern of VUR clearly is suggestive of a
strong genetic influence. Familial studies of VUR are consistent with
autosomal dominant transmission, and linkage to the major histocompatibility genes has been reported. Identification of infants with reflux
detected on the basis of abnormalities seen on prenatal ultrasound
examinations before urinary tract infection occurs may provide an
opportunity for prevention of reflux nephropathy. In persons with VUR
detected at the time of diagnosis of a urinary tract infection, avoidance
of further infections may prevent renal injury. Nevertheless, the situation is far from clear. Most children with reflux nephropathy already
have renal scars demonstrable at the time of the urinary tract infection
that prompts the diagnosis of VUR. Most children found to have VUR
do not develop further renal scarring after diagnosis, even after subsequent urinary tract infections. Other children may develop renal scars
in the absence of further urinary tract infections. The best treatment of
CHAPTER
8.2
VUR has not yet been firmly established. No clear advantage has
been demonstrated for surgical correction of VUR versus medical
therapy with prophylactic antibiotics after 5 years of follow-up
examinations. New surgical techniques such as the submucosal
injection of bioinert substances may have a role in select cases.
The term obstructive nephropathy is used to describe the functional and pathologic changes in the kidney that result from
obstruction to the flow of urine. Obstruction to the flow of urine
usually is accompanied by hydronephrosis, an abnormal dilation

of the renal pelvis, and calices. However, because hydronephrosis
can occur without functional obstruction, the terms obstructive
nephropathy and hydronephrosis are not synonymous. Hydronephrosis is found at autopsy in 2% to 4% of cases. Obstructive
nephropathy is responsible for approximately 4% of end-stage
renal failure. Obstruction to the flow of urine can occur anywhere
in the urinary tract and has many different causes.
CAUSES OF OBSTRUCTIVE NEPHROPATHY

Intraluminal
Calculus, clot, renal papilla, fungus ball
Intrinsic
Congenital:
Calyceal infundibular obstruction
Ureteropelvic junction obstruction
Ureteral stricture or valves
Posterior urethral valves
Anterior urethral valves
Urethral stricture
Meatal stenosis
Prune-belly syndrome
Neoplastic:
Carcinoma of the renal pelvis, ureter, or bladder
Polyps
Extrinsic
Congenital (aberrant vessels):
Congenital hydrocalycosis
Ureteropelvic junction obstruction
Retrocaval ureter
Neoplastic tumors:
Benign tumors:
Benign prostatic hypertrophy
Pelvic lipomatosis
Cysts
Primary retroperitoneal tumors:
Mesodermal origin (eg, sarcoma)
neurogenic origin (eg, neurofibroma)
Embryonic remnant (eg, teratoma)
Retroperitoneal extension of pelvic or abdominal tumors:
Uterus, cervix
Bladder, prostate
Rectum, sigmoid colon
Metastatic tumor:
Lymphoma
Inflammatory:
Diverticulitis
Infection or abscess
Gynecologic:
Pregnancy
Uterine prolapse
Surgical disruption or ligation
Functional
Neurogenic bladder
Drugs(anticholinergics, antidepressants, calcium channel
blockers)
FIGURE 8-1
Obstructive nephropathy is responsible for
end-stage renal failure in approximately 4%
of persons. Obstruction to the flow of urine
can occur anywhere in the urinary tract.
Obstruction can be caused by luminal bodies; mural defects; extrinsic compression by
vascular, neoplastic, inflammatory, or other
processes; or dysfunction of the autonomic
nervous system or smooth muscle of the
urinary tract. The functional and clinical
consequences of urinary tract obstruction
depend on the developmental stage of the
kidney at the time the obstruction occurs,
severity of the obstruction, and whether the
obstruction affects one or both kidneys.
Reflux and Obstructive Nephropathy
8.3
Anatomy of Vesicoureteric Reflux
Intramural
ureter
FIGURE 8-2
Anatomy of the ureterovesical junction. The ureterovesical junction permits free antegrade
urine flow from the upper urinary tract into the bladder and prevents retrograde urinary
reflux from the bladder into the ureter and kidney. Passive compression of the distal submucosal portion of the ureter against the detrusor muscle as a result of bladder filling
impedes vesicoureteral reflux (VUR). An active mechanism preventing reflux also has been
proposed in which contraction of longitudinally arranged distal ureteral muscle fibers
occludes the ureteral lumen, impeding retrograde urine flow [13]. (From Politano [4];
with permission.)
Submucosal
ureter
Bladder wall
Ureter
B
12 mm
A'
C
8 mm
B'
D
5 mm
C'
E
2 mm
D'
0 mm
FIGURE 8-3
Tissue sagittal sections (upper panels) and
cystoscopic appearances (lower panels) of
the ureterovesical junction illustrating varying submucosal tunnel lengths. The length of
the submucosal segment of the distal ureter
is an important factor in determining the
effectiveness of the ureteral valvular mechanism in preventing vesicoureteral reflux
(VUR). In children without VUR, the ratio
of tunnel length to ureteral diameter is significantly greater than in children with VUR
[5,6]. (From Kramer [7]; with permission.)
E'
Cytoscopic view
FIGURE 8-4
Simple and compound papillae are illustrated [8,9]. Two types of
renal papillae have been identified. Simple papillae are the most
common type. They have slitlike papillary duct openings on their
convex surface. These papillae are compressed by increases in
pelvic pressure, preventing urine from entering the papillary ducts
(intrarenal reflux). Compound papillae are formed by the fusion of
two or more simple papillae. In compound papillae, some ducts
open onto a flat or concave surface at less oblique angles.
Increased intrapelvic pressure may permit intrarenal reflux.
Compound papillae usually are found in the renal poles.
8.4
Pathogenesis of Vesicoureteric Reflux

and Reflux Nephropathy
FIGURE 8-5
Experimental vesicoureteric reflux in pigs. This pathology specimen
demonstrates surgically induced vesicoureteric reflux in a 2-weekold male piglet. Note that the submucosal canal of one of the
ureters has been unroofed.
FIGURE 8-7
Experimental vesicoureteric reflux in pigs. The polar location of
acute suppurative pyelonephritis and evolution of parenchymal
FIGURE 8-6
Experimental vesicoureteric reflux in pigs: cystourethrogram showing intrarenal reflux. Reflux of radiocontrast medium into the
renal parenchyma is seen. The pressure required to produce
intrarenal reflux is lower in young children than it is in older children or adults, which is consistent with the observation that reflux
scars occur more commonly in younger children [10].
C
scars. In urinary tract infections, reflux of urine from the renal
pelvis into the papillary ducts of compound papillae predominantly

located in the poles (intrarenal reflux) provides bacteria access
to the renal parenchyma, resulting in suppurative pyelonephritis
and subsequent polar scarring [11,12]. Intact (A, C, E) and coronally sectioned (B, D, F) kidneys illustrating the three stages of
8.5
F
reflux nephropathy: Hemorrhagic with polymorphonuclear cell
infiltrate (A, B); white, not retracted, with prominent mononuclear cell infiltrate (C, D), and retracted scan with prominent
fibrosis (E, F).
Experimental vesicoureteric reflux (VUR) in pigs: mesangiopathic
lesions. Reflux of infected urine can result in glomerular lesions
characterized by activation of mesangial cells, mesangial expansion, mesangial hypercellularity, and the presence of large granules.
The granules test positive on periodic acidSchiff reaction and are
located inside cells with the appearance of macrophages. These
glomerulopathic lesions occur by a process that does not require
contiguity with the infected interstitium nor intrarenal reflux.
These lesions are not related to reduction of renal mass. Similar
glomerular lesions have been identified in piglets after intravenous
administration of endotoxin. Whether similar glomerular lesions
occur in infants or young children with VUR and reflux nephropathy is not known [13].

Experimental vesicoureteric reflux (VUR) in pigs: 99mTechnetium-dimercaptosuccinic acid
(DMSA) scan demonstrating reflux nephropathy. Radionuclide imaging using DMSA has
been found to be safe and effective in investigating reflux nephropathy [14]. DMSA is
localized to the proximal renal tubules of the renal cortex. Parenchymal scars appear as a
defect in the kidney outline, with reduced uptake of DMSA or by contraction of the whole
kidney. Currently, DMSA radionuclide renal scanning is the most sensitive modality used
to detect renal scars relating to reflux. New areas of renal scarring can be seen earlier with
DMSA than with intravenous pyelography [15].
8.6
Integrative View of Pathogenetic Mechanisms in Reflux Nephropathy

Defective mesonephric mesoderm
(ureteral bud)
Abnormal induction of
metanephric mesoderm
VUR
High-voiding
pressures
(In utero)
IRR
+
Virulent
bacterial strain
+
Immune
complexes
Bacterial
fragments
Endotoxin
Susceptible
host
Focal exudative
reaction
Glomerulopathy
Dysplasia
Inhibition
of ureteral
peristalsis
Toxic urine
component
Delayed
hypersensitivity
Pyelonephritic
scar
Reduced nephron
population
Hyperfiltration
Glomerulosclerosis
Sterile scar
Back-pressure
atrophy
Diffuse interstitial
fibrosis
High-protein diet
Hypertension
Pregnancy
FIGURE 8-10
Integrative view of pathogenetic mechanisms in reflux nephropathy. Abnormalities of ureteral embryogenesis may result in a defective antireflux mechanism, permitting vesicoureteral reflux (VUR),
incomplete bladder emptying, urinary stasis, and infection.
Bacterial virulence factors modify the pathogenicity of different
bacterial strains. Bacterial surface appendages such as fimbriae may
interact with epithelial cell receptors of the urinary tract, enhancing
bacterial adhesion to urothelium. Endotoxin is capable of inhibiting ureteral peristalsis, contributing to the extension of the infection into the upper urinary tract even in the absence of VUR.
Inoculation of the renal parenchyma with bacteria produces an
acute inflammatory response, resulting in the release of inflammatory mediators into the surrounding tissue. The acute inflammatory
response elicited by the presence of infecting bacteria is responsible
for the subsequent renal parenchymal injury. In addition, it is possible that immune complexes, bacterial fragments, and endotoxin
resulting from infection may produce a glomerulopathy.
Even in the absence of urinary tract infection, VUR associated
with elevated intravesical pressure is capable of producing renal
parenchymal scars. The developing kidney appears to be particularly susceptible. Renal tubular distention resulting from high
intrapelvic pressure may exert an injurious effect on renal tubular
epithelium. Compression of the surrounding peritubular capillary
network by distended renal tubules may produce ischemia. During
micturition, elevated intravesical pressure is transmitted to the
renal pelvis and renal tubule. This transient pressure elevation may
produce tubular disruption. Extravasation of urine into the surrounding parenchyma results in an immune-mediated interstitial
nephritis and further renal injury.
The reduction in functional renal mass produced by the interaction
of the pathogenetic factors listed here induces compensatory hemodynamic changes in renal blood flow and the glomerular filtration
rate. Over time, these compensatory changes may be maladaptive,
may produce hyperfiltration and glomerulosclerosis, and may eventuate in renal insufficiency. (From Kramer [16]; with permission.)
Progressive renal insufficiency
FIGURE 8-11
Vesicoureteral reflux and renal dysplasia. An abnormal ureteral
bud resulting from defective ureteral embryogenesis may penetrate
the metanephric blastema at a site other than that required for
optimum renal development, potentially resulting in renal dysplasia
or hypoplasia [17].
8.7
Diagnosis of Vesicoureteric Reflux and Reflux Nephropathy
II
III
IV
FIGURE 8-12
International system of radiographic grading of vesicoureteral reflux
(VUR). The severity of VUR is most frequently classified according to
the International Grading System of Vesicoureteral Reflux, using a
standardized technique for performance of voiding cystourethrography. The definitions of this system are illustrated in Figure 8-4 and
are as follows. In grade I, reflux only into the ureter occurs. In grade
II, reflux into the ureter, pelvis, and calyces occurs. No dilation
occurs, and the calyceal fornices are normal. In grade III, mild or
moderate dilation, tortuosity, or both of the ureter are observed, with
mild or moderate dilation of the renal pelvis. No or only slight blunting of the fornices is seen. In grade IV, moderate dilation, tortuosity,
or both of the ureter occur, with moderate dilation of the renal pelvis
and calyces. Complete obliteration of the sharp angle of the fornices
is observed; however, the papillary impressions are maintained in
most calyces. In grade V, gross dilation and tortuosity of the ureter
occur; gross dilation of the renal pelvis and calyces is seen. The papillary impressions are no longer visible in most calyces [18].
Types of renal scarring
Mild
Severe
C "Back-pressure"
D End-stage
FIGURE 8-13
Grading of renal scarring associated with vesicoureteral reflux.
Reflux renal parenchymal scarring detected on intravenous pyelography can be classified according to the system adopted by the
International Reflux Study Committee consisting of four grades of

severity. In grade 1, mild scarring in no more than two locations is
seen. More severe and generalized scarring is seen in grade 2 but
with normal areas of renal parenchyma between scars. In grade 3, or
so-called backpressure type, contraction of the whole kidney occurs
and irregular thinning of the renal cortex is superimposed on widespread distortion of the calyceal anatomy, similar to changes seen in
obstructive uropathy. Grade 4 is characterized by end-stage renal disease and a shrunken kidney having very little renal function [19].
Parenchymal scarring detected by radionuclide renal scintigraphy
is classified similarly. A, In grade 1, no more than two scarred
areas are detected. B, In grade 2, more than two affected areas are
seen, with some areas of normal parenchyma between them. C,
Grade 3 renal scarring is characterized by general damage to the
entire kidney, similar to obstructive nephropathy. D, In grade 4, a
contracted kidney in end-stage renal failure is seen, with less than
10% of total overall function [14].
FIGURE 8-14
Voiding cystourethrogram demonstrating bilateral grade 5 vesicoureteral reflux. Voiding
cystourethrography is performed by filling the bladder with radiocontrast material and
observing for reflux under fluoroscopy, either during the phase of bladder filling or during micturition. Contrast material is infused through a small urethral catheter under
gravity flow.
8.8
FIGURE 8-15
Radionuclide cystogram demonstrating bilateral vesicoureteral reflux (VUR). This method
using 99mtechnetium pertechnetate is useful in detecting VUR. Advantages of radionuclide
cystography include lower radiation exposure, less interference with overlying bowel contents and bones, and higher sensitivity in detection of VUR. Radionuclide cystography is
useful in follow-up examinations of patients known to have VUR, as a screening test in
asymptomatic siblings of children with reflux and girls with urinary tract infections, and in
serial examinations of children with neuropathic bladders at risk for developing VUR.
Disadvantages of this method include less anatomic detail and inadequacy in evaluating
the male urethra, making it unsuitable for screening boys for urinary tract infections [7].
FIGURE 8-16
A, Intravenous pyelogram and, B, nephrotomogram demonstrating
grade 2 reflux nephropathy. Historically, this testing modality has
been the one most commonly used to evaluate reflux nephropathy
[7]. Irregular renal contour, parenchymal thinning, small renal size,
and calyceal blunting all are radiographic signs of reflux nephropathy on intravenous pyelography [17]. Radiographic changes may
not be visible immediately after renal infection, because scars may

not be fully developed for several years [20]. The advantages of
intravenous pyelography in evaluating reflux nephropathy include
precision in delineating renal anatomic detail and providing baseline measurements for future follow-up evaluations, renal growth,
and scar formation.
FIGURE 8-17
A, Posterior and, B, anterior views of
99mtechnetium-dimercaptosuccinic acid
(DMSA) renal scan showing bilateral grade
2 reflux nephropathy. This nephropathy is
characterized by focal areas of decreased
radionuclide uptake predominantly affecting the lower renal poles.
8.9

13
12
Predicted mean
95% predicted limits
11
Renal length, cm
10
9
8
7
6
5
4
3
2
0 2 4 6 8 10 12
Months
10
15
Years
FIGURE 8-18
Prenatal detection of vesicoureteral reflux (VUR). A,
Ultrasonography showing mild fetal hydronephrosis. B, Postnatal
voiding cystourethrogram (VCUG) showing grade 4 VUR. C,
Graph showing small renal size in the same infant. Vesicoureteral
reflux has been identified in neonates in whom prenatal ultrasonography examination reveals hydronephrosis [2128]. Normal
infants do not have VUR, even when born prematurely [29,30].
The severity of reflux often is not predictable on the basis of
appearance on ultrasonography [22,31]. Hydronephrosis greater
than 4 mm and less than 10 mm in the anteroposterior dimension
on ultrasound examination after 20 weeks gestational age has
been termed mild fetal hydronephrosis. Mild fetal hydronephrosis
is associated with VUR in a significant percentage of infants
[26,31]. Despite the absence of a previous urinary tract infection,
many kidneys affected prenatally exhibit decreased function
[22,24,32,33]. Unlike the focal parenchymal scars seen in infectionassociated reflux nephropathy, the parenchymal abnormalities seen
in prenatal VUR are most commonly manifested by a generalized
decrease in renal size (reflux nephropathy grade 3 or 4) [34,35].
8.10
90
80
70
60
50
40
30
20
10
0
83
Male
Female
FIGURE 8-19
Prenatal detection of vesicoureteral reflux (VUR): gender distribution versus VUR detected
after urinary tract infection (UTI). VUR detected as part of the evaluation of prenatal
hydronephrosis is most commonly identified in boys. In an analysis of six published studies of VUR diagnosed in a total of 124 infants with antenatally detected hydronephrosis,
83% of those affected were boys [33]. Conversely, VUR detected after a UTI most commonly affects girls. In the International Reflux Study in Children (IRSC) and Southwest
Pediatric Nephrology Study Group (SWPNSG) investigations of VUR detected in a total of
380 children after UTI, 77% of those affected were girls [20,36].
77
23
17
Prenatally
detected
Detected
after UTI
Clinical Course of Vesicoureteric Reflux

50
50
40
30
30
20
20
21
10
0
1
Patients studied, %
FIGURE 8-20
Resolution of vesicoureteral reflux (VUR) detected prenatally at follow-up examinations over 2 years. Spontaneous resolution of VUR
can occur in infants with reflux detected during the postnatal evaluation of prenatal urinary tract abnormalities. In an analysis of six
investigations of VUR detected neonatally with a follow-up period
of 2 years, resolution was seen in 50% of infants with grades I and
II. High-grade reflux (grades IV to V) resolved in only 20% [33].
Grade 1
Grade 2
Grade 3
Grade 45
82 80
53
43
40
31
18 20
17 16
Resolution
Improvement
90
80
70
60
50
40
30
20
10
0
Grade 1
Grade 2
Grade 3
Vesicoureteral reflux grade
90
80
70
60
50
40
30
20
10
0
Resolved VUR, %
50
Unchanged
3
Years follow-up
FIGURE 8-21
Resolution of vesicoureteral reflux (VUR) detected postnatally
after urinary tract infection: mild to moderate VUR. The Southwest
Pediatric Nephrology Study Group (SWPNSG) prospectively observed
113 patients aged 4 months to 5 years with grades I to III VUR
detected after urinary tract infection. The SWPNSG reported on 59
children followed up with serial excretory urograms and voiding cystourethrography for 5 years. Mild (grade I and II) VUR resolved after
5 years in the ureters of 80% of these children, and in most cases
within 2 to 3 years. Grade III VUR resolved in only 46% of ureters
in children with VUR [20].
FIGURE 8-22
Resolution of vesicoureteral reflux (VUR) detected postnatally after
urinary tract infection at follow-up examinations over 5 years. Mild
to moderate VUR spontaneously resolves in a significant percentage
of children, whereas high-grade reflux resolves only rarely. The
Southwest Pediatric Nephrology Study Group (SWPNSG) found
that grades I and II VUR resolved in 80% of children with refluxing
ureters at follow-up examinations over 5 years. In the Birmingham
Reflux Study Group (BRSG), International Reflux Study in Children
(IRSC), and SWPNSG investigations of high-grade VUR (grades III
to V) in children, improvement in reflux severity was seen in 30%
to 40% of affected ureters. Spontaneous resolution was rare and
occurred in only 16% to 17% of children with refluxing ureters at
follow-up examinations over 5 years [20,37,38].
8.11
FIGURE 8-23
Resolution of grades III to V vesicoureteral reflux (VUR) detected
postnatally after urinary tract infection: bilateral versus unilateral
VUR. Spontaneous resolution of high-grade VUR is much more
likely to occur in unilateral reflux. The International Reflux Study
in Children (IRSC) showed that grades III to V VUR resolved in
children in whom both kidneys were affected nearly five times as
often (39%) as in those in whom VUR was bilateral (8%). In bilateral VUR, spontaneous resolution did not occur after 2 years of
observation [38].
40
Unilateral
Bilateral
Resolved VUR, %
35
30
25
20
15
10
5
0
Scarred or thinned, %
60
21
33
Months follow-up
45
57
IRSC
BRSG
New scar formation, %
50
40
30
20
10
0
0
III
III
IV
Dilated
Vesicoureteral reflux grade
FIGURE 8-24
Frequency of parenchymal scarring at the time of diagnosis of vesicoureteral reflux (VUR). Many children in whom VUR is detected
after a urinary tract infection already have evidence of renal
parenchymal scarring. In two large prospective studies the frequency of scars seen in persons with VUR increased with VUR severity.
The International Reflux Study in Children (IRSC) studied 306
children under 11 years of age with grades III to V VUR [36]. The
frequency of parenchymal scarring or thinning increased from 10%
in children with nonrefluxing renal units (in children with contralateral VUR) to 60% in those with severely refluxing grade V
kidneys. In another large prospective study, the Birmingham Reflux
Study Group (BRSG) reported renal scarring in 54% of 161 children under 14 years of age with severe VUR resulting in ureteral
dilation (greater than grade 3 using the classification system adopted by the International Reflux Study in Children group) at the time
reflux was detected [39]. Participants in these studies were children
previously diagnosed as having had urinary tract infection.
18
16
14
12
10
8
6
4
2
0
IRSC
SWPNSG
3
Years follow-up
FIGURE 8-25
Development of parenchymal scarring after diagnosis of
vesicoureteral reflux (VUR). Parenchymal scarring occurs after
diagnosis and initiation of therapy as well. The Southwest
Pediatric Nephrology Study Group (SWPNSG) followed up 59
children with mild to moderate VUR (grades I to III) diagnosed
after urinary tract infection [20]. None of the children studied
had parenchymal scarring on intravenous pyelography at the
time of diagnosis. Parenchymal scars were seen to develop in
10% of children over the course of 5 years of follow-up examinations, including some children without documented urinary
tract infections during the period of observation. In this group,
renal scarring occurred nearly three times more commonly in
grade 3 VUR than it did in grades 1 and 2 VUR. In the
International Reflux Study in Children (IRSC) (European
group), a prospective study of high-grade VUR (grades III and
IV), new scars developed in 16% of 236 children after 5 years
observation [40].
FIGURE 8-26
Development of new renal scars versus age at diagnosis of vesicoureteral reflux
(VUR). The frequency of new scar formation appears to be inversely related to age.
The International Reflux Study in Children (IRSC) examined children with high-grade
VUR and found that new scars developed in 24% under 2 years of age, 10% from 2
to 4 years of age, and 5% over 4 years of age [40].
8.12
Renal scarring, %
Treatment of Vesicoureteric Reflux

18
16
14
12
10
8
6
4
2
0
Surgical
Medical
10
15
20
25 30 35 40
Months follow-up
45
50
55
60
UTI versus pyelonephritis, %
Urinary tract infections, %
FIGURE 8-27
Effectiveness of medical versus surgical treatment: new scar formation at follow-up examinations over 5 years in children with highgrade vesicoureteral reflux (VUR). The International Reflux Study
in Children (IRSC) (European group) was designed to compare the
effectiveness of medical versus surgical therapy of VUR in children
diagnosed after urinary tract infection. Surgery was successful in
40
35
30
25
20
15
38
39
34
28
21
10
5
0
40
35
30
25
20
15
10
5
0
Nonpyelonephritic
UTI
Pyelonephritis
17
29
21
10
Medical Surgical
therapy therapy
BRSG-Surgical
BRSG- Medical
IRSC-Medical
IRSC-Surgical
SWPNSG
correcting VUR in 97.5% of 231 reimplanted ureters in 151 children randomized to surgical therapy. Medical therapy consisted of
long-term antibiotic uroprophylaxis using nitrofurantoin, trimethoprim, or trimethoprim-sulfa. No statistically significant advantage
was demonstrable for either treatment modality with respect to
new scar formation after 5 years of observation in either study.
New scars were identified in 20 of the 116 children treated surgically (17%) and 19 of the 155 children treated medically (16%) at
follow-up examinations over 5 years. Those children treated surgically who developed parenchymal scars generally did so within the
first 2 years after ureteral repeat implantation, whereas scarring
occurred throughout the observation period in the group that did
not have surgery. VUR persisted in 80% of children randomized to
medical treatment after follow-up examinations over 5 years.
The results of the IRSC paralleled the findings of the
Birmingham Reflux Study Group (BRSG) investigation of medical
versus surgical therapy for VUR in 161 children. After 2 years of
observation, progressive or new scar formation was seen in 16% of
children with refluxing ureters in the group treated surgically and
19% in the group treated medically. In contrast to the IRSC, however, new scar formation was rare after 2 years of observation in
both groups [37,40].
FIGURE 8-28
Effectiveness of medical versus surgical treatment: incidence of urinary tract infections. Vesicoureteral reflux (VUR) predisposes affected
persons to urinary tract infection owing to incomplete bladder emptying and urinary stasis. Medical therapy with uroprophylactic antibiotics and surgical correction of VUR have as a goal the prevention of
urinary tract infection. In three prospective studies of 400 children
with VUR (Southwest Pediatric Nephrology Study Group [SWPNSG],
International Reflux Study in Children [IRSC], Birmingham Reflux
Study Group [BRSG]) treated either medically or surgically and who
were observed over 5 years the rate of infection was similar, ranging
from 21% to 39%. The rate of infection was no different between the
group treated medically and that treated surgically [20,37,39].
FIGURE 8-29
Effectiveness of medical versus surgical treatment: incidence of urinary tract infection versus pyelonephritis in severe vesicoureteral reflux (VUR). Although the incidence of urinary tract infections (UTIs) is the same in surgically and medically treated children with
VUR, the severity of infection is greater in those treated medically. The International
Reflux Study in Children (IRSC) (European group) studied 306 children with VUR and
observed them over 5 years; 155 were randomized to medical therapy, and 151 had surgical correction of their reflux. Although the incidence of UTI statistically was no different
between the groups (38% in the medical group, 39% in the surgical group), children
treated medically had an incidence of pyelonephritis twice as high (21%) as those treated
surgically (10%) [41].
VUR detected
Associated GU anomalies
expected to affect VUR?
Yes
No
Treat appropriately
Severity of VUR
Mild (I-III)
Severe (IV-V)
Uroprophylaxis
Hygiene education
Surveillance urine cultures
Annual VCUG
Functional study
(Radionuclide or ExU)
Nonfunctioning
kidney
Urinary tract infections?
Consider
nephrectomy
Yes
No
Consider surgery
Resolution of VUR after 2 years
Yes
Female
Consider
surgery
Surgical
correction
Resolution of VUR after 2 years
Male
Consider
surgery
Uroprophylaxis
Annual VCUG
No
Long term
followup to
detect UTI
Functioning
kidney
Consider observation
off antibiotics
Yes
No
Long term
followup
Surgery
FIGURE 8-30
Proposed treatment of vesicoureteral reflux (VUR) in children. This algorithm provides an
approach to evaluate and treat VUR in children. In VUR associated with other genitourinary anomalies, therapy for reflux should be part of a comprehensive treatment plan
directed toward correcting the underlying urologic malformation. Children with mild VUR
should be treated with prophylactic antibiotics, attention to perineal hygiene and regular
bowel habits, surveillance urine cultures, and annual voiding cystourethrogram (VCUG).
Children with recurrent urinary tract infection on this regimen should be considered for
8.13
surgical correction. In children in whom

VUR resolves spontaneously, a high index
of suspicion for urinary tract infection
should be maintained, and urine cultures
should be obtained at times of febrile illness
without ready clinical explanation.
In persons in whom mild VUR fails to
resolve after 2 to 3 years of observation,
consideration should be given to voiding pattern. A careful voiding history and an evaluation of urinary flow rate may reveal abnormalities in bladder function that impede resolution of reflux. Correction of
dysfunctional voiding patterns may result in
resolution of VUR. In the absence of dysfunctional voiding, it is controversial
whether older women with persistent VUR
are best served by surgical correction or
close observation with uroprophylactic
antibiotic therapy and surveillance urine cultures, especially during pregnancy. Males
with persistent low-grade VUR may be candidates for close observation with surveillance urine cultures while not receiving
antibiotic therapy, especially if they are over
4 years of age and circumcised. Circumcision
lowers the incidence of urinary tract infection. In severe VUR the function of the
affected kidney should be evaluated with a
functional study (radionuclide renal scan).
High-grade VUR in nonfunctioning kidneys
is unlikely to resolve spontaneously, and
nephrectomy may be indicated to decrease
the risk of urinary tract infection and avoid
the need for uroprophylactic antibiotic therapy. In patients with functioning kidneys who
have high-grade VUR, the likelihood for resolution should be considered. Severe VUR,
especially if bilateral, is unlikely to resolve
spontaneously. Proceeding directly to repeat
implantation may be indicated in some cases.
Medical therapy with uroprophylactic antibiotics and serial VCUG may also be used,
reserving surgical therapy for those in whom
resolution fails to occur.
Complications of Reflux Nephropathy

FIGURE 8-31
Development of hypertension in 55 normotensive subjects with reflux nephropathy at follow-up examinations over 15 years. The incidence of hypertension in persons with reflux
nephropathy increases with age and appears to develop most commonly in young adults
within 10 to 15 years of diagnosis. In a cohort of 55 normotensive persons with reflux
nephropathy observed for 15 years, 5% became hypertensive after 5 years. This percentage increased to 16% at 10 years, and 21% at 15 years. The grading system for severity of
scarring was different from the system adopted by the International Reflux Study
Committee. Nevertheless, using this system, 78% of persons in the group could be classified as having reflux nephropathy severity scores between 1 and 4 [42].
Hypertensive, %
25
20
15
10
5
0
0
10
Years
15
8.14
FIGURE 8-32
Frequency of hypertension versus severity of parenchymal scarring. The frequency of
hypertension in persons with vesicoureteral refluxrelated renal scars is higher than in the
normal population. In adults with reflux nephropathy the incidence of hypertension can be
correlated with the severity of renal scarring. Adding the individual grade of reflux (04)
for the two kidneys results in a scale ranging from 0 (no scars) to 8 (severe bilateral scarring). Persons with cumulative scores of parenchymal scarring from 1 to 4 have a 30%
incidence of hypertension, whereas 60% of those with scarring scores ranging from 5 to 8
have hypertension [42,43].
Hypertensive, %
100
80
60
40
20
0
14
58
Cumulative reflux scarring severity score
FIGURE 8-33
Glomerular hypertrophy and focal segmental glomerulosclerosis (FSGS) in severe
reflux nephropathy. Reflux nephropathy resulting in reduced renal functional mass
induces compensatory changes in

glomerular and vascular hemodynamics.
These changes initially maintain the
glomerular filtration rate but are maladaptive over time. AD, Compensatory
hyperfiltration results in renal injury
manifested histologically by glomerular
hypertrophy and FSGS and clinically as
persistent proteinuria [44]. In reflux
nephropathy, proteinuria is a poor prognostic sign, indicating that renal injury
has occurred. The severity of proteinuria
is inversely proportional to functioning
renal mass and the glomerular filtration
rate and directly proportional to the
degree of global glomerulosclerosis.
Surgical correction of vesicoureteral
reflux has not been found to prevent
further deterioration of renal function
after proteinuria has developed. Hyperfiltration resulting from decreased renal
mass continues and produces progressive
glomerulosclerosis and loss of renal function. Evidence exists that inhibition of the
renin-angiotensin system through the use of
angiotensin-converting enzyme inhibitors
decreases the compensatory hemodynamic
changes that produce hyperfiltration
injury. Thus, these inhibitors may be
effective in slowing the progress of renal
failure in reflux nephropathy.
8.15
Pathogenesis of Obstructive Nephropathy

FIGURE 8-34
Consequences of urinary tract obstruction for the developing kidney in animals. The
effects of urinary tract obstruction on the developing kidney depend on the time of onset,
location, and degree of obstruction. Ureteral obstruction during early pregnancy results in
disorganization of the renal parenchyma (dysplasia) and a reduction in the number of
nephrons. Partial or complete ureteral obstruction in neonates causes vasoconstriction,
glomerular hypoperfusion, impaired ipsilateral renal growth, and interstitial fibrosis. The
degree of impairment of the ipsilateral kidney, in the case of partial unilateral ureteral
obstruction, and of compensatory hypertrophy of the contralateral kidney, in the case of
partial or complete unilateral ureteral obstruction, is inversely related to the age of the animal at the time of obstruction. The older the animal, the less the impairment of the ipsilateral kidney and the less the compensatory growth of the contralateral kidney. In addition,
the recovery of renal function after relief of urinary tract obstruction also decreases with
the age of the animal [45].
Birth
Neonate
Fetus
Adult
Dysplasia
Number of
nephrons
Renal growth
Compensatory hypertrophy*
Recovery of function
after relief of obstruction
*When unilateral
FIGURE 8-35
Renal hemodynamic response to mild partial ureteral obstruction. Renal blood flow and
the glomerular filtration rate may not change in mild partial ureteral obstruction, despite a
significant reduction in glomerular capillary ultrafiltration coefficient (Kf). This is due to
the increase in glomerular capillary hydraulic pressure (PGC) caused by a prostaglandin
E2induced reduction of afferent arteriolar resistance (RA) and an angiotensin IIinduced
elevation of efferent arteriolar resistance (RE). It is likely that other vasoactive factors,
such as thromboxane A2, also play a role, particularly in more severe ureteral obstruction
accompanied by reductions in renal blood flow and glomerular filtration rate [46].
PGE2prostaglandin E2; PGI2prostaglandin I2; Pttubule hydrostatic pressure.
PGE2, PGI2
Angiotensin II
RA
PGC
RE
Kf
Pt
2 h post-obstruction
24 h post-obstruction
PGE2, PGI2
N0
RA
PGC
Endothelin
TBX A 2
RE
RBF (120%)
GFR (80%)
PGC
RA
PGC
RE
RE
RBF (50%)
GFR (20%)
(Activation of
renin-angiotensin)
Unilateral
Pt
RA
(Macrophage
infiltration)
Angiotensin II
Pt
RA
PGC
RE
+ ANP
RBF (120%)
GFR (80%)
Pt
RBF (50%)
GFR (20%)
Bilateral
Pt
FIGURE 8-36
Acute renal hemodynamic response to unilateral or bilateral complete ureteral obstruction. In the first 2 hours after unilateral complete ureteral obstruction, there is a reduction in preglomerular
vascular resistance and an increase in renal blood flow mediated by

increased production of prostaglandin E2 (PGE2), prostacyclin, and
nitric oxide (NO). The increase in renal blood flow (RBF) and
glomerular capillary pressure maintain the glomerular filtration rate
(GFR) at approximately 80% of normal, despite an increase in
intratubular pressure. As the ureteral obstruction persists, activation
of the renin-angiotensin system and increased production of thromboxane A2 (TBXA2) and endothelin result in progressive vasoconstriction, with reductions in renal blood flow and glomerular capillary pressure. The glomerular filtration rate decreases to approximately 20% of baseline, despite normalization of the intratubular
pressures. The hemodynamic changes in the early phase (02 h) of
bilateral ureteral obstruction are similar to those observed after unilateral obstruction. As bilateral obstruction persists, however, there is
an accumulation of atrial natriuretic peptide (ANP) that does not
occur after unilateral obstruction. The increased ANP levels attenuate the afferent and enhance the efferent vasoconstrictions, with
maintenance of normal glomerular capillary and elevated tubular
pressures. Despite these differences in hemodynamic changes
between unilateral and bilateral ureteral obstruction, the reductions
in renal blood flow and glomerular filtration rate 24 hours after
obstruction are similar [4749]. PGCglomerular capillary hydraulic
pressure; PGI2prostaglandin I2; Pttubule hydrostatic pressure;
RAafferent arteriolar resistance; REefferent arteriolar resistance.
8.16
Change from baseline, %
300
Intrapelvic pressure
Renal blood flow
200
100
FIGURE 8-37
Chronic renal hemodynamic response to complete unilateral ureteral obstruction. During complete ureteral obstruction, renal blood
flow progressively decreases. Renal blood flow is 40% to 50% of
normal after 24 hours, 30% at 6 days, 20% at 2 weeks, and 12%
at 8 weeks [48].
Baseline
50
0
Weeks after obstruction
Cortex
Cortex
Medulla
40
Leukocytes, 105/g
Leukocytes, 105/g
40
30
20
Medulla
Release of obstruction
Release of obstruction
30
20
10
10
0
0
Control 4 h
12 h
24 h
Cortex
Medulla
Control 4 h
12 h
24 h
3 4
Days
3 4
Days
FIGURE 8-38
Development of interstitial cellular infiltrates in the renal cortex
and medulla after ureteral obstruction. After ureteral obstruction
there is a rapid influx of macrophages and suppressor T lymphocytes in the cortex and medulla (A) that is accompanied by an
increase in urinary thromboxane B2 and a decrease in the glomerular filtration rate. The production of thromboxane A2 by the infiltrating macrophages (B) contributes to the renal vasoconstriction
of chronic urinary tract obstruction. After release of the obstruction the cellular infiltration is slowly reversible, requiring several
days to revert to near normal levels (C) [50,51].
Tubular obstruction
Pt
PDGF
Osteopontin
MCP
Renin, angiotensinogen,
ACE, AT1 receptor
Bradykinin
Macrophages
TGF-
Nitric oxide
O2
H 2O 2
EGF
bcl2
CuZnSOD
Catalase
TIMP
Collagen
Fibroblasts,
myofibroblasts
Apoptosis,
tubular drop-out
Tubulointerstitial
fibrosis
FIGURE 8-39
Pathogenesis of tubulointerstitial fibrosis in obstructive nephropathy. This pathogenesis
has been extensively studied. Increased expression of renin, angiotensinogen, angiotensinconverting enzyme (ACE), and the angiotensin II type 1 (AT1) receptor occurs in the
Obstruction
100
80
60
40
20
0
0
12
14
16
18
Weeks after obstruction
20
22
24
8.17
obstructed kidney. Angiotensin II can

induce the synthesis of transforming growth
factor (TGF-), a cytokine that stimulates
extracellular matrix synthesis and inhibits
its degradation. Obstructive nephropathy
is accompanied by downregulation of the
kallikrein-kinin system and nitric oxide
production that can be reversed by administration of a converting enzyme inhibitor or
of L-arginine. The rapid upregulation of
chemotactic factors such as monocyte
chemoattractant peptide 1 (MCP-1) and
osteopontin in the tubular epithelial cells,
in response to increased intratubular pressure, contributes to the recruitment of
macrophages. Macrophages produce
fibroblast growth factor and induce fibroblast proliferation and myofibroblast transformation. The downregulation of epidermal growth factor (EGF), Bcl 2, and antioxidant enzymes and the increased production
of superoxide and hydrogen peroxide
(H2O2) contribute to an increased rate of
apoptosis and tubular dropout [51 57].
PDGFplatelet-derived growth factor;
SODsuperoxide dismutase; TIMPtissue
inhibitor of metalloproteinases.
FIGURE 8-40
Recovery of renal function after relief of complete unilateral
ureteral obstruction of variable duration. The recovery of the ipsilateral glomerular filtration rate after relief of a unilateral complete ureteral obstruction has been best studied in dogs and
depends on the duration of the obstruction. Complete recovery
occurs after 1 week of obstruction. The degree of recovery after 2
and 4 weeks of obstruction is only of 58% and 36%, respectively.
No recovery occurs after 6 weeks of obstruction [58]. Rare
reports of recovery of renal function in patients with longer periods of unilateral ureteral obstruction may represent high-grade
partial obstruction rather than complete obstruction or may
reflect differences in lymphatic drainage and renal anatomy
between the human and canine kidneys [59].
8.18
Clinical Manifestations of Obstructive Nephropathy

Functional
abnormalities
in obstructed
kidneys
(unilteral or
bilateral)
Damage to
inner medulla
Na+reabsorption
Loop of Henle
Medullary
blood flow
( Na+/K+ ATPase)
Collecting duct
Corticomedullary
concentration gradient
Resistance
to ADH
Intraluminal
negative potential
Na+ wasting
Concentration defect
Consequences
of bilateral
obstruction
H+ secretion
K+ secretion
H+-ATPase
Na+/K+ ATPase
ECFV excess
ANP
Osmotic load (urea)
Clinical
correlates
Excessive replacement
Postobstructive diuresis after
relief of bilateral obstruction
(volume contraction,
hypomagnesemia, other
electrolyte abnormalities)
Hypernatremia
when free
water intake is
inadequate
FIGURE 8-42
Clinical manifestations of obstructive nephropathy. These manifestations depend on the cause of the obstruction, its anatomic location, its severity, and its rate of development [61,68,69].
Unilateral
Partial or complete
Pain (dull aching Renin-dependent
renal colic)
hypertension
Susceptibility to Erythrocytosis
urinary tract
(rare)
infection and
nephrolithiasis
Bilateral or solitary kidney
Partial
Hyperkalemic
metabolic acidosis
in partial bilateral
ureteral obstruction
FIGURE 8-41
Clinical correlates of abnormalities of tubular function in obstructive nephropathy.
Acute ureteral obstruction stimulates tubular
reabsorption, resulting in increased urine
osmolality and reduced urine sodium concentration [60]. In contrast, obstructive
nephropathy is characterized by a reduced
ability to concentrate the urine, reabsorb
sodium, and secrete hydrogen ions (H+) and
potassium. In unilateral obstructive
nephropathy, these functional abnormalities
do not have a clinical correlate because of
the reduced glomerular filtration rate and
immaterial contribution of the obstructed
kidney to total renal function. Hyperkalemic
metabolic acidosis and, when the intake of
free water is not adequate, hypernatremia
can occur in patients with partial bilateral
ureteral obstruction or partial ureteral
obstruction in a solitary kidney. Similarly,
postobstructive diuresis can occur only after
relief of bilateral ureteral obstruction or
ureteral obstruction in a solitary kidney but
not after relief of unilateral obstruction
[6167]. ADH>\#209>antidiuretic hormone;
ANPatrial natriuretic peptide; ECFV
extracellular fluid volume; Na-K ATPase
sodium-potassium adenosine triphosphatase.
Complete
Polyuria, polydipsia Anuria Bladder

Uremia symptoms
Hypernatremia
Fluctuating
Volume contraction
urine
Hyperkalemic
output
metabolic acidosis
Uremia
Volume-dependent
hypertension
8.19
Diagnosis of Obstructive Nephropathy

1.0
Furosemide
Obstruction
Tracer activity
Baseline
Saline
Saline + furosemide
0.8
RI
0.6
0.4
Hydronephrosis
without obstruction
0.2
Normal
0.0
Time
Partial obstruction
FIGURE 8-43
Diagnosis of obstructive nephropathy. A, Diuresis renography. B, Doppler ultrasonography. C, D, Magnetic resonance urogram utilizing a single shot fast spin echo technique
with anterior-posterior projection (C) and left posterior oblique projection (D). Images
demonstrate a widely patent right ureteropelvic junction in a patient with abdominal pain
and suspected ureteropelvic junction obstruction. Administration of gadolinium is not
required for this technique. Note also the urine in the bladder, cerebrospinal fluid in the
spinal canal, and fluid in the small bowel.
Ultrasonography is the procedure of choice to determine the presence or absence of a
dilated renal pelvis or calices and to assess the degree of associated parenchymal atrophy.
Contralateral kidney
Nevertheless, obstruction rarely can occur

without hydronephrosis, when the ureter
and renal pelvis are encased in a fibrotic
process and unable to expand. In contrast,
mild dilation of the collecting system of no
functional significance is not unusual. Even
obvious hydronephrosis in some cases may
not be associated with functional obstruction [70]. Diuresis renography is helpful
when the functional significance of the
dilation of the collecting system is in question [71,72]. Renal Doppler ultrasonography before and after administration of normal saline and furosemide also has been
used to differentiate obstructive from
nonobstructive pyelocaliectasis [73]. Other
techniques such as excretory urography,
computed tomography, and retrograde or
antegrade ureteropyelography are helpful
to determine the cause of the urinary tract
obstruction. The utility of excretory urography is limited in patients with advanced
renal insufficiency. In these cases magnetic
resonance urography can provide coronal
imaging of the renal collecting systems and
ureters similar to that of conventional
urography without the use of iodinated
contrast. RI resistive index. (C, D,
Courtesy of B. F. King, MD.)
FIGURE 8-44
Diagnosis of obstructive nephropathy by postnatal renal ultrasonography, showing hydronephrosis in ureteropelvic junction
obstruction. Renal ultrasonography is a sensitive test to detect
hydronephrosis. The absence of ureteral dilation is consistent with
obstruction at the level of the ureteropelvic junction.
8.20
Before Furosemide
After Furosemide
1 min.
5 min.
10 min.
15 min.
Lt
Rt
Lt
Rt
FIGURE 8-45
Mercaptoacetyltriglycine-3 renal scan with furosemide in a newborn with left ureteropelvic junction obstruction. A diuretic renal
scan using 99mtechnetium-mercaptoacetyltriglycine (99mTc-MAG-3)
showing differential renal function (47% right kidney; 53% left
kidney) at 1 to 2 minutes after radionuclide administration is seen.
A significant amount of radionuclide remains in each kidney 15
minutes after administration. After administration of furosemide,
however, the isotope is seen to disappear rapidly from the right
kidney (t1/2 of radioisotope washout in 4.9 minutes) but persists
in the hydronephrotic left kidney (t1/2 in 50.1 minutes). A t1/2 of
the radioisotope in less than 10 minutes is thought to reflect a lack
of significant obstruction. A t1/2 of over 20 minutes is suggestive
of obstruction. Intermediate values of washout are indeterminate.
The most appropriate therapy for infants with delayed renal pelvic
radioisotope washout and diagnosis of ureteropelvic junction
obstruction is controversial. Some authors advocate pyeloplasty to
alleviate the obstruction based on renal scan results, whereas others advocate withholding surgery unless renal function deteriorates
or hydronephrosis progresses.
8.21
Posterior Urethral Valves
Type I
FIGURE 8-46
Posterior urethral valves. A, Illustrative
diagram. B, Pathology specimen. Valvular
obstruction at the posterior urethra is the
most common cause of lower urinary tract
obstruction in boys. Anatomically, the
lesion most commonly is comprised of an
oblique diaphragm with a slitlike perforation arising from the posterior urethra distal to the verumontanum and inserting at
the midline anterior urethra. (From Kaplan
and Scherz [74]; with permission.)
FIGURE 8-47
Excretory urogram of a patient with posterior urethral valves. Bladder outlet obstruction results in bladder wall thickening, trabeculation, and formation of diverticula.
Increased intravesical pressure may result
in vesicoureteral reflux, as is seen on the
left. Obstruction resulting in increased
intrarenal pressure may result in rupture
at the level of a renal fornix, producing a
urinoma, or perirenal collection of urine,
as seen on the right.
B
FIGURE 8-48
Voiding cystourethrogram (VCUG) demonstrating posterior urethral valves and dilation
of the posterior urethra. Urethral valves are best detected by VCUG. The obstructing
valves are seen as oblique or perpendicular folds with proximal urethral dilation and elongation. Distal to the valves the urinary stream is diminished. Alleviating the bladder outlet
obstruction is indicated, either by lysis of the valves themselves or by way of vesicostomy,
in small infants until sufficient growth occurs to make valve resection technically feasible.
8.22
Ureterovesical Junction Obstruction

FIGURE 8-49
Excretory urogram showing ureterovesical junction obstruction in a 2-year-old girl.
Retroperitoneal Fibrosis
A
FIGURE 8-50
AH, Idiopathic retroperitoneal fibrosis: computed tomography
scans of the abdomen before (left panels, note right ureteral stent
and mild left ureteropyelocaliectasis) and 7 years after ureterolysis
(right panels, note omental interposition). Retroperitoneal fibrosis
is characterized by the accumulation of inflammatory and fibrotic
tissue around the aorta, between the renal hila and the pelvic brim.
Most cases are idiopathic; the remainder are associated with
immune-mediated connective tissue diseases, ingestion of drugs
such as methysergide, abdominal aortic aneurysms, or malignancy.
Idiopathic retroperitoneal fibrosis can be associated with mediasti-
B
nal fibrosis, sclerosing cholangitis, Riedels thyroiditis, and fibrous
pseudotumor of the orbit. In the clinical setting, patients with idiopathic retroperitoneal fibrosis exhibit systemic symptoms such as
malaise, anorexia and weight loss, and abdominal or flank pain.
Renal insufficiency is often seen and is caused by bilateral ureteral
obstruction. Laboratory test results usually demonstrate anemia
and an elevated sedimentation rate. The treatment is directed to the
release of the ureteral obstruction, which initially can be achieved
by placement of ureteral stents. Administration of corticosteroids is
helpful to control the systemic manifestations of the disease and

often to reduce the bulk of the tumor and relieve the ureteral
obstruction. Administration of corticosteroids, however, should be
considered only when malignancy and retroperitoneal infection can
be ruled out. As in other chronic renal diseases, administration of
corticosteroids should be kept at the minimal level capable of controlling symptoms. Surgical ureterolysis, which consists of freeing
8.23
the ureters from the fibrotic mass, lateralizing them, and wrapping
them in omentum to prevent repeat obstruction, is often necessary.
Other immunosuppressive agents have been used rarely when the
systemic manifestations of the disease cannot be controlled with
safe doses of corticosteroids. In most cases the long-term outcome
of idiopathic retroperitoneal fibrosis is satisfactory [7577].
8.24
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8.25
62. Campbell HT, Bello-Reuss E, Klahr S: Hydraulic water permeability

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J Med 1996, 335:650655.
Cystic Diseases
of the Kidney
Yves Pirson
Dominique Chauveau
kidney cyst is a fluid-filled sac arising from a dilatation in any

part of the nephron or collecting duct. A sizable fraction of all
kidney diseasesperhaps 10% to 15%are characterized by
cysts that are detectable by various imaging techniques. In some, cysts
are the prominent abnormality; thus, the descriptor cystic (or polycystic). In others, kidney cysts are an accessory finding, or are only
sometimes present, so that some question whether they are properly
classified as cystic diseases of the kidney. In fact, the commonly
accepted complement of cystic kidney diseases encompasses a large
variety of disorders of different types, presentations, and courses.
Dividing cystic disorders into genetic and nongenetic conditions
makes sense, not only conceptually but clinically: in the former cystic
involvement of the kidney often leads to renal failure and is most often
associated with extrarenal manifestations of the inherited defect,
whereas in the latter cysts rarely jeopardize renal function and generally are not part of a systemic disease.
In the first section of this chapter we deal with nongenetic (ie,
acquired and developmental) cystic disorders, emphasizing the imaging
characteristics that enable correct identification of each entity. Some
common pitfalls are described. A large part of the section on genetic
disorders is devoted to the most common ones (eg, autosomal-dominant polycystic kidney disease), focusing on genetics, clinical manifestations, and diagnostic tools. Even in the era of molecular genetics, the
diagnosis of the less common inherited cystic nephropathies relies on
proper recognition of their specific renal and extrarenal manifestations.
Most of these features are illustrated in this chapter.
CHAPTER
9.2
General Features
FIGURE 9-1
Principal cystic diseases of the kidney.
Classification of the renal cystic disorders,
with the most common ones printed in bold
type. (Adapted from Fick and Gabow [1];
Welling and Grantham [2]; Pirson, et al. [3].)
PRINCIPAL CYSTIC DISEASES OF THE KIDNEY

Nongenetic
Genetic
Acquired disorders
Simple renal cysts (solitary or multiple)
Cysts of the renal sinus (or peripelvic lymphangiectasis)
Acquired cystic kidney disease (in patients with
chronic renal impairment)
Multilocular cyst (or multilocular cystic nephroma)
Hypokalemia-related cysts
Developmental disorders
Multicystic dysplastic kidney
Pyelocalyceal cysts
Autosomal-dominant
Autosomal-dominant polycystic kidney disease
Tuberous sclerosis complex
von Hippel-Lindau disease
Glomerulocystic kidney disease
Autosomal-recessive
Autosomal-recessive polycystic kidney disease
Nephronophthisis
X-linked
Orofaciodigital syndrome, type I
IMAGING CHARACTERISTICS OF THE MOST COMMON RENAL CYSTIC DISEASES

Disease
Kidney Size
Cyst Size
Cyst Location
Liver
Simple renal cysts

Acquired renal cystic disease
ADPKD
ARPKD
NPH
Normal
Most often small, sometimes large
Normal or slightly enlarged
Enlarged
Enlarged
Small
Variable (mm10 cm)

0.52 cm
mm
Variable (mm10 cm)
mm increase with age
mm2 cm (when present)
All
All
Precalyceal
All
All
Medullary
Normal
Normal
Normal (most often)
Cysts (most often)
CHF
Normal
FIGURE 9-2
Characteristics of the most common renal cystic diseases detectable
by imaging techniques (ultrasonography, computed tomography,
magnetic resonance). In the context of family history and clinical
findings, these allow the clinician to establish a definitive diagnosis
in the vast majority of patients. ADPKDautosomal-dominant

polycystic kidney disease; ARPKDautosomal-recessive polycystic
kidney disease; CHFcongenital hepatic fibrosis; NPH
nephronophthisis.
9.3
Cystic Diseases of the Kidney
Nongenetic Disorders
FIGURE 9-3
Solitary simple cyst. Large solitary cyst found incidentally at ultrasonography (longitudinal scan) in the lower pole of the right kidney. Criteria for the diagnosis of simple cyst include absence of
internal echoes, rounded outline, sharply demarcated, smooth
walls, bright posterior wall echo (arrows). The latter occur because
less sound is absorbed during passage through cyst than through
the adjacent parenchyma. If these criteria are not satisfied, computed tomography can rule out complications and other diagnoses.
PREVALENCE OF SIMPLE RENAL CYSTS DETECTED BY ULTRASONOGRAPHY

Prevalence, %
1 Cyst
2 Cysts*
3 Cysts*
1 Cyst in Each Kidney
Age group, y
1529
3049
5069
70
0
2
15
32
0
1
7
15
0
0
2
17
0
1
1
8
0
0
1
6
0
1
1
3
0
0
2
9
0
1
1
3
*Unilateral or bilateral. Mmale; FFemale.
FIGURE 9-4
Prevalence of simple renal cysts detected by ultrasonography
according to age in an Australian population of 729 persons
prospectively screened by ultrasonography. The prevalence
increases with age and is higher in males. Cyst size also increases
with age. Most simple cysts are located in the cortex. (From
Ravine et al. [4]; with permission.)
9.4
A
FIGURE 9-5
A and B, Multiple simple cysts (one 7 cm in diameter in the lower
pole of the left kidney and three 4 to 5 cm in diameter in the right
kidney) detected by contrast-enhanced computed tomography (CT).
Additional millimetric cysts might be suspected in both kidneys.
A
FIGURE 9-6
A, Contrast-enhanced computed tomography (CT) shows a
simple, 3-cm wide cyst of the renal sinus (arrows) found during
investigation of renal calculi. Note subcapsular hematoma
(arrowheads) detected after lithotripsy. B, Contrast-enhanced
CT shows bilateral multiple cysts of the renal sinus, leading to
chronic compression of the pelvis and subsequent renal atrophy.
B
Each cyst exhibits the typical features of an uncomplicated simple
cyst on CT: 1) homogeneous low density, unchanged by contrast
medium; 2) rounded outline; 3) very thin (most often indetectable)
wall; 4) distinct delineation from adjacent parenchyma.
B
Ultrasonographic appearance mimicked hydronephrosis. Also
known as hilar lymphangiectasis or peripelvic (or parapelvic)
cysts, this acquired disorder consists of dilated hilar lymph
channels. Its frequency is about 1% in autopsy series. Although
usually asymptomatic, cysts of the renal sinus can cause severe
urinary obstruction, B.
9.5
FIGURE 9-7
A, Acquired cystic kidney disease (ACKD) detected by contrastenhanced computed tomography (CT) in a 71-year-old man on
hemodialysis for 4 years. A, Note the several intrarenal calcifications, which are not unusual in dialysis patients. ACKD is characterized by the development of many cysts in the setting of chronic
uremia. It can occur at any age, including childhood, whatever the
original nephropathy. The diagnosis is based on detection of at
least three to five cysts in each kidney in a patient who has chronic
renal failure but not hereditary cystic disease. The prevalence of
ACKD averages 10% at onset of dialysis treatment and subsequently increases, to reach 60% and 90% at 5 and 10 years into
Age <55 and > 3 years No

on RRT and good
clinical condition?
No
screening
Yes
Echography:
ACKD?
No
Yes
Suspicion of
renal neoplasm?
No
Yes
No
Enhanced CT:
confirmed neoplasm?
Yes
Nephrectomy
and annual
follow-up of
contralateral kidney
Biennial echo
hemodialysis and peritoneal dialysis, respectively [5]. In the early

stage, kidneys are small or even shrunken and cysts are usually
smaller than 0.5 cm. Cyst numbers and kidney volume increase
with time, as seen on this patients scan (B) repeated 8 years into
dialysis. Advanced ACKD can mimic autosomal-dominant polycystic disease. ACKD sometimes regresses after successful transplantation; it can involve chronically rejected kidney grafts. Although
ACKD is usually asymptomatic it may be complicated by bleedingconfined to the cysts or extending to either the collecting system (causing hematuria) or the perinephric spacesand associated
with renal cell carcinoma. (Courtesy of M. Jadoul.)
FIGURE 9-8
Screening for acquired cystic kidney disease (ACKD) and renal neoplasms in patients receiving renal replacement therapy (RRT). The major clinical concern with ACKD is the risk of
renal cell carcinoma, often the tubulopapillary type, associated with this disorder: the incidence is 50-times greater than in the general population. Moreover, ACKD-associated renal
carcinoma is more often bilateral and multicentric; however, only a minority of them evolve
into invasive carcinomas or cause metastases [5]. There is no doubt that imaging should be
performed when a dialysis patient has symptoms such as flank pain and hematuria, the
question of periodic screening for ACKD and neoplasms in asymptomatic dialysis patients
is still being debated. Using decision analysis incorporating morbidity and mortality associated with nephrectomy in dialysis patients, Sarasin and coworkers [6] showed that only the
youngest patients at risk for ACKD benefit from periodic screening. On the basis of this
analysis, it has been proposed that screening be restricted to patients younger than 55 years,
who have been on dialysis at least 3 years and are in good general condition. Recognized
risk factors for renal cell carcinoma in ACKD are male gender, uremia of long standing,
large kidneys, and analgesic nephropathy.
9.6
FIGURE 9-9
Multilocular cyst (or multilocular cystic
nephroma) of the right kidney, detected by
ultrasonography (A) and contrast-enhanced
CT-scan (B). Both techniques show the
characteristic septa (arrow) dividing the
mass into multiple sonolucent locules. This
rare disorder is usually a benign tumor,
though some lesions have been found to
contain foci of nephroblastoma or renal
clear cell carcinoma. The imaging appearance is actually indistinguishable from
those of the cystic forms of Wilms tumor
and renal clear cell carcinoma. (Courtesy
of A. Dardenne.)
B
FIGURE 9-10
A, contrast-enhanced computed tomography (CT) for evaluation
of a left renal stone in a 67-year-old man. A cystic mass was found
at the lower pole of the right kidney. Only careful examination
revealed that the walls of the mass (arrows) were too thick for a
simple cyst (see Fig. 9-5 for comparison). B, The echo pattern of
the mass was very heterogeneous (arrows), clearly different from
the echo-free appearance of a simple cyst (see Fig. 9-3 for comparison). C, Magnetic resonance imaging showed thick, irregular
walls and a hyperintense central area (arrows). At surgery, the
mass proved to be a largely necrotic renal cell carcinoma. Thus,
although renal carcinoma is not a true cystic disease, it occasionally has a cystic appearance on CT and can mimic a simple cyst.
(Courtesy of A. Dardenne.)
9.7
FIGURE 9-11
Medullary sponge kidney (MSK) diagnosed by intravenous urography in 53-year-old
woman with a history of recurrent kidney stones. Pseudocystic collections of contrast medium in the papillary areas (arrows) are the typical feature of MSK. They result from congenital dilatation of collecting ducts (involving part or all of one or both kidneys), ranging
from mild ectasia (appearing on urography as linear striations in the papillae, or papillary
blush) to frank cystic pools, as in this case (giving a spongelike appearance on section of
the kidney). MSK has an estimated prevalence of 1 in 5000 [2]. It predisposes to stone formation in the dilated ducts: on plain films, clustering of calcifications in the papillary areas
is very suggestive of the condition. MSK may be associated with a variety of other congenital and inherited disorders, including corporeal hemihypertrophy, Beckwith-Wiedemann
syndrome (macroglossia, omphalocele, visceromegaly, microcephaly, and mental retardation), polycystic kidney disease (about 3% of patients with autosomal-dominant polycystic
kidney disease have evidence of MSK), congenital hepatic fibrosis, and Carolis disease [7].
FIGURE 9-12
Multicystic dysplastic kidney (MCDK) found incidentally by
enhanced CT in a 34-year-old patient. The dysplastic kidney is
composed of cysts with mural calcifications (arrows). Note the
compensatory hypertrophy of the right kidney and the incidental
simple cysts in it. MCDK consists of a collection of cysts frequently
described as resembling a bunch of grapes and an atretic ureter. No
function can be demonstrated. Only unilateral involvement is compatible with life. Usually, the contralateral kidney is normal and
exhibits compensatory hypertrophy. In some 30% of cases, however, it is also affected by some congenital abnormalities such as dysplasia or pelviureterical junction obstruction. In fact, among the
many forms of renal dysplasia, MCDK is thought to represent a
cystic variety.
FIGURE 9-13
Intravenous urography demonstrates multiple calyceal diverticula
(arrows) in a 38-year-old woman who complained of intermittent
flank pain. Previously, the ultrasonographic appearance had suggested the existence of polycystic kidney disease. Although usually
smaller than 1 cm in diameter, pyelocalyceal diverticula occasionally are much larger, as in this case. They predispose to stone formation. Since ultrasonography is the preferred screening tool for
cystic renal diseases, clinicians must be aware of both its pitfalls
(exemplified in this case and in the case of parapelvic cysts; see
Fig. 9-6) and its limited power to detect very small cysts.
9.8
Genetic disorders
GENETICS OF ADPKD
Gene
Chromosome
PKD1
PKD2
PKD3
16
4
?
Product
Patients with ADPKD, %
Polycystin 1
Polycystin 2
?
8090
1020
Very few
NH2
Cysteine-rich domain
Leucine-rich domain
PKD1 domain
C
L
B
C
L
B
C-type lectin domain

Lipoprotein A domain
R
E
J
REJ domain
Transmembrane segment
Alpha helix coiled-coil

R
E
J
Out
Membrane
In
NH2
HOOC
Polycystin 1
COOH
Polycystin 2
FIGURE 9-14
Genetics of autosomal-dominant polycystic kidney disease
(ADPKD). ADPKD is by far the most frequent inherited kidney disease. In white populations, its prevalence ranges from 1 in 400 to 1
in 1000. ADPKD is characterized by the development of multiple
renal cysts that are variably associated with extrarenal (mainly
hepatic and cardiovascular) abnormalities [1,2,3]. It is caused by
mutations in at least three different genes. PKD1, the gene responsible in approximately 85% of the patients, located on chromosome
16, was cloned in 1994 [8]. It encodes a predicted protein of 460
kD, called polycystin 1. The vast majority of the remaining cases
are accounted for by a mutation in PKD2, located on chromosome
4 and cloned in 1996 [9]. The PKD2 gene encodes a predicted protein of 110 kD called polycystin 2. Phenotypic differences between
the two main genetic forms are detailed in Figure 9-19. The existence of (at least) a third gene is suggested by recent reports.
FIGURE 9-15
Autosomal-dominant polycystic kidney disease: predicted structure
of polycystin 1 and polycystin 2 and their interaction. Polycystin 1
is a 4302-amino acid protein, which anchors itself to cell membranes by seven transmembrane domains [10]. The large extracellular portion includes two leucine-rich repeats usually involved in
protein-protein interactions and a C-type lectin domain capable of
binding carbohydrates. A part of the intracellular tail has the
capacity to form a coiled-coil motif, enabling either self-assembling
or interaction with other proteins. Polycystin 2 is a 968-amino acid
protein with six transmembrane domains, resembling a subunit of
voltage-activated calcium channel. Like polycystin 1, the C-terminal end of polycystin 2 comprises a coiled-coil domain and is able
to interact in vitro with PKD2 [11]. This C-terminal part of polycystin 2 also includes a calcium-binding domain. On these grounds,
it has been hypothesized that polycystin 1 acts like a receptor and
signal transducer, communicating information from outside to
inside the cell through its interaction with polycystin 2. This coordinated function could be crucial during late renal embryogenesis.
It is currently speculated that both polycystins play a role in the
maturation of tubule epithelial cells. Mutation of polycystins could
thus impair the maturation process, maintaining some tubular cells
in a state of underdevelopment. This could result in both sustained
cell proliferation and predominance of fluid secretion over absorption, leading to cyst formation (see Fig. 9-16 and references 12 and
13 for review). (From Hughes et al. [10] and Germino [12].)
Thickened tubular
basement membrane
Fluid
Accumulation
Isolated cyst
disconnected from
its tubule of
origin
Monoclonal
proliferation
leading to
cyst formation
Occurrence
of somatic
mutation of the
normal PKD1
allele in one
tubular cell
(the "second hit")
Normal tubule
with germinal
PKD1
mutation
in each cell
FIGURE 9-16
Hypothetical model for cyst formation in autosomal-dominant polycystic kidney disease
(ADPKD), relying on the two-hit mechanism as the primary event. The observation that
only a minority of nephrons develop cysts, despite the fact that every tubular cell harbors germinal PKD1 mutation, is best accounted for by the two-hit model. This model implies that, in
addition to the germinal mutation, a somatic (acquired) mutation involving the normal PKD1
Basolateral
Aden
ylate
Na+ cAMP
K+
2Cl
Apical
cycla
ATP
se
(CFTR)
Cl
PKA
Bumetanide
DPC
2K
ATP
+ +
(Na -K -ATPase)
3Na+
ADP + Pi
Ouabain
H 2O
AQP)
Lumen
H 2O
Q
(A P)
Na+
9.9
allele is required to trigger cyst formation

(ie, a mechanism similar to that demonstrated for tumor suppressor genes in tuberous
sclerosis complex and von Hippel-Lindau disease). The hypothesis is supported by both
the clonality of most cysts and the finding of
loss of heterozygosity in some of them [12].
Cell immaturity resulting from mutated
polycystin would lead to uncontrolled
growth, elaboration of abnormal extracellular matrix, and accumulation of fluid.
Aberrant cell proliferation is demonstrated by
the existence of micropolyps, identification of
mitotic phases, and abnormal expression of
proto-oncogenes. Abnormality of extracellular matrix is evidenced by thickening and
lamination of the tubular basement membrane; involvement of extracellular matrix
would explain the association of cerebral
artery aneurysms with ADPKD. As most
cysts are disconnected from their tubule of
origin, they can expand only through net
transepithelial fluid secretion, just the reverse
of the physiologic tubular cell function [13].
Figure 9-17 summarizes our current knowledge of the mechanisms that may be involved
in intracystic fluid accumulation.
FIGURE 9-17
Autosomal-dominant polycystic kidney disease (ADPKD): mechanisms of intracystic fluid accumulation [13,14]. The primary mechanism of intracystic fluid accumulation seems to be a net transfer
of chloride into the lumen. This secretion is mediated by a
bumetanide-sensitive Na+-K+-2Cl- cotransporter on the basolateral
side and cystic fibrosis transmembrane regulator (CFTR) chloride
channel on the apical side. The activity of the two transporters is
regulated by protein kinase A (PKA) under the control of cyclic
adenosine monophosphate (AMP). The chloride secretion drives
movement of sodium and water into the cyst lumen through electrical and osmotic coupling, respectively. The pathway for transepithelial Na+ movement has been debated. In some experimental
conditions, part of the Na+ could be secreted into the lumen via a
mispolarized apical Na+-K+-ATPase (sodium pump); however, it
is currently admitted that most of the Na+ movement is paracellular and that the Na+-K+-ATPase is located at the basolateral side.
The movement of water is probably transcellular in the cells that
express aquaporins on both sides and paracellular in others [13,
14]. AQPaquaporine; DPCdiphenylamine carboxylic acid.
ADPKD: CLINICAL MANIFESTATIONS

Manifestation
Renal
Hypertension
Pain (acute and chronic)
Gross hematuria
Urinary tract infection
Calculi
Renal failure
Hepatobiliary (see Fig. 923)
Cardiovascular
Cardiac valvular abnormality
Intracranial arteries
Aneurysm
Dolichoectasia
? Ascending aorta dissection
? Coronary arteries aneurysm
Other
Pancreatic cysts
Arachnoid cysts
Hernia
Inguinal
Umbilical
Spinal Meningeal Diverticula
Prevalence, %
Reference
Increased with age

(80 at ESRD)
60
50
Men 20; women 60
20
50 at 60 y
[15]
[3,16]
[3,16]
[3]
[17]
[18]
Odds ratio (95% Cl) PKD2 vs. PKD1
0.46
(0.22-0.98)
1.0
0.47
(0.28-0.81)
0.8
0.6
0.28
(0.16-0.48)
0.18
(0.07-0.47)
0.4
0.2
0.0
20
[16]
8
2
Rare
Rare
[3]
[19]
9
8
[20]
[21]
13
7
0.2
[22]
[22]
[23]
Hypertension Renal infection Subarachnoid

history
hemorrhage
80
70
60
75
74
PKD2
PKD1
Abdominal
hernia
70
61
60
50
Age, y
9.10
40
35
30
20
FIGURE 9-18
Main clinical manifestations of autosomal-dominant polycystic kidney disease (ADPKD). Renal involvement may be totally asymptomatic at early stages. Arterial hypertension is the presenting clinical
finding in about 20% of patients. Its frequency increases with age.
Flank or abdominal pain is the presenting symptom in another
20%. The differential diagnosis of acute abdominal is detailed in
Figure 9-22. Gross hematuria is most often due to bleeding into a
cyst, and more rarely to stone. Renal infection, a frequent reason
for hospital admission, can involve the upper collecting system,
renal parenchyma or renal cyst. Diagnostic data are obtained by
ultrasonography, excretory urography and CT: use of CT in cyst
infection is described in Figure 9-21. Frequently, stones are radiolucent or faintly opaque, because of their uric acid content. The main
determinants of progression of renal failure are the genetic form of
the disease (see Fig. 9-19) and gender (more rapid progression in
males). Hepatobiliary and intracranial manifestations are detailed
in Figures 9-23 to 9-26. Pancreatic and arachnoid cysts are most
usually asymptomatic. Spinal meningeal diverticula can cause postural headache. ESRDend-stage renal disease.
10
0
Clinical
presentation
End-stage
renal failure
Median age
Death
FIGURE 9-19
Autosomal-dominant polycystic kidney disease (ADPKD): phenotype PKD2 versus PKD1. Families with a PKD2 mutation have a
milder phenotype than those with a PKD1 mutation. In this study
comparing 306 PKD2 patients (from 32 families) with 288 PKD1
patients (17 families), PKD2 patients were, for example, less likely
to be hypertensive, to have a history of renal infection, to suffer a
subarachnoid hemorrhage, and to develop an abdominal hernia. As
a consequence of the slower development of clinical manifestations,
PKD2 patients were, on average, 26 years older at clinical presentation, 14 years older when they started dialysis, and 5 years older
when they died. Early-onset ADPKD leading to renal failure in
childhood has been reported only in the PKD1 variety. (Data from
Hateboer [24].)
FIGURE 9-20
Autosomal-dominant polycystic kidney disease (ADPKD): kidney
involvement. Examples of various cystic involvements of kidneys in
ADPKD. Degree of involvement depends on age at presentation and
disease severity. A, With advanced disease as in this 54-year-old
woman, renal parenchyma is almost completely replaced by innumerable cysts. Note also the cystic involvement of the liver. B,
Marked asymmetry in the number and size of cysts between the two
9.11
kidneys may be observed, as in this 36-year-old woman. In the early

stage of the disease, making the diagnosis may be more difficult (see
Fig. 9-28 for the minimal sonographic criteria to make a diagnosis
of ADPKD in PKD1 families). C, D, Contrast-enhanced CT is more
sensitive than ultrasonography in the detection of small cysts. The
presence of liver cysts helps to establish the diagnosis, as in this 38year-old man with PKD2 disease and mild kidney involvement.
9.12
FIGURE 9-21
Autosomal-dominant polycystic kidney disease (ADPKD): kidney
cyst infection. Course of severe cyst infection in the right kidney of
a patient with ADPKD who was admitted for fever and acute right
flank pain. Blood culture was positive for Escherichia coli. A, CT
performed on admission showed several heterogeneous cysts in the
right kidney (arrows). Infection did not respond to appropriate
ADPKD: SPECIFIC CAUSES OF

ACUTE ABDOMINAL PAIN
Cause
Renal
Cyst Bleeding
Stone
Infection
Liver Cyst
Infection
Bleeding
Frequency
Fever
++++
++
+
Mild (<38C, maximum 2 days) or none

With pyonephrosis
High; prolonged with cyst involved
Rare
Very Rare
High, prolonged
Mild (<38C, maximum 2 days) or none
antibiotherapy (fluoroquinolone). B, CT repeated 17 days later

showed considerable enlargement of the infected cysts (arrows).
Percutaneous drainage failed to control infection, and nephrectomy
was necessary. This case illustrates the potential severity of cyst
infection and the contribution of sequential CT in the diagnosis
and management of complicated cysts.
FIGURE 9-22
Autosomal-dominant polycystic kidney disease (ADPKD): specific
causes of acute abdominal pain. The most frequent cause of acute
abdominal pain related to ADPKD is intracyst bleeding. Depending
on the amount of bleeding, it may cause mild, transient fever. It may
or may not cause gross hematuria. Cyst hemorrhage is responsible for
most high-density cysts and cyst calcifications demonstrated by CT.
Spontaneous resolution is the rule. Excretory urography or enhanced
CT is needed mostly to locate obstructive, faintly opaque stones.
Stones may be treated by percutaneous or extracorporal lithotripsy.
Renal infection may involve the upper collecting system,
renal parenchyma, or cyst. Parenchymal infection is evidenced
by positive urine culture and prompt response to antibiotherapy;
cyst infection by the development of a new area of renal tenderness,
quite often a negative urine culture (but a positive blood culture),
and a slower response to antibiotherapy. CT demonstrates the heterogeneous contents and irregularly thickened walls of infected
cysts. Cyst infection warrants prolonged anti-biotherapy [3]. An
example of severe, intractable cyst infection is shown in Figure 9-21.
9.13
ADPKD: HEPATOBILIARY MANIFESTATIONS

Finding
Frequency
Asymptomatic liver cysts
Very common; increased prevalence with

age (up to 80% at age 60)
Uncommon (male/female ratio: 1/10)
Symptomatic polycystic liver disease

Complicated cysts (hemorrhage,
infection)
Massive hepatomegaly
Chronic pain/discomfort
Early satiety
Supine dyspnea
Abdominal hernia
Obstructive jaundice
Hepatic venous outflow obstruction
Congenital hepatic fibrosis
Idiopathic dilatation of intrahepatic or
extrahepatic biliary tract
Cholangiocarcinoma
Rare (not dominantly transmitted)

Very rare
Very rare
FIGURE 9-23
Autosomal-dominant polycystic kidney disease (ADPKD): hepatobiliary manifestations. Liver cysts are the most frequent extrarenal
manifestation of ADPKD. Their prevalence increases dramatically
from the third to the sixth decade of life, reaching a plateau of 80%
thereafter [25, 26]. They are observed earlier and are more numerous and extensive in women than in men. Though usually mild and
asymptomatic, cystic liver involvement occasionally is massive and
symptomatic (see Figure 9-24). Rare cases have been reported of
congenital hepatic fibrosis or idiopathic dilatation of the intrahepatic
or extrahepatic tract associated with ADPKD [25, 26].
A
FIGURE 9-25
Autosomal-dominant polycystic kidney disease (ADPKD):
intracranial aneurysm detection. Magnetic resonance angiography (MRA), A, and spiral computed tomography (CT) angiography, B, in two different patients, both with ADPKD, show an
asymptomatic intracranial aneurysm (ICA) on the posterior communicating artery (arrow), A, and the anterior communicating
artery (arrow), B, respectively.
The prevalence of asymptomatic ICA in ADPKD is 8%, as
compared with 1.2% in the general population. It reaches 16%
in ADPKD patients with a family history of ICA [27]. The risk of
FIGURE 9-24
Autosomal-dominant polycystic kidney disease (ADPKD): polycystic liver disease. Contrast-enhanced CT in a 32-year-old woman
with ADPKD, showing massive polycystic liver disease contrasting
with mild kidney involvement.
Massive polycystic liver disease can cause chronic pain, early
satiety, supine dyspnea, abdominal hernia, and, rarely, obstructive
jaundice, or hepatic venous outflow obstruction. Therapeutic
options include cyst sclerosis and fenestration, hepatic resection,
and, ultimately, liver transplantation [25, 26].
B
ICA rupture in ADPKD is ill-defined. ICA rupture entails 30% to
50% mortality. It is generally manifested by subarachnoid hemorrhage, which usually presents as an excruciating headache. In this
setting, the first-line diagnostic procedure is CT. Management
should proceed under neurosurgical guidance [27].
Given the severe prognosis of ICA rupture and the possibility
of prophylactic treatment, screening ADPKD patients for ICA has
been considered. Screening can be achieved by either MRA or spiral CT angiography. Current indications for screening are presented in Figure 9-26. (Courtesy of T. Duprez and F. Hammer.)
9.14
Age 1840 years

and family history
of ICA?
No
No
screening
Yes
Brain MR angiography No
or spiral CT scan:
ICA?
Yes
Repeat every
5 years
FIGURE 9-26
Autosomal-dominant polycystic kidney disease (ADPKD): intracranial aneurysm (ICA)
screening. On the basis of decision analyses (taking into account ICA prevalence, annual
risk of rupture, life expectancy, and risk of prophylactic treatment), it is currently proposed to screen for ICA 18 to 40-year-old ADPKD patients with a family history of ICA
[25, 27]. Screening could also be offered to patients in high-risk occupations and those
who want reassurance. Guidelines for prophylactic treatment are the same ones used in
the general population: the neurosurgeon and the interventional radiologist opt for either
surgical clipping or endovascular occlusion, depending on the site and size of ICA.
Conventional
angiography
Discuss management
with neurosurgeon
ADPKD: PRESYMPTOMATIC DIAGNOSIS

Presymptomatic diagnosis
Is advisable in families when early management of affected patients would be altered
(eg, because of history of intracranial aneurysm)
Should be made available to persons at risk who are 18 years or older who request
the test
Should be preceded by information about the possibility of inconclusive results and
the consequences of the diagnosis:
If negative, reassurance
If positive, regular medical follow-up, possible psychological burden,
risk of disqualification from employment and insurances
FIGURE 9-27
Autosomal-dominant polycystic kidney disease (ADPKD): presymptomatic diagnosis. Presymptomatic diagnosis is aimed at both detecting affected persons (to provide follow-up and genetic counseling)
and reassuring unaffected ones. Until a specific treatment for ADPKD
is available, presymptomatic diagnosis in children is not advised
except in rare families where early-onset disease is typical. Presymptomatic diagnosis is recommended when a family is planned and
when early management of affected patients would be altered. The
mainstay of screening is ultrasonography; diagnostic echographic
criteria according to age in PKD1 families are depicted in Figure 9-28,
and diagnosis by gene linkage in Figure 9-29.
ADPKD: ULTRASONOGRAPHIC
DIAGNOSTIC CRITERIA
Age
Cysts
1529
3059
60
2, uni- or bilateral
2 in each kidney
4 in each kidney
Minimal number of cysts to establish a diagnosis of ADPKD in PKD1 families at risk.
FIGURE 9-28
Autosomal-dominant polycystic kidney disease (ADPKD): ultrasonographic diagnostic criteria. Ultrasound diagnostic criteria for
the PKD1 form of ADPKD, as established by Ravines group on the
basis of both a sensitivity and specificity study [4, 28]. Note that
the absence of cyst before age 30 years does not rule out the diagnosis, the false-negative rate being inversely related to age. When
ultrasound diagnosis remains equivocal, the next step should be
either contrast-enhanced CT (more sensitive than ultrasonography
in the detection of small cysts) or gene linkage (see Figure 9-29). A
similar assessment is not yet available for the PKD2 form. (From
Ravine et al. [28]; with permission.)
Deceased
Unaffected
Affected
? Unknown status
II
1
5
1
b
III
1
2
a
IV
2
b
2
3
b
2
b
4
a
5
a
2
a
3
b
3
b
2
b
1
b
3
b
5
a
2
a
Life expectancy <5 yrs

or contraindication to surgery
or to immunosuppressants?
History of
cyst infection?
Yes
Yes
Pretransplant workup:
Eligibility for transplantation?
No
No
Very large kidneys
or abdominal hernia?
Yes
No
Remove
kidney(s)?
Transplantation
or
Peritoneal dialysis
FIGURE 9-29
Example of the use of gene linkage to identify ADPKD gene carriers
among generation IV of a PKD1 family. Two markers flanking the
PKD1 gene were used. The first one (3 HVR) has six possible alleles (1 through 6) and the other (p 26.6) is biallelic (a, b). In this
family, the haplotype 2a is transmitted with the disease (see affected
persons II5, III1, and III3). Thus, IV4 has a 99% chance of being a
carrier of the mutated PKD1 gene, whereas her sisters (IV1, IV2,
IV3) have a 99% chance of being disease free.
Until direct gene testing for PKD1 and PKD2 is readily available,
genetic diagnosis will rest on gene linkage. Such analysis requires
that other affected and unaffected family members (preferably from
two generations) be available for study. Use of markers on both
sides of the tested gene is required to limit potential errors due to
recombination events. Linkage to PKD1 is to be tested first, as it
accounts for about 85% of cases.
5
a
No
Yes
9.15
Hemodialysis
FIGURE 9-30
Autosomal-dominant polycystic kidney disease (ADPKD): renal
replacement therapy. Transplantation nowadays is considered in any
ADPKD patient with a life expectancy of more than 5 years and
with no contraindications to surgery or immunosuppression.
Pretransplant workup should include abdominal CT, echocardiography, myocardial stress scintigraphy, and, if needed (see Figure 9-26),
screening for intracranial aneurysm. Pretransplant nephrectomy is
advised for patients with a history of renal cyst infection, particularly
if the infections were recent, recurrent, or severe. Patients not eligible
for transplantation may opt for hemodialysis or peritoneal dialysis.
Although kidney size is rarely an impediment to peritoneal dialysis,
this option is less desirable for patients with very large kidneys,
because their volume may reduce the exchangeable surface area and
the tolerance for abdominal distension. Outcome for ADPKD
patients following renal replacement therapy is similar to that of
matched patients with another primary renal disease [29, 30].
9.16
CLINICAL FEATURES
Finding
Skin
Hypomelanotic macules
Facial angiofibromas
Forehead fibrous plaques
Shagreen patches (lower back)
Periungual fibromas
Cortical tubers
Subependymal tumors
(may be calcified)
focal or generalized seizures
Mental retardation/
behavioral disorder
Kidney
Angiomyolipomas
Cysts
Renal cell carcinoma
Eye
Retinal hamartoma
Retinal pigmentary abnormality
Liver (angiomyolipomas, cysts)
Heart (rhabdomyoma)
Lung (lymphangiomyomatosis;
affects females)
Frequency, %
Age at onset, y
90
80
30
30
30
Childhood
515
5
10
15
90
90
Birth
Birth
80
50
01
05
60
30
2
Childhood
Childhood
Adulthood
50
10
40
2
1
Childhood
Childhood
Childhood
Childhood
20
FIGURE 9-31
Tuberous sclerosis complex (TSC): clinical features. TSC is an autosomal-dominant multisystem disorder with a minimal prevalence of
1 in 10,000 [30, 31]. It is characterized by the development of multiple hamartomas (benign tumors composed of abnormally arranged
and differentiated tissues) in various organs. The most common
manifestations are dermatologic (see Fig. 9-32) and neurologic (see
Fig. 9-33). Renal involvement occurs in 60% of cases and includes
cysts (see Fig. 9-34). Retinal involvement, occurring in 50% of
cases, is almost always asymptomatic. Liver involvement, occurring
in 40% of cases, includes angiomyolipomas and cysts. Involvement
of other organs is much rarer [31, 32].

Tuberous sclerosis complex (TSC): skin involvement. Facial angiofibromas, forehead
plaque, A, and ungual fibroma, B, characteristic of TSC. Previously (and inappropriately)
called adenoma sebaceum, facial angiofibromas are pink to red papules or nodules, often
concentrated in the nasolabial folds. Forehead fibrous plaques appear as raised, soft patches of red or yellow skin. Ungual fibromas appear as peri- or subungual pink tumors; they
are found more often on the toes than on the fingers and are more common in females.
Other skin lesions include hypomelanotic macules and shagreen patches (slightly elevated
patches of brown or pink skin). (Courtesy of A. Bourloud and C. van Ypersele.)
9.17
FIGURE 9-33
Tuberous sclerosis complex (TSC): central nervous system involvement. Brain CT shows
several subependymal, periventricular, calcified nodules characteristic of TSC. Subependymal
tumors and cortical tubers are the two characteristic neurologic features of TSC. Calcified
nodules are best seen on CT, whereas noncalcified tumors are best detected by magnetic
resonance imaging. Clinical manifestations are seizures (including infantile spasms) occurring in 80% of infants, and varying degrees of intellectual disability or behavioral disorder,
reported in 50% of children [32].
A
FIGURE 9-34
Tuberous sclerosis complex (TSC): kidney involvement. Contrastenhanced CT, A, and gadolinium-enhanced T1 weighted magnetic
resonance images, B, of a 15-year-old woman with TSC, show
both a large, hypodense, heterogeneous tumor in the right kidney
(arrows) characteristic of angiomyolipoma (AML) and multiple
bilateral kidney cysts. Kidney cysts had been detected at birth.
AML is a benign tumor composed of atypical blood vessels,
smooth muscle cells, and fat tissue. While single AML is the most
frequent kidney tumor in the general population, multiple and bilateral AMLs are characteristic of TSC. In TSC, AMLs develop at a
younger age in females; frequency and size of the tumors increase
with age. Diagnosis of AML by imaging techniques (ultrasonography
[US], CT, magnetic resonance imagine [MRI]) relies on identification
B
of fat into the tumor, but it is not always possible to distinguish
between AML and renal cell carcinoma. The main complication of
AML is bleeding with subsequent gross hematuria or potentially lifethreatening retroperitoneal hemorrhage.
Cysts seem to be restricted to the TSC2 variety (see Fig. 9-35)
[33]. Their extent varies widely from case to case. Occasionally,
polycystic kidneys are the presenting manifestation of TSC2 in early
childhood: in the absence of renal AML, the imaging appearance is
indistinguishable from ADPKD. Polycystic kidney involvement leads
to hypertension and renal failure that reaches end stage before age
20 years. Though the frequency of renal cell carcinoma in TSC is
small, the incidence is increased as compared with that of the general population. (Courtesy of J. F. De Plaen and B. Van Beers.)
9.18
VHL: ORGAN INVOLVEMENT
HG loci
PKD1
TSC2
Death
16 pter
Chromosome 16
FIGURE 9-35
Tuberous sclerosis complex (TSC): genetics. Representative examples
of various contiguous deletions of the PKD1 and TSC2 genes in
five patients with TSC and prominent renal cystic involvement (the
size of the deletion in each patient is indicated).
TSC is genetically heterogeneous. Two genes have been identified.
The TSC1 gene is on chromosome 9, and TSC2 lies on chromosome
16 immediately adjacent and distal to the PKD1 gene. Half of affected families show linkage to TSC1 and half to TSC2. Nonetheless,
60% of TSC cases are apparently sporadic, likely representing new
mutations (most are found in the TSC2 gene) [34]. The proteins
encoded by the TSC1 and TSC2 genes are called hamartin and
tuberin, respectively. They likely act as tumor suppressors; their precise cellular role remains largely unknown. The diseases caused by
type 1 and type 2 TSC are indistinguishable except for renal cysts,
which, so far, have been observed only in TSC2 patients [33], and
for intellectual disability, which is more common in TSC2 patients
[34]. (Adapted from Sampson, et al. [33].)
Findings
Hemangioblastoma
Cerebellar
Spinal cord
Endolymphatic sac tumor
Eye/Retinal hemangioblastoma
Kidney
Clear cell carcinoma
Cysts
Adrenal glands/
Pheochromocytoma
Pancreas
Cysts
Microcystic adenoma
Islet cell tumor
Carcinoma
Liver (cysts)
Frequency, %
Mean age (range)

at diagnosis, y
30 (971)
60
20
Rare
60
25 (870)
40
30
15
40 (1870)
35 (1560)
20 (560)
30 (1370)
40
4
2
1
Rare
FIGURE 9-36
Von Hippel-Lindau disease (VHL): organ involvement. VHL is an
autosomal-dominant multisystem disorder with a prevalence rate of
roughly 1 in 40,000 [32, 35]. It is characterized by the development
of tumors, benign and malignant, in various organs. VHL-associated
tumors tend to arise at an earlier age and more often are multicentric
than the sporadic varieties. Morbidity and mortality are mostly related to central nervous system hemangioblastoma and renal cell carcinoma. Involvement of cerebellum, retinas, kidneys, adrenal glands,
and pancreas is illustrated (see Figures 9-37 to 9-41).
The VHL gene is located on the short arm of chromosome 3 and
exhibits characteristics of a tumor suppressor gene. Mutations are
now identified in 70% of VHL families [36].
FIGURE 9-37
Von Hippel-Lindau disease (VHL): central nervous system involvement. Gadolinium-enhanced brain magnetic resonance image of a
patient with VHL, shows a typical cerebellar hemangioblastoma,
appearing as a highly vascular nodule (arrow) in the wall of a cyst
(arrowheads) located in the posterior fossa. Hemangioblastomas are
benign tumors whose morbidity is due to mass effect. Cerebellar
hemangioblastomas may present with symptoms of increased
intracranial pressure. Spinal cord involvement may be manifested
as syringomyelia. (Courtesy of S. Richard.)
9.19

Von Hippel-Lindau disease (VHL): retinal
involvement. Ocular fundus, A, and corresponding fluorescein angiography, B, in a
patient with VHL, shows two typical retinal hemangioblastomas. The smaller tumor
(arrow) appears at the fundus as an intense
red spot, whereas the larger (arrow heads)
appears as a pink-orange lake with dilated,
tortuous afferent and efferent vessels. Small
peripheral lesions are usually asymptomatic, whereas large central tumors can
impair vision. (Courtesy of B. Snyers.)
B
A
FIGURE 9-39
Von Hippel-Lindau disease (VHL): kidney involvement. Contrastenhanced CT of a patient with VHL, showing the polycystic aspect
of the kidneys. Renal involvement of VHL includes cysts (simple,
atypical, and cystic carcinoma) and renal cell carcinoma [36, 37].
The latter is the leading cause of death from VHL. Occasionally,
polycystic kidney involvement may mimic autosomal-dominant
polycystic kidney disease. Both cystic involvement and sequelae
of surgery can lead to renal failure. Nephron-sparing surgery is
recommended [37].
FIGURE 9-40
Von Hippel-Lindau disease (VHL): adrenal gland involvement.
Gadolinium-enhanced abdominal magnetic resonance image of a
patient with VHL shows bilateral pheochromocytoma (arrows).
Renal lesions include cysts and solid carcinomas (arrow heads).
Pheochromocytoma may be the first manifestation of VHL. It
tends to cluster within certain VHL families [36]. (Courtesy of
H. Neumann.)
9.20
FIGURE 9-41
Von Hippel-Lindau disease (VHL): pancreas involvement. Contrastenhanced abdominal CT in a patient with VHL shows multiple cysts
in both pancreas (especially the tail, arrows) and kidneys. The majority of pancreatic cysts are asymptomatic. When they are numerous
and large, they can induce diabetes mellitus or steatorrhea. Other,
rare pancreatic lesions include microcystic adenoma, islet cell tumor,
and carcinoma.
VHL: SCREENING PROTOCOL

Study
Affected persons
Relatives at risk
24-h Urine collection for
metadrenaline and
normetadrenaline
Funduscopy
Gadolinium MRI brain scan
Abdomen
Annual
Annual
Annual
Annual
Annual
Every 3 y (from age 10)
Annual gadolinium MRI
Annual (age 5 to 60)

Every 3 y (age 15 to 60)
Annual echography or
gadolinium MRI
(age 15 to 60)
FIGURE 9-42
Von Hippel-Lindau disease. As most manifestations of VHL are
potentially treatable, periodic examination of affected patients is
strongly recommended. Though genetic testing is now very useful
for presymptomatic identification of affected persons, it must be
remembered that a mutation in the VHL gene currently is detected
in only 70% of families. For persons at risk in the remaining families,
a screening program is also proposed.
FIGURE 9-43
Medullary cystic disease (MCD). Contrast-enhanced CT in a 35year-old man with MCD. Multiple cysts are seen in the medullary
area. Two daughters were also found to be affected. MCD is a very
rare autosomal-dominant disorder characterized by medullary cysts
detectable by certain imaging techniques (preferably computed
tomography) and progressive renal impairment leading to endstage disease between 20 and 40 years of age. Dominant inheritance and early detection of kidney cysts distinguish MCD from
autosomal-recessive nephronophthisis (see Fig. 9-48), even though
the two may be indistinguishable on histologic examination.
9.21
THERE IS A WHITE
BOX PLACED OVER
HANDWRITTEN
TYPE.
C
FIGURE 9-44
Glomerulocystic kidney disease (GCKD). Contrast-enhanced CT, A,
in a 23-year-old woman with the sporadic form of GCKD shows
ARPKD: CLINICAL MANIFESTATIONS

Renal
Antenatal (ultrasonographic changes)
Oligohydramnios with empty bladder
Increased renal volume and echogenicity
Neonatal period
Dystocia and oligohydramnios
Enlarged kidneys
Renal failure
Respiratory distress with pulmonary hypoplasia (possibly fatal)
Infancy of childhood
Nephromegaly (may regress with time)
Hypertension (often severe in the first year of life)
Chronic renal failure (slowly progressive, with a 60% probability of renal survival at
15 years of age and 30% at 25 years of age)
Hepatic
Portal fibrosis
Intrahepatic biliary tract ectasia
multiple cysts, typically small cortical ones. This cystic pattern was
verified in the nephrectomy specimen, B, obtained 8 months later
at the time of kidney transplantation, and GCKD was confirmed
by histopathologic examination with Massons trichrome stain.
C, Cysts consisted of a dilatation of Bowmans space surrounding
a primitive-looking glomerulus.
GCKD may be sporadic or genetically dominant. Among the
familial cases, some patients are infants who have early-onset autosomal-dominant polycystic disease. In others (children or adults) the
disease is unrelated to PKD1 and PKD2 and may or not progress to
end-stage renal failure [38]. (Courtesy of D. Droz.)
FIGURE 9-45
Autosomal-recessive polycystic kidney disease (ARPKD): clinical manifestations. ARPKD is characterized by the development of cysts originating from collecting tubules and ducts, invariably associated with
congenital hepatic fibrosis. Its prevalence is about 1 in 40,000 [39].
In the most severe cases, with marked oligohydramnios and an empty
bladder, the diagnosis may be suspected as early as the 12th week of
gestation. Some neonates die from either respiratory distress or renal
failure. In most survivors, the disease is recognized during the first
year of life. The ultrasonographic (US) kidney appearance is depicted
in Figure 9-46. Excretory urography shows medullary striations
owing to tubular ectasia. Kidney enlargement may regress with time.
End-stage renal failure develops before age 25 in 70% of patients.
Liver involvement consists of portal fibrosis (see Fig. 9-47) and
intrahepatic bilary ectasia, frequently resulting in portal hypertension
(leading to hypersplenism and esophageal varices) and less often in
cholangitis, respectively. US may show dilatation of the biliary ducts,
and even cysts. The respective severity of kidney and liver involvement vary widely between families and even in a single kindred.
A comparison of the diagnostic features of autosomal-dominant
polycystic kidney disease (ADPKD) and ARPKD is summarized in
Figure 9-2. Renal US of the parents of a child with ARPKD is, of
course, normal. It should be noted that congenital hepatic fibrosis is
found in rare cases of ADPKD with early-onset renal disease. The
gene responsible for ARPKD has been mapped to chromosome 6.
There is no evidence of genetic heterogeneity [40].
9.22
FIGURE 9-46
A and B, Autosomal-recessive polycystic
kidney disease (ARPKD): renal imaging. On
ultrasonography of a child with ARPKD
the kidneys appear typically enlarged and
uniformly hyperechogenic (owing to the
presence of multiple small cysts), and
demarcations of cortex, medulla, and sinus
are lost. The ultrasonographic appearance
is different in older children, because cysts
can grow and become round; then they
resemble the appearance of ADPKD. Figure
9-2 describes how to differentiate the two
conditions. (Courtesy of P. Niaudet.)
FIGURE 9-47
Autosomal-recessive polycystic kidney disease (ARPKD): liver histology. Liver biopsy specimen from a child with ARPKD shows
typical congenital hepatic fibrosis (hematoxylin eosin safran [HES]
stain). This portal space is enlarged by fibrosis, and the number of
biliary channels is increased, many of them being enlarged and all
being irregular in outline. (Courtesy of S. Gosseye.)
FIGURE 9-48
Nephronophthisis (NPH): renal involvement. Kidney biopsy specimen
visualized by light microscopy with periodic acidSchiff stain, in a
patient with juvenile NPH of an early stage. Note the typical thickening and disruption of the tubular basement membrane (appearing
in red); the histiolymphocytic infiltration present at this stage is progressively replaced by interstitial fibrosis.
NPH is an autosomal recessive disorder, accounting for 10% to
15% of all children admitted for end-stage renal failure. Although
classified as a renal cystic disorder, NPH is characterized by chronic
diffuse tubulointerstitial nephritis; the presence of cysts at the corticomedullary boundary (thus, the alternative term medullary cystic
disease, now preferably reserved for the autosomal-dominant form;
see Fig. 9-43) is a late manifestation of the disease. Clinical features
include early polyuria-polydypsia, unremarkable urinalysis, frequent
absence of hypertension, and eventually, end-stage renal failure at a
median age of 13 (range 3 to 23) years. Ultrasonographic features
are summarized in Figure 9-2; medullary cysts are sometimes detected.
Associated disorders are detailed in Figure 9-49. A gene called NPH1
that has been identified on chromosome 2 accounts for about 80%
of cases [41, 42]. In two thirds of them, a large homozygous deletion is detected in this gene [43]. (Courtesy of P. Niaudet.)
NPH: EXTRARENAL INVOLVEMENT

Retinitis pigmentosa (Senior-Loken syndrome)
Multiple organ involvement, including
Liver fibrosis
Other rare features
Skeletal changes (cone-shaped epiphyses)
Cerebellar ataxia
Mental retardation
9.23
FIGURE 9-49
Nephronophthisis (NPH): extrarenal involvement. Extrarenal involvement occurs in 20% of NPH cases. The most frequent finding is
tapetoretinal degeneration (known as Senior-Loken syndrome), which
often results in early blindness or progressive visual impairment.
Other rare manifestations include liver (hepatomegaly, hepatic fibrosis), bone (cone-shaped epiphysis), and central nervous system (mental
retardation, cerebellar ataxia) abnormalities, quite often in association.
FIGURE 9-50
Orofaciodigital syndrome (OFD). Contrast-enhanced CT,
A, and the hands, B, of a 26-year-old woman with OFD type 1
(OFD1) [43]. Multiple cysts involve both kidneys. Note that
they are smaller and more uniform than in ADPKD and that
renal contours are preserved. Some cysts were also detected in
liver and pancreas (arrow). Syndactyly was surgically corrected,
and the digits of the hands are shortened (brachydactyly).
OFD1 is a rare X-linked, dominant disorder, diagnosed
almost exclusively in females, as affected males die in utero.
Characteristic dysmorphic features include oral (hyperplastic

frenulum, cleft tongue, cleft palate or lip, malposed teeth), facial
(asymmetry, broad nasal root), and digit (syn-brachy-polydactyly) abnormalities. Mental retardation is present in about half the
cases. Kidneys may be involved by multiple (usually small) cysts,
mostly of glomerular origin; renal failure occurs between the
second and the seventh decade of life. Recognition of the dysmorphic features is the key to the diagnosis [44, 45]. (Courtesy
of F. Scolari.)
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10. Hughes J, Ward CJ, Peral B, et al.: The polycystic kidney disease 1
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11. Qian F, Germino FJ, Cai Y, et al.: PKD1 interacts with PKD2 through
a probable coiled-coil domain. Nature Genet 1997, 16:179183.
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problems of transplantation in autosomal dominant polycystic kidney
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33. Sampson JR, Maheshwar MM, Aspinwall R, et al.: Renal cystic disease in tuberous sclerosis: Role of the polycystic kidney disease 1
gene. Am J Human Genet 1997, 61:843851.
16. Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J

Med 1993, 329:332342.
17. Torres WE, Wilson DM, Hattery RR, Segura JW: Renal stone disease
in autosomal dominant polycystic kidney disease. Am J Kidney Dis
1993, 22:513519.
18. Choukroun G, Itakura Y, Albouze G, et al.: Factors influencing progression of renal failure in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1995, 6:16341642.
19. Schievink WI, Torres VE, Wiebers DO, Huston J III: Intracranial arterial
dolichoectasia in autosomal dominant polycystic kidney disease. J Am
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20. Torra R, Nicolau C, Badenas C, et al.: Ultrasonographic study of pancreatic cysts in autosomal dominant polycystic kidney disease. Clin
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21. Schievink WI, Huston J III, Torres VA, Marsh WR: Intracranial cysts
in autosomal dominant polycystic kidney disease. J Neurosurg 1995,
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22. Gabow PA: Autosomal dominant polycystic kidney diseasemore
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Hippel-Lindau disease. Kidney Int 1996, 50:944951.
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Cameron JS, Grnfeld JP, et al. Oxford:Oxford University Press;
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40. Zerres K, Mcher G, Bachner L, et al.: Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome
6p21-cen. Nature Genet 1994, 7:429432.
41. Antignac C, Arduy CH, Beckmann JS, et al.: A gene for familial juvenile nephronophthisis (recessive medullary cystic kidney disease) maps
to chromosome 2p. Nature Genet 1993, 3:342345.
42. Hildebrandt F, Otto E, Rensing C, et al.: A novel gene encoding an
SH3 domain protein is mutated in nephronophthisis type 1. Nature
Genet 1997, 17:149153.
43. Konrad M, Saunier S, Heidet L, et al.: Large homozygous deletions of
the 2q13 region are a major cause of juvenile nephronophthisis. Hum
Molec Genet 1996, 5: 367371.
44. Scolari F, Valzorio B, Carli O, et al.: Oral-facial-digital syndrome type
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45. Feather SA, Winyard PJD, Dodd S, Woolf AS: Oral-facial-digital syndrome type 1 is another dominant polycystic kidney disease: Clinical,
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Dial Transplant 1997, 12:13541361.
Toxic Nephropathies
Jean-Louis Vanherweghem
ubular interstitial structures of the kidney are particularly vulnerable in face of toxic compounds. High concentration of the
toxics in de medulla as well as medullary hypoxia and renal
hypoperfusion could explain this particularity. Clinical nephrotoxicity involves toxins of diverse origin. The culprits are often registered
and non registered drugs either prescribed or purchased over the
counter. Other major causes result from occupational and industrial
exposures. Sometimes, the identification of the nephrotoxin requires
astuteness and long investigations especially in cases of environmental
toxins or prolonged intake of unregulated drugs or natural products.
A correct diagnosis of the causes is, however, the key for future prevention of renal diseases. The diagnosis of chronic interstitial nephritis of unknown origin should, therefore, no longer be used.
CHAPTER
10
10.2
Exposure to Nephrotoxins
FIGURE 10-1
Chronic exposure to drugs, occupational hazards, or environmental
toxins can lead to chronic interstitial renal diseases. The following
are the major causes of chronic interstitial renal diseases: occupational exposure to heavy metals; abuse of over-the-counter analgesics;
misuse of germanium; chronic intake of mesalazine for intestinal disorders, lithium for depression, and cyclosporine in renal and nonrenal diseases; and environmental or iatrogenic exposure to fungus or
plant nephrotoxins (ochratoxins, aristolochic acids).
TOXIC CAUSES OF CHRONIC

TUBULOINTERSTITIAL RENAL DISEASES
Metals (Environmental or Occupational Exposure)
Lead
Cadmium
Drugs or Additives (Use, Misuse, or Abuse)
Lithium
Germanium
Analgesics
Cyclosporine
Mesalazine
Fungus and Plant Toxins (Environmental or Iatrogenic Exposure)
Ochratoxins
Aristolochic acids
Exposure to Metals
FIGURE 10-2
Occupational exposure to metals and risks for chronic renal failure. Comparison of the occupational histories of 272 patients with
chronic renal failure with those of a matched control group having
normal renal function has shown an increased risk of chronic renal
failure after exposure to mercury, tin, chromium, copper, and lead.
In this study the increased risk with exposure to cadmium was not
statistically significant. Squares indicate odds ratios; circles indicate
CIs. (Adapted from Nuyts and coworkers [1]; with permission.)
Odds ratio
(95% confidence intervals)
30
25
20
15
10
5
0
Mercury
Tin
Chromium Copper
Lead
Cadmium
Odds ratio
C1 >
C1 <
Mercury
5130
1020
25,700
Tin
3720
1220
11,300
Chromium
2770
1210
6330
Copper
2540
1160
5530
Lead
2110
1230
4360
Cadmium
2200
900
8250
Toxic Nephropathies
10.3
Lead nephropathy
CAUSES OF LEAD NEPHROPATHY
CLINICAL MANIFESTATIONS OF LEAD NEPHROPATHY

Gout
Arterial hypertension
Renal failure (interstitial type)
Environmental
Eating paint from lead-painted furniture, woodwork, and toys in children
Lead-contaminated flour
Home lead-contaminated drinking water from lead pipes
Drinking of moonshine whiskey
Occupational
Lead-producing plants: lead smelters, battery plants
FIGURE 10-3
Lead nephropathy associated with environmental and occupational
exposure. Epidemiologic observations have established the relationship between lead exposure and renal failure in association with
children eating lead paint in their homes, chronic ingestion of leadcontaminated flour, lead-loaded drinking water in homes, and
drinking of illegal moonshine whiskey [2,3]. Occupational exposure in lead-producing industries also has been associated with a
higher incidence of renal dysfunction.
Days
8 AM
8 PM
EDTA 1 g
1g
IM
IM
FIGURE 10-5
Ethylenediamine tetraacetic acid (EDTA)lead mobilization test in lead nephropathy.
EDTA (calcium disodium acetate) for detecting lead nephropathy. This test consists of a
24-hour urinary lead excretion over 3 consecutive days after administration of 2 g of EDTA
by intramuscular route on the first day in divided doses 12 hours apart. Persons without
excessive lead exposure excrete less than 0.6 mg of lead during the day after receiving 2 g
of EDTA parenterally. In the presence of renal failure, the excretion is delayed; however,
the cumulative total remains less than 0.6 mg over 3 days (From Batuman and coworkers
Urinary
collection
FIGURE 10-4
Gout and hypertension are the major clinical manifestations of lead
nephropathy. The prominent feature of early hyperuricemia in lead
nephropathy may explain the confusion between lead nephropathy
and gout nephropathy. Lead urinary excretion after ethylenediamine tetraacetic acid (EDTA)lead mobilization testing may help
with the correct diagnosis [3].
Lead,
mg
Excessive lead exposure:
120
1500
II
IV
100
80
60
40
III
IV
Lead, mg/72 h
Creatinine clearance, mL/min
No < 0.6
Yes >0.6
20
0
Blood pressure N
Gout
A
1000
III
II
500
I
FIGURE 10-6
Ethylenediamine tetraacetic acid (EDTA)
lead mobilization test in chronic renal
failure of uncertain origin (AC). In a
study of 296 patients without history of
lead exposure, the results of this test were
abnormal in 15.4% (II) of patients with
hypertension and normal renal function
and in 56.1% of patients with renal failure of uncertain origin (in 44.1% of the
patients without associated gout (III) and
in 68.7% of the patients with associated
gout (IV), respectively).
10.4
Patients with abnormal test

results, %
The EDTAlead mobilization test was normal in normotensive subjects with normal renal
function and in patients with chronic renal failure (I) of well-known origin (V). (Adapted
from Sanchez-Fructuoso and coworkers [4].)
IV
50
III
II
Glomerular filtration rate,

mL/min/1.73 m2
Cadmium nephropathy
FIGURE 10-7
Decrease in renal function after 25-year exposure to cadmium (Cd). In workers exposed to
cadmium for an average time of 25 years, a progressive decrease in renal function occurs
during a 5-year follow-up period, despite removal from cadmium exposure 10 years earlier.
On average, the glomerular filtration rate was shown to be decreased to 31 mL/min/1.73
m2 after 5 years instead of the expected age-related value of 5 mL/min/1.73 m2. (Adapted
from Roels and coworkers [5].)
110
105
100
95
90
85
80
75
70
Expected values
Cd exposure
6
8
9
7
10 11
Removal from Cd exposure, y
Graph values
I
II
III
IV
NEP
43
53
50
76
CC16
16
17
25
124
RBP
80
122
132
594
2-m
73
112
102
834
Creatinine, g/g
800
600
*
834
NEP
CC16
RBP
2m
*P < 0.05
*
594
200
*
*
0
I
II
III
IV
II
III
IV
Creatinine
clearance, mL/min
103
103
90*
79*
Urinary Cd,
g/g/creatinine
0.55
1.34
3.28*
8.45*
FIGURE 10-8
Tubular markers in cadmium workers. Impairment of renal proximal
tubular epithelium induced by cadmium can be documented by an
increase in urinary excretion of urinary neutral endopeptidase 24.11
(NEP), an enzyme of the proximal tubule brush borders, as well as
by an increase in microproteinuria: Clara cell protein (CC16),
retinol-binding protein (RBP) and 2-microglobulin (2-m). The data
were obtained from 106 healthy persons working in cadmium smelting plants. These markers could be used for the screening of cadmium workers. (Adapted from Nortier and coworkers [6].)
Toxic Nephropathies
10.5
Lithium nephropathy
LITHIUM NEPHROTOXICITY
Reversible polyuria and polydipsia
Persistent nephrogenic diabetes insipidus
Incomplete distal tubular acidosis
Chronic renal failure (chronic interstitial fibrosis)
FIGURE 10-9
Lithium acts both distally and proximally to antidiuretic hormoneinduced generation of cyclic adenosine monophosphatase.
Polyuria and polydipsia can occur in up to 40% of patients on
lithium therapy and are considered harmless and reversible.
However, nephrogenic diabetes insipidus may persist months after
lithium has been discontinued [7]. Lithium also induces an impairment of distal urinary acidification. Chronic renal failure secondary
to chronic interstitial fibrosis may appear in up to 21% of patients
on maintenance lithium therapy for more than 15 years [8].
However, these observations are still a matter of debate [7].

Lithium nephropathy. A 22-year-old female patient was on maintenance lithium therapy (lithium carbonate 750 mg/d) for 5 years.
She presented with polyuria (6500 mL/d) and moderate renal failure (creatinine clearance, 60 mL/min). Proteinuria was not present,
and the urinary sediment was unremarkable. A renal biopsy
showed focal interstitial fibrosis with scarce inflammatory cell infiltrate, tubular atrophy, and characteristic dilated tubule (microcyst
formation). Half of the glomeruli (not shown) were sclerotic.
(Magnification 125, periodic acidSchiff reaction.)
Germanium nephropathy
CIRCUMSTANCES OF CHRONIC RENAL FAILURE
SECONDARY TO GERMANIUM SUPPLEMENTS
Ge-dioxyde elixir, food additives, or capsules (used to improve health

in normal persons [Japan])
Ge-lactate-citrate (used to rebuild the immune system) in patients
with HIV infection (Switzerland)
Ge-lactate-citrate (used to improve health) in patients with cancer
(the Netherlands)
Ge-dioxyde elixir (used to restore health) in patients with chronic
hepatitis (Japan)
FIGURE 10-11
Germanium (atomic number, 32; atomic weight, 72.59) is contained in soil, plants, and animals as a trace metal. It is widely
used in the industrial fields because of its semiconductive capacity.
The increased use of natural remedies and trace elements to protect, improve, or restore the health has lead regular supplementation with germanium salts either through food addition or by the
means of elixirs and capsules. The chronic supplementation by
germanium salts was at the origin of the development of chronic
renal failure secondary to a tubulointerstitial nephritis [912].
10.6
FIGURE 10-12
Light microscopy of renal tissue in a patient with chronic renal
failure secondary to the chronic intake of germanium, showing
focal tubular atrophy and focal interstitial lymphocyte infiltration. A, Hematoxylin and eosin stain. (Magnification 162.)
Renal tubular epithelial cells show numerous dark small inclusions. B, Periodic acidSchiff reaction. (Magnification, 350).
(From Hess and coworkers [12]; with permission).
Exposure to Analgesics
Normal papilla
Swollen
Forniceal erosion
Detachment
Calcification
FIGURE 10-13
Analgesic nephropathy and papillary necrosis. The characteristic
feature of analgesic nephropathy is the papillary necrosis process
that begins with swollen papillae and continues with forniceal erosion, detachment, and calcification of necrotic papillae.
FIGURE 10-14
Pathology of analgesic nephropathy. Nephrectomy showing a kidney reduced in size with necrosed and calcified papillae.
10.7
Toxic Nephropathies
CLINICAL FEATURES OF ANALGESIC NEPHROPATHY

Daily consumption of analgesic mixtures
Women
Headache
Gastrointestinal disturbances
Urinary tract infection
Papillary necrosis (clinical)
Papillary calcifications (computed tomography scan)
FIGURE 10-15
Radiologic appearance of papillary necrosis in analgesic nephropathy. The pyelogram was obtained by pyelostomy. It shows a swollen
papilla (upper calyx), forniceal erosions (middle calyx), and detachment of papilla, or filling defect (lower calyx).
25
FIGURE 10-16
Classic analgesic nephropathy is a slowly progressive disease
resulting from the daily consumption over several years of mixtures containing analgesics usually combined with caffeine,
codeine, or both. Caffeine and codeine create psychological dependence. Most cases of analgesic nephropathy occur in women. In
80% of the cases, analgesics were taken for persistent headache.
Gastrointestinal complaints are also frequent, as are urinary tract
infections. Evidence of clinical papillary necrosis (fever and pain)
is present in 20% of cases. Calcifications of papillae (detected by
computed tomography scan) are present in 65% of persons who
abuse analgesics [13].
FIGURE 10-17
Worldwide epidemiology of analgesic nephropathy. The frequency
of analgesic nephropathy in patients with end-stage renal diseases
(ESRD) varies greatly within and among countries [1416]. The
highest prevalence rates of end-stage renal disease from analgesic
nephropathy occur in South Africa (22%), Switzerland and Australia
(20%), Belgium (18%), and Germany (15%). In Belgium, the prevalence is 36% in the north and 10% in the south. In Great Britain,
the rate is 1% nationwide; in Scotland it is 26%. In United States,
the rate is 5% nationwide, 13% in North Carolina, and 3% in
Washington, DC. In Canada, the rate is 6% nationwide.
EPIDEMIOLOGY OF ANALGESIC NEPHROPATHY

AMONG ESRD PATIENTS
Australia
Belgium
Canada
Germany
South Africa
Switzerland
United Kingdom
United States
20%
18%
6%
15%
22%
20%
1%
5%
Prevalence (EDTA, 1989)

Unknown cause
20
15
10
5
in
Spa
y
Ital
nce
Fra
al
Por
tug
rlan
ds
the
Ne
any
rm
Ge
F.R
.
stri
a
Au
Bel
giu
m
itze
rlan
d
Sw
100%
80%
80%
3540%
3048%
20%
65%
FIGURE 10-18
Prevalence of analgesic nephropathy versus
nephropathy with unknown cause. Crossnational comparisons in Europe indicate
that the proportion of cases of end-stage
renal disease attributed to analgesics varies
considerably; however, it is inversely proportional to unknown causes. These findings suggest an underestimation of the
prevalence of analgesic nephropathy in several countries, probably owing to the lack
of well-defined criteria for diagnosis
[13,15]. EDTAEuropean Dialysis and
Transplant Association. (From Elseviers and
coworkers [13]; with permission).
10.8
1983 sales of mixtures containing two

analgesic components
Pills taken in lifetime

< 5000
5000
Odds ratio,
95% confidence intervals
10.0
5.0
1.0
0
3000
Belgium
Rs = 0.86
P< 0.001
2000
1000
0
0
Acetaminiophen
Aspirin
40
30
10
20
1991 prevalence of analgesic
nephropathy, %
50
FIGURE 10-19
Risk of analgesic nephropathy associated with specific types of analgesics. The initial
reports of analgesic nephropathy chiefly concerned phenacetin mixtures. Phenacetin
Renal volume
Right kidney
Indentations
RA
RV
RA
SP
B
B
Decreased: A + B < 103 mm (males)
< 96 mm (females)
Criteria
Decrease in renal size
Bumpy contours
Left kidney
Sensitivity, %
95
50
87
12
35
Bumpy contours
D. PERCENTAGES OF SENSITIVITY AND SPECIFICITY
has been replaced with acetaminophen

in analgesia mixtures without significant changes in the cause of analgesic
nephropathy in some countries [15].
A, The risk factor for end-stage renal
disease of unknown cause is increased in
relationship to the cumulative intake of
acetaminophen as well as nonsteroidal
anti-inflammatory drugs but not to
aspirin. Moreover, mixtures containing
several analgesic compounds were
shown to be more nephrotoxic than are
simple drugs. B, In Belgium, the prevalence of analgesic nephropathy in 1991
was strongly correlated with sales of
analgesic mixtures in 1983. Rscoefficient of correlation. (A, Adapted from
Perneger and coworkers [17]; B, adapted from Elseviers and De Broe [18];
with permission).
Specificity, %
10
90
97
>5
FIGURE 10-20
High performance of computed tomography (CT) scan for diagnosing analgesic nephropathy. Three criteria may be used to diagnose
analgesic nephropathy by CT scan: decrease in renal size, measured
by the sum of both sides of the rectangle enclosing the kidney at
the level of the renal vessels (A); indentations counted at the level
at which most indentations are present (more than three are qualified of bumpy contours) (B); and papillary calcifications (C).
Percentages of sensitivity and specificity are given for the three criteria (D). Example of papillary calcifications on CT scan (E). RA
renal artery; RVrenal vein; SPspine. (Adapted from Elseviers
and De Broe [19]; with permission).
Toxic Nephropathies
HONCOCH3
OC2H5
NCOCH3
OH
OH
FIGURE 10-21
Malignancies of the urinary tract and their association with analgesic nephropathy. Malignancies of the renal pelvis and ureters were
reported in up to 9% of patients with analgesic nephropathy. This
high prevalence can be explained by the appearance of carcinogenic
substances in the major pathways of the metabolism of phenacetin.
Probable carcinogenic substances are indicated by a plus sign.
N-hydroxyp-ocetophenetidine
HNCOCH3
HNCOCH3
NH2
HNOH
10.9
NO
OH
[OH]
OC2H5
OC2H5
OC2H5
Phenacetin
(p-ocetophenetidine)
HNCOCH3
NH2
OC2H5
OC2H5
N-hydroxyp-phenetidine
p-nitrosophenetidine
H 2N
OH
OC2H5
OH
N-acetyl-p-amino- 2-hydroxyphenol (NAPA)
phenetidine
OH
NH2
OC2H5
Arene oxide
OC2H5
NIH shift
FIGURE 10-22
Malignant uroepithelial tumors of the
upper urinary tract in patients with analgesic nephropathy. A, Pyelogram showing
a filling defect, indicating a tumor of the
renal pelvis. B, Retrograde pyelography
showing a long malignant stricture of
the ureter, causing ureteral dilation and
hydronephrosis. (Courtesy of W Lornoy,
MD, OL Vrouwziekenhuis, MD.)
10.10
Exposure to Cyclosporine
Cyclosporine toxicity
Cyclosporine induced hypertension
Cyclosporine
Cyclosporine
Intestinal
absorption
2530%
Acute effects
Liver
cytochrome
P450
Inactive
metabolites
Sympathetic
nervous
system
Chronic effects
Endothelium
Thromboxane
Endothelin
Renal vasoconstruction
Inhibition
Ketoconazole
Verapamil
Diltiazem
Erythromycin
Cytosol
calcium
Chronic
renal failure
Sodium chloride
retention
Hypertension
FIGURE 10-23
Toxicity of cyclosporine. Cyclosporine is a neutral fungal
hydrophobic 11-amino acid cyclic polypeptide. Cyclosporine is
metabolized by hepatic cytochrome P450 to multiple less active
and less toxic metabolites. Drugs that inhibit cytochrome P450
enzymes such as ketoconazole, verapamil, diltiazem, and erythromycin increase the concentration of cyclosporine and may
thus precipitate renal side effects [20,21].
Mechanisms of cyclosporine renal injury

Cyclosporine
Renin
Sustained
vasoconstriction
Angiotensin II
Renal ischemia
TGF-
Interstitial
fibrosis
FIGURE 10-24
Cyclosporine and hypertension. Hypertension can develop in 10%
to 80% of patients treated with cyclosporine, depending on dosage
and length of the exposure. Cyclosporine increases cytosol calcium
and, thus, enhances arteriolar smooth muscle responsiveness to
vasoconstrictive stimuli. Vasoconstrictive effects of cyclosporine
also are mediated by enhanced thromboxane action, sympathetic
nerve stimulation, and release of endothelin. Renal vasoconstriction results in salt retention and hypertension. In chronic exposure
to cyclosporine, hypertension also is a part of cyclosporine-induced
chronic renal failure [22].
FIGURE 10-25
Pathogenesis of cyclosporine nephropathy. Chronic administration of cyclosporine may
induce sustained renal vasoconstriction. Impairment of renal blood flow leads to tubulointerstitial fibrosis. Cyclosporine increases the recruitment of renin-containing cells along the
afferent arteriole. Hyperplasia of the juxtaglomerular apparatus increases angiotensin II
levels that, in turn, stimulate tumor growth factor- (TGF-) secretion, resulting in interstitial fibrosis [20].
Toxic Nephropathies
CyA, 7.5 mg/kg
60
40
20
60
40
20
0
8 Weeks
CyA, 5 mg/kg
80
60
40
20
0
0
24 Months
Uveitis
80
60
40
20
0
Psoriasis
100
% of normal values
80
CyA, 10 to 6 mg/kg
100
% of normal values
80
CyA, 9.3 mg/kg
100
% of normal values

% of normal values
100
10.11
13 Months
Autoimmune diseases
36 Months
Cardiac transplantations
FIGURE 10-26
Cyclosporine (CyA) nephrotoxicity in nonrenal diseases. A, Patients treated with
cyclosporine (7.5 mg/kg) for psoriasis experienced a median decrease to 84% of the initial
values in the glomerular filtration rate after 8 weeks of therapy. B, Of patients treated with
cyclosporine (9.3 mg/kg) for autoimmune diseases, 21% showed cyclosporine nephropathy
on biopsy, with a decrease to 60% of the initial values in renal function. C, Patients with
cardiac transplantation treated with high doses of cyclosporine (10 to 6 mg/kg) developed
a reduction to 57% of the initial values in renal function 36 months after transplantation.
Patients treated with azathioprine did not show any reduction in renal function. D,
Patients receiving cyclosporine (5 mg/kg) for uveitis for 2 years showed a decrease in
glomerular filtration rate to 65% of the initial values. (Panel A adapted from Ellis and
coworkers [23]; panel B adapted from Feutren and Mihatsch [24]; panel C adapted from
Myers and Newton [25]; and panel D adapted from Deray and coworkers [26].)
A
FIGURE 10-27
Morphology of cyclosporine nephropathy on renal biopsy of a
patient with cardiac transplantation. Two different types of lesions
are seen in cyclosporine nephropathy. A, Arteriolopathy: Hyalin,
paucicellular thickening of the intima with focal wall necrosis
results in narrowing of the vascular lumen (magnification 300
B
periodic acidSchiff reaction). B, A striped form of interstitial
fibrosis characterized by irregularly distributed areas of stripes of
interstitial fibrosis and tubular atrophy in the renal cortex. Tubules
in other areas were normal (magnification x 100 periodic
acidSchiff reaction).
10.12
Exposure to Aminosalicylic Acid

10.6
C.P. man born
January 19, 1971
8
6
4.0
B
FIGURE 10-28
Aminosalicylic acid and chronic tubulointerstitial nephritis. A, A
36-year-old man suffering from Crohns disease exhibited severe
renal failure after 23 months of treatment with 5-aminosalicylic
acid (5-ASA, or Pentasa, Hoechst Marion Roussel, Kansas City,
MO). B, The first renal biopsy showing widening and massive
cellular infiltration of the interstitium, tubular atrophy, and relative spacing of glomeruli. C, The second renal biopsy 8 months,
after discontinuation of the drug and moderate improvement of
the renal function, again showing important cellular infiltration
y1
, 19
96
De
c1
, 19
96
Methyl- 16 mg/d
prednisolone
Ma
Hemodialysis
rch
199
1
199
2
rch
t 3,
Ma
Oc
Renal biopsy
23,
199
4
2, 1
994
Oral Pentasa 500 mg/d, 3 x per day
3.9
32 mg/d
Renal biopsy
v2
2
De , 1994
c2
De , 1994
c2
De 2, 199
c3
1, 4
Jan 1994
6, 1
995
1.1
No
2
0
4.2
IBD diagnosis
Ma
4.9
Feb
Seerum creatinine, mg/dL
10
C
of the interstitium tubular atrophy, and fibrosis. Several atrophic
tubules are surrounded by one or more layers of -smooth muscle actin positive cells. The patient had normal renal function on
beginning treatment with 5-ASA. After 5 years of 5-ASA therapy,
the patient demonstrated severe impaired renal function. The
association between the use of 5-ASA and development of chronic tubulointerstitial nephritis in patients with inflammatory bowel
disease (IBD) has gained recognition in recent years [27,28].
(Courtesy of ME De Broe, MD.)
Toxic Nephropathies
10.13
Exposure to Ochratoxins
FIGURE 10-29
Ochratoxin nephropathy. Ochratoxin A is a mycotoxin produced by various species of
Aspergillus and Penicillium. Ochratoxins contaminate foods (mainly cereals) for humans as
well as for cattle. Ochratoxins are mutagenic, oncogenic, and nephrotoxic. Ochratoxins are
responsible for chronic nephropathy in pigs and also may be the cause of endemic Balkan
nephropathy and some chronic interstitial nephropathies seen in North Africa and France [29].
Ochratoxin A
OH
COOH
CH2- CH-NH-CO-
CH3
CI
R. Danube
Contamination of cereals
Chronic nephropathy in pigs
Endemic Balkan nephropathy
Chronic interstitial nephritis in Tunisia
Chronic interstitial nephritis in France (?)
Austria
Slovenia
R. Sava
CLINICAL FEATURES OF BALKAN NEPHROPATHY
Hungary
Croatia
R. S
ava
Romania
Slavonski
Brod
Bneljina
Bosnia and
Herezgovina
Oravita
Turn Severin
Belgrade
Lazarevac
Paracin
Sarajevo
Nis
be
anu
R. D
Mikhaylovgrad
Yugoslavia
Vratsa
Italy
Sofia
Residence in an endemic area

Occupational history of farming
Progressive renal failure
Microproteinuria of tubular type
Unremarkable urinary sediment
Small and shrunken kidneys
Associated urothelial tumors
Bulgaria
Macedonia
Albania
Greece
FIGURE 10-30
Endemic Balkan nephropathy. Endemic nephropathy is encountered in some well-defined areas of the Balkans. Distribution (dark
areas) is along the affluents of the Danube, in a few areas on the
plains and low hills owing to high humidity and rainfall. (From
Stefanovic and Polenakovic [30]; with permission.)
FIGURE 10-31
Clinical features in Balkan nephropathy. Balkan nephropathy is
characterized by progressive renal failure in residents (generally
farmers) living in endemic areas for over 10 years. The urinary
sediment is unremarkable and no proteinuria is seen, except for
a microproteinuria of tubular type. The kidneys are small and
shrunken. Urothelial cancers are frequently associated with Balkan
nephropathy [29,30].
10.14
FIGURE 10-32
Pathology of Balkan nephropathy. Balkan nephropathy is characterized
by pure interstitial fibrosis with marked tubular atrophy (A) and by
hyperplasia of the myocythial cells with narrowing of the lumen of the

vessel (B) (From Stefanovic and M. Polenakovic [30]; with permission).
80
12.8
10
1.6
0
Endemic
Nonendemic
Areas of Balkan nephropathy
FIGURE 10-34
Balkan nephropathy and ochratoxin A in food. A survey of homeproduced foodstuffs in the Balkans has revealed that contamination
with ochratoxin A is more frequent in areas in which endemic
nephropathy is prevalent (endemic areas) than in areas in which
nephropathy is absent. (Adapted from Krogh and coworkers [31].)
Number of urothelial cancers

per million inhabitants
Cereal samples contaminated

by ochratoxin, %
FIGURE 10-33
Pathology of ochratoxin nephropathy. In addition to interstitial
fibrosis, large hyperchromatic nuclei in tubular epithelial cells are
shown by the arrow (interstitial caryomegalic nephropathy).
(Masson trichrome stain, magnification x 160.) The renal biopsy
was obtained from a woman from France who had renal failure
(creatinine clearance 40 mL/min) without significant proteinuria
and urinary sediment abnormalities. Ochratoxin levels were 367
and 1810 ng/mL, respectively, in the patients blood and urine.
(From Godin and coworkers [29].)
74.2
70
60
50
40
30
20
10
0
3.2
Endemic
Nonendemic
Areas of Balkan nephropathy
FIGURE 10-35
Balkan nephropathy and urothelial cancers. Urothelial cancers
appear as a frequent complication of Balkan nephropathy. An
increased prevalence of upper tract urothelial tumors is described
in inhabitants of areas in which Balkan nephropathy is endemic.
(Adapted from Godin and coworkers [29].)
Toxic Nephropathies
10.15
Exposure to Chinese Herbs

FIGURE 10-36
Epidemiology of Chinese herbs nephropathy. Chinese herbs
nephropathy was described for the first time in Belgium in 1993
[32]. A peak incidence of new cases of women with rapidly progressive interstitial nephritis in Brussels during 1992 lead to suspicion of a new cause of renal disease. The relationship between this
new renal disease and the recent introduction of Chinese herbs
(namely, Stephania tetrandra) in a slimming regimen was established [32]. The withdrawal from the market of this herb has
decreased the incidence of interstitial nephritis in Brussels, Belgium.
Chinese herb nephropathy

(number of new cases)
Release of Chinese herb

(so-called Stephania tetrandra)
on Belgian market
40
90
92
32
31
30
24
20
15
10
7
1
1989
1990
0
1991
1992 1993
Year
1994
1995
1996
A. CHINESE HERBAL MEDICINE

Chinese Name
Western name
Chemical Marker
Han fang-ji
Guang fang-ji
Stephania tetrandra
Aristolochia fang chi
Tetrandrine
Aristolochic acid
30
Chinese herbs
(Number of batches)
30
20
10
7
5
+A, +T +A, T A, +T A, T
+A, aristolochic acid present
A, aristolochic acid absent
+T, tetrandrine present
T, tetrandine absent
FIGURE 10-37
Role of Aristolochia in Chinese herbs nephropathy. Stephania tetrandra was the Chinese herb chronologically associated with the development of Chinese herbs nephropathy. However, tetrandrine, the alkaloid characterizing Stephania tetrandra was not found in the capsules
taken by the patients. In fact, confusion between Stephania tetrandra
and Aristolochia fang chi was done in the delivery of Chinese herbs in
Belgium [33]. Chinese characters and the pingin name of Stephania
tetrandra (Han fang-ji) are identical to that of Aristolochia fang chi
(Guang fang-ji). Investigations conducted on batches of Stephania
tetrandra powders distributed in Belgium have shown that most of
them contained aristolochic acids (characteristic of Aristolochia) and
not tetrandrine (From Vanhaelen and coworkers [33] and P Daenens,
Katholiek Universiteit Leuven, Belgium, report of expertise 1996.)
10.16
DNA ADDUCTS FORMED BY

ARISTOLOCHIC ACID IN RENAL TISSUE
Chinese Herb Nephropathy (n = 5)
Controls (n = 6)
0.75.3 per 107 nucleotides
FIGURE 10-38
DNA aristolochic acid adducts in kidney tissues of patients with
Chinese herbs nephropathy. The role of Aristolochia in the pathogenesis of Chinese herbs nephropathy was confirmed by the demonstration of DNA aristolochic acid adducts (a biomarker of aristolochic
acids exposure) in renal tissue of patients with Chinese herbs
nephropathy, whereas these adducts were absent in the renal tissue
of control cases. (Adapted from Schmeiser and coworkers [34].)
CLINICAL FEATURES OF CHINESE HERB NEPHROPATHY

Rapidly progressive renal failure
Microproteinuria of tubular type
Unremarkable urinary sediment
Small and shrunken kidneys
Valvular hear diseases (dexfenfluramine-associated therapy), 30%
Associated urothelial cancers
FIGURE 10-39
The clinical features of Chinese herbs nephropathy are characterized by rapidly progressive renal failure without both urinary sediment abnormalities and proteinuria except for a microproteinuria
of tubular type. The kidneys are small and shrunken. Vascular
heart diseases are associated in 30% of cases (probably owing to
dexfenfluramine administered with the Chinese herbs for slimming
purposes) [35]. Some cases of associated urothelial cancers also are
described [36,37].
FIGURE 10-40
Photographic image of the pathology of Chinese herbs nephropathy. Chinese herbs nephropathy is characterized by a large reduction in kidney volume. Moreover, an associated tumor of the lower
ureter is shown.

Pathology of Chinese herb nephropathy. The major pathologic
lesion consists of extensive interstitial fibrosis with atrophy
and loss of the tubules, predominantly located in superficial
cortex [38,39]. A, A low-power view of transition between
superficial cortex (left) and deep cortex (right) shows an
extensive interstitial fibrosis with relative sparing of glomeruli.

(Masson trichrome stain, magnification 50.) B, A normal
glomerulus surrounded by a paucicellular interstitial fibrosis
and atrophic tubules. (Massons trichrome stain, magnification
300.)
10.17
Toxic Nephropathies
NEP
log ug/24 h
ug/24 h
40
30
20
5
log ug/24 h
20
10
Normal
Renal End-stage
renal function failure renal disease
After exposure to Chinese herbs
RBP
4
3
2
4
3
2
1
0
Controls
B2m
30
10
Controls
CC16
40
log ug/24 h
50
Normal
Renal End-stage
Controls
Normal
Renal End-stage
FIGURE 10-42
AD, Microproteinuria and neutral endopeptidase enzymuria in Chinese herbs nephropathy.
Proximal tubular injury in Chinese herbs nephropathy is demonstrated by a significant
increase in urinary excretion of microproteins (Clara cell protein, CC16; 2-microglobulin
[2-m] and retinol binding protein [RBP]) as well as a decrease in urinary excretion of neutral endopeptidase (NEP) a marker of the brush border tubular mass. (Adapted from Nortier
1
0
Controls Normal
Renal End-stage
FIGURE 10-43
Chinese herbs nephropathy and renal pelvic carcinoma. Urothelial cancers are associated
with Chinese herbs nephropathy [36,37]. Shown is a filling defect (arrow) in the renal
pelvis in an antegrade pyelogram obtained from a patient with Chinese herbs nephropathy
and hematuria. (From Vanherweghem and coworkers [37]; with permission).
10.18
FIGURE 10-44
Pathology of urothelial tumors associated with Chinese herbs
nephropathy. Microscopic pattern is shown of a lower urothelial tumor obtained by ureteronephrectomy of a native kidney
in a patients with transplantation who has Chinese herbs
nephropathy (the macroscopic appearance of the nephrectomy
1/P creatinine ratio
0.7
Controls, n = 23
Steroids, n = 12
0.6
is shown in Fig. 10-40). A, Part of the urothelial proliferation.

Plurifocal thickening of the urothelium is present. (Hematoxylin
and eosin stain x 50.) B, In situ transitional cell carcinoma
with high mitotic rate. (Magnification x 400 periodic acid
Schiff reaction.)
TOXIC CHRONIC INTERSTITIAL NEPHROPATHIES

WITH UROTHELIAL CANCERS
0.5
0.4
Analgesic nephropathy (phenetidin compounds)

Balkan nephropathy (ochratoxins)
Chinese herbs nephropathy (aristolochic acids)
0.3
0.2
0.1
6
3
6
Months
12
FIGURE 10-45
Effects of steroids on the evolution of renal failure in Chinese herbs
nephropathy. Steroid therapy was shown to decrease the evolution
of renal failure in a subgroup of patients with Chinese herbs
nephropathy [41]. The evolution is shown of the 1/P creatinine
ratio of patients with Chinese herbs nephropathy, 12 of whom
were treated with steroids as compared with 23 not treated with
steroids (control group). In the control group the 1/P creatinine
curve was limited to 6 months of follow-up because at 12 months,
17 of the 23 patients were on renal replacement therapy. (From
Vanherweghem and coworkers [41]; with permission.)
FIGURE 10-46
Of interest is the association between chronic renal interstitial
fibrosis and urothelial cancers. This association appears, at least,
in three chronic toxic nephropathies: analgesic nephropathy,
Balkan nephropathy, and Chinese herbs nephropathy. This association indicates that nephrotoxins promoting interstitial fibrosis
(analgesics, ochratoxins, and aristolochic acids) also may be
oncogenic substances.
Toxic Nephropathies
10.19
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13. Elseviers MM, Bosteels V, Cambier P, et al.: Diagnostic criteria of

analgesic nephropathy in patients with end-stage renal failure:
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14. Drukker W, Schwarz A, Vanherweghem JL: Analgesic nephropathy:
an underestimated cause of end-stage renal disease. Int J Artif Organs
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17. Perneger TV, Whelton PK, Klag MJ: Risk of kidney failure associated
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18. Elseviers MM, De Broe ME: Analgesic nephropathy in Belgium is
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Metabolic Causes of
Steven J. Scheinman
variety of metabolic conditions produce disease of the renal

interstitium and tubular epithelium. In many cases, disease
reflects the unique functional features of the nephron, in
which the ionic composition, pH, and concentration of both the
tubular and interstitial fluid range widely beyond the narrow confines seen in other tissues. Recent genetic discoveries have offered
new insights into the molecular basis of some of these conditions, and
have raised new questions. This chapter discusses nephrocalcinosis,
the relatively nonspecific result of a variety of hypercalcemic and
hypercalciuric states, as well as the renal consequences of hyperoxaluria, hypokalemia, and hyperuricemia.
CHAPTER
11
11.2
Hypercalcemia
inhibits reabsorption
of NaCl, Ca, and Mg
Hypercalcemia
inhibits
reabsorption
of water
RENAL EFFECTS OF CALCIUM

Hypercalcemia
Collecting duct
Resistance to vasopressin, leading to isotonic polyuria
Thick ascending limb of the loop of Henle
Impaired sodium chloride reabsorption, leading to modest salt wasting
Inhibition of calcium transport, leading to hypercalciuria
Inhibition of magnesium transport, leading to hypomagnesemia
Renal vasculature
Arteriolar vasoconstriction
Reduction in ultrafiltration coefficient
Hypercalciuria
Microscopic hematuria
Nephrocalcinosis
Impaired urinary acidification
FIGURE 11-1
The recent discovery of the calcium-sensing
receptor and increased understanding of its
expression along the nephron have provided
explanations for many of the known effects
of hypercalcemia to cause clinical disturbances in renal tubular function [1]. In the
parathyroid gland the calcium-sensing receptor allows the cell to sense extracellular levels
of calcium and transduce that signal to regulate parathyroid hormone production and
release. In the nephron, expression of the
calcium receptor can be detected on the apical surface of cells of the papillary collecting
duct, where calcium inhibits antidiuretic
hormone action. Thus, hypercalcemia impairs
urinary concentration and leads to isotonic
polyuria. The most intense expression of the
calcium receptor is in the thick ascending
limb of the loop of Henle, particularly the
cortical portion, where the calcium receptor
protein is located on the basolateral side of
the cells; this explains the known effects of
hypercalcemia in inhibiting reabsorption of
calcium, magnesium, and sodium chloride
in the thick ascending limb [2]. In addition,
hypercalcemia causes hypercalciuria through
an increased filtered calcium load and
suppression of parathyroid hormone release
with a consequent reduction in calcium
reabsorption. Cacalcium; Mgmagnesium; NaClsodium chloride.
FIGURE 11-2
Hypercalcemia leads to renal vasoconstriction and a reduction in
the glomerular filtration rate. However, no expression of the calcium-sensing receptor has been reported so far in renal vascular or
glomerular tissue. Calcium receptor expression is present in the
proximal convoluted tubule, on the basolateral side of cells of the
distal convoluted tubule, and on the basolateral side of macula
densa cells. Functional correlates of calcium receptor expression
at these sites are not yet clear [3].
Hypercalciuria leads to microscopic hematuria and, in fact, is
the most common cause of microscopic hematuria in children. The
mechanism is presumed to involve microcrystallization of calcium
salts in the tubular lumen. Conflicting effects of calcium on urinary
acidification have been reported in clinical settings in which other
factors, such as parathyroid hormone levels, may explain the observations. whether or not it is the result of renal tubular acidosis,
Nephrocalcinosis often is associated with impaired urinary acidification, whether or not it is the result of renal tubular acidosis.
Metabolic Causes of Tubulointerstitial Disease
CAUSES OF NEPHROCALCINOSIS
Medullary (total)
Primary hyperparathyroidism
Distal renal tubular acidosis
Idiopathic hypercalciuria
Dents disease
Milk-alkali syndrome
Oxalosis
Hypomagnesemia-hypercalciuria
Sarcoidosis
Renal papillary necrosis
Hypervitaminosis D
Other*
Undiscovered causes
Cortical (total)
97.6
32.4
19.5
11.3
5.9
4.3
3.2
3.2
1.6
1.6
1.6
1.6
4.0
6.7
2.4
Adapted from Wrong [3]; with permission.
11.3
FIGURE 11-3
Nephrocalcinosis represents calcification of the renal parenchyma. It
is primarily medullary in most cases except in dystrophic calcification
associated with inflammatory, toxic, or ischemic disease. Nephrocalcinosis can be seen in association with chronic or severe hypercalcemia or in a variety of hypercalciuric states. The spectrum of causes
of nephrocalcinosis is described by Wrong [3]. The numbers represent
the percentage of the total of 375 patients. It is likely that the case mix
is affected to some extent by Wrongs interests in, eg, renal tubular
acidosis (RTA) and Dents disease, but this is by far the largest published series. As in other studies, the most important causes of
nephrocalcinosis are primary hyperparathyroidism, distal RTA, and
medullary sponge kidney. The primary factor predisposing patients
to renal calcification in many of these conditions is hypercalciuria,
as occurs in idiopathic hypercalciuria, Dents disease, milk-alkali
syndrome, sarcoidosis, hypervitaminosis D, and often in distal RTA.
In distal RTA and milk-alkali syndrome, relative or absolute urinary
alkalinity promote precipitation of calcium phosphate crystals in the
tubular lumena, and hypocitraturia is an important contributing
factor in distal RTA. Causes of cortical nephrocalcinosis in this study
included acute cortical necrosis, chronic glomerulonephritis, and
chronic pyelonephritis.
* Other causes include Bartter syndrome, idiopathic Fanconi syndrome, hypothy-
roidism, and severe acute tubular necrosis.
Impaired urinary acidification
Alkaline urine
Systemic
acidosis
Hypercalciuria
Hypokalemia
Decreased urinary
citrate excretion
Resorption of
bone mineral
Reduced renal
tubular calcium
reabsorption
Hypercalciuria
CaPO4 precipitation
FIGURE 11-4
Nephrocalcinosis in type I (distal) renal tubular acidosis. Nephrocalcinosis and
nephrolithiasis are common complications in distal renal tubular acidosis (RTA-1).
Several factors contribute to the pathogenesis. The most important of these factors
are a reduction in urinary excretion of citrate and a persistently alkaline urine. Citrate
inhibits the growth of calcium stones; its excretion is reduced in RTA-1 as a result of
both systemic acidosis and hypokalemia.

The high urine pH favors precipitation of
calcium phosphate (CaPO4). Thus, RTA-1
should be suspected in any patient with
pure calcium phosphate stones [4].
Systemic acidosis also promotes hypercalciuria, although not all patients with
RTA-1 have excessive urinary calcium
excretion [5]. Hypercalciuria results from
resorption of bone mineral and the consequent increased filtered load of calcium as
acidosis leads to consumption of bone
buffers. Acidosis also has a direct effect of
inhibiting renal tubular calcium reabsorption. Conversely, nephrocalcinosis from
other causes can impair urinary acidification and lead to RTA in some patients.
The mainstay of therapy for RTA-1 is
potassium citrate, which corrects acidosis,
replaces potassium, restores urinary citrate excretion, and reduces urinary loss of
calcium [5]. (From Buckalew [5]; with
permission.)
11.4
Lumen
NKCC2
Epithelial cell of the thick ascending

limb of the loop of Henle
Na+
2Cl
K+
ROMK
Blood
ClC-Kb
K+
Na+
ATP
K+
FIGURE 11-5
Bartter syndrome. Bartter syndrome is a hereditary renal functional
disorder characterized by hypokalemic metabolic alkalosis, renal
salt wasting with normal or low blood pressure, polyuria, and
hypercalciuria. Other features include juxtaglomerular hyperplasia,
secondary hyperreninemia and hyperaldosteronism, and excessive
urinary excretion of prostaglandin E. It often has been noted that
patients with Bartter syndrome appear as if they were chronically
exposed to loop diuretics; in fact, the major differential diagnosis is
with diuretic abuse. Bartter syndrome often presents with growth
retardation in children, and nephrocalcinosis is common. Bartter
syndrome is inherited as an autosomal recessive trait.
The speculation that this syndrome could be explained by
impaired reabsorption in the loop of Henle has now been confirmed
by molecular studies. R.P. Liftons group [68] identified loss-offunction mutations in three genes encoding different proteins, each
involved in the coordinated transport of salt in the thick ascending

limb of the loop of Henle. In this nephron segment, sodium chloride
is transported into the cell together with potassium by the bumetamide-inhibitible sodium-potassium-2 chloride cotransporter
(NKCC2). Recycling of potassium back to the lumen through an
apical potassium channel (ROMK) allows an adequate supply of
potassium for optimal activity of the NKCC2. Chloride exits the
basolateral side of the cell through a voltage-gated chloride channel
(ClC-Kb), and sodium is expelled separately by the sodium-potassium adenosine triphosphatase cotransporter. Inactivating mutations
in NKCC2, ROMK, and ClC-Kb have been identified in patients
with Bartter syndrome [68].
Approximately 20% of filtered calcium is reabsorbed in the
thick ascending limb, and inactivation of any of these three transport proteins can lead to hypercalciuria. Nephrocalcinosis occurs
in almost all patients with mutations in NKCC2 or ROMK, but it
is less common in patients with a mutation in the basolateral chloride channel ClC-Kb, even though patients with chloride-channel
mutations currently make up the largest reported group [8]. This
interesting observation is unexplained at present. In addition, a significant number of patients with Bartter syndrome have been found
to have normal coding sequences for all three of these genes, indicating that mutations in other gene(s) may explain Bartter
syndrome in some patients.
In contrast, the Gitelman variant of Bartter syndrome is associated
with hypocalciuria. In this respect these patients resemble people
treated with thiazide diuretics. In fact, mutations have been found
in the thiazide-sensitive sodium chloride cotransporter of the distal
tubule [9]. Hypomagnesemia is common and often severe, and
patients with Gitelman syndrome do not develop nephrocalcinosis.
ATPadenosine triphosphate. (From Simon and coworkers [8];
with permission.)
FIGURE 11-7
Noncontrast
abdominal
radiograph in a
24-year-old man
with X-linked
nephrolithiasis
(Dents disease).
The patient had
recurrent calcium
nephrolithiasis
beginning in childhood and developed
end-stage renal
disease requiring
dialysis at 40 years
of age. Extensive
medullary calcinosis
is evident.
FIGURE 11-6
Nephrocalcinosis. Ultrasound image of right kidney in a patient
with primary hyperparathyroidism. Echogenicity of the renal
cortex is comparable to that of the adjacent liver. The dense
nephrocalcinosis is entirely medullary. (Courtesy of Robert
Botash, MD.)
X-LINKED NEPHROLITHIASIS (DENTS DISEASE)
Low molecular weight proteinuria

Other defects in proximal tubular function
Hypercalciuria
Nephrocalcinosis
Calcium stones
Renal failure
Rickets
Males who are affected
Females who are carriers
Extreme
Variable
Occurs early in most
Nearly all have it
Common but not universal
Common but not universal
Present in some
Absent, mild, or moderate

Uncommon
Present in half
Rare
Uncommon
Rare
Not reported
FIGURE 11-8
Syndromes of X-linked nephrolithiasis have been
reported under various names, including Dents disease
in the United Kingdom, X-linked recessive hypophosphatemic rickets in Italy and France, and a syndrome of
low molecular weight (LMW) proteinuria with hypercalciuria and nephrocalcinosis in Japanese schoolchildren. Mutations in a gene encoding a voltage-gated chloride channel (ClC-5) are present in all of these syndromes, establishing that they represent variants of one
disease [10]. The disease occurs most often in boys,
with microscopic hematuria, proteinuria, and hypercalciuria. Many but not all have recurrent nephrolithiasis
from an early age. Affected males excrete extremely
large quantities of LMW proteins, particularly 2microglobulin and retinol-binding protein. Other defects
of proximal tubular function, including hypophosphatemia, aminoaciduria, glycosuria, or hypokalemia,
occur variably and often intermittently. Many affected
males have mild to moderate polyuria and nocturia, and
they often exhibit this symptom on presentation.
Urinary acidification is usually normal, and patients do
not have acidosis in the absence of advanced renal
insufficiency. Nephrocalcinosis is common by the
teenage years, and often earlier. Renal failure is common
and often progresses to end-stage renal disease by the
fourth or fifth decade, although some patients escape it.
Renal biopsy documents a nonspecific pattern of interstitial fibrosis and tubular atrophy, with glomerular sclerosis that is probably secondary [11].
Rickets occurs early in childhood in some patients but

is absent in most patients with X-linked nephrolithiasis
(Dents disease). In a few families, all affected males have
had rickets. In other families, rickets is present in only
one of several males sharing the same mutation. At present, the variability of this feature and other features of
the disease is unexplained and may reflect dietary or environmental factors or the participation of other genes in
the expression of the phenotype.
Females who are carriers often have mild to moderate LMW proteinuria. This abnormality can be used
clinically as a screening test, but LMW protein excretion will not be abnormal in all heterozygous females.
Approximately half of women who are carriers have
hypercalciuria, but other biochemical abnormalities are
rare. Although symptomatic nephrolithiasis and even
renal insufficiency have been reported in female carriers, they are very uncommon.
The gene for ClC-5 that is mutated in X-linked nephrolithiasis (Dents disease) is expressed in the endosomal
vacuoles of the proximal tubule; it appears to be important in acidification of the endosome. Thus, defective
endosomal function would explain the LMW proteinuria.
The mechanism of hypercalcinuria remains unexplained
at present. This gene belongs to the family of voltagegated chloride channels that includes ClC-Kb, one of the
gene mutations in some patients with Bartter syndrome.
To date, 32 mutations have been reported in 40 families,
and nearly all are unique [11].
11.5
11.6
HYPEROXALURIA
Type
Mechanism
Clinical consequences
Primary (genetic):
PH1
Functional deficiency of AGT
Nephrolithiasis
Nephrocalcinosis and progressive renal failure
Systemic oxalosis (kidneys, bones, cartilage, teeth, eyes, peripheral
nerves, central nervous system, heart, vessels, bone marrow)
Nephrolithiasis
PH2
Secondary:
Dietary
Enteric
Metabolism from excess of precursors

Pyridoxine deficiency
Functional deficiency of DGDH

Sources include for example spinach, rhubarb, beets, peanuts,
chocolate, and tea
Enhanced oxalate absorption because of increased oxalate solubility, bile salt malabsorption, and altered gut flora (eg, inflammatory bowel disease and bowel resection)
Ascorbate
Ethylene glycol, glycine, glycerol, xylitol, methoxyflurane
Cofactor for AGT
FIGURE 11-9
Oxalate is a metabolic end-product of limited solubility in physiologic
solution. Thus, the organism is highly dependent on urinary excretion,
which involves net secretion. Normal urine is supersaturated with
respect to calcium oxalate. Crystallization is prevented by a number of
endogenous inhibitors, including citrate. A mild excess of oxalate load,
as occurs with excessive dietary intake, contributes to nephrolithiasis.
A more severe oxalate overload, as in type 1 primary hyperoxaluria,
can lead to organ damage through tissue deposition of calcium oxalate
and possibly through the toxic effects of glyoxalate [12].
Two types of primary hyperoxaluria (PH) have been identified
(Fig. 11-10), of which type 1 (PH1) is much more common. PH1
results from absolute or functional deficiency of the liver-specific
enzyme alanine:glyoxalate aminotransferase (AGT). This deficiency
leads to calcium oxalate nephrolithiasis in childhood, with nephrocalcinosis and progressive renal failure. Because the kidney is the
main excretory route for oxalate, in the face of excessive oxalate
production even mild degrees of renal insufficiency can lead to
systemic deposition of oxalate in a wide variety of tissues. It is interesting that the liver itself is spared from calcium oxalate deposition.
Clinical consequences include heart block and cardiomyopathy,
severe peripheral vascular insufficiency and calcinosis cutis, and bone
pain and fractures. Many of these conditions are exacerbated by the
effects of end-stage renal disease. In contrast, PH2 is much more rare
than is PH1. Patients with PH2 have recurrent nephrolithiasis.
Nephrocalcinosis, renal failure, and systemic oxalosis have not been
reported in PH2. The metabolic defect in PH2 appears to be a functional deficiency of D-glycerate dehydrogenase (DGDH) [12].
Secondary causes of hyperoxaluria include dietary excess, enteric
hyperabsorption, and enhanced endogenous production resulting
Increased risk of nephrolithiasis

Nephrolithiasis
Nephrocalcinosis
Systemic oxalosis (rarely)
Nephrolithiasis
Tubular obstruction by crystals leading to acute renal failure
Nephrolithiasis
from either exposure to metabolic precursors of oxalate or pyridoxine deficiency. Normally, dietary sources of oxalate account for
only approximately 10% of urinary oxalate. Restriction of dietary
oxalate can be effective in some patients with kidney stones who
are hyperoxaluric, but even conscientious adherence to dietary
restriction is disappointing in many patients who may have mild
metabolic hyperoxaluria, an entity that probably exists but is poorly
understood. Intestinal absorption of oxalate can be enhanced
markedly in patients with bowel disease, particularly inflammatory
bowel disease or after extensive bowel resection or jejunoileal bypass.
In this setting, several mechanisms have been described including a)
enhanced oxalate solubility as a consequence of binding of calcium
to fatty acids in patients with fat malabsorption; b) a direct effect
of malabsorbed bile salts to enhance absorption of oxalate by
intestinal mucosa, and c) altered gut flora with reduction in the
population of oxalate-metabolizing bacteria [4,12]. Because of
the important role of the colon in absorbing oxalate, ileostomy
abolishes enteric hyperoxaluria [4].
Excessive endogenous production of oxalate occurs in patients
ingesting large quantities of ascorbic acid, which may increase the
risk of nephrolithiasis. In the setting of acute exposure to large
quantities of metabolic precursors, such as ingestion of ethylene
glycol or administration of glycine or methoxyflurane, tubular
obstruction by calcium oxalate crystals can lead to acute renal
failure. Pyridoxine deficiency is associated with increased oxalate
excretion clinically in humans and experimentally in animals; it
can contribute to mild hyperoxaluria. In all patients with primary
hyperoxaluria, a trial of pyridoxine therapy should be given,
because some patients will have a beneficial response.
Primary hyproxaluria metabolism

Peroxisome
Cytosol
Glycolate
Glycolate
DGDH
Glycine
Block in PH2
Glyoxylate
Glycine
AGT
Block in PH1
Oxalate
Oxalate
FIGURE 11-10
Metabolic events in the primary hyperoxalurias. Primary hyperoxaluria type 1 (PH1) results from functional deficiency of the
peroxisomal enzyme alanine:glyoxalate aminotransferase (AGT).
PH2 results from a deficiency of the cytosolic enzyme d-glycerate
dehydrogenase (DGDH), which also functions as glyoxalate reductase. This figure presents a simplified illustration of the metabolic
A
FIGURE 11-11
Sequential biopsies of a transplanted kidney documenting progressive
recurrence of renal oxalosis. This patient with primary hyperoxaluria
type I received renal transplantation, without liver transplantation, at
24 years of age. Panels AD show tissue stained with hematoxylin
11.7
consequences of these defects. Both diseases are inherited as autosomal recessive traits.
In PH1, much clinical, biochemical, and molecular heterogeneity
exists. Liver AGT catalytic activity is absent in approximately two
thirds of patients with PH1. It is detectable in the remaining third,
however, in whom the enzyme is targeted to the mitochondria
rather than peroxisomes. Absence of peroxisomal AGT activity
leads to impaired transamination of glyoxalate to glycine, with
excessive production of oxalate and, usually, glycolate. In PH2,
deficiency of cytosolic DGDH results in overproduction of oxalate
and glycine. Mild cases of PH1, without nephrocalcinosis or systemic
oxalosis, resemble PH2 clinically, but the two usually can be distinguished by measurement of urinary glycolate and glycine. Assay of
AGT activity in liver biopsy specimens can be diagnostic in PH1
even when renal failure prevents analysis of urinary excretion.
The gene encoding AGT has been localized to chromosome
2q37.3 and has been cloned and sequenced. Mutations in this gene
have been identified in patients with absent enzymatic activity,
abnormal enzyme targeting to mitochondria, aggregation of AGT
within peroxisomes, and absence of both enzymatic activity and
immunoreactivity. However, mutations have not been identified in
all patients with PH1 who have been studied, and molecular
diagnosis is not yet routinely available [12]. (Adapted from
Danpure and Purdue [12].)
B
and eosin. Panels AC show specimens viewed by polarization
microscopy, all at the same low-power magnification, from biopsies taken after transplantation within the first year (A), third
year (B),
11.8
Multinucleated
giant cells
Ox
Oxalate crystals
Ox
Ox
Ox
Ox
Ox
Ox

and fifth year (C), following renal transplantation. Deposition of
oxalate crystals became progressively more severe with time, and the
kidney failed after 5 years. Panel D illustrates a higher-power magnification, without polarization, of the biopsy at 5 years, showing a
radial array of oxalate crystals and phagocytosis of small crystals by

multinucleated giant cells (E).
Conservative treatment of PH1 is of limited efficacy. Dietary
restriction has little effect on the course of the disease. High-dose
pyridoxine should be tried in all patients, but many patients do not
respond. Strategies to prevent calcium oxalate stone formation
include a high fluid intake (recommended in all patients), magnesium
oxide (because magnesium increases the solubility of calcium oxalate
salts), and inorganic phosphate. Lithotripsy or surgery may be necessary but do not alter the progression of nephrocalcinosis [12,13].
Hemodialysis is superior to peritoneal dialysis in its ability to
remove oxalate, but neither one is able to maintain a rate of
oxalate removal sufficient to keep up with the production rate in
patients with PH1. Once end-stage renal disease develops, hemodialysis does not prevent the progression of systemic oxalosis. In
some patients, renal transplantation accompanied by an aggressive
program of management has been followed by a good outcome for
years [14]. However, oxalosis often recurs in the transplanted kidney, particularly if any degree of renal insufficiency develops for
any reason. In recent years, liver transplantation has been used
with success, with or without renal transplantation, and offers the
prospect of definitive cure. Results of liver transplantation are best
in patients who have not yet developed significant renal insufficiency [12]. (Courtesy of Paul Shanley, MD.)
11.9
URIC ACID AND RENAL DISEASE

Disease
Clinical setting
Features
Therapeutic issues
Uric acid nephrolithiasis
Hyperuricosuria
Cytotoxic chemotherapy for leukemia or

lymphoma; occasionally spontaneous
Uric acid nephrolithiasis

Calcium nephrolithiasis
Intratubular obstruction by uric acid crystals
in acidic urine
Chronic gouty nephropathy
Gout or hyperuricemia in the setting of

hypertension, preexisting renal disease,
advanced age, vascular disease, inflammatory reaction, and chronic exposure
to lead
Autosomal dominant inheritance
Allopurinol; alkalinize urine

Allopurinol
Prevention with allopurinol, fluids,
and alkalinization
Acute dialysis as indicated
Hemodialysis for renal failure
Familial hyperuricemic nephropathy
FIGURE 11-12
Uric acid contributes to the risk of kidney stones in several ways. Pure
uric acid stones occur in patients with hyperuricosuria, particularly
when the urine is acidic. Thus, therapy involves both allopurinol and
alkalinization with potassium alkali salts. Hyperuricosuria also promotes calcium oxalate stone formation. In these patients, calcium
nephrolithiasis can be prevented by therapy with allopurinol. The
mechanism may involve heterogenous nucleation of calcium oxalate
by uric acid microcrystals, binding of endogenous inhibitors of calcium crystallization, or salting out of calcium oxalate by urate [4].
Acute uric acid nephropathy occurs most often in the setting of
brisk cell lysis from cytotoxic therapy or radiation for myeloproliferative or lymphoproliferative disorders or other tumors highly
responsive to therapy. Uric acid nephropathy can uncommonly
occur spontaneously in malignancies or other states of high uric
acid production. Examples are infants with the Lesch-Nyhan syndrome who have excessive uric acid production resulting from deficiency of hypoxanthine-guanine phosphoribosyltransferase deficiency
and, rarely, adults with gout who become volume-contracted and
whose urine is concentrated and acidic. The mechanism involves
intratubular obstruction by crystals of uric acid in the setting of an
acute overwhelming load of uric acid, particularly in acidic urine. In
recent years, the widespread use of an effective prophylactic regimen
for chemotherapy has made acute uric acid nephropathy much less
common [15]. This regimen includes preparation of the patient with
high-dose allopurinol, volume-expanding the patient to maintain a
dilute urine, and alkaline diuresis. In patients whose tumor lysis
leads to hyperphosphatemia, however, it is important to discontinue
urinary alkalinization or else calcium phosphate precipitation may
occur. Occasionally, patients will develop renal failure despite these
measures. In such patients, hemodialysis is preferable to peritoneal
Intrarenal tophi; sodium urate crystals in

interstitium with accompanying destructive
inflammatory reaction
Interstitial fibrosis, chronic inflammation;

crystals are rare
No consensus regarding allopurinol
dialysis because of the higher clearance rates for uric acid. Frequent
hemodialysis, even multiple times per day, may be necessary to prevent extreme hyperuricemia and facilitate recovery of renal function. A modification of continuous arteriovenous hemodialysis has
recently been reported to be effective in management of these
patients [16].
Chronic gouty nephropathy is a term referring to deposition of
sodium urate crystals in the renal interstitium, with an accompanying
destructive inflammatory reaction. As a specific entity with intrarenal
tophi, gouty nephropathy appears to have become uncommon. It
appears clear that long-standing hyperuricemia alone is not sufficient
to cause this condition in most patients, and that renal failure in
patients with hyperuricemia or gout is almost always accompanied
by other predisposing conditions, particularly hypertension or exposure to lead [17].
Familial hyperuricemic nephropathy is an entity that now has been
reported in over 40 kindreds. It is characterized by recurrent gout,
often occurring in youth and even childhood; hyperuricemia; and
renal failure. Histopathology reveals interstitial inflammation and
fibrosis, almost always without evidence of urate crystal deposition,
although this has been found in two patients. In contrast to gouty
nephropathy, hypertension usually is absent until renal failure is
advanced. The hyperuricemia appears to reflect decreased renal
excretion of urate rather than overproduction of urate. Although
hyperuricemia precedes and is disproportionate to any degree of
renal failure, the role, if any, that uric acid plays in the pathogenesis
of the renal failure remains unclear. These is no consensus among
authors regarding the potential value of allopurinol in this disease.
The inheritance follows an autosomal dominant pattern, but, beyond
this, the genetics of the disease are not understood [18,19].
11.10
References
1. Hebert SC: Extracellular calcium-sensing receptor: implications for
calcium and magnesium handling in the kidney. Kidney Int 1996,
50:21292139.
2. Riccardi D, Hall A, Xu J, et al.: Localization of the extracellular Ca2+
(polyvalent) cation-sensing receptor in kidney. Am J Physiol (Renal
Fluid Electrolyte Physiol), 1998, in press.
3. Wrong OM: Nephrocalcinosis. In The Oxford Textbook of Clinical
Nephrology. Edited by Davison AM, et al. London: Oxford
4. Coe FL, Parks JH, Asplin JR: The pathogenesis and treatment of
kidney stones. N Engl J Med 1992, 327:11411152.
5. Buckalew VM: Nephrolithiasis in renal tubular acidosis. J Urol 1989,
141:731737.
6. Simon DB, Karet FE, Hamdan JM, et al.: Bartters syndrome,
hypokalaemic alkalosis with hypercalciuria, is caused by mutations in
the Na-K-2Cl cotransporter NKCC2. Nature Genet 1996, 13:183188.
7. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogeneity of Bartters syndrome revealed by mutations in the K+ channel,
ROMK. Nature Genet 1996, 14:152156.
8. Simon DB, Bindra RS, Mansfield TA, et al.: Mutations in the chloride
channel gene, CLCNKB, cause Bartters syndrome type III. Nature
Genet 1997, 17:171178.
9. Simon DB, Nelson-Williams C, Bia MJ, et al.: Gitelmans variant of
Bartters syndrome, inherited hypokalaemic alkalosis, is caused by
mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet
1996, 12:2430.
10. Lloyd SE, Pearce SHS, Fisher SE, et al.: A common molecular basis
for three inherited kidney stone diseases. Nature 1996, 379:445449.
11. Scheinman SJ: X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int 1998, 53:317.
12. Danpure CJ, Purdue PE: Primay hyperoxaluria. In The Metabolic and
Molecular Bases of Inherited Disease, edn 6. Edited by Scriver CR, et
al. New York: McGraw-Hill; 1995:23852424.
13. Scheinman JI: Primary hyperoxaluria. Miner Electrolyte Metab 1994,
20:340351.
14. Katz A, Freese D, Danpure CJ, et al.: Success of kidney transplantation in oxalosis is unrelated to residual hepatic enzyme activity.
Kidney Int 1992, 42:14081411.
15. Razis E, Arlin ZA, Ahmed T, et al.: Incidence and treatment of tumor
lysis syndrome in patients with acute leukemia. Acta Haematol 1994,
91:171174.
16. Pichette V, Leblanc M, Bonnardeaux A, et al.: High dialysate flow
rate continuous arteriovenous hemodialysis: a new approach for the
treatment of acute renal failure and tumor lysis syndrome. Am J
Kidney Dis 1994, 23:591596.
17. Beck LH: Requiem for gouty nephropathy. Kidney Int 1986,
30:280287.
18. Puig JG, Miranda ME, Mateos FA, et al. Hereditary nephropathy
associated with hyperuricemia and gout. Arch Intern Med 1993,
153:357365.
19. Reiter L, Brown MA, Edmonds J: Familial hyperuricemic nephropathy.
Am J Kidney Dis 1995, 25:235241.
Renal Tubular Disorders

Lisa M. Guay-Woodford
nherited renal tubular disorders involve a variety of defects in renal

tubular transport processes and their regulation. These disorders
generally are transmitted as single gene defects (Mendelian traits),
and they provide a unique resource to dissect the complex molecular
mechanisms involved in tubular solute transport. An integrated
approach using the tools of molecular genetics, molecular biology,
and physiology has been applied in the 1990s to identify defects in
transporters, channels, receptors, and enzymes involved in epithelial
transport. These investigations have added substantial insight into the
molecular mechanisms involved in renal solute transport and the
molecular pathogenesis of inherited renal tubular disorders. This
chapter focuses on the inherited renal tubular disorders, highlights
their molecular defects, and discusses models to explain their underlying pathogenesis.
CHAPTER
12
12.2
Overview of Renal Tubular Disorders

OVERVIEW OF RENAL TUBULAR DISORDERS
INHERITED AS MENDELIAN TRAITS
Inherited disorder
Renal glucosuria
Glucose-galactose malabsorption syndrome
Acidic aminoaciduria
Transmission mode
Defective protein
Cystinuria
AR
Lysinuric protein intolerance
AR
Hartnup disease
Blue diaper syndrome
Neutral aminoacidurias:
Methioninuria
Iminoglycinuria
Glycinuria
with hypercalciuria
?
AR
AR
Sodium-glucose transporter 2
Sodium-glucose transporter 1
Sodium-potassiumdependent
glutamate transporter
Apical cystine-dibasic amino acid
transporter
Basolateral dibasic amino acid
transporter
?
Kidney-specific tryptophan transporter
?
AR
? Sodium-phosphate cotransporter
Inherited Fanconis syndrome isolated disorder

Inherited Fanconis syndrome associated with
inborn errors of metabolism
Carbonic anhydrase II deficiency
Distal renal tubular acidosis
Bartter-like syndromes:
Antenatal Bartter variant
Classic Bartter variant
Gitelmans syndrome
Pseudohypoparathyroidism:
Type Ia
Type Ib
Low-renin hypertension:
Glucocorticoid-remedial aldosteronism
Liddles syndrome
Apparent mineralocorticoid excess
Pseudohypoaldosteronism:
Type 1
Type 2 (Gordons syndrome)
Nephrogenic diabetes insipidus:
X-linked
Autosomal
Urolithiases:
Cystinuria
Dents disease
X-linked recessive nephrolithiasis
X-linked recessive hypophosphatemic rickets
Hereditary renal hypouricemia
?AR, AD
AR
AR
X-linked dominant
AR and AD
AR
AR
AR
AD
AR
AR
AR
Phosphate-regulating with endopeptidase features on the X chromosome

?
Carbonic anhydrase type II

?
Basolateral anion exchanger (AE1)
NKCC2, ROMK, ClC-K2
ClC-K2b
NCCT
AD
?
Guanine nucleotidebinding protein
AD
AD
AR
Chimeric gene (11-hydroxylase and

aldosterone synthase)
and subunits of the sodium channel
11--hydroxysteroid dehydrogenase
AR and AD
AD
and subunits of the sodium channel

?
X-linked recessive
AR and AD
Arginine vasopressin 2 receptor

Aquaporin 2 water channel
AR
Apical cystinedibasic amino

acid transporter
Renal chloride channel (ClC-5)
? Urate transporter
X-linked
X-linked
X-linked
AR
ADautosomal dominant; ARautosomal recessive; ClC-K2renal chloride channel; NCCTthiazide-sensitive

cotransporter; NKCC2bumetanide-sensitive cotransporter; ROMKinwardly rectified.
FIGURE 12-1
Inherited renal tubular disorders generally
are transmitted as autosomal dominant,
autosomal recessive, X-linked dominant,
or X-linked recessive traits. For many of
these disorders, the identification of the
disease-susceptibility gene and its associated
defective protein product has begun to provide insight into the molecular pathogenesis
of the disorder.
12.3
Renal Glucosuria
400
Tmax
Observed curve
Threshold
Glucose reabsorption, mg/min 1.73m2
200
0
0
200
400
600
400
Normal
Type B renal glucosuria
200
Type A renal glucosuria
0
0
200
400
Filtered glucose load, mg/min 1.73m2
600
FIGURE 12-2
Physiology and pathophysiology of glucose titration curves. Under
normal physiologic conditions, filtered glucose is almost entirely
reabsorbed in the proximal tubule by way of two distinct sodiumcoupled glucose transport systems. In the S1 and S2 segments, bulk
reabsorption of glucose load occurs by way of a kidney-specific
high-capacity transporter, the sodium-glucose transporter-2 (SGLT2)
[1]. The residual glucose is removed from the filtrate in the S3 segment by way of the high-affinity sodium-glucose transporter-1
(SGLT1) [2]. This transporter also is present in the small intestine.
As are all membrane transport systems, glucose transporters are
saturable. The top panel shows that increasing the glucose concentration in the tubular fluid accelerates the transport rate of the
glucose transporters until a maximal rate is achieved. The term
threshold applies to the point that glucose first appears in the
urine. The maximal overall rate of glucose transport by the proximal tubule SGLT1 and SGLT2 is termed the Tmax. Glucose is
detected in urine either when the filtered load is increased (as in
diabetes mellitus) or, as shown in the bottom panel, when a defect
occurs in tubular reabsorption (as in renal glucosuria). Kinetic
studies have demonstrated two types of glucosuria caused by either
reduced maximal transport velocity (type A) or reduced affinity of
the transporter for glucose (type B) [3]. Mutations in the gene
encoding SGLT1 cause glucose-galactose malabsorption syndrome,
a severe autosomal recessive intestinal disorder associated with
mild renal glucosuria (type B). Defects in SGLT2 result in a comparatively more severe renal glucosuria (type A). However, this disorder is clinically benign. Among members of the basolateral glucose transporter (GLUT) family, only GLUT1 and GLUT2 are relevant to renal physiology [4]. Clinical disorders associated with
mutations in the genes encoding these transporters have yet to be
described. (From Morris and Ives [5]; with permission.)
12.4
Aminoacidurias
CLASSIFICATION OF INHERITED AMINOACIDURIAS
Major categories
Forms
OMIM number*
Amino acids involved
Acidic amino acids

Basic amino acids and cystine
Acidic aminoaciduria
Cystinuria
Lysinuric protein intolerance
Isolated cystinuria
Lysinuria
Hartnup disease
222730
220100, 600918, 104614
222690, 222700, 601872
238200
234500, 260650
Blue diaper syndrome

Iminoglycinuria
Glycinuria
Methioninuria
211000
242600
138500
Glutamate, aspartate
Cystine, lysine, arginine, ornithine
Lysine, arginine, ornithine
Cystine
Lysine
Alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine,
serine, threonine, tryptophan, tyrosine, valine
Tryptophan
Glycine, proline, hydroxyproline
Glycine
Methionine
Neutral amino acids
*OMIMOnline Mendelian Inheritance in Man (accessible at http://www3.ncbi.nlm.nih.gov/omin/).
FIGURE 12-3
Over 95% of the filtered amino acid load is normally reabsorbed in
the proximal tubule. The term aminoaciduria is applied when more
than 5% of the filtered load is detected in the urine. Aminoaciduria
can occur in the context of metabolic defects, which elevate plasma
amino acid concentrations and thus increase the glomerular filtered
load. Aminoaciduria can be a feature of generalized proximal tubular dysfunction caused by toxic nephropathies or Fanconis syndrome. In addition, aminoaciduria can arise from genetic defects in
one of the several amino acid transport systems in the proximal
tubule. Three distinct groups of inherited aminoacidurias are distinguished based on the net charge of the target amino acids at neutral
pH: acidic (negative charge), basic (positive charge), and neutral
(no charge) [5].
Acidic aminoaciduria involves the transport of glutamate and
aspartate and results from a defect in the high-affinity sodiumpotassiumdependent glutamate transporter [6]. It is a clinically
benign disorder.
Four syndromes caused by defects in the transport of basic
amino acids or cystine have been described: cystinuria, lysinuric
protein intolerance, isolated cystinuria, and isolated lysinuria.
Cystine actually is a neutral amino acid that shares a common

carrier with the dibasic amino acids lysine, arginine, and ornithine.
The transport of all four amino acids is disrupted in cystinuria. The
rarer disorder, lysinuric protein intolerance, results from defects in
the basolateral transport of dibasic amino acids but not cystine.
Increased intracelluar concentrations of lysine, arginine, and
ornithine are associated with disturbances in the urea cycle and
consequent hyperammonemia [7].
Disorders involving the transport of neutral amino acids include
Hartnup disease, blue diaper syndrome, methioninuria, iminoglycinuria, and glycinuria. Several neutral amino acid transporters
have been cloned and characterized. Clinical data suggest that
Hartnup disease involves a neutral amino acid transport system
in both the kidney and intestine, whereas blue diaper syndrome
involves a kidney-specific tryptophan transporter [5]. Methioninuria
appears to involve a separate methionine transport system in the
proximal tubule. Case reports describe seizures, mental retardation,
and episodic hyperventilation in affected patients [8]. The pathophysiologic basis for this phenotype is unclear. Iminoglycinuria
and glycinuria are clinically benign disorders.
ROSENBERG CLASSIFICATION OF CYSTINURIAS

Category
Phenotype
Intestinal transport defect
Heterozygote
Homozygote
No abnormality
Cystinuria, basic aminoaciduria, cystine stones
Cystinine, basic amino acids
Heterozygote
Homozygote
Excess excretion of cystine and basic amino acids

Basic amino acids only
Heterozygote
Homozygote
Excess excretion of cystine and basic amino acids

None
II
III
From Morris and Ives [5]; with permission.
12.5
FIGURE 12-4
In this autosomal recessive disorder the apical
transport of cystine and the dibasic amino
acids is defective. Differences in the urinary
excretion of cystine in obligate heterozygotes
and intestinal amino acid transport studies in
homozygotes have provided the basis for
defining three distinct phenotypes of cystinuria [9]. Genetic studies have identified
mutations in the gene (SCL3A1) encoding a
high-affinity transporter for cystine and the
dibasic amino acids in patients with type I
cystinuria [10,11]. In patients with type III
cystinuria, SCL3A1 was excluded as the
disease-causing gene [12]. A second cystinuria-susceptibility gene recently has been
mapped to chromosome 19 [13].
FIGURE 12-5
Urinary cystine crystals. Excessive urinary excretion of cystine (250 to
1000 mg/d of cystine/g of creatinine) coupled with its poor solubility
in urine causes cystine precipitation with the formation of characteristic urinary crystals and urinary tract calculi. Stone formation often
causes urinary tract obstruction and the associated problems of renal
colic, infection, and even renal failure. The treatment objective is to
reduce urinary cystine concentration or to increase its solubility.
High fluid intake (to keep the urinary cystine concentration below
the solubility threshold of 250 mg/L) and urinary alkalization are the
mainstays of therapy. For those patients refractory to conservative
management, treatment with sulfhydryl-containing drugs, such as
D-penicillamine, mercaptopropionylglycine, and even captopril can
be efficacious [14,15].
12.6
Renal Hypophosphatemic Rickets

INHERITED FORMS OF HYPOPHOSPHATEMIC RICKETS
Disorder
Vitamin D
Parathyroid hormone
Serum calcium
Urinary calcium
Treatment

with hypercalciuria
Low, low normal

Elevated
Normal, high normal

Low, low normal
Low, normal
Normal
Elevated
Elevated
Calciferol, phosphate supplementation

Phosphate supplementation
Vitamin D1,25-dihydroxy-vitamin D3
FIGURE 12-6
Several inherited disorders have been described that result in isolated
renal phosphate wasting. These disorders include X-linked hypophosphatemic rickets (HYP), hereditary hypophosphatemic rickets
with hypercalciuria (HHRH), hypophosphatemic bone disease (HBD),
autosomal dominant hypophosphatemic rickets (ADHR), autosomal
recessive hypophosphatemic rickets (ARHR), and X-linked recessive
hypophosphatemic rickets (XLRH). These inherited disorders share
two common features: persistent hypophosphatemia caused by
decreased renal tubular phosphate (Pi) reabsorption (expressed as
decreased ratio of plasma concentration at which maximal phosphate
reabsorption occurs [TmP] to glomerular filtration rate [GFR],
[TmP/GFR], a normogram derivative of the fractional excretion of
PEX (endopeptidase)
Phosphatonin
Na
Degradation
ATP
3Na+
2K+
Pi
1-hydroxylase
25-Vitamin D
Lumen
ADP
1,25-Vitamin D
Interstitium
FIGURE 12-7
Proposed pathogenesis of X-linked hypophosphatemic rickets (HYP).
HYP, the most common defect in renal phosphate (Pi) transport, is
transmitted as an X-linked dominant trait. The disorder is character-
Pi); and associated metabolic bone disease, eg, rickets in children or

osteomalacia in adults [5]. These disorders can be distinguished on
the basis of the renal hormonal response to hypophosphatemia, the
biochemical profile, and responsiveness to therapy. In addition, the
rare disorder XLRH is associated with nephrolithiasis. The clinical
features of the two most common disorders HYP and HHRH are
contrasted here. Whereas both disorders have defects in renal Pi
reabsorption, the renal hormonal response to hypophosphatemia is
impaired in HYP but not in HHRH. Indeed, in children with
HHRH, phosphate supplementation alone can improve growth rates,
resolve the radiologic evidence of rickets, and correct all biochemical
abnormalities except the reduced TmP GFR [5].
ized by growth impairment in children, metabolic bone disease, phosphaturia, and abnormal bioactivation of vitamin D [16]. Cell culture,
parabiosis, and transplantation experiments have demonstrated that
the defect in HYP is not intrinsic to the kidney but involves a circulating humoral factor other than parathyroid hormone [16,17].
Phosphate is transported across the luminal membrane of the
proximal tubule by a sodium-phosphate cotransporter (NaPi). This
transporter is regulated by multiple hormones. Among these is a putative phosphaturic factor that has been designated phosphatonin [18].
It is postulated that phosphatonin inhibits Pi reabsorption by way of
the sodium-coupled phosphate cotransporter, and it depresses serum
1,25-dihydroxy-vitamin D3 production by inhibiting 1--hydroxlase
activity and stimulating 24-hydroxylase activity. Positional cloning
studies in families with HYP have identified a gene, designated PEX
(phosphate-regulating gene with homologies to endopeptidases on the
X chromosome), that is mutated in patients with X-linked hypophosphatemia [19]. PEX, a neutral endopeptidase, presumably inactivates
phosphatonin. Defective PEX activity would lead to decreased
phosphatonin degradation, with excessive phosphaturia and deranged
vitamin D metabolism. A similar scenario associated with increased
phosphatonin production has been proposed as the basis for
oncogenic hypophosphatemic osteomalacia, an acquired disorder
manifested in patients with tumors of mesenchymal origin [17].
Na+sodium ion; K+potassium ion.
12.7
Fanconis Syndrome
FIGURE 12-8
Fanconis syndrome is characterized by two components: generalized dysfunction of the proximal tubule, leading to impaired net
reabsorption of bicarbonate, phosphate, urate, glucose, and amino
acids; and vitamin Dresistant metabolic bone disease [20]. The
clinical manifestations in patients with either the hereditary or
acquired form of Fanconis syndrome include polyuria, dehydration, hypokalemia, acidosis, and osteomalacia (in adults) or
impaired growth and rickets (in children). Inherited Fanconis syndrome occurs either as an idiopathic disorder or in association with
various inborn errors of metabolism.
INHERITED FANCONIS SYNDROME

Disorder
OMIM number*
Idiopathic
Cystinosis
Hepatorenal tyrosinemia (tyrosinemia type I)
Hereditary fructose intolerance
Galactosemia
Glycogen storage disease type I
Wilsons disease
Oculocerebrorenal (Lowes) syndrome
Vitamin-Ddependent rickets
227700, 227800
219800, 219900, 219750
276700
229600
230400
232200
277900
309000
264700
*OMIMOnline Mendelian Inheritance in Man (accessible at

http://www3.ncbi.nlm.nih.gov/omin/).
From Morris and Ives [5]; with permission.
Na+
Na
(1)
Na+
(4)
ATP
3Na+
(2)
2K+
S
ADP
(3)
ADP
H+
ATP
ATP
Lumen
Interstitium
FIGURE 12-9
Proposed pathogenic model for Fanconis syndrome. The underlying pathogenesis of Fanconis syndrome has yet to be determined.
It is likely, however, that the various Mendelian diseases associated
with Fanconis syndrome cause a global disruption in sodiumcoupled transport systems rather than a disturbance in specific
transporters. Bergeron and coworkers [20] have proposed a pathophysiologic model that involves the intracellular gradients of sodium,
adenosine triphosphate (ATP), and adenosine diphosphate (ADP).
A transepithelial sodium gradient is established in the proximal
tubule cell by sodium (Na) entry through Na-solute cotransport
systems (Na-S) (1) and Na exit through the sodium-potassium
adenosine triphosphatase (Na-K ATPase) (2). This Na gradient
drives the net uptake of cotransported solutes. A small decrease in
the activity of the Na-K ATPase cotransporter may translate into
a proportionally larger increment in the Na concentration close
to the luminal membrane, thus decreasing the driving force that
energizes all Na-solute cotransport systems. Concomitantly,
reciprocal ATP and ADP gradients are established in the cell by
the activity of membrane bound ATPases (Na-K ATPase (2) and
hydrogen-ATPase (3)) and mitochondrial (4) ATP synthesis. A small
reduction in mitochondrial rephosphorylation of ADP may result
in a juxtamembranous accumulation of ADP and a reciprocal
decrease in ATP, altering the ADP-ATP ratio and downregulating
pump activities. Therefore, a relatively small mitochondrial defect
may be amplified by the effects on the intracellular sodium gradients and ADP-ATP gradients and may lead to a global inhibition
of Na-coupled transport. H+hydrogen ion.
12.8
Renal Tubular Acidoses

FIGURE 12-10
Renal tubular acidosis (RTA) is characterized by hyperchloremic
metabolic acidosis caused by abnormalities in renal acidification,
eg, decreased tubular reabsorption of bicarbonate or reduced urinary
excretion of ammonium (NH4+). RTA can result from a number of
disease processes involving either inherited or acquired defects. In
addition, RTA may develop from an isolated defect in tubular transport; may involve multiple tubular transport abnormalities, eg,
Fanconis syndrome; or may be associated with a systemic disease
process. Isolated proximal RTA (type II) is rare, and most cases of
proximal RTA occur in the context of Fanconis syndrome. Inherited
forms of classic distal RTA (type I) are transmitted as both autosomal dominant and autosomal recessive traits. Inherited disorders in
which RTA is the major clinical manifestation are summarized.
INHERITED RENAL TUBULAR ACIDOSES

Disorder
Transmission mode
Isolated proximal RTA
Autosomal recessive
Carbonic anhydrase II deficiency
Autosomal recessive
Isolated distal RTA
Autosomal dominant
Distal RTA with sensorineural deafness
Autosomal recessive
RTArenal tubular acidosis.
Distal tubule: intercalated cell

Cl
Proximal tubule
Interstitium
K+
CO2 + H2O
H2CO3
CA2
H+
HCO3
Na+ HCO3
Na+
H
HCO3
OH
CO2
K+
HCO3
CA2
H+
Na+
Cl
H2CO3
CA4
CO2
H+
K+
H+
Lumen
HCO3
FIGURE 12-11
Carbonic anhydrase II deficiency. Carbonic anhydrase II deficiency is an autosomal recessive
disorder characterized by renal tubular acidosis (RTA), with both proximal and distal components, osteopetrosis, and cerebral calcification. Carbonic anhydrase catalyzes the reversible
hydration of carbon dioxide (CO2), and thereby accelerates the conversion of carbon dioxide
and water to hydrogen ions (H+) and bicarbonate (HCO-3) [21]. A least two isoenzymes
of carbonic anhydrase are expressed in the
kidney and play critical roles in urinary
acidification. In the proximal tubule, bicarbonate reabsorption is accomplished by the
combined action of both luminal carbonic
anhydrase type IV (CA4) and cytosolic carbonic anhydrase type II (CA2), the luminal
sodium-hydrogen exchanger, and the basolateral sodium-bicarbonate exchanger.
Impaired bicarbonate reabsorption in the
proximal tubule is the underlying defect in
type II or proximal RTA. In the distal
nephron, carbonic anhydrase type II is
expressed in the intercalated cells of the
cortical collecting duct. There carbonic
anhydrase type II plays a critical role in
catalyzing the condensation of hydroxy ions,
generated by the proton-translocating H+adenosine triphosphatase (H+ ATPase), with
carbon dioxide to form bicarbonate. In
carbonic anhydrase type II deficiency, the
increase in intracellular pH impairs the
activity of the proton-translocating H-ATPase.
Carbonic anhydrase inhibitors (eg, acetazolamide) act as weak diuretics by blocking
bicarbonate reabsorption. Cl-chloride ion;
H2CO3carbonic acid; K+potassium ion;
Na+sodium ion.

Cl
Cortical
collecting
duct
K+
Principal cell
Cl
intercalated
cell
intercalated
cell
HCO3
CA2
OH
CO2
K+
Lumen
Na+
K+
H+
K+
H+
Cl
Outer
medullary
collecting
duct
K+
Principal cell
Cl
HCO3
K+
Lumen +
H 2O
H+
K+
H+
FIGURE 12-12
Distal renal tubular acidosis (RTA). The collecting duct is the principal site of distal tubule
acidification, where the final 5% to 10% of the filtered bicarbonate load is reabsorbed
12.9
and the hydrogen ions (H+) generated from

dietary protein catabolism are secreted. The
distal nephron is composed of several distinct
segments, eg, the connecting tubule, cortical
collecting duct, and medullary collecting duct.
The tubular epithelia within these segments
are composed of two cell types: principal cells
that transport sodium, potassium, and water;
and intercalated cells that secrete hydrogen
ions and bicarbonate (HCO-3) [22].
Urinary acidification in the distal nephron
depends on several factors: an impermeant
luminal membrane capable of sustaining
large pH gradients; a lumen-negative potential difference in the cortical collecting duct
that supports both hydrogen and potassium
ion (K+) secretion; and secretion of hydrogen
ions by the intercalated cells of the cortical
and medullary collecting ducts at a rate sufficient to regenerate the bicarbonate consumed
by metabolic protons [22]. Abnormalities in
any of these processes could result in a distal
acidification defect.
Recent studies in families with isolated
autosomal dominant distal RTA have
identified defects in the basolateral chloridebicarbonate exchanger, AE1 [23,24]. Defects
in various components of the H+-adenosine
triphosphatase (H+ ATPase) and subunits of
the H+-K+ ATPase (H+\K+ ATPase) also have
been proposed as the basis for other hereditary forms of distal RTA. CA2cytosolic
carbonic anhydrase type II; Cl-chloride
ion; CO2carbon dioxide; Na+sodium
ion; OH-hydroxy ions.
Bartter-like Syndromes
CLINICAL FEATURES DISTINGUISHING BARTTER-LIKE SYNDROMES
Feature
Age at presentation
Prematurity, polyhydramnios
Delayed growth
Delayed cognitive development
Polyuria, polydipsia
Tetany
Serum magnesium
Urinary calcium excretion
Nephrocalcinosis
Urine prostaglandin excretion
Clinical response to
indomethacin
Classic Bartters
syndrome
Gitelmans
syndrome
Antenatal Bartters
syndrome
Infancy, early childhood

+/++
+/++
Rare
Low in 20%
Normal to high
+/High
+/-
Childhood, adolescence
+
++
Low in about 100%
Low
Normal
-
In utero, infancy
++
+++
+
+++
Low-normal to normal
Very high
++
Very high
Often life-saving
From Guay-Woodford [25]; with permission.
FIGURE 12-13
Familial hypokalemic, hypochloremic metabolic alkalosis, or Bartters syndrome, is not
a single disorder but rather a set of closely
related disorders. These Bartter-like syndromes share many of the same physiologic
derangements but differ with regard to the
age of onset, presenting symptoms, magnitude of urinary potassium and prostaglandin
excretion, and extent of urinary calcium
excretion. At least three clinical phenotypes
have been distinguished: classic Bartters
syndrome, the antenatal hypercalciuric
variant (also called hyperprostaglandin E
syndrome), and hypocalciuric-hypomagnesemic Gitelmans syndrome [25].
12.10
Lumen
FIGURE 12-14
Transport systems involved in transepithelial sodium-chloride transport in the thick ascending limb (TAL). Clinical data suggest that
the primary defect in the antenatal and classic Bartter syndrome
variants involves impaired sodium chloride transport in the TAL.
Under normal physiologic conditions, sodium chloride is transported
across the apical membrane by way of the bumetanide-sensitive
sodium-potassium-2chloride (Na-K-2Cl) cotransporter (NKCC2).
This electroneutral transporter is driven by the low intracellular sodium and chloride concentrations generated by the sodium-potassium
pump and the basolateral chloride channels and potassium-chloride
cotransporter. In addition, apical potassium recycling by way of the
low-conductance potassium channel (ROMK) ensures the efficient
functioning of the Na-K-2Cl cotransporter. The activity of the ROMK
channel, in turn, is regulated by a number of cell messengers, eg,
calcium (Ca2+) and adenosine triphosphate (ATP), as well as by the
calcium-sensing receptor (CaR), prostaglandin EP3 receptor, and vasopressin receptor (V2R) by way of cAMP-dependent pathways and
arachidonic acid (AA) metabolites, eg, 20-hydroxy-eicosatetraenoic
acid (20-HETE). The positive transluminal voltage (Vte) drives the
paracellular reabsorption of calcium ions and magnesium ions
(Mg2+) [25]. cAMPcyclic adenosine monophosphate; PGE2
prostaglandin E2; PKAprotein kinase A.
Interstitium
Ca2+
sensing
receptor
AA
Na+
K+
2Cl
3Na+
2K+
K+
Cl
20 HETE
K+
Ca2+
Cl
ATP
ATP
V2R
cAMP
Stimulatory
Inhibitory
EP3
PGE2
Vte + Ca2+
Mg2+
Defective
NKCC2
Gene defect
Pathophysiology
Defective
ROMK
Defective
CIC-Kb
Defective NaCl
transport in TAL
Volume
contraction
NaCl delivery to
the distal nephron
Voltage-driven
paracellular
reabsorption of
Ca2+ and Mg2+
Renin
Angiotensin II (AII)
Kallikrein
Aldosterone
Normotension
Blunted vascular
response to AII and
norepinephrine
H+ and K+
secretion
Metabolic alkalosis
Hypokalemia
PGE2
Urinary
prostaglandins
Bone
reabsorption
Fever
Hypercalciuria
Hypermagnesuria
Impaired
vasopressinstimulated
urinary
concentration
Hyposthenuria
FIGURE 12-15
Proposed pathogenic model for the antenatal
and classic variants of Bartters syndrome.
Genetic studies have identified mutations in
the genes encoding the bumetanide-sensitive
sodium-potassium-2chloride cotransporter
(NKCC2), luminal ATPregulated potassium channel (ROMK), and kidney-specific
chloride channel (ClC-K2). These findings
support the theory of a primary defect in
thick ascending limb (TAL) sodium-chloride
(Na-Cl) reabsorption in, at least, subsets of
patients with the antenatal or classic variants
of Bartters syndrome. In the proposed model
the potential interrelationships of the complex set of pathophysiologic phenomena are
illustrated. The resulting clinical manifestations are highlighted in boxes [25]. Ca2+
calcium ion; H+hydrogen ion; K+potassium ion; Mg2+magnesium ion; PGE2
prostaglandin E2.
12.11
Gene defect
Pathophysiologic model
DefectiveHypercalciuria
NaCl transport in DCT
Volume
contraction
FIGURE 12-16
Proposed pathogenic model for Gitelmans
syndrome. The electrolyte disturbances
evident in Gitelmans syndrome also are
observed with administration of thiazide
diuretics, which inhibit the sodium-chloride
(Na-Cl) cotransporter in the distal convoluted
tubule (DCT). In families with Gitelmans
syndrome, genetic studies have identified
defects in the gene encoding the thiazidesensitive cotransporter (NCCT) protein.
The proposed pathogenic model is predicated
on loss of function of the NCCT protein
and, thus, most closely applies to those
patients who inherit Gitelmans syndrome
as an autosomal recessive trait. Given that
the physiologic features of this syndrome
are virtually indistinguishable in familial
and sporadic cases, it may be reasonable
to propose the same pathogenesis for all
patients with Gitelmans syndrome. However, it is important to caution that evidence
for NCCT mutations in sporadic cases has
not yet been established [25]. Ca2+calcium ion; Cl-chloride ion; H+hydrogen ion;
K+potassium ion; Mg2+magnesium ion;
Na+sodium ion.
Defective NCCT
NaCl delivery to
the distal nephron
Cl efflux mediates
cell hyperpolarization
H+ and K+ secretion
Ca2+ reabsorption
Metabolic alkalosis
hypokalemia
Hypocalciuria
?
Na+-dependent
Mg2+ reabsorption
in DCT
Renin
Angiotensin II (AII)
Aldosterone
Hypermagnesuria
Pseudohypoparathyroidism
CLINICAL SUBTYPES OF PSEUDOHYPOPARATHYROIDISM
Disorder
Pathophysiology
Pseudohypoparathyroidism type Ia
Pseudohypoparathyroidism type Ib
Defect in guanine nucleotidebinding protein

Resistance to parathyroid hormone, normal guanine
nucleotidebinding protein activity
? Defect in parathyroid hormone receptor
FIGURE 12-17
Pseudohypoparathyroidism applies to a heterogeneous group of hereditary disorders whose common feature is resistance to parathyroid
hormone (PTH). Affected patients are hypocalcemic and hyperphosphatemic, despite elevated plasma PTH levels. Hypocalcemia and
hyperphophatemia result from the combined effects of defective PTHmediated calcium reabsorption in the distal convoluted tubule and
reduced formation of 1,25-dihydroxy-vitamin D3. The latter leads to
defects in renal phosphate excretion, calcium mobilization from bone,
and gastrointestinal calcium reabsorption. Differences in clinical features and urinary cyclic adenosine monophosphate response to infused
PTH provide the basis for distinguishing three distinct subtypes of
pseudohypoparathyroidism (type Ia, type Ib, and type II) [26].
Skeletal anomalies
Associated endocrinopathies
Yes
No
Yes
No
Pseudohypoparathyroidism type Ia (Albrights hereditary osteodystrophy) is associated with a myriad of physical abnormalities
and resistance to multiple adenylate cyclasecoupled hormones,
most notably thyrotropin and gonadotropin [27]. The molecular
defect in a guanine nucleotidebinding protein (Gs) blocks the
coupling of PTH and other hormone receptors to adenylate cyclase.
The molecular defect has not been identified in type Ib, although
specific resistance to PTH suggests a defect in the PTH receptor.
Oral supplementation with 1,25 dihydroxy-vitamin D3 and, if
necessary, oral calcium, is used to correct the hypocalcemia and
minimize PTH-induced bone disease [26]. Pseudohypoparathroidism type II may be an acquired disease.
12.12
Disorders of Aldosterone-Regulated Transport

(A) GRA chimeric gene
Aldosterone synthetase
11-OHase
Unequal crossover
Aldosterone synthetase
Chimeric gene
11-OHase
(B)
Amiloride-sensitive
Na+ channel
Na+
Na+
K+
Aldosterone
(A)
K+ channel
(A) GRA
(B) Liddle's
(C) AME
MR
Degradation
Cortisol
(C)
FIGURE 12-18
Aldosterone-regulated transport in the cortical collecting duct and
defects causing low-renin hypertension. The mineralocorticoid aldosterone regulates electrolyte excretion and intravascular volume by
way of its action in the principal cells of the cortical collecting duct.
The binding of aldosterone to its nuclear receptor (MR) leads directly
or indirectly to increased activity of the apical sodium (Na) channel
and the basolateral sodium-potassium adenosine triphosphatase

(Na-K ATPase). Sodium moves from the lumen into the cell and
down its electrochemical gradient, thus generating a lumen-negative
transepithelial voltage that drives potassium secretion from the
principal cells and hydrogen secretion from the intercalated cells.
The type I mineralocorticoid receptor (MR) is nonspecific and can
bind both aldosterone and cortisol, but not cortisone. The selective
receptor specificity for aldosterone is mediated by the kidney isoform
of the enzyme, 11--hydroxysteroid dehydrogenase, which oxidizes
intracellular cortisol to its metabolite cortisone.
Three hypertensive syndromes, glucocorticoid-remedial aldosteronism (GRA), Liddles syndrome, and apparent mineralocorticoid
excess (AME), share a common clinical phenotype that is characterized by normal physical examinations, hypokalemia, and very
low plasma renin activity. The molecular defect in GRA derives
from an unequal crossover event between two adjacent genes
encoding 11--hydroxylase and aldosterone synthase (A). The
resulting chimeric gene duplication fuses the regulatory elements
of 11--hydroxylase and the coding sequence of aldosterone synthase.
Consequently, aldosterone is ectopically synthesized in the adrenal
zona fasciculata and its synthesis regulated by adrenocorticotropic
hormone rather than its physiologically normal secretagogue, angiotensin II [28]. Activating mutations in the and regulatory subunits of the epithelial sodium channel (B) are responsible for
Liddles syndrome [29]. Deficiency of the kidney type 2 isozyme
of 11--hydroxysteroid dehydrogenase (C) can render type I MR
responsive to cortisol and produce the syndrome of apparent mineralocorticoid excess [30]. Inhibitors of this enzyme (eg, licorice) also can
produce an acquired form of apparent mineralocorticoid excess.
Medical management of these disorders focuses on dietary sodium
restriction, blocking the sodium channel with the potassium-sparing
diuretics triamterene and amiloride, downregulating the ectopic
aldosterone synthesis with glucocorticoids (GRA), or blocking
the MR using the competitive antagonist spironolactone (GRA
and AME).
Low-renin hypertension
Family history
+ Family history
Abnormal PE
Serum
Virilization
Low
serum K+
11-hydroxylase
deficiency
Gordon's
syndrome
Diagnosis:
Hypogonadism
Low-normal
High-normal
Urinary
steroid profile:
Normal PE
K+
TH180x0F
THAD
Negligible urinary
aldosterone
GRA
Liddle's syndrome
17-hydroxylase
deficiency
Autosomal recessive
Autosomal dominant
(Gordons syndrome)
FIGURE 12-19
Algorithm for evaluating patients with lowrenin hypertension. Glucocorticoid-remedial
aldosteronism (GRA), Liddles syndrome,
and apparent mineralocorticoid excess (AME)
can be distinguished from one another by
characteristic urinary steroid profiles [31].
K+potassium ion; PEphysical examination; TH18oxoF/THADratio of urinary
18-oxotetrahydrocortisol (TH18oxoF) to
urinary tetrahydroaldosterone (normal:
00.4; GRA patients: >1); THF + alloTHF/THEratio of the combined urinary
tetrahydrocortisol and allotetrahydrocortisol
to urinary tetrahydrocortisone (normal:
<1.3; AME patients: 510-fold higher).
THF + alloTHF
THE
AME
CLINICAL SUBTYPES OF PSEUDOHYPOALDOSTERONISM

Disorder
12.13
Clinical features
Treatment
Dehydration, severe neonatal salt wasting,

hyperkalemia, metabolic acidosis
Elevated plasma renin activity
Severity of electrolyte abnormalities may
diminish after infancy
Mild salt wasting
Hypertension, hyperkalemia, mild hyperchloremic metabolic acidosis
Undetectable plasma renin activity
Sodium chloride
supplementation
Ion-binding resin; dialysis
Thiazide diuretics
FIGURE 12-20
Mineralocorticoid resistance with hyperkalemia (pseudohypoaldosteronism) includes at
least three clinical subtypes, two of which are hereditary disorders. Pseudohypoaldosteronism type I (PHA1) is characterized by severe neonatal salt wasting, hyperkalemia,
and metabolic acidosis. The diagnosis is supported by elevated plasma renin and plasma
aldosterone concentrations. Life-saving interventions include aggressive sodium chloride
supplementation and treatment with ion-binding resins or dialysis to reduce the hyperkalemia. This autosomal recessive form of
PHA1 results from inactivating mutations in
the or subunits of the epithelial sodium
channel [32]. A milder form of PHA1 with
autosomal dominant inheritance also has
been described; however, the molecular defect
remains unexplained [33]. Adolescents or
adults with hyperkalemic, hyperchloremic
metabolic acidosis, low-normal renin and
aldosterone levels, and hypertension have
been recently described and classified as
having pseudohypoaldosteronism type II
(PHA2) or Gordons syndrome [34]. Phenotypically, this disorder is the mirror image of
Gitelmans syndrome; however, the thiazidesensitive cotransporter (NCCT) has been
excluded as a candidate gene [35].
12.14
Nephrogenic Diabetes Insipidus

FIGURE 12-21
The relationship between urine osmolality and plasma arginine
vasopressin (AVP). Nephrogenic diabetes insipidus (NDI) is characterized by renal tubular unresponsiveness to the antidiuretic hormone AVP or its antidiuretic analogue 1-desamino-8-D-arginine
vasopressin (DDAVP). In both the congenital and acquired forms
of this disorder the clinical picture is dominated by polyuria, polydipsia, and hyposthenuria despite often elevated AVP levels [17].
(From Robertson et al. [36]; with permission.)
Primary polydipsia
Pituitary diabetes insipidus
1200
Urine osmolality, mOsm/kg
1000
800
600
400
NDI
200
0
0
3
4
5
Plasma AVP, pg/mL
10
15
Physiologic
AQP3
ADH
Pathophysiologic
AQP2
H 2O
X-linked
NDI
V2R
AQP3
H 2O
V2R
AQP4
AQP4
Autosomal
recessive
NDI
AQP2
AQP3
+ADH
AQP2
AQP3
ATP
ATP
H 2O
V2R
H 2O
V2R
cAMP
cAMP
AQP4
Interstitium
AQP2
AQP4
Lumen
Interstitium
Lumen
FIGURE 12-22
Pathogenic model for nephrogenic diabetes insipidus (NDI). The principle cell of the inner
medullary collecting duct is the site where fine tuning of the final urinary composition and
volume occurs. As shown, the binding of

arginine vasopressin (AVP) to the vasopressin V2 receptor (V2R) stimulates a
series of cyclic adenosine monophosphate
(cAMP) mediated events that results in the
fusion of cytoplasmic vesicles carrying
water channel proteins (aquaporin-2
[AQP2]), with the apical membrane,
thereby increasing the water permeability
of this membrane. Water exits the cell
through the basolateral water channels
AQP3 and AQP4. In the absence of AVP,
water channels are retrieved into cytoplasmic
vesicles and the water permeability of the
apical membrane returns to its baseline
low rate [37].
Genetic studies have identified mutations
in two proteins involved in this water transport process, the V2 receptor and AQP2
water channels. Most patients (>90%)
inherit NDI as an X-linked recessive trait.
In these patients, defects in the V2 receptor
have been identified. In the remaining
patients, the disease is transmitted as either
an autosomal recessive or autosomal dominant trait involving mutations in the AQP2
gene [38,39]. ADH antidiuretic hormone;
ATPadenosine triphosphate.
12.15
Urolithiases
INHERITED CAUSES OF UROLITHIASES
Disorder
Stone characteristics
Treatment
Cystinuria
Cystine
Dents disease
X-linked recessive nephrolithiasis
X-linked recessive hypophosphatemic rickets
Hereditary renal hypouricemia
Calcium-containing
Calcium-containing
Calcium-containing
High fluid intake, urinary alkalization

Sulfhydryl-containing drugs
Hypoxanthine-guanine phosphoribosyltransferase deficiency

Xanthinuria
Primary hyperoxaluria
Uric acid
Uric acid, calcium oxalate
Xanthine
Calcium oxalate

Allopurinol
Allopurinol
High fluid intake, dietary purine restriction
High fluid intake, dietary oxalate restriction
Magnesium oxide, inorganic phosphates
FIGURE 12-23
Urolithiases are a common urinary tract abnormality, afflicting 12% of men and 5% of women
in North America and Europe [40]. Renal stone formation is most commonly associated with
hypercalciuria. Perhaps in as many as 45% of these patients, there seems to be a familial
predisposition. In comparison, a group of relatively rare disorders exists, each of which is
transmitted as a Mendelian trait and causes a variety of different crystal nephropathies. The
most common of these disorders is cystinuria, which involves defective cystine and dibasic
amino acid transport in the proximal tubule.

Cystinuria is the leading single gene cause of
inheritable urolithiasis in both children and
adults [41,42]. Three Mendelian disorders,
Dents disease, X-linked recessive nephrolithiasis, and X-linked recessive hypophosphatemic rickets cause hypercalciuric urolithiasis.
These disorders involve a functional loss of
the renal chloride channel ClC-5 [43]. The
common molecular basis for these three
inherited kidney stone diseases has led to
speculation that ClC-5 also may be involved
in other renal tubular disorders associated
with kidney stones. Hereditary renal hypouricemia is an inborn error of renal tubular
transport that appears to involve urate reabsorption in the proximal tubule [16].
In addition to renal transport deficiencies,
defects in metabolic enzymes also can cause
urolithiases. Inherited defects in the purine
salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine
phosphoribosyltransferase (APRT) or in the
catabolic enzyme xanthine dehydrogenase
(XDH) all can lead to stone formation [44].
Finally, defective enzymes in the oxalate
metabolic pathway result in hyperoxaluria,
oxalate stone formation, and consequent
loss of renal function [45].
Acknowledgment
The author thanks Dr. David G. Warnock for critically reviewing this manuscript.
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The Kidney in Blood

Pressure Regulation
L. Gabriel Navar
L. Lee Hamm
espite extensive animal and clinical experimentation, the

mechanisms responsible for the normal regulation of arterial
pressure and development of essential or primary hypertension remain unclear. One basic concept was championed by Guyton
and other authors [14]: the long-term regulation of arterial pressure
is intimately linked to the ability of the kidneys to excrete sufficient
sodium chloride to maintain normal sodium balance, extracellular fluid
volume, and blood volume at normotensive arterial pressures.
Therefore, it is not surprising that renal disease is the most common
cause of secondary hypertension. Furthermore, derangements in renal
function from subtle to overt are probably involved in the pathogenesis
of most if not all cases of essential hypertension [5]. Evidence of generalized microvascular disease may be causative of both hypertension and
progressive renal insufficiency [5,6]. The interactions are complex
because the kidneys are a major target for the detrimental consequences
of uncontrolled hypertension. When hypertension is left untreated, positive feedback interactions may occur that lead progressively to greater
hypertension and additional renal injury. These interactions culminate
in malignant hypertension, stroke, other sequelae, and death [7].
In normal persons, an increased intake of sodium chloride leads to
appropriate adjustments in the activity of various humoral, neural,
and paracrine mechanisms. These mechanisms alter systemic and
renal hemodynamics and increase sodium excretion without increasing
arterial pressure [3,8]. Regardless of the initiating factor, decreases in
sodium excretory capability in the face of normal or increased sodium
intake lead to chronic increases in extracellular fluid volume and
blood volume. These increases can result in hypertension. When the
derangements also include increased levels of humoral or neural factors
that directly cause vascular smooth muscle constriction, these effects
increase peripheral vascular resistance or decrease vascular capacitance.
Under these conditions the effects of subtle increases in blood volume
are compounded because of increases in the blood volume relative to
CHAPTER
1.2
Hypertension and the Kidney
Aortic pressure,
mm Hg
160
Isolated systolic hypertension

(61 y)
120
Aortic blood
flow, mL/s
80
400
0
Normotensive
(56 y)
Arterial pressure, mm Hg
the capacitance, often referred to as the effective blood volume.

Through the mechanism of pressure natriuresis, however, the
increases in arterial pressure increase renal sodium excretion,
allowing restoration of sodium balance but at the expense of
persistent elevations in arterial pressure [9]. In support of this
overall concept, various studies have demonstrated strong
relationships between kidney disease and the incidence of
hypertension. In addition, transplantation studies have shown
that normotensive recipients from genetically hypertensive
donors have a higher likelihood of developing hypertension
after transplantation [10].
This unifying concept has helped delineate the cardinal role
of the kidneys in the normal regulation of arterial pressure as
well as in the pathophysiology of hypertension. Many different
200
180
160
140
120
100
80
60
40
20
extrinsic influences and intrarenal derangements can lead to

reduced sodium excretory capability. Many factors also exist
that alter cardiac output, total peripheral resistance, and cardiovascular capacitance. Accordingly, hypertension is a multifactorial
dysfunctional process that can be caused by a myriad of different
conditions. These conditions range from stimulatory influences
that inappropriately enhance tubular sodium reabsorption to
overt renal pathology, involving severe reductions in filtering
capacity by the renal glomeruli and associated marked reductions in sodium excretory capability. An understanding of the
normal mechanisms regulating sodium balance and how
derangements lead to altered sodium homeostasis and hypertension provides the basis for a rational approach to the treatment
of hypertension.
PP = 72 mm Hg
PP = 40 mm Hg
PP = 30 mm Hg
500
600 700 800 900

Arterial volume, mL
FIGURE 1-1
Aortic distensibility. The cyclical pumping nature of the heart places a heavy demand on
the distensible characteristics of the aortic tree. A, During systole, the aortic tree is rapidly
filled in a fraction of a second, distending it and increasing the hydraulic pressure. B, The
distensibility characteristics of the arterial tree determine the pulse pressure (PP) in response to
a specific stroke volume. The normal relationship is shown in curve A, and arrows designate
the PP. A highly distensible arterial tree, as depicted in curve B, can accommodate the stroke
volume with a smaller PP. Pathophysiologic processes and aging lead to decreases in aortic distensibility. These decreases lead to marked increases in PP and overall mean arterial pressure
for any given arterial volume, as shown in curve C. Decreased distensibility is partly responsible for the isolated systolic hypertension often found in elderly persons. Recordings of actual
aortic pressure and flow profiles in persons with normotension and systolic hypertension are
shown in panel A [11,12]. (Panel B Adapted from Vari and Navar [4] and Panel A from
Nichols et al. [12].)
HEMODYNAMIC DETERMINANTS
For any vascular bed:
Arterial pressure gradient
Blood flow =
Vascular resistance
For total circulation averaged over time:
Blood flow = cardiac output
Therefore,
Arterial pressure - right atrial pressure
Cardiac output =
Total peripheral resistance
and:
Mean arterial pressure =
Cardiac output total peripheral resistance
FIGURE 1-2
Hemodynamic determinants of arterial
pressure. During the diastolic phase of the
cardiac cycle, the elastic recoil characteristics of the arterial tree provide the kinetic
energy that allows a continuous delivery of
blood flow to the tissues. Blood flow is
dependent on the arterial pressure gradient
and total peripheral resistance. Under normal conditions the right atrial pressure is
near zero, and thus the arterial pressure is
the pressure gradient. These relationships
apply for any instant in time and to timeintegrated averages when the mean pressure
is used. The time-integrated average blood
flow is the cardiac output that is normally
5 to 6 L/min for an adult of average weight
(70 to 75 kg).
1.3
The Kidney in Blood Pressure Regulation
Dietary
Insensible losses
Urinary
intake (skin, respiration, fecal) excretion
Arterial baroreflexes
Atrial reflexes
Renin-angiotensin-aldosterone
Adrenal catecholamines
Vasopressin
Natriuretic peptides
Endothelial factors:
nitric oxide, endothelin
kallikrein-kinin system
Prostaglandins and other eicosanoids
Net sodium and

fluid balance
ECF volume
Arterial
pressure
Blood
volume
Mean circulatory
pressure
(Autoregulation)
Neurohumoral
systems
Total peripheral
resistance
Interstitial
fluid volume
Venous
return
Heart rate and

contractility
Cardiac
output
FIGURE 1-3
Volume determinants of arterial pressure.
The two major determinants of arterial
pressure, cardiac output and total peripheral
resistance, are regulated by a combination
of short- and long-term mechanisms. Rapidly
adjusting mechanisms regulate peripheral
vascular resistance, cardiovascular capacitance,
and cardiac performance. These mechanisms
include the neural and humoral mechanisms
listed. On a long-term basis, cardiac output
is determined by venous return, which is
regulated primarily by the mean circulatory
pressure. The mean circulatory pressure
depends on blood volume and overall cardiovascular capacitance. Blood volume is closely
linked to extracellular fluid (ECF) volume
and sodium balance, which are dependent
on the integration of net intake and net
losses [13]. (Adapted from Navar [3].)
Cardiovascular
capacitance
If increased
Concentrated urine: Increased

free water reabsorption
Thirst:
Increased water intake
Na+ and Cl
Quantity of Extracellular concentrations
=
NaCl in ECF fluid volume in ECF volume
If decreased
NaCl losses
(urine
insensible)
Blood volume, L
Antidiuretic hormone
release
NaCl
intake
Decreased water intake

Increased salt intake
FIGURE 1-4
A, Relationship between net sodium balance and extracellular fluid
(ECF) volume. Sodium balance is intimately linked to volume balance
because of powerful mechanisms that tightly regulate plasma and
ECF osmolality. Sodium and its accompanying anions constitute the
major contributors to ECF osmolality. The integration of sodium
intake and losses establishes the net amount of sodium in the body,
which is compartmentalized primarily in the ECF volume. The quotient
of these two parameters (sodium and volume) determines the sodium
concentration and, thus, the osmolality. Osmolality is subject to very
tight regulation by vasopressin and other mechanisms. In particular,
vasopressin is a very powerful regulator of plasma osmolality; however, it achieves this regulation primarily by regulating the relative
solute-free water retention or excretion by the kidney [1315]. The
important point is that the osmolality is rapidly regulated by adjusting
the ECF volume to the total solute present. Corrections of excesses
in extracellular fluid volume involve more complex interactions that
regulate the sodium excretion rate.
4
3
2
Antidiuretic hormone inhibition

Dilute urine:
Increased solute-free
water excretion
Edema
0
10
15
Extracellular fluid volume, L
20
B, Relationship between the ECF volume and blood volume. Under

normal conditions a consistent relationship exists between the total
ECF volume and blood volume. This relationship is consistent as
long as the plasma protein concentration and, thus, the colloid
osmotic pressure are regulated appropriately and the microvasculature
maintains its integrity in limiting protein leak into the interstitial
compartment. The shaded area represents the normal operating
range [13]. A chronic increase in the total quantity of sodium chloride
in the body leads to a chronic increase in ECF volume, part of
which is proportionately distributed to the blood volume compartment.
When accumulation is excessive, disproportionate distribution to
the interstitium may lead to edema. Chronic increases in blood
volume increase mean circulatory pressure (see Fig. 1-3) and lead
to an increase in arterial pressure. Therefore, the mechanisms
regulating sodium balance are primarily responsible for the
chronic regulation of arterial pressure. (Panel B adapted from
Guyton and Hall [13].)
1.4
Intrarenal Mechanisms Regulating Sodium Balance

Sodium excretion, normal
6
High sodium intake
Normal sodium intake
Low sodium intake
4
3
Elevated
sodium intake
2
1
5
1
Normal
sodium intake
Reduced
0
60
80
100
120
140
160
Renal arterial pressure, mm Hg
180
200
Filtered sodium load,

mol/min/g
FIGURE 1-5
Arterial pressure and sodium excretion. In principle, sodium balance
can be regulated by altering sodium intake or excretion by the kidney.
However, intake is dependent on dietary preferences and usually is
excessive because of the abundant salt content of most foods. Therefore, regulation of sodium balance is achieved primarily by altering
urinary sodium excretion. It is therefore of major significance that,
for any given set of conditions and neurohumoral environment,
acute elevations in arterial pressure produce natriuresis, whereas
150
100
50
Low
Normal
High
Fractional sodium
reabsorption, %
100
98
96
94
92
Fractional sodium
excretion, %
8
6
4
2
0
75
100 125 150 175
reductions in arterial pressure cause antinatriuresis [9]. This phenomenon of pressure natriuresis serves a critical role linking arterial
pressure to sodium balance. Representative relationships between
arterial pressure and sodium excretion under conditions of normal,
high, and low sodium intake are shown. When renal function is
normal and responsive to sodium regulatory mechanisms, steady
state sodium excretion rates are adjusted to match the intakes.
These adjustments occur with minimal alterations in arterial pressure,
as exemplified by going from point 1 on curve A to point 2 on
curve B. Similarly, reductions in sodium intake stimulate sodiumretaining mechanisms that prevent serious losses, as exemplified by
point 3 on curve C. When the regulatory mechanisms are operating
appropriately, the kidneys have a large capability to rapidly adjust
the slope of the pressure natriuresis relationship. In doing so, the
kidneys readily handle sodium challenges with minimal long-term
changes in extracellular fluid (ECF) volume or arterial pressure. In
contrast, when the kidney cannot readjust its pressure natriuresis
curve or when it inadequately resets the relationship, the results are
sodium retention, expansion of ECF volume, and increased arterial
pressure. Failure to appropriately reset the pressure natriuresis is
illustrated by point 4 on curve A and point 5 on curve C. When
this occurs the increased arterial pressure directly influences sodium
excretion, allowing balance between intake and excretion to be
reestablished but at higher arterial pressures. (Adapted from Navar [3].)
FIGURE 1-6
Intrarenal responses to changes in arterial pressure at different levels of sodium intake.
The renal autoregulation mechanism maintains the glomerular filtration rate (GFR) during
changes in arterial pressure, GFR, and filtered sodium load. These values do not change
significantly during changes in arterial pressure or sodium intake [3,16]. Therefore, the
changes in sodium excretion in response to arterial pressure alterations are due primarily
to changes in tubular fractional reabsorption. Normal fractional sodium reabsorption is
very high, ranging from 98% to 99%; however, it is reduced by increased sodium chloride
intake to effect the large increases in the sodium excretion rate. These responses demonstrate the importance of tubular reabsorptive mechanisms in modulating the slope of the
pressure natriuresis relationship. (Adapted from Navar and Majid [9].)
RA
B<1
ga=25
PB=20
Pg=60
EFP=9
GFR=Kf EFP
ge=37
i=8
Tubular reabsorption
Pi=6
RE
Pc=20
15
c=37
25
RV
PCU=Kr ERP
Vascular resistance,
mm Hgming/mL

mL/ming
FIGURE 1-7
Hemodynamic mechanisms regulating sodium excretion. Many different neurohumoral
mechanisms, paracrine factors, and drugs exist that can influence sodium excretion and the
pressure natriuresis relationship. These modulators may influence sodium excretion by altering changes in filtered load or changes in tubular reabsorption. Filtered load depends primarily on hemodynamic mechanisms that regulate the forces operating at the glomerulus. As
shown, the glomerular filtration rate (GFR) is determined by the filtration coefficient (Kf)
and the effective filtration pressure (EFP). The EFP is a distributed force determined by the
glomerular pressure (Pg), the pressure in Bowmans space (PB), and the plasma colloid osmotic pressure within the glomerular capillaries (g). The g increases progressively along the length
0.6
0.4
0.2
0
RA
20
15
RE
10
5
0
Renal blood flow,

mL/ming
5
4
3
2
1
0
0
50
100
150
200
1.5
of the glomerular capillaries as protein-free

fluid is filtered such that filtration is greatest in
the early segments of the glomerular capillaries, as designated by the large arrow. The
glomerular forces, EFP, and blood flow are
regulated by mechanisms that control the vascular smooth muscle tone of the afferent and
efferent arterioles and of the intraglomerular
mesangial cells. The filtration coefficient also
is subject to regulation by neural, humoral,
and paracrine influences [17]. Changes in
tubular reabsorption can result from alterations of various processes governing both
active and passive transport along the
nephron segments. Peritubular capillary
uptake (PCU) of the tubular reabsorbate is
mediated by the net colloid osmotic pressure
gradient (c - i). As a result of the filtration
of protein-free filtrate, the plasma colloid
osmotic pressure entering the peritubular capillaries is markedly increased. Thus, the colloid
osmotic gradient exceeds the outwardly
directed hydrostatic pressure gradient (Pc - Pi).
Appropriate responses of one or more of
these modulating mechanisms allow the kidneys to respond rapidly and efficiently to
changes in sodium chloride intake [3,17].
Bcolloid osmotic pressure in Bowmans
space; gacolloid osmotic pressure in initial
parts of glomerular cappillaries; gecolloid
osmotic pressure in terminal segments of
glomerular capillaries; RAresistance of
preglomerular arterioles; REefferent
resistance; RVvenous resistance.
(Adapted from Navar [3].)
FIGURE 1-8
Renal autoregulatory mechanism. Because the glomerular filtration rate (GFR) is so
responsive to changes in the glomerular forces, highly efficient mechanisms have been
developed to maintain a stable intrarenal hemodynamic environment [16]. These powerful
mechanisms adjust vascular smooth muscle tone in response to various extrinsic disturbances.
During changes in arterial pressure, renal blood flow and the GFR are autoregulated with
high efficiency as a consequence of adjustments in the vascular resistance of the preglomerular
arterioles. Although efferent resistance also can be regulated by other mechanisms, it does
not participate significantly over most of the autoregulatory range. The GFR, filtered sodium
load, and the intrarenal pressures are maintained stable in the face of various extrarenal
disturbances by the autoregulatory mechanism. (Adapted from Navar [3].)
1.6
Arterial
pressure
Plasma colloid Proximal tubular

osmotic pressure and loop of Henle
reabsorption
Collection
pipette
Macula
densa
Wax blocking
pipette
Perfusion
pipette
Glomerulotubular
balance
Glomerular
pressure and
plasma flow
Glomerular
filtration
rate
Preglomerular
resistance
Proximal to
distal tubule
flow
Vascular effector
(afferent arteriole)
Early distal tubule:

flow-related changes
in fluid composition
40
30
Single nephron GFR, nL/min
Proximal
tubule
Macula densa:
Sensor mechanism
Transmitter
High sodium intake,

ECF volume expansion
20
Normal
10
Low sodium intake
Decreased ECF volume
0
0
Distal
tubule
10
20
30
Late proximal perfusion rate, nL/min
40
FIGURE 1-9
Tubuloglomerular feedback (TGF) and myogenic mechanisms. Two
mechanisms are responsible for efficient renal autoregulation: the
TGF and myogenic mechanisms. The TGF mechanism is explained
here. A, Increases in distal tubular flow past the macula densa generate
signals from the macula densa cells to the afferent arterioles to elicit
vasoconstriction, whereas decreases in flow cause afferent vasodilation

[16,18,19]. Blocking flow to the distal tubule or interrupting the feedback loop attenuates the autoregulatory efficiency of the glomerular
filtration rate (GFR), glomerular pressure, and renal blood flow.
B, Individual tubules can be blocked and perfused downstream,
while collections are made or pressure measured in an early tubular
segment. C, When the tubule is perfused at increased flows, the
glomerular pressure and GFR of that nephron decrease. The shaded
area in the normal relationship represents the normal operating
level of the TGF mechanism. This mechanism helps stabilize the
filtered load and the solute and sodium load to the distal nephron
segment. The responsiveness of the TGF mechanism is modulated
by changes in sodium intake and in extracellular fluid (ECF) volume
status. At high sodium intake and ECF volume expansion the sensitivity of the TGF mechanism is low, thus allowing greater spillover
of salt to the distal nephron. During low sodium intake and other
conditions associated with ECF volume contraction, the sensitivity
of the TGF mechanism is markedly increased to minimize spillover
into the distal nephron and maximize sodium retention. The hormonal and paracrine mechanisms responsible for regulating TGF
sensitivity are discussed subsequently.
The myogenic mechanism is intrinsic to the vessel wall and
responds to changes in wall tension to regulate vascular smooth
muscle tone. Preglomerular arteries and afferent arterioles but not
efferent arterioles exhibit myogenic responses to changes in wall
tension [16,20]. The residual autoregulatory capacity that exists
during blockade of the tubuloglomerular feedback mechanism
indicates that the myogenic mechanism contributes about half to
the autoregulatory efficiency of the renal vasculature. (Figure
adapted from Navar [3].)

Agents that increase cytosolic calcium:
Angiotensin II, vasopressin, epinephrine (),
TXA2, leukotrienes, adenosine (A1),
ATP, norepinephrine, endothelin
VoltageReceptoroperated
operated
channel 2+
Ca
channel 2+
Ca
Agents that increase cAMP (or cGMP):

Epinephrine (), PTH, PGI2,
PGE2, ANP, dopamine, nitric oxide,
adenosine (A2)
Calcium-activated
potassium channel
K+
Chloride
channel_
Cl
+
Ca2+
Ca2+
R
R
cAMP
Gq
Na+
PLC
Phosphoinositides
Gi
Ad Cy
Ca2+
Phosphorylated MLCK
(inactive)
DAG + IP3
SR
Active MLCK
Ca2+-Cal
Calmodulin
cAMP
PKA
Ca2+
PKC
Gs
MLC
MLCK
Phosphorylated
MLC
Tension
development
Actin
Smooth muscle cell
FIGURE 1-10
Cellular mechanisms of vascular smooth muscle contraction. The vascular resistances of different arteriolar
segments are ultimately regulated by the contractile
tone of the corresponding vascular smooth muscle
cells. Shown are the various membrane activation
mechanisms and signal transduction events leading to
a change in cytosolic calcium ions (Ca2+), cyclic AMP
(cAMP), and phosphorylation of myosin light chain
kinase. Many of the circulating hormones and paracrine
factors that increase or decrease vascular smooth muscle
tone are identified. Ad Cyadenylate cyclase;

ANPatrial natriuretic protein; Calcalmodulin;
cGMPcyclic GMP; DAG1,2-diacylglycerol; Gq,
Gi, GsG proteins; IP3inositol 1,4,5-triphosphate;
MLCmyosin light chain; MLCKmyosin light chain
kinase; PGE2prostaglandin E2; PGI2prostaglandin
I2; PKAprotein kinase A; PKCprotein kinase C;
PLCphospholipase C; PTHparathyroid hormone;
Rreceptor; SRsarcoplasmic reticulum; TXA2
thromboxane A2. (Adapted from Navar et al. [16].)
FIGURE 1-11
Differential activating mechanisms in afferent and efferent arterioles.
The relative contributions of the activation pathways are different
in afferent and efferent arterioles. Increases in cytosolic Ca2+ in
afferent arterioles appear to be primarily by calcium ion (Ca2+)
entry by way of receptor- and voltage-dependent Ca2+ channels.
The efferent arterioles are less dependent on voltage-dependent
Ca2+ channels. These differential mechanisms in the renal vasculature
are exemplified by comparing the afferent and efferent arteriolar
responses to angiotensin II before and after treatment with Ca2+
channel blockers. A, These experiments were done using the
juxtamedullary nephron preparation that allows direct visualization
of the renal microcirculation [21]. AAafferent arteriole;
ArAarcuate artery; PCperitubular capillaries; Vvein;
VRvasa recta.
1.7
1.8
Afferent arteriole
30

B, Both afferent and efferent arterioles constrict in response to
angiotensin II [22]. Ca2+ channel blockers, dilate only the afferent
arterioles and prevents the afferent vasoconstriction responses to
angiotensin II. In contrast, Ca2+ channel blockers do not significantly vasodilate efferent arterioles and do not block the vasoconstrictor effects of angiotensin II. Thus, afferent and efferent arterioles can be differentially regulated by various hormones and
paracrine agents. (Panel A from Casellas and Navar [21]; panel B
from Navar et al. [23].)
Efferent arteriole
Diameter,
25
20
Control
Ca2+ channel blockers
15
0.1 nM 10 nM
0.1 nM 10 nM
10
Control
Angiotensin II
Control
Angiotensin II
Smooth muscle cell

Vasoconstriction
Vasodilation
EDHF
NO PGI
2
Relaxing factors
EDCF
PGF2
Endothelin
Constricting factors
TXA2
Angiotensin II
ACE
Endothelial cell
Angiotensin I
Shear
stress
Thrombin Insulin
Bradykinin
Platelet
activating ATP-ADP
Serotonin
Leukotrienes factor
Acetylcholine
Histamine
FIGURE 1-12
Endothelial-derived factors. In addition to serving as a diffusion barrier, the endothelial
cells lining the vasculature participate actively in the regulation of vascular function. They
do so by responding to various circulating hormones and physical stimuli and releasing
Sodium excretion, normal
Renal
arterial
pressure
Shear
stress
Endothelial
nitric oxide
release
Vascular dilation
but counteracted
by autoregulation
Diffusion to
tubules
3
2
1
Control
NOS inhibition
50 75
100
125 150
Epithelial
cGMP
Decreased sodium
reabsorption
Sodium
excretion
paracrine agents that alter vascular smooth

muscle tone and influence tubular transport
function. (Examples are shown.) Angiotensinconverting enzyme (ACE) is present on
endothelial cells and converts angiotensin I
to angiotensin II. Nitric oxide is formed by
nitric oxide synthase, which cleaves nitric
oxide from L-arginine. Nitric oxide diffuses
from the endothelial cells to activate soluble
guanylate cyclase and increases cyclic
GMP (cGMP) levels in vascular smooth
muscle cells, thus causing vasodilation.
Agents that can stimulate nitric oxide
are shown. The relative amounts of the
various factors released by endothelial
cells depend on the physiologic circumstances and pathophysiologic status.
Thus, endothelial cells can exert vasodilator
or vasoconstrictor effects. At least one
major influence participating in the normal
regulation of vascular tone is nitric oxide.
EDCFendothelial derived constrictor
factor; EDHFendothelial derived hyperpolarizing factor; PGF2prostaglandin
F2; PGI2prostaglandin I2; TXA2
thromboxane A2. (Adapted from Navar
et al. [16].)
FIGURE 1-13
Nitric oxide in mediation of pressure natriuresis. Several recent studies
have demonstrated that nitric oxide also directly affects tubular sodium transport and may be an important mediator of the changes
induced by arterial pressure in sodium excretion, as described in Figure
1-5 [9,24]. Increases in arteriolar shear stress caused by increases in
arterial pressure stimulate production of nitric oxide. Nitric oxide may
exert direct effects to inhibit tubule sodium reabsorptive mechanisms
and may elicit vasodilatory actions. Nitric oxide increases intracellular
cyclic GMP (cGMP) in tubular cells, which leads to a reduced reabsorption rate through cGMP-sensitive sodium entry pathways [24,25].
When formation of nitric oxide is blocked by agents that prevent nitric
oxide synthase activity, sodium excretion is reduced and the pressure
natriuresis relationship is markedly suppressed. Thus, nitric oxide may
exert a critical role in the regulation of arterial pressure by influencing
vascular tone throughout the cardiovascular system and by serving as
a mediator of the changes induced by the arterial pressure in tubular
sodium reabsorption. (Adapted from Navar [3].)
DCT
PCT
60%
7%
CCD
PST
TALH
30%
DLH
2% 3%
OMCD
IMCD
ALH
< 1%
Filtered NA+ load = Plasma Na Glomerular filtration rate
= 140 mEq/L 0.120 L/min
= 16.8 mEq/min 1440 min/d
= 24,192 mEq/min
Urinary Na+ excretion = 200 mEq/d
Fractional Na excretion = 0.83%
Fractional Na reabsorption = 99.17%
Peritubular capillary
Lateral
intercellular
P
space
Na K
()
Na
Active
transcellular
[K ]
+
Na
K
K
Na+
()
Cells
Tubule lumen
Paracellular
(passive)
[Na+]
1.9
FIGURE 1-14
Tubular transport processes. Sodium excretion is the difference
between the very high filtered load and net tubular reabsorption
rate such that, under normal conditions less than 1% of the filtered
sodium load is excreted. The percentage of reabsorption of the filtered
load occurring in each nephron segment is shown. The end result is
that normally less than 1% of the filtered load is excreted; however,
the exact excretion rate can be changed by many mechanisms. Despite
the lesser absolute sodium reabsorption in the distal nephron segments, the latter segments are critical for final regulation of sodium
excretion. Therefore, any factor that changes the delicate balance
existing between the hemodynamically determined filtered load and
the tubular reabsorption rate can lead to marked alterations in
sodium excretion. ALHthin ascending limb of the loop of Henle;
CCDcortical collecting duct; DCTdistal convoluted tubule;
DLHthin descending limb of the loop of Henle; IMCDinner
medullary collecting duct; OMCDouter medullary collecting
duct; PCTproximal convoluted tubule; PSTproximal straight
tubule; TALHthick ascending limb of the loop of Henle.
FIGURE 1-15
Proximal tubule reabsorptive mechanisms. The proximal tubule is
responsible for reabsorption of 60% to 70% of the filtered load of
sodium. Reabsorption is accomplished by a combination of both
active and passive transport mechanisms that reabsorb sodium and
other solutes from the lumen into the lateral spaces and interstitial
compartment. The major driving force for this reabsorption is the
basolateral sodium-potassium ATPase (Na+-K+ ATPase) that transports
Na+ out of the proximal tubule cells in exchange for K+. As in most
cells, this maintains a low intracellular Na+ concentration and a
high intracellular K+ concentration. The low intracellular Na+
concentration, along with the negative intracellular electrical
potential, creates the electrochemical gradient that drives most of
the apical transport mechanisms. In the late proximal tubule, a lumen
to interstitial chloride concentration gradient drives additional net
solute transport. The net solute transport establishes a small
osmotic imbalance that drives transtubular water flow through
both transcellular and paracellular pathways. In the tubule, water
and solutes are reabsorbed isotonically (water and solute in equivalent
proportions). The reabsorbed solutes and water are then further
reabsorbed from the lateral and interstitial spaces into the peritubular
capillaries by the colloid osmotic pressure, which establishes
a predominant reabsorptive force as discussed in Figure 1-7.
Ptranscapillary hydrostatic pressure gradient; transcapillary
colloid osmotic pressure gradient.
1.10
Proximal tubule cells
Lumen
Regulation of reabsorption
_
ATP
Na+
Glucose
ADP
Na+
H+
Anion
Na+ _
HCO3
CO3
Ca2+
3Na+
Cl
3Na+
2 K+
Stimulation
Angiotensin II
Adrenergic agents or increased
renal nerve activity
Increased luminal flow or
solute delivery
Increased filtration fraction
Inhibition
Volume expansion (via
increased backleak)
Dopamine
Increased interstitial pressure
FIGURE 1-16
Major transport pathways across proximal tubule cells. At the apical membrane, sodium is
transported in conjunction with organic solutes (such as glucose, amino acids, and citrate)
and inorganic anions (such as phosphate and sulfate). The major mechanism for sodium
entry into the cells is sodium-hydrogen exchange (the isoform NHE3). Chloride transport
Lumen
Furosemide Cell
_
2Cl-
Thick ascending
limb cells
ATP
Na
K+
or
NH4+
+10mv
ADP
K+
Na+
H+
CI
Regulation of reabsorbtion
Stimulation
Antidiuretic hormone
3Na+ -adrenergic agents
2 K+ Mineralocorticoids
Inhibition
Hypertonicity
Prostaglandin E2
Acidosis
Calcium
pathways across the apical membrane may

include a coupled sodium chloride entry
step or chloride anion exchange that is
coupled with sodium-hydrogen exchange.
Major transport pathways at the basolateral
membrane include the ubiquitous and
preeminent sodium-potassium ATPase
(Na+-K+ ATPase) that creates the major
driving force. The other major pathway
is a sodium-bicarbonate transport system
that transports the equivalent of one sodium
ion coupled with the equivalent of three
bicarbonate ions (HCO-3). Because this
transporter transports two net charges
out the electrically negative cell, membrane
voltage partially drives this transport
pathway. A basolateral sodium-calcium
exchanger is important in regulating cell
calcium. Not shown are several other
pathways that predominantly transport
protons or other ions and organic substrates. Several major regulatory factors
are listed.
FIGURE 1-17
Sodium transport mechanisms in the thick ascending limb of the
loop of Henle. The major sodium chloride reabsorptive mechanism
in the thick ascending limb at the apical membrane is the sodiumpotassium-chloride cotransporter. This electroneutral transporter is
inhibited by furosemide and other loop diuretics and is stimulated
by a variety of factors. Potassium is recycled across the apical
membrane into the lumen, creating a positive voltage in the lumen.
An apical sodium-hydrogen exchanger also exists that may function
to reabsorb some sodium bicarbonate. The sodium-potassium
ATPase (Na+-K+ ATPase) at the basolateral membrane again is the
driving force. The basolateral chloride channel and possibly other
chloride cotransporters are important in mediating chloride efflux
across the basolateral membrane. Sodium and chloride are reabsorbed without water in this segment because water is impermeable
across the apical membrane of the thick ascending limb. Thus, the
tubular fluid osmolality in this nephron segment is hypotonic.
Thiazides
Distal tubule and

connecting tubule cells
_
Na
_
Cl
ATP
3Na+
2 K+
Amiloride
Na+
1.11
FIGURE 1-18
Mechanisms of sodium chloride reabsorption in the distal tubule. The distal convoluted
tubule and subsequent connecting tubule have a variety of sodium transport mechanisms.
The distal tubule has predominantly a sodium chloride cotransporter, which is inhibited
by thiazide diuretics. In the connecting tubule, sodium channels and a sodium-hydrogen
exchange mechanism also are present. Amiloride inhibits sodium channel activity. Again
the sodium-potassium ATPase (Na+-K+ ATPase) on the basolateral membrane provides
most of the driving force for sodium reabsorption.
ADP
Na+
H+
Collecting duct principal cell

Lumen
Cell
ATP
Na+
ADP
_
Amiloride
K+
Regulation of reabsorbtion
Stimulation
Aldosterone
3Na+ Antidiuretic hormone
2 K+ Inhibition
Prostaglandins
Nitric oxide
Bradykinin
Na+_
2CI
K+
(IMCD)
FIGURE 1-19
Mechanism of sodium chloride reabsorption in collecting duct cells.
Sodium transport in the collecting duct is mainly via amiloridesensitive sodium channels in the apical membrane. Some evidence for
other mechanisms such as an electroneutral sodium-chloride cotransport mechanism and a different sodium channel also has been
reported. Again, the basolateral sodium-potassium ATPase (Na+-K+
ATPase) creates the driving force for overall sodium transport.
There are some differences between the cortical collecting duct and
the deeper inner medullary collecting duct (IMCD). In the cortical
collecting duct, sodium transport occurs in the predominant principal
cell type interspersed between acid-base transporting intercalated
cells. The principal cell also is an important site of potassium
secretion by way of apical potassium channels and water transport
via antidiuretic sensitive water channels. Regulation of sodium
channels may involve either insertion (from subapical compartments)
or activation of preexisting sodium channels.
1.12
Systemic Factors Regulating Arterial

Pressure and Sodium Excretion
Medulla
Baroreceptor
firing rate, impulses/s
NTS
Normal
Glossopharyngeal
nerve
Afferents
Resetting
Carotid
sinus
NA
DN
Efferents
100
Atrial
receptors
Bulbospinal
pathway epinephrine
Vagus
nerve
Arterial
pressure
Aortic
arch
Preganglionic
sympathetics
(acetylcholine)
Heart
rate
Postganglionic
Sympathetics
Vascular smooth
muscle
TPR
FIGURE 1-20
Neural and sympathetic influences. The neural reflexes serve as the
principal mechanisms for the rapid regulation of arterial pressure.
The neural reflexes also exert a long-term role by influencing sodium
excretion. The pathways and effectors of the arterial baroreflex
and atrial pressure-volume reflex are depicted. The arrows indicate
increased or decreased activity in response to an acute reduction in
arterial pressure which is sensed by the baroreceptors in the aortic
arch and carotid sinus.
The insert depicts the relationship between the arterial blood
pressure and baroreflex primary afferent firing rate. At the normal
level of mean arterial pressure of approximately 100 mm Hg, the
sensitivity (I/P) is set at the maximum level. After chronic resetting
of the baroreceptors, the peak sensitivity and threshold of activation
are shifted to a higher level of arterial pressure.
The cardiovascular reflexes involve high-pressure arterial receptors in the aortic arch and carotid sinus and low-pressure atrial
receptors. In response to decreases in arterial pressure or vascular
volume, increased sympathetic stimulation participates in shortterm control of arterial pressure. This increased stimulation does
Norepinephrine
Adrenal
medulla
Kidney
RBF
GFR
Reabsorption
Na+ excretion
Epinephrine
so by enhancing cardiac performance and stimulating vascular

smooth muscle tone, leading to increased total peripheral resistance and decreased capacitance. The direct effects of the sympathetic nervous system on kidney function lead to decreased sodium
excretion caused by decreases in filtered load and increases in
tubular reabsorption [26].
The decreases in the glomerular filtration rate (GFR) and
filtered sodium load are due to increases in both afferent and
efferent arteriolar resistances and to decreases in the filtration
coefficient (see Fig. 1-7). Sympathetic activation also enhances
proximal sodium reabsorption by stimulating the sodium-hydrogen
(Na+-H+) exchanger mechanism (see Fig. 1-16) and by increasing
the net chloride reabsorption by the thick ascending limb of the
loop of Henle. The indirect effects include stimulation of renin
secretion and angiotensin II formation, which, as discussed next,
also stimulates tubular reabsorption. Ichange in impulse firing;
Pchange in pressure; DNdorsal motor nucleus; NAnucleus
ambiguous; NTSnucleus tractus solitarii; RBFrenal blood flow;
TPRtotal peripheral resistance. (Adapted from Vari and Navar [4].)
Angiotensinogen
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Val-Tyr-Ser-R
Renin
NaCl
intake
Arterial
pressure
ECF
volume
Stress
trauma
Angiotensin I
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
Angiotensinconverting
enzyme,
chymase (heart)
Macula densa mechanism

Baroreceptor mechanism
Sympathetic nervous system
Angiotensin II
Juxtaglomerular apparatus
Cytosolic Ca2+
cAMP
Renin
release
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
Angiotensinases
Metabolites
AT1, AT2, AT?

Receptor binding and
Biologic actions
Angiotensin (17)
Angiotensin (28)
Angiotensin (38)
Inactive fragments
FIGURE 1-21
Renin-angiotensin system. The renin-angiotensin system serves as one of the most
powerful regulators of arterial pressure
and sodium balance. In response to various
stimuli that compromise blood volume,
extracellular fluid (ECF) volume, or arterial
pressureor those associated with stress
and traumathree major mechanisms are
activated. These mechanisms stimulate renin
release by the cells of the juxtaglomerular
apparatus that act on angiotensinogen to
form angiotensin I. Angiotensinogen is an
2 globulin formed primarily in the liver
and to a lesser extent by the kidney. Angiotensin I is a decapeptide that is rapidly
converted by angiotensin-converting
enzyme (ACE) and to a lesser extent by
chymase (in the heart) to angiotensin II, an
octapeptide. Recent studies have indicated
that other angiotensin metabolites such as
angiotensin (28), angiotensin (17), and
angiotensin (38) have biologic actions.
Angiotensin II and/or active metabolites
Adrenal
cortex
Aldosterone
Distal
nephron
reabsorption
Kidney
Intestine
Peripheral nervous
system
Central nervous
system
Proximal and
distal sodium + water
Reabsorption by
intestine
Vascular smooth
muscle
Adrenergic
facilitation
Sympathetic
discharge
Vasoconstriction
transport effects
Thirst, salt appetite
Heart
Growth
factors
Contractility
Proliferation
Vasoconstriction
Vasopressin release
Water reabsorption
Maintain or increase
extracellular fluid volume
FIGURE 1-22
Multiple actions of angiotensin. Angiotensin II and
some of the other angiotensin II metabolites have a
myriad of actions on many different vascular beds
and organ systems. Angiotensin II exerts short- and
long-term actions, including vasoconstriction and
stimulation of aldosterone release. Angiotensin II also
Total peripheral
resistance
1.13
Cardiac
output
Hypertrophy
interacts with the sympathetic nervous system by

facilitating adrenergic transmission and has long-term
actions on vascular smooth muscle proliferation by
interacting with growth factors. Angiotensin II exerts
several important effects on the kidney that contribute
to sodium conservation. (Adapted from Navar [3].)
1.14

Enhance proximal
tubular reabsorption
PT
BS
Decrease Kf
GC
EA
PC
FIGURE 1-23
Angiotensin II actions on renal hemodynamics. Systemic and
intrarenal angiotensin II exert powerful vasoconstrictive actions on
the kidney to decrease renal blood flow and sodium excretion. At
the level of the glomerulus, angiotensin II is a vasoconstrictor of
both afferent (AA) and efferent arterioles (EA) and decreases the
filtration coefficient Kf. Angiotensin II also directly inhibits renin
release by the juxtaglomerular apparatus. Increased intrarenal
angiotensin II also is responsible for the increased sensitivity of the
tubuloglomerular feedback mechanism that occurs with decreased
sodium chloride intake (see Fig. 1-9) [17,27,28]. BSBowmans
space; GCglomerular capillaries; PCperitubular capillaries;
PTproximal tubule; TALthick ascending limb; TGFtubuloglomerular feedback mechanism. (Adapted from Arendshorst and
Navar [17].)
Inhibit renin release
Efferent
arteriolar
vasoconstriction
Afferent arteriolar
vasoconstriction
TAL
Increased
sensitivity
of TGF
mechanism
AA
Angiotensin
Angiotensin
G
PLA
H+
Tubule
lumen
_
+
Na+
HCO3
Na+
cAMP
K+
Na+
FIGURE 1-24
Angiotensin II actions on tubular transport. Angiotensin II receptors
are located on both the luminal and basolateral membranes of the
proximal and distal nephron segments. The proximal effect has
been studied most extensively. Activation of angiotensin II-AT1
receptors leads to increased activities of the sodium-hydrogen
(Na+-H+) exchanger and the sodium-bicarbonate (Na+-HCO-3)
cotransporter. These increased activities lead to augmented volume
reabsorption. Higher angiotensin II concentrations can inhibit the
tubular sodium reabsorption rate; however, the main physiologic
role of angiotensin II is to enhance the reabsorption rate [28].
cAMPcyclic AMP; GG protein; PLAphospholipase A.
(Adapted from Mitchell and Navar [28].)
1.15
SNGFR
Enhancement of proximal reabsorption rate
Stimulation of apical amiloride-sensitive Na-H exchanger
Stimulation of basolateral Na-HCO3 cotransporter
Sustained changes
in distal volume
and sodium delivery
Increased sensitivity of afferent arteriole to signals from macula densa cells
Distal
delivery
Glomerular pressure, mm Hg
Reabsorption 60
Proximal
A. SYNERGISTIC RENAL ACTIONS OF ANGIOTENSIN II
55
50
45
40
35
30
0
Proximal reabsorption 60
SNGFR
Distal
delivery
55
50
45
40
35
30
0
Lumen
10
20
30
End proximal fluid flow, nL/min
40
Principal cell
Mitochondria
ATP
Na+
Proteins
3Na+
2 K+
ADP
mRNA
K+
Nucleus
MR
Aldosterone
_ Spironolactone
10
20
30
End proximal fluid flow, nL/min
40
FIGURE 1-25
AC, Synergistic effects of angiotensin II on proximal reabsorption
and tubuloglomerular feedback mechanisms. The actions of
angiotensin II on proximal nephron reabsorption and the ability
of angiotensin II to enhance the sensitivity of the tubuloglomerular
feedback (TGF) mechanism prevent a compensatory increase in
glomerular filtration rate caused by the reduced distal tubular flow.
These actions allow elevated angiotensin II levels to exert a
sustained reduction in sodium delivery to the distal nephron
segment. This effect is shown here by the shift of operating levels
to a lower proximal fluid flow under the influence of elevated
angiotensin II [27]. The effects of angiotensin II to enhance TGF
sensitivity allow the glomerular pressure (GP) and nephron filtration rate to be maintained at a reduced distal volume delivery rate
that would occur as a consequence of the angiotensin II effects on
reabsorption. SNGFRsingle nephron glomerular filtration rate.
(Panels B and C adapted from Mitchell et al. [27].)
FIGURE 1-26
Effects of aldosterone on distal nephron sodium reabsorption.
A, Mechanism of action of aldosterone. Angiotensin II also is
a very powerful regulator of aldosterone release by the adrenal
gland. The increased aldosterone levels synergize with the direct
effects of angiotensin II to enhance distal tubule sodium reabsorption. Aldosterone increases sodium reabsorption and potassium
secretion in the distal segments of the nephron by binding to the
cytoplasmic mineralocorticoid receptor (MR). On binding, the
receptor complex migrates to the nucleus where it induces
transcription of a variety of messenger RNAs (mRNAs). The
mRNAs encode for proteins that stimulate sodium reabsorption
by increasing sodium-potassium ATPase (Na+-K+ ATPase) protein
and activity at basolateral membranes, increasing mitochondrial
ATP formation, and increasing the sodium and potassium channels
at the luminal membrane [29]. Growing evidence also exists for
nongenomic actions of aldosterone to activate sodium entry
pathways such as the amiloride-sensitive sodium channel [30].
1.16
14
Filtered sodium remaining, %
12
Aldosterone blockade
10

B, The net effect of aldosterone is to stimulate sodium reabsorption
along the distal nephron segment, decreasing the remaining sodium
to only 2% or 3% of the filtered load. The direct action of aldosterone
can be blocked by drugs such as spironolactone that bind directly
to the mineralocorticoid receptor.
8
6
4
Normal
2
0
0
20
40
60
Distal nephron length, %
Lumen
80
100
Principal cell
Mitochondria
Na+
ATP
Proteins
ADP
3Na+
2 K+
mRNA
Aldosterone
MR
K+
Nucleus
Cortisone
Cortisol
II-_OHSD defect or
glycyrrhizic acid or
carbenoxolone
Lumen
Principal cell
Mitochondria ATP
3Na+
Na+
Proteins
ADP
mRNA
K+
Nucleus
2K+
Primary
hyperaldosteronism
Adrenal enzymatic
disorder
Adenoma
Glucorticoid-remediable
aldosteronism
MR
Aldosterone
FIGURE 1-27
Syndrome of apparent mineralocorticoid excess and hypertension.
Aldosterone increases sodium reabsorption and potassium secretion
in the distal segments of the nephron by binding to the cytoplasmic
mineralocorticoid receptor (MR). Cortisol, the glucocorticoid that
circulates in plasma at much higher concentrations than does aldosterone, also binds to MR. However, cortisol normally is prevented
from this by the action of 11--hydroxysteroid dehydrogenase (11-OHSD), which metabolizes cortisol to cortisone in mineralocorticoid-sensitive cells. A deficiency or defect in this enzyme has been
found to be responsible for a rare form of hypertension in persons
with the hereditary syndrome of apparent mineralocorticoid excess.
In these persons, cortisol binds to the MR receptor, causing sodium
retention and hypertension [31]. This enzyme also is blocked by glycyrrhizic acid (in some forms of licorice) and carbenoxolone. The
diuretic spironolactone acting by way of inhibition of MR is able to
block this excessive action of cortisol on the MR receptor.
FIGURE 1-28
Hyperaldosteronism and glucocorticoid-remediable aldosteronism.
Hypertension can result from increased aldosterone or from
increases in other closely related steroids derived from abnormal
adrenal metabolism (11--hydroxylase deficiency and 17-hydroxylase deficiency). The most common cause is an aldosterone-producing adenoma; bilateral hyperplasia of the adrenal
zona glomerulosa is the next most common cause. In glucocorticoid-remediable aldosteronism, a DNA crossover mutation results
in a chimeric gene in which aldosterone production is regulated by
adrenocorticotropic hormone (ACTH). Increases in aldosterone
also can result secondarily from any state of increased renin such
as renal artery stenosis, which leads to increased circulating concentrations of angiotensin II and stimulation of aldosterone release
[31]. MRmineralocorticoid receptor; mRNAmessenger RNA.
Lumen Cell
Liddle's
syndrome
Na+
pp
pp
pp
ATP
ADP
Liddle's
syndrome
3Na+
2 K+
K+
1.17
FIGURE 1-29
Excess epithelial sodium channel activity in Liddles syndrome. The
epithelial sodium channel responsible for sodium reabsorption in
much of the distal portions of the nephron is a complex of three
homologous subunits, , , and each with two membrane-spanning domains. Liddles syndrome, an autosomal dominant disorder
causing low renin-aldosterone hypertension often with hypokalemia,
results from mutated or subunits. These mutations increase the
sodium reabsorptive rate by way of these channels by keeping them
open longer, increasing sodium channel density on the membranes,
or both. The specific problem appears to reside with proline (P)-rich
domains in the carboxyl terminal region of or that are involved
in regulation of the channel membrane localization or activity. The
net result is excess sodium reabsorption and a reduced capability to
increase sodium excretion in response to volume expansion [31,32].
Extracellular fluid volume

Blood volume
Intrathoracic
blood volume
Atrial stretch
receptors
Na Cl
Gitleman's
syndrome
Sodium
excretion
Aldosterone
Renin
Tubular sodium
reabsorption
Vascular
resistance
Vasodilation
Na+
L
Na+2Cl
_
Cl K+ K+
Pseudohypoaldosteronism
Bartter's
syndrome
FIGURE 1-30
Syndromes of diminished sodium reabsorption and hypotension.
Recently, a variety of syndromes associated with salt wasting, and
usually hypotension, have been attributed to specific molecular
defects in the distal nephron. Bartters syndrome, which usually is
accompanied by metabolic alkalosis and hypokalemia, has been
found to be associated with at least three separate defects (the three
transporters shown) in the thick ascending limb. These defects are
at the level of the sodium-potassium-2chloride (Na+-K+-2Cl-)
cotransporter, apical potassium channel, and basolateral chloride
channel (see Fig. 1-17). Malfunction in any of these three proteins
results in diminished sodium chloride reabsorption similar to that
occurring with administration of loop diuretics. Gitelmans syndrome,
which was originally described as a variant of Bartters syndrome,
represents a defect in the sodium chloride cotransport mechanism
in the distal tubule. Pseudohypoaldosteronism results from a defect
in the apical sodium channels in the collecting ducts. In contrast to
Bartters and Gitelmans syndromes, hyperkalemia may be present.
These rare disorders illustrate that defects in sodium chloride reabsorptive mechanisms can result in abnormally low blood pressure
as a consequence of excessive sodium excretion in the urine. Although
these conditions are rare, similar but more subtle defects of the
heterozygous state may contribute to protection from hypertension
in some persons [31]. Bbasolateral side; Llumen of tubule.
Atrial
natriuretic peptide
FIGURE 1-31
Atrial natriuretic peptide (ANP). In response to increased intravascular volume, atrial distention stimulates the release of ANP from
the atrial granules where the precursor is stored. Extracellular fluid
volume expansion is associated with increased ANP levels, whereas
reductions in vascular volume and dehydration elicit decreases in
plasma ANP levels. ANP participates in arterial pressure regulation
by sensing the degree of vascular volume expansion and exerting
direct vasodilator actions and natriuretic effects. ANP has been
shown to markedly increase the slope of the pressure natriuresis
relationship (see Figs. 1-5 and 1-6). The vasorelaxant and transport
actions are mediated by stimulation of membrane-bound guanylate
cyclase, leading to increased cyclic GMP levels. ANP also inhibits
renin release, which reduces circulating angiotensin II levels
[3335]. Related peptides, such as brain natriuretic peptides, have
similar effects on sodium excretion and renin release [36].
1.18
Membrane phospholipids
Phospholipase A2
COOH
Arachidonic acid
Cytochrome P450
monooxygenases
Cyclooxygenase
Endoperoxides
PGI2/PGE2
(vasodilation,
natriuresis)
EETs
(vasodilation )
Lipoxygenases
HPETEs
HETEs
(vasoconstriction)
Leukotrienes
(vasoconstriction)
TXA2/PGH2
(vasoconstriction)
HETEs
Lipoxins
FIGURE 1-32
Arachidonic acid metabolites. Several eicosanoids (arachidonic acid metabolites) are
released locally and exert both vasoconstrictor and vasodilator effects as well as effects on
tubular transport [16,37]. Phospholipase A2 catalyzes formation of arachidonic acid (an
unsaturated 20-carbon fatty acid) from membrane phospholipids. The cyclooxygenase pathway and various prostaglandin synthetases are responsible for the formation of endoperoxides (PGH2), prostaglandins E2 (PGE2) and I2 (PGI2), and thromboxane (TXA2) [38,39].
Kallikrein-kinin system
Low molecular weight kininogen
High molecular weight kininogen
Tissue kallikrein
Plasma kallikrein
Bradykinin
Kininase II (ACE)
NEP
Kininase I
Des Arg-bradykinin
B1-receptor
Kinin degradation products

B2-receptor
Endothelium-dependent
Nitric oxide
PGE2
Vasodilation natriuresis
States of volume depletion and hypoperfusion stimulate prostaglandin synthesis

[16,17,38].
The vasodilator prostaglandins attenuate
the influence of vasoconstrictor substances
during activation of the renin-angiotensin
system, sympathetic nervous system, or both
[33]. These prostaglandins also have transport effects on renal tubules through activation of distinct prostaglandin receptors
[40]. In some pathophysiologic conditions,
enhanced production of TXA2 and other
vasoconstrictor prostanoids may occur. The
vasoconstriction induced by TXA2 appears
to be mediated primarily by calcium influx
[17,40].
Leukotrienes are hydroperoxy fatty acid
products of 5-hydroperoxyeicosatetraenoic
acid (HPETE) that are synthesized by way of
the lipoxygenase pathway. Leukotrienes are
released in inflammatory and immunologic
reactions and have been shown to stimulate
renin release. The cytochrome P450 monooxygenases produce several vasoactive
agents [16,37,41,42] usually referred to as
EETs and hydroxy-eicosatetraenoic acids
(HETEs). These substances exert actions
on vascular smooth muscle and epithelial
tissues [16,41,42]. (Adapted from Navar [3].)
FIGURE 1-33
Kallikrein-kinin system. Plasma and tissue kallikreins are functionally different serine protease enzymes that act on kininogens (inactive 2 glycoproteins) to form the biologically active kinins
(bradykinin and lysyl-bradykinin [kallidin]). Kidney kallikrein and
kininogen are localized in the distal convoluted and cortical collecting tubules. Release of kallikrein into the tubular fluid and interstitium can be stimulated by prostaglandins, mineralocorticoids,
angiotensin II, and diuretics. B1 and B2 are the two major
bradykinin receptors that exert most of the vascular actions.
Although glomerulus and distal nephron segments contain both B1
and B2 receptors, most of the renal vascular and tubular effects
appear to be mediated by B2-receptor activation [16,17,43,44].
Bradykinin and kallidin elicit vasodilation and stimulate nitric
oxide, prostaglandin E2 (PGE2) and I2 (PGI2), and renin release
[45,46]. Kinins are inactivated by the same enzyme that converts
angiotensin I to angiotensin II, angiotensin-converting enzyme
(ACE). The kallikrein-kinin system is stimulated by sodium depletion, indicating it serves as a mechanism to dampen or offset the
effects of enhanced angiotensin II levels [47,48]. Des Arg
bradykinin; NEPneutral endopeptidase.
Plasma vasopressin, pg/mL
10
FIGURE 1-34
Vasopressin. Vasopressin is synthesized by the paraventricular and supraoptic nuclei of
the hypothalamus. Vasopressin is stored in the posterior pituitary gland and released in
response to osmotic or volume-dependent baroreceptor stimuli, or both. Atrial filling
inhibits vasopressin release. Increases in plasma osmolality increase vasopressin release;
however, the relationship is shifted by the status of extracellular fluid (ECF) volume, with
decreases in the ECF volume increasing the sensitivity of the relationship. Stress and trauma
also increase vasopressin release [15]. Therefore, when ECF volume and blood volume are
diminished, vasopressin is released to help guard against additional losses of body fluids.
(Adapted from Navar [8].)
Normal
ECF
volume
Decreased
ECF
volume
8
6
Increased
ECF
volume
4
2
0
260
340
280
300
320
Plasma osmolality, mOsm/kg
Collecting duct
principal cell
Plasma membrane
Adenylate
cyclase
Tubule
lumen
ATP
cAMP + PPi
GTP
Protein kinase A
G
G
G
G
Circulating
vasopressin
V2
1.19
H 2O
Aquaporin 2
water
channels
GTP
GDP
Aquaporin 2
FIGURE 1-35
Vasopressin receptors. Vasopressin exerts its cellular actions through
two major receptors. Activation of V1 receptors leads to vascular
smooth muscle constriction and increases peripheral resistance.
Vasopressin stimulates inositol 1,4,5-triphosphate and calcium ion
(Ca2+) mobilization from cytosolic stores and also increases Ca2+
entry from extracellular stores as shown in Figure 1-10. The vasoconstrictive action of vasopressin helps increase total peripheral
resistance and reduces medullary blood flow, which enhances the
concentrating ability of the kidney. V2 receptors are located primarily on the basolateral side of the principal cells in the collecting
duct segment. Vasopressin activates heterotrimeric G proteins that
activate adenylate cyclase, thus increasing cyclic AMP levels. Cyclic
AMP (cAMP) activates protein kinase A, which increases the density
of water channels in the luminal membrane. Water channels (aquaporin proteins) reside in subapical vesicles and on activation fuse
with the apical membrane. Thus, vasopressin markedly increases
the water permeability of the collecting duct and allows conservation
of fluid and excretion of a concentrated urine. An intact vasopressin
system is essential for the normal regulation of urine concentration
by the kidney that, in turn, is the major mechanism for coupling
the solute to solvent ratio (osmolality) of the extracellular fluid.
As discussed in Figure 1-4, this tight coupling allows the confluence of homeostatic mechanisms regulating sodium balance
with those regulating extracellular fluid volume. G and
Gproteins; PPi inorganic pyrophosphate. (Adapted from
Vari and Navar [4].)
1.20
Hypertensinogenic Process
Initial increase in
vascular resistance
Initial increase
in volume
Neurogenic or
humoral stimuli
Volume
Renal volume
retention
Vasoconstrictor
effects
Effective blood
volume
Cardiac output
Tissue blood flow
Autoregulatory
resistance
adjustments
Capacitance
Increased vascular resistance
Increased arterial
blood pressure
FIGURE 1-36
Overview of mechanisms mediating hypertension. From a pathophysiologic perspective, the development of hypertension requires
either a sustained absolute or relative overexpansion of the blood
volume, reduction of the capacitance of the cardiovascular system,
or both [4,49,50]. One type of hypertension is due primarily to
overexpansion of either the actual or the effective blood volume
compartment. In such a condition of volume-dependent hypertension,
Cumulative sodium balance,

mmol/kg BW
Mean arterial pressure,

mm Hg
180
Angiotensin II +
Aldosterone
160
140
Aldosterone
120
100
80
14
12
10
8
6
4
2
0
Renal perfusion pressure

Reduce renal perfusion pressure
Angiotensin II +
Aldosterone
Aldosterone
1
2
3
4
Reduced renal pressure, d
either one or more of the physiologic mechanisms described in

this chapter fails to respond appropriately to intravascular expansion or some pathophysiologic process causes excess production of
one or more sodium-retaining factors such as mineralocorticoids or
angiotensin II [51,52]. Through mechanisms delineated earlier,
overexpansion leads to increased cardiac output that results in overperfusion of tissues; the resultant autoregulatory-induced increases
in peripheral resistance contribute further to an increase in total
peripheral resistance and elevated arterial pressure [2,53,54].
Hypertension also can be initiated by excess vasoconstrictor
influences that directly increase peripheral resistance, decrease
cardiovascular capacitance, or both. Examples of this type of
hypertension are enhanced activation of the sympathetic nervous
system and overproduction of catecholamines such as that occurring
with a pheochromocytoma [45,54,55]. When hypertension caused
by a vasoconstrictor influence persists, however, it must also exert
significant renal vasoconstrictor and sodium-retaining actions.
Without a renal effect the elevated arterial pressure would cause
pressure natriuresis, leading to a compensatory reduction in extracellular fluid volume and intravascular volume. Thus, the elevated
systemic arterial pressure would not be sustained [2,8,54]. Derangements that activate both a vasoconstrictor system and produce
sodium-retaining effects, such as inappropriate elevations in the
activity of the renin-angiotensin-aldosterone system, lead to an
even more powerful hypertensinogenic mechanism that is not easily
counteracted [27]. These dual mechanisms are why the reninangiotensin system has such a critical role in the cause of many
forms of hypertension, leaving only the option to increase arterial
pressure and elicit a pressure natriuresis. (Adapted from Navar [3].)
FIGURE 1-37
Predominance of the renin-angiotensin-aldosterone mechanisms. Collectively, the various
mechanisms discussed provide overlapping influences responsible for the highly efficient
regulation of sodium balance, extracellular fluid (ECF) volume, blood volume, and arterial
pressure. Nevertheless, the synergistic actions of the renin-angiotensin-aldosterone system
on both vasoconstrictor as well as sodium-retaining mechanisms exert a particularly powerful influence that is not easily counteracted. In a recent study by Seeliger and coworkers
[56], renal perfusion pressure was lowered to 90 to 95 mm Hg. The angiotensin II and
aldosterone levels were not allowed to decrease and were fixed at normal levels by continuous infusions. The results demonstrated that all compensatory mechanisms (such as
increased release of atrial natriuretic peptide and reduced activity of the sympathetic system) could not overcome the hypertensinogenic influence of maintained aldosterone or
aldosterone plus angiotensin II as long as renal perfusion pressure was not allowed to
increase. Thus, under conditions of increased activity of the renin-angiotensin system, an
increased renal arterial pressure seems essential to reestablish sodium balance.
In conclusion, regardless of the specific intrarenal mechanism involved, the net effect of a
long-term hypertensinogenic derangement is a reduced capability for sodium excretion at
normotensive arterial pressures that cannot be completely compensated by other neural,
humoral, or paracrine mechanisms, leaving only the option to increase arterial pressure
and elicit a pressure natriuresis. (Adapted from Seeliger et al. [56].)
1.21
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1.22
48. Siragy HM: Evidence that intrarenal bradykinin plays a role in regulation of renal function. Am J Physiol (Endocrinol Metab28) 1993,
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Raven Press; 1995, 78:13111326.
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273:R646R654.
Renal Parenchymal Disease

and Hypertension
Stephen C. Textor
ypertension and parenchymal disease of the kidney are closely

interrelated. Most primary renal diseases eventually disturb
sodium and volume control sufficiently to produce clinical
hypertension. Both on theoretical and practical grounds, many authors
argue that any sustained elevation of blood pressure depends ultimately
on disturbed renal sodium excretion, ie, altered pressure natriuresis.
Hence, some investigators argue that a clinical state of hypertension
represents de facto evidence of disturbed (or reset) renal function
even before changes in glomerular filtration can be measured.
Many renal insults further induce inappropriate activation of vasoactive
systems such as the renin-angiotensin system, adrenergic sympathetic
nerve traffic, and endothelin. These mechanisms may both enhance
vasoconstriction and act as mediators of additional tissue injury by
altering the activity of inflammatory cytokines and promoters of interstitial fibrosis.
Arterial hypertension itself accelerates many forms of renal disease
and hastens the progression to advanced renal failure. Recent studies
have firmly established the importance of blood pressure reduction as
a means to slow the progression of many forms of renal parenchymal
injury, particularly those characterized by massive proteinuria. Over
the long term, damage to the heart and cardiovascular system resulting
from hypertension represents the major causes of morbidity and mortality for patients with end-stage renal disease.
Here are illustrated the roles of renal parenchymal disease in sustaining
hypertension and of arterial pressure reduction in slowing the progression
of renal injury. As discussed, parenchymal renal disease may refer to
either unilateral (uncommon) or bilateral conditions.
CHAPTER
2.2
FORMS OF UNILATERAL RENAL

PARENCHYMAL DISEASE RELATED
TO HYPERTENSION
Atherosclerosis and fibromuscular lesions (Chapter X)
Small vessel disease
Vasculitis
Atheroembolic renal infarction
Thrombosis and infarction
Traumatic injury
Renal fracture
Perirenal fibrosis (Page kidney)
Radiation injury
Arteriovenous malformation or fistulas
Other diseases
Renal carcinoma
Enlarging renal cyst
Multiple renal cysts
Renin-secreting tumors (rare)
FIGURE 2-1
Forms of unilateral renal parenchymal diseases related to hypertension. Many unilateral
abnormalities, such as congenital malformations, renal agenesis, reflux nephropathy, and
stone disease, do not commonly produce hypertension. However, some unilateral lesions
can produce blood pressure elevation. Data for each of these are based primarily on
demonstrating unilateral secretion of renin and resolution with unilateral nephrectomy. It
should be emphasized that unilateral renal disease does not reduce the overall glomerular
filtration rate beyond that expected in patients with a solitary kidney. It follows that additional reductions in the glomerular filtration rate must reflect bilateral renal injury.
FIGURE 2-2
Angiogram and nephrogram of a persistent fractured kidney. The kidney damage shown here
produced hypertension in a young woman 2 years after a motor vehicle accident. Measurement
of renal vein renins confirmed unilateral production of renin from the affected side. Blood
pressure control was achieved with blockade of the renin-angiotensin system using an
angiotensin II receptor antagonist (losartan). Many traumatic injuries to the kidney produce
temporary hypertension when a border of viable but underperfused renal tissue remains.
Prevalence of Hypertension in Chronic Renal Disease

FIGURE 2-3
Prevalence of hypertension in chronic renal parenchymal disease.
Most forms of renal disease are associated with hypertension. This
association is most evident with glomerular diseases, including diabetic
nephropathy (DN) and membranoproliferative glomerulonephritis
(MPGN), in which 70% to 80% of patients are affected. Minimal
change nephropathy (MCN) is a notable exception. Tubulointerstitial
disorders such as analgesic nephropathy, medullary cystic diseases,
and chronic reflux nephropathies are less commonly affected.
APKDadult-onset polycystic kidney disease; CINchronic interstitial nephritis; FSGNfocal segmental glomerulonephritis; MGN
membranous glomerulonephritis. (Data from Smith and Dunn [1].)
Prevalence of hypertension, %
80
70
60
50
40
30
20
10
0
CIN
APKD
MCN
IgA
MGN
DN
MPGN FSGN
Renal Parenchymal Disease and Hypertension
100
90
40
30
20
10
0
MDRD:
Study B*
NHANES estimates
50
Mean GFR=39 mL/min/1.73 m2
60
Mean GFR=18.5 mL/min/1.73 m2
80
70
*n=255 patients
MDRD:
Study A
FIGURE 2-4
Prevalence of hypertension requiring therapy as a function of the degree of chronic renal
failure in the Modification of Diet in Renal Disease (MDRD) trial on progressive renal
failure. The mean age of these patients was 52 years, with glomerular disease (25%) and
polycystic disease (24%) being the most common renal diagnoses in this trial. In Study B,
more than 90% of patients were treated with antihypertensive agents, including diuretics,
to achieve an overall average blood pressure of 133/81 mm Hg. In general, the more
severe the level of renal dysfunction, the more antihypertensive therapy is required to
achieve acceptable blood pressures. Patients with glomerular filtration rates (GRFs) below
10 mL/min were hypertensive in 95% of cases. NHANESNational Health and Nutrition
Examination Survey. (Data from Klahr and coworkers [2].)
US
Population
Early
Late
80
Prevalence of hypertension, %
2.3
70
60
50
40
30
FIGURE 2-5
Hypertension in acute renal disease. Acute renal failure is defined as transient increases in
serum creatinine above 5.0 mg/dL. During the course of acute renal failure, worsening of
preexisting levels or newly detected hypertension (>140/90 mm Hg) is common and almost
universally observed in patients with acute glomerulonephritis (GN). Many of these
patients have lower pressures as the course of acute renal injury subsides, although residual abnormalities in renal function and sediment may remain. Blood pressure returns to
normal in some but not all of these patients. Overall, 39% of patients with acute renal
failure develop new hypertension. INinterstitial nephritis. (Adapted from RodriguezIturbe and coworkers [3]; with permission.)
20
10
0
Acute GN
Acute IN

Micrograph of an onion skin lesion from a patient with malignant
hypertension.
2.4
Pathophysiology of Hypertension in Renal Disease
Increased vasoconstriction
Increased adrenergic stimuli
Inappropriate
renin-endothelin release
Increased endothelin-derived
contracting factor
Increased thromboxane
Decreased vasodilation
Decreased prostacyclin
Decreased nitric oxide
Intake and output of water and salt

(x normal)
5
4
High intake
E s se
n
hyp tial
erte
nsio
n
3
2
Normal intake
Low intake
0
0
50
4
3
High intake
ass
lm
na
e
r
of
ss
D
Lo
C
2
Normal intake
Low intake
100
150
kid
G o ld
ne
blat
t
ys
Al
do
ste
ron
e-s
tim
ula
ted
Increased
contraction
Increased
adrenergic
activation
Normal
Intake and output of water and salt

(x normal)
Increased extracellular fluid volume

Decreased glomerular filtration rate
Impaired sodium excretion
Increased renal nerve activity
Ineffective natriuresis, eg, atrial
natriuretic peptide resistance
Cardiac output
Normal
Blood pressure =
FIGURE 2-7
Pathophysiologic mechanisms related to
hypertension in parenchymal renal disease:
schematic view of candidate mechanisms. The
balance between cardiac output and systemic
vascular resistance determines blood pressure.
Numerous studies suggest that cardiac output
is normal or elevated, whereas overall extracellular fluid volume is expanded in most
patients with chronic renal failure. Systemic
vascular resistance is inappropriately elevated
relative to cardiac output, reflecting a net shift
in vascular control toward vasoconstricting
mechanisms. Several mechanisms affecting
vascular tone are disturbed in patients with
chronic renal failure, including increased
adrenergic tone and activation of the reninangiotensin system, endothelin, and vasoactive prostaglandins. An additional feature in
some disorders appears to depend on reduced
vasodilation, such as in impaired production
of nitric oxide.
B
H
0
200
FIGURE 2-8
A, The relationship between renal artery perfusion pressure and
sodium excretion (which defines pressure natriuresis) has been
the subject of extensive research. Essential hypertension is characterized by higher renal perfusion pressures required to achieve
daily sodium balance. B, Distortion of this relationship routinely
occurs in patients with parenchymal renal disease, illustrated here
50
100
150
200
as loss of renal mass. Similar effects are observed in conditions

with disturbed hormonal effects on sodium excretion (aldosterone-stimulated kidneys) or reduced renal blood flow as a
result of an arterial stenosis (Goldblatt kidneys). In all of these
instances, higher arterial pressures are required to maintain
sodium balance.
2.5
35
30
122
118
Cumulative daily
sodium intake
0
Cumulative urinary sodium loss
400
Sodium, mEq
Percentage of body weight, kg
126
40
Total blood volume, mL/cm
200
Hemodialysis
130
800
1200
F
W TH
Days
Sodium losses during

hemodialysis or ultrafiltration
Net sodium loss
M
1600
Total net loss of

sodium=1741 mEq
Blood pressure, mm Hg
Plasma renin
activity, mg/mL/h
10.0
Uremic
control
subjects
5.0
180
Captopril, 25 mg
140
100
FIGURE 2-9
Sodium expansion in chronic renal failure. The degree of sodium
expansion in patients with chronic renal failure can be difficult to
ascertain. A, Shown are data regarding body weight, plasma renin
Blood
pressure, mm Hg
Angiotensin II inhibitor, g/kg/min

5
10 50 100 10 10
Saline infusion
L40
200
150
Plasma renin Cumulative sodium

balance, mEq
activity, ng/mL/hr
100
200
100
0
100
50
0
0
11 35 38 41
Hours
65 67
M T
W TH F
Days
S M
activity, and blood pressure (before and after administration of an

ACE inhibitor) over 11 days of vigorous fluid ultrafiltration.
Sequential steps were undertaken to achieve net negative sodium
and volume losses by means of restricting sodium intake (10 mEq/d)
and initiating ultrafiltration to achieve several liters of negative
balance with each treatment. A negative balance of nearly 1700 mEq
was required before evidence of achieving dry weight was observed,
specifically a reduction of blood pressure. Measured levels of plasma
renin activity gradually increased during sodium removal, and blood
pressure became dependent on the renin-angiotensin system, as
defined by a reduction in blood pressure after administration of the
angiotensin-converting enzyme inhibitor captopril. Achieving adequate
reduction of both extracellular fluid volume and sodium is essential
to satisfactory control of blood pressure in patients with renal failure.
B, Daily and cumulative sodium balance.
FIGURE 2-10
Interaction between sodium balance and angiotensin-dependence in malignant hypertension.
Studies in a patient with renal dysfunction and accelerated hypertension during blockade
of the renin-angiotensin system using Sar-1-ala-8-angiotensin II demonstrate the interaction
between angiotensin and sodium. Reduction of blood pressure induced by the angiotensin
II antagonist was reversed during saline infusion with a positive sodium balance and reduction
in circulating plasma renin activity. Administration of a loop diuretic (L40 [furosemide],
40 mg intravenously) induced net sodium losses, restimulated plasma renin activity, and
restored sensitivity to the angiotensin II antagonist. Such observations further establish the
reciprocal relationship between the sodium status and activation of the renin-angiotensin
system [5]. (From Brunner and coworkers [5]; with permission.)
2.6
15 s
Normal
person
Hemodialysis,
bilateral
nephrectomy
Hemodialysis, no
nephrectomy
Neurogram
Electrocardiogram
3s
Systolic blood pressure, mm Hg
200
Sham
Renal denervated
190
180
170
160
150
140
130
120
110
NS
NS
<0.01 <0.001 <0.001 <0.01 <0.05 <0.05 <0.05
NS
5
10
15
20
25
30
Deoxycorticosterone acetatesalt administration, d
35
FIGURE 2-11
A, Sympathetic neural activation in chronic
renal disease. Adrenergic activity is disturbed in chronic renal failure and may participate in the development of hypertension.
Microneurographic studies in patients
undergoing hemodialysis demonstrate
enhanced neural traffic (panel A) that
relates closely to peripheral vascular tone [6].
Studies in patients in whom native kidneys
are removed by nephrectomy demonstrate
normal levels of neural traffic, suggesting that
afferent stimuli from the kidney modulate
central adrenergic outflow. B, Delayed onset
hypertension in denervated rats. Panel B
shows evidence from experimental studies in
denervated animals subjected to deoxycorticosteronesalt hypertension. The role of the
renal nerves in modifying the development
of hypertension is supported by studies of
renal denervation that show a delayed onset
of hypertension, although no alteration in
the final level of blood pressure was achieved.
NSnot significant. (Panel A from
Converse and coworkers [6]; with permission. Panel B from Katholi and coworkers
2.7
MAJOR CANDIDATE MECHANISMS THAT MAY

ELEVATE PERIPHERAL VASCULAR RESISTANCE
IN RENAL PARENCHYMAL DISEASE
Increased vasoconstrictors
Impaired or relatively inadequate vasodilators
Renin-angiotensin system
Endothelin
Prostanoids: thromboxane
Arginine vasopressin
Endogenous digitalis-like
substance: ouabain (?)
Nitric oxide: inadequate compensation

Vasodilator prostaglandins: prostacyclin 2
Natriuretic peptides: atrial natriuretic peptide
Kallikrein-kinin system
FIGURE 2-12
Major candidate mechanisms that may elevate peripheral vascular
resistance in renal parenchymal disease. Some data support each of
these pathways, although rarely does one mechanism predominate.
Experimental studies suggest that endothelin-1 may magnify interstitial
fibrosis and contribute to hypertension in some models; however,
rarely is the effect major [8,9]. Most levels of vasodilators, including
nitric oxide, prostacyclin, and atrial natriuretic peptide, are normal
or elevated in patients with renal disease. The vasodilators appear
to buffer the vasoconstrictive actions of angiotensin II, which may
be increased abruptly if the vasodilator is removed, as occurs with
inhibition of cyclo-oxygenase with the use of nonsteroidal antiinflammatory drugs.
Urinary endothelin, ng/d
80
Mean SEM
*P<0.01 vs pretransplantation
P<0.01 vs normal subjects
60
40
20
Normal
Urinary endothelin excretion, pg/d
Sham-operated rats
Rats with renal mass reduction
Horizontal bars=mean values

P<0.01 vs basal
160
120
80
40
0
200
Pretransplantation
12 mo
24 mo
FIGURE 2-13
Urinary endothelin in renal disease. A, Urinary endothelin levels in
patients with cyclosporine-induced renal dysfunction and hypertension
before and after liver transplantation. These patients had near-normal
kidney function before liver transplantation, after which their glomerular filtration rates decreased from 85 to 55 mL/min, on average. These
data underscore the observation that the kidney itself is a rich source
of vasoactive materials and that renal excretion of substances such as
endothelin is independent of circulating blood levels [10]. Endothelin has
properties that both facilitate vasoconstriction and enhance mitogenic
and fibrogenic responses, perhaps accelerating interstitial fibrosis in
the kidney. Early withdrawal of cyclosporine leads to reversal of a
Basal
Day 45
Basal
Day 45
diminished glomerular filtration rate. With time, however, these

changes lose the feature of reversibility [11]. B, Renal ablation.
Urinary endothelin levels in rats exposed to reduced renal mass
achieved by 5/6 nephrectomy. As in humans, plasma levels of
endothelin were dissociated from urinary levels, and injected
endothelin was not excreted. These results suggest that urinary levels
were of renal origin. These studies further support the concept that the
diminished nephron number elicits production of potent vasoactive
and inflammatory materials that may accelerate irreversible parenchymal injury. (Panel A from Textor and coworkers [10]; with permission. Data in panel B from Benigni and coworkers [12].)
2.8
PHARMACOLOGIC AGENTS THAT COMMONLY

AGGRAVATE OR INDUCE HYPERTENSION IN
PARENCHYMAL RENAL DISEASE
Renal parenchymal disease
Decreased afferent
resistance
Decreased efferent
resistance
Increased angiotensin
Increased norepinephrine
Increased endothelin
Systemic
hypertension
Impaired
autoregulation
Increased glomerular
pressure
Increased cytokine
Increased growth
factors
Cellular
proliferation
Over-the-counter sympathomimetic
agents, eg, phenylpropanolamine
Supplements containing ephedrine
Oral contraceptives
(less common with low-dose forms)
Amphetamines and stimulants,
eg, methylphenidate hydrochloride
and cocaine
FIGURE 2-15
Many pharmacologic agents affect blood pressure levels or the
effectiveness of antihypertensive therapy. Shown here are several
agents that commonly lead to worsening hypertension and are likely to be administered to patients with renal disease.
160
120
150
90
Control
10 g LNAME
50 g LNAME
140
60
130
30
120
1 min
280
L-Arginine
100 mg kg-1
300 mg kg-1
FIGURE 2-16
Increase in arterial pressure induced by inhibition of nitric oxide.
A, Intra-arterial pressure in rabbits during N-nitro-L-arginine
methyl ester (L-NAME) infusion. B, Decrease in renal plasma flow
and glomerular filtration rate in the blood pressures of rats during
nitric oxide inhibition.
Glomerular filtration
rate, mL/min
L-NAME
Renal plasma
flow, mL/min
110
240
200
Mean arterial
pressure, mL/min
Blood
pressure, mm Hg
FIGURE 2-14
Mechanisms of glomerular injury in hypertension and progressive
renal failure. This schematic diagram summarizes the general mechanisms by which disturbances linked to elevated arterial pressure in
patients with parenchymal renal disease may lead to further tissue
injury. Hemodynamic changes lead to increased glomerular perfusion
pressures, whereas local activation of growth factors, angiotensin,
and probably several other factors both worsen peripheral resistance
and increase tissue fibrotic mechanisms. (From Smith and Dunn [1].)
Heart rate, bpm
Corticosteroids
Cyclosporine
Erythropoietin
volume
pressure
Other agents
Results=meansstandard error
*P<0.05 compared with controls
4.0
*
3.0
2.0
*
*
120'
180'
1.0
1.2
*
*
1.0
0.8
Control
60'
Control
10 g/kg/min L NAME
50 g/kg/min L NAME
Urinary sodium
excretion, Eq/min
21
19
15
*
*
11
9
140
Urinary flow
rate, mL/min

C, Urine flow rate and urinary sodium excretion over time. Inhibition
of nitric oxide synthesis from L-arginine by a competitive substrate
such as L-NAME produces dose-dependent and widespread vasoconstriction, leading to an increase in blood pressure [13]. Within
specific regional beds such as the kidney, inhibition of nitric oxide
produces a decrease in renal plasma flow, diminished glomerular
filtration, and sodium retention [14]. The magnitude of these changes
in normal animals and humans suggests that tonic nitric oxide production is a major endothelial buffering mechanism preserving vascular
tone. The degree to which renal parenchymal disease alters the production of nitric oxide is not known precisely. In some situations,
such as nephrotoxicity associated with cyclosporine administration,
endothelial production of nitric oxide appears to be substantially
impaired [15]. (Panel A from Rees and coworkers [13]; with permission. Panel B from Lahera and coworkers [14]; with permission.)
17
13
Results=meansstandard error
*P<0.05 compared with controls
2.9
120
100
80
*
60
Control
60'
120'
180'
Clinical Features of Hypertension in Renal Disease

A. HYPERTENSION IN PARENCHYMAL RENAL DISEASE:
CLINICAL MANIFESTATIONS OF HYPERTENSIVE DISEASE
Progressive renal injury
Myocardial infarction
Atherosclerotic vascular disease
Claudication and limb ischemia
Aneurysm
Stroke
Intracerebral hemorrhage
End-stage renal disease

Increased proteinuria
Percentage of total
100
90
Cardiac
Vascular
Infection
Other
80
70
60
50
40
30
20
10
0
B
FIGURE 2-17
A and B, Major target organ manifestations of hypertension producing cardiovascular
morbidity and mortality in patients with renal disease. More than half of deaths are related
to cardiovascular disease in both patients on dialysis and transplantation recipients. These
observations underscore the major risk for cardiovascular morbidity and mortality associated
with hypertension in the population with chronic renal failure. (From Whitworth [16];
with permission.)
Transplantation Dialysis
2.10
Left ventricular
hypertrophy
40
Congestive
heart failure
35
Percentage of total
Blood pressure
Death: Congestive heart failure

Overall mortality
Blood pressure
30
25
20
15
10
5
FIGURE 2-18
Based on average blood pressure values, a strong direct relationship
was found between arterial pressure and left ventricular hypertrophy,
left ventricular chamber dilation (by echocardiography), and systolic
dysfunction in patients undergoing dialysis for end-stage renal disease.
After prolonged follow-up, blood pressures fell with the onset of
congestive heart failure and manifest coronary artery disease. With
the onset of cardiac failure, there appeared to be an inverse relationship between arterial pressure and mortality. From the outset,
the strongest predictor of congestive heart failure was elevated
blood pressure. (Adapted from Foley and coworkers [17].)
0
Left ventricular Systolic Left ventricular
chamber dilation dysfunction hypertrophy
250
Awake: 156/101 mm Hg
Nocturnal: 167/100 mm Hg
Blood pressure values

Heart rate
200
150
140
100
90
50
MMMM
Rx F d
MMMM
Fd ZZZZZ
Rx
RxZZZ
ZZZZZZZZZZZZZZZZZZ
MMMM
0
0.0
10a
12n
2p
4p
6p
8p
10p 12m
Real time data
2a
4a
6a
8a
FIGURE 2-19
Around-the-clock ambulatory blood pressure
monitoring in a patient with renal disease.
Loss of diurnal blood pressure patterns
have been implicated in increased rates of
target organ injury in patients with hypertension. In normal persons with essential
hypertension, nocturnal pressures decreased
by at least 10% and were associated with a
decrease in heart rate. Several conditions have
been associated with a loss of the nocturnal
decrease in pressure, particularly chronic
steroid administration and chronic renal
failure. Such a loss in normal circadian
rhythm, in particular loss of the nocturnal
decrease in blood pressure is more commonly
associated with left ventricular hypertrophy
and lacunar strokes (manifested as enhanced
T-2 signals in magnetic resonance images)
and increased rates of microalbuminuria.
Data from a single subject with end-stage
renal disease studied with are depicted here.
2.11
1/Creatinine
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
May
1979

Hypertension accelerates the rate of progressive renal failure in
patients with parenchymal renal disease. A, Photomicrograph of
malignant phase hypertension. Regardless of the cause of renal disease,
untreated hypertension leads to more rapid loss of remaining nephrons
and decline in glomerular filtration rates. A striking example of
pressure-related injury may be observed in patients with malignant
phase hypertension. This image is an open biopsy specimen obtained
from a patient with papilledema, an expanding aortic aneurysm, and
Aug
1987
May
1990
Date
Jan
1993
Oct
1995
Jul
1998
blood pressure level at approximately 240/130 mm Hg. The biopsy

specimen shows the following features of malignant nephrosclerosis:
these patients develop vascular and glomerular injury, which can
progress to irreversible renal failure. Before the introduction of antihypertensive drug therapy, patients with malignant phase hypertension
routinely proceeded to uremia. Effective antihypertensive therapy can
slow or reverse this trend in some but not all patients. B, Progressive
renal failure in malignant hypertension over 8 years.
100
n=11,912 men
P<0.001
White=300,645
Black=20,222
SBP>180
0.10
0.08
0.06
165<SBP180
0.04
0.02
SBP165
Incidence per 100,000 person-years, %
0.12
Proportion with ESRD
Nov
1984
0.00
80
83.1
N=332,544 men
60
37.21
40
32.37
27.34
20
26.18
15.83
5.43
14.22
5.41
9.1
0
0
Feb
1982
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Years from beginning therapy to ESRD
FIGURE 2-21
Blood pressure levels and rates of end-stage renal disease (ESRD). A,
Line graph showing Kaplan-Meier estimates of ESRD rates; 15-year
follow-up. B, Age-adjusted 16-year incidence of all-cause ESRD in
men in the Multiple Risk Factor Intervention Trial (MRFIT). Largescale epidemiologic studies indicate a progressive increase in the risk
for developing ESRD as a function of systolic blood pressure levels.
Follow-up of nearly 12,000 male veterans in the United States
established that systolic blood pressure above 165 mm Hg at the initial
visit was predictive of progressively higher risk of ESRD over a 15-year
<117
117123
124130
131140
>140
follow-up period [18]. Similarly, follow-up studies after 16 years of

more than 300,000 men in MRFIT demonstrated a progressive increase
in the risk for ESRD, most pronounced in blacks [19]. These data
suggest that blood pressure levels predict future renal disease. However,
it remains uncertain whether benign essential hypertension itself
induces a primary renal lesion (hypertensive renal disease nephrosclerosis) or acts as a catalyst in patients with other primary renal disease,
otherwise not detected at initial screening. SBPsystolic blood
pressure. (Panel A from Perry and coworkers [18]; with permission.)
2.12
30
Chronic glomerulonephritis:
Rates of progression over time decrease
after reduction of BP from 149/102 mm Hg
to treated level, 136/90 mm Hg.
20
mL/mmol-1
Cr-1/s,
40
Decrease in glomerular
filtration rate, mL/min/y
Ccr, mL/min
50
12
15
18
400
200
Days
+200
12
15
Study A: mean GFR: 39 mL/min/1.73 m2

N=585: range: 2555 mL/min
86
1
Protein excretion, g/d

00.25
1.03.0
0.251
3.0
92
98
Mean follow-up MAP, mm Hg
18
107
+400
FIGURE 2-22
Rates of progression in glomeruloneophritis. The decrease in glomerular filtration rate is illustrated. The rates of decline decreased considerably with administration of antihypertensive drug therapy.
Among other mechanisms, the decrease in arterial pressure lowers
transcapillary filtration pressures at the level of the glomerulus [20].
This effect is correlated with a reduction in proteinuria and slower
development of both glomerulosclerosis and interstitial fibrosis. A
distinctive feature of many glomerular diseases is the massive proteinuria and nephron loss associated with high single-nephron
glomerular filtration, partially attributable to afferent arteriolar
vasodilation. The appearance of worsening proteinuria (>3 g/d) is
related to progressive renal injury and development of renal failure.
Reduction of arterial pressure can decrease urinary protein excretion and slow the progression of renal injury. Ccrcreatinine clearance rate; Cr-1/sreciprocal creatinine, expressed as 1/creatinine.
(From Bergstrom and coworkers [20]; with permission.)
FIGURE 2-23
Blood pressure, proteinuria, and the rate of renal disease progression:
results from the Modification of Diet in Renal Disease (MDRD)
trial. Shown are rates of decrease of glomerular filtration rate
(GFR) for patients enrolled in the MDRD trial, depending on level
of achieved treated blood pressure during the trial [21]. A component
of this trial included strict versus conventional blood pressure control.
The term strict was defined as target mean arterial pressure (MAP)
of under 92 mm Hg. The term conventional was defined as MAP
of under 107 mm Hg. The rate of decline in GFR increased at higher
levels of achieved MAP in patients with significant proteinuria
(>3.0 g/d). No such relationship was evident over the duration of
this trial (mean, 2.2 years) for patients with less severe proteinuria.
These data emphasize the importance of blood pressure in determining disease progression in patients with proteinuric nondiabetic
renal disease. No distinction was made in this study regarding the
relative benefits of specific antihypertensive agents. (From Peterson
and coworkers [21]; with permission.)
Slope of 1/creatinine vs time, dL/mg mo
Effects of Antihypertensive Therapy

on Renal Disease Progression
0.006
0.008
0.010
0.012
0
8590
7085
9096
96113
Range of diastolic blood pressure (mm Hg) for
each quartile of the population
FIGURE 2-24
Blood pressure and rate of progressive renal failure. Rates of disease
progression (defined as the slope of 1/creatinine) were determined in
86 patients who reached end-stage renal disease and dialytic therapy.
The rates of progression were defined between mean creatinine levels
of 3.8 mg/dL (start) and 11.4 mg/dL (end) over a mean duration of
33 months [22]. Brazy and coworkers [22] demonstrated that the
slope of disease progression appeared to be related to the range of
achieved diastolic blood pressure during this interval. Hence, these
authors argue that more intensive antihypertensive therapy may
delay the need for replacement therapy in patients with end-stage
renal disease. As noted in the Modification of Diet in Renal Disease
trial, such benefits are most apparent in patients with proteinuria
over a shorter follow-up period. (From Brazy and coworkers [22];
with permission.)
CLASSES OF ANTIHYPERTENSIVE AGENTS USED

IN TREATMENT OF CHRONIC RENAL DISEASE
Diuretics:
Thiazide class
Loop diuretics
Potassium-sparing agents
Adrenergic inhibitors
Peripheral agents, eg, guanethidine
Central -agonists, eg, clonidine, methyldopa, and guanfacine
-Blocking agents, eg, doxazosin
-Blocking agents
Combined - blocking agents, eg, labetalol
Vasodilators
Hydralazine
Minoxidil
Classes of calcium-channel blocking agents
Verapamil
Diltiazem
Dihydropyridine
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
50
45
40
35
Rate of change in GFR, mL/min/1.73 m2/y
Conventional
Strict
n=87 patients
Bars=95% confidence
intervals for GFR
estimates
55
GFR, mL/min/1.73 m2/y
FIGURE 2-25
The current classification of agents applied for chronic treatment
of hypertension as summarized in the report by the Joint National
Committee on Prevention, Detection, Evaluation and Treatment of
High Blood Pressure [23]. Attention must be given to drug accumulation and limitations of individual drug efficacy as glomerular
filtration rates decrease in chronic renal disease. Potassium levels
may increase during administration of potassium-sparing agents
and medications that inhibit the renin-angiotensin system, especially in patients with impaired renal function [24].
60
30
Mean
SEM
0
1
2
25
3
6
2.13
12
18
24
30
Time, mo
36
42
48
FIGURE 2-26
Strict blood pressure control and progression of hypertensive
nephrosclerosis. Whether vigorous blood pressure reduction reduces
progression of early parenchymal renal disease in blacks with
nephrosclerosis is not yet certain. A and B, A randomized prospective
trial comparing strict (panel A) blood pressure control (defined as
diastolic blood pressure [DBP] <80 mm Hg) with conventional (panel
B) levels of diastolic control between 85 and 95 mm Hg for more
than 3 years could not identify a reduction in rates of disease progression [25]. Of patients, 68 of 87 were black. Rates of progression in
Strict
Conventional
Blood pressure control group
these patients were low. It should be emphasized that entry criteria

excluded patients with diabetes and massive proteinuria. Initial
studies from the African American Study of Kidney Disease trial
confirm that biopsy findings in most patients with clinical features of
hypertension were considered consistent with primary hypertensive
disease [26]. Whether lower than normal levels of blood pressure in
these patients will prevent progression to end-stage renal disease over
longer time periods remains to be determined. GFRglomerular
filtration rate. (From Toto and coworkers [25]; with permission.)
2.14

100
90
Patients who died or needed

dialysis or transplantation, %
80
70
60
50
P=0.002
40
30
20
10
P=0.14
0
0.5
1.0
1.5
Creatinine 1.5 mg/dL

Placebo 49
48
Captopril 53
53
0.0
2.0
2.5
Years of follow-up
44
52
40
51
33
48
Creatinine <1.5 mg/dL

Placebo 153
150
Captopril 154
154
148
152
146
150
138
147
3.0
3.5
4.0
23
36
16
25
7
17
1
8
98
104
84
78
52
47
25
29
2.6
FIGURE 2-27
Angiotensin-converting enzyme (ACE)
inhibitors and chronic renal disease.
Progression of type I diabetic nephropathy
to renal failure was reduced in the ACE
inhibitor arm of a trial comparing conventional antihypertensive therapy with a
regimen containing the ACE inhibitor
captopril. All patients in this trial had
significant proteinuria (>500 mg/d). The
most striking effect of the ACE inhibitor
regimen was seen in patients with higher
serum creatinine levels (>1.5 mg/dL) as
shown in the top two lines. It should be
noted that calcium channel blocking drugs
were excluded from this trial and the ACE
inhibitor arm had somewhat lower arterial
pressures during treatment. These data offer
support to the concept that ACE inhibition
lowers intraglomerular pressures, reduces
proteinuria, and delays the progression of
diabetic nephropathy by more mechanisms
than can be explained by pressure reduction
alone. (Data from Lewis and coworkers [27].)
2.6
Benazepril: n=583 patients; creatinine=1.54.0
Placebo
Benazepril: n=583 patients; creatinine=1.54.0

Placebo
239
2.4
117
2.4
137
262
2.2
2.2
2.0
2.0
Years
FIGURE 2-28
Angiotensin-converting enzyme (ACE) inhibition in nondiabetic renal
disease. A and B, Shown here are serum creatinine levels from the
12-month (panel A) and 36-month (panel B) cohorts followed in the
benazepril trial. In this trial, 583 patients were randomized to therapy
with or without benazepril [28]. Slight reductions in the rates of
increase in creatinine and of stop points in the ACE inhibitor group
occurred; however, these reductions were modest. Whereas these
Years
data support a role for ACE inhibition, the results are considerably
less convincing than are those for diabetic nephropathy. These results
argue that some groups may not experience major benefit from ACE
inhibition over the short term. Preliminary reports from recent studies
limited to patients with proteinuria suggest that rates of progression
were substantially reduced by treatment with ramipril [29]. (From
Maschio and coworkers [28]; with permission.)
CONCLUSIONS AND RECOMMENDATIONS OF THE SIXTH REPORT OF

THE JOINT NATIONAL COMMITTEE ON PREVENTION, DETECTION,
EVALUATION AND TREATMENT OF HIGH BLOOD PRESSURE, 1997
1. Hypertension may result from renal disease that reduces functioning nephrons.
2. Evidence shows a clear relationship between high blood pressure and end-stage renal disease.
3. Blood pressure should be controlled to 130/85 mm Hg (<125/75 mm Hg) in patients with proteinuria
in excess of 1 g/24 h.
4. Angiotensin-converting enzyme inhibitors work well to lower blood pressure and slow progression of renal failure.
2.15
FIGURE 2-29
Conclusions and Recommendations of the
Sixth Report of the Joint National
Committee (JNC) on Prevention, Detection,
Evaluation and Treatment of High Blood,
1997 [23]. The JNC Committee has emphasized the importance of vigorous blood
pressure control with any agents needed,
rather than specific classes of medication.
in proteinuric disease are the exception.
References
1. Smith MC, Dunn MJ: Hypertension in renal parenchymal disease. In
Hypertension: Pathophysiology, Diagnosis and Management. Edited by
Laragh JH, Brenner BM. New York: Raven Press; 1995:20812102.
2. Klahr S, Levey AS, Beck GJ, et al.: The effects of dietary protein
restriction and blood-pressure control on the progression of chronic
renal disease. N Engl J Med 1994, 330:877884.
3 Rodriguez-Iturbe B, Baggio B, Colina-Chouriao J, et al.: Studies on the
renin-aldosterone system in the acute nephritic syndrome. Kidnet Int
1981, 445453
4. Curtiss JJ, Luke RG, Dustan HP, et al.: Remission of essential hypertension after renal transplantation. N Engl J Med 1983, 309:10091015.
5. Brunner HR, Gavras H, Laragh JH: Specific inhibition of the reninangiotensin system: a key to understanding blood pressure regulation.
Prog Cardiovasc Dis 1974; 17:8798.
6. Converse RL, Jacobsen TN, Toto RD, et al.: Sympathetic overactivity in
patients with chronic renal failure. N Engl J Med1992, 327:19121918.
7. Katholi RE, Nafilan AJ, Oparil S: Importance of renal sympathetic
tone in the development of DOCA-salt hypertension in the rat.
Hypertension 1980, 2:266273.
8. Benigni A, Zoja C, Cornay D, et al.: A specific endothelin subtype A
receptor antagonist protects against injury in renal disease progression.
Kidney Int 1993, 44:440444.
9. Levin ER: Mechanisms of disease: endothelins. N Engl J Med 1995,
333:356363.
10. Textor SC, Burnett JC, Romero JC, et al.: Urinary endothelin and renal
vasoconstriction with cyclosporine or FK506 after liver transplantation.
Kidney Int 1995, 47:14261433.
11. Sandborn WJ, Hay JE, Porayko MK, et al.: Cyclosporine withdrawal for
nephrotoxicity in liver transplant recipients does not result in sustained
improvement in kidney function and causes cellular and ductopenic
rejection. Hepatology 1994, 19:925932.
12. Benigni A, Perico N, Gaspari F, et al.: Increased renal endothelin production in rats with renal mass reduction. Am J Physiol 1991,
260:F331F339.
13. Rees DD, Palmer RMJ, Moncada S: Role of endothelium-derived nitric
oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A
1989, 86:33753378.
14. Lahera V, Salom MG, Miranda-Guardiola F, et al.: Effects of N-nitroL-arginine methyl ester on renal function and blood pressure. Am J
Physiol 1991, 261:F1033F1037.
15. Gaston RS, Schlessinger SD, Sanders PW, et al.: Cyclosporine inhibits
the renal response to L-arginine in human kidney transplant recipients.
J Am Soc Nephrol 1995, 5:14261433.
16. Whitworth JA: Renal parenchymal disease and hypertension. In

Clinical Hypertension. Edited by Robertson JIS. Amsterdam: Elsevier,
1992:326350.
17. Foley RN, Parfrey PS, Harnett JD, et al.: Impact of hypertension on
cardiomyopathy, morbidity and mortality in end-stage renal disease.
Kidney Int 1996, 49:13791385.
18. Perry HM, Miller JP, Fornoff JR, et al.: Early predictors of 15-year
end-stage renal disease in hypertensive patients. Hypertension 1995,
25(part 1):587594.
19. Klag MJ, Whelton PK, Randall BL, et al.: End-stage renal disease in
African-American and White men. JAMA 1997, 277:12931298.
20. Bergstrom J, Alvestrand A, Bucht H, Guttierrez A: Progression of chronic
renal failure in man is retarded with more frequent clinical follow-ups
and better blood pressure control. Clin Nephrol 1986, 25:16.
21. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control, proteinuria and the progression of renal disease. Ann Intern Med 1995;
123:754762.
22. Brazy PC, Stead WW, Fitzwilliam JF: Progression of renal insufficiency:
role of blood pressure. Kidney Int 1989, 35:670674.
23. JNC Committee: Sixth Report of the Joint National Committee on
Prevention, Detection, Evaluation and Treatment of High Blood Pressure.
Bethesda, MD: National Institutes of Health Publication; 1997.
24. Textor SC: Renal failure related to ACE inhibitors. Semin Nephrol
1997, 17:6776.
25. Toto RD, Mitchell HC, Smith RD, et al.: Strict blood pressure control
and progression of renal disease in hypertensive nephrosclerosis.
Kidney Int 1995, 48:851859.
26. Fogo A, Breyer JA, Smith MC, et al.: Accuracy of the diagnosis of
hypertensive nephrosclerosis in African-Americans: a report from the
African American Study of Kidney Disease (ASSK) trial. Kidney Int
1997; 51:244252.
27. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. N Engl J Med
1993, 329:14561462.
28. Maschio G, Alberti D, Janin G, et al.: Effect of the angiotensin-converting
enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996, 334:939945.
29. Ruggenenti P, Perna A, Mosconi M, et al.: The angiotensin converting
enzyme inhibitor ramipril slows the rate of GFR decline and the progression to end-stage renal failure in proteinuric, non-diabetic chronic
renal diseases [abstract]. J Am Soc Nephrol 1997, 8:147A.
30. Giatras I, Lau J, Levey AS: Effect of angiotensin-converting enzyme
inhibitors on the progression of non-diabetic renal disease: a metaanalysis of randomized trials. Ann Intern Med 1997, 127:345.
Renovascular Hypertension
and Ischemic Nephropathy
Marc A. Pohl
he major issues in approaching patients with renal artery stenosis relate to the role of renal artery stenosis in the management
of hypertension, ie, renovascular hypertension, and to the
potential for vascular compromise of renal function, ie, ischemic
nephropathy. Ever since the original Goldblatt experiment in 1934,
wherein experimental hypertension was produced by renal artery
clamping, countless investigators and clinicians have been intrigued by
the relationship between renal artery stenosis and hypertension. Much
discussion has focused on the pathophysiology of renovascular hypertension, the renin angiotensin system, diagnostic tests to detect presumed renovascular hypertension, and the relative merits of surgical
renal revascularization (SR), percutaneous transluminal renal angioplasty (PTRA), and drug therapy in managing patients with renal
artery stenosis and hypertension. Hemodynamically significant renal
artery stenosis, when bilateral or affecting the artery to a solitary functioning kidney, can also lead to a reduction in kidney function
(ischemic nephropathy). This untoward observation may be reversed
by interventive maneuvers, eg, surgical renal revascularization, PTRA,
or renal artery stenting. The syndrome of ischemic renal disease or
ischemic nephropathy now looms as an important clinical condition and has attracted the fascination of nephrologists, vascular surgeons, and interventional cardiologists and radiologists.
The detection of renal artery stenosis in a patient with hypertension usually evokes the assumption that the hypertension is due to the
renal artery stenosis. However, renal artery stenosis is not synonymous with renovascular hypertension. On the basis of autopsy
studies and clinical angiographic correlations, high-grade atherosclerotic renal artery stenosis (ASO-RAS) in patients with mild blood
pressure elevation or in patients with normal arterial pressure is well
recognized. The vast majority of patients with ASO-RAS who have
hypertension have essential hypertension, not renovascular hypertension. These hypertensive patients with ASO-RAS are rarely cured of
their hypertension by interventive procedures that either bypass or
CHAPTER
3.2
dilate the stenotic lesion. Thus, it is critical to distinguish

between the anatomic presence of renal artery stenosis, in
which a stenotic lesion is present but not necessarily causing
hypertension, and the syndrome of renovascular hypertension
in which significant arterial stenosis is present and sufficient to
produce renal tissue ischemia and initiate a pathophysiologic
sequence of events leading to elevated arterial pressure. In the
final analysis, proof that a patient has the entity of renovascular hypertension rests with the demonstration that the
hypertension, presumed to be renovascular, can be eliminated or substantially ameliorated following removal of the stenosis by surgical or endovascular intervention, or by removing
the kidney distal to the stenosis.
Although the great majority of patients diagnosed as having
renovascular hypertension have this syndrome because of main renal
artery stenosis, hypertension following unilateral renal trauma,
CLASSIFICATION OF RENAL
ARTERY DISEASE
Disease
Incidence, %*
Atherosclerosis
Fibrous dysplasia
Medial (30%)
Perimedial (5%)
Intimal (5%)
chronic subcapsular hematoma, and unilateral ureteral obstruction

may also be associated with hypertension that is relieved when
the affected kidney is removed. These clinical analogues of the
experimental Page kidney reflect the syndrome of renovascular
hypertension (RVHT), but without main renal artery stenosis.
Takayasus arteritis and atheroembolic renal disease are additional
examples of RVHT without main renal artery stenosis.
Accordingly, the anatomic presence of renal artery stenosis
should not be equated with renovascular hypertension and the
syndrome of RVHT need not reflect renal artery stenosis.
This chapter reviews the types of renal arterial disease associated with RVHT, the pathophysiology of RVHT, clinical
features and diagnostic approaches to renal artery stenosis and
RVHT, evolving concepts regarding ischemic nephropathy, and
management considerations in patients with renal artery stenosis,
presumed RVHT, and ischemic renal disease.
FIGURE 3-1
Classification of renal artery disease. Two main types of renal arterial lesions form the
anatomic basis for renal artery stenosis. Atherosclerotic renal artery disease (ASO-RAD)
is the most common cause of renal artery disease, accounting for 60% to 80% of all renal
artery lesions. The fibrous dysplasias are the other major category of renal artery disease,
and as a group account for 20% to 40% of renal artery lesions. Arterial aneurysm and
arteriovenous malformation are rarer types of renal artery disease.
6080
2040
*Percent of renal artery lesions.
FIGURE 3-2
Angiographic examples of atherosclerotic renal artery disease (ASO-RAD). A, Aortogram
demonstrating severe nonostial atherosclerotic renal artery disease of the left main renal artery.
B, Intra-arterial digital subtraction aortogram showing severe proximal right renal artery stenosis
(ostial lesion) and moderately severe narrowing of the left renal artery due to atherosclerosis.
Atherosclerotic renal artery disease is typically associated with atherosclerotic changes

of the abdominal aorta (see panel B). ASORAD predominantly affects men and women
in the fifth to seventh decades of life but is
uncommon in women under the age of 50.
Anatomically, the majority of these patients
demonstrate atherosclerotic plaques located
in the proximal third of the main renal artery.
In the majority of cases (70% to 80%), the
obstructing lesion is an aortic plaque invading the renal artery ostium (ostial lesion).
Twenty to 30 percent of patients with ASORAD demonstrate atherosclerotic narrowing
1 to 3 cm beyond the takeoff of the renal
artery (nonostial lesion). Nonostial lesions
are technically more amenable to percutaneous transluminal renal angioplasty (PTRA)
than ostial ASO-RAD lesions, which are
technically difficult to dilate and have a high
restenosis rate after PTRA. Renal artery
stenting has gained wide acceptance for ostial
lesions. Endovascular intervention for nonostial lesions includes both PTRA and stents.
Surgical renal revascularization is used for
both ostial and nonostial ASO-RAD lesions.
(From Pohl [1]; with permission.)
3.3
Renovascular Hypertension and Ischemic Nephropathy
NATURAL HISTORY OF ATHEROSCLEROTIC RENOVASCULAR DISEASE: REPORTS OF SERIAL ANGIOGRAMS

First author
Year
Months of follow-up, n/n
Patients, n
Progression, n (%)
Total occlusion
Wollenweber
Meaney
Dean
Schreiber
Tollefson
1968
1968
1981
1984
1991
12/88
6/120
6/102
12/60
15/180
30
39
35
85
48
21 (70)
14 (36)
10 (29)
37 (44)
34 (71)
NA
3 (8)
4 (11)
14 (I6)
7 (15)
237
116 (49)
28 (14)
Total
FIGURE 3-3
Natural history of atherosclerotic renovascular disease.
Retrospective studies, based on serial renal angiograms, suggest
that atherosclerotic renal artery disease (ASO-RAD) is a progressive disorder. This figure summarizes retrospective series on the
natural history of ASO-RAD. A large series from the Cleveland
Clinic in nonoperated patients indicated progression of renal artery
obstruction in 44%; progression to total occlusion occurred in
16% of these patients. Reduction in ipsilateral renal size is associated with angiographic evidence of progression in contrast to
patients with nonprogressive (angiographically) ASO-RAD.
Zierler and coworkers have prospectively studied the progression of ASO-RAD by sequential duplex ultrasonography. The
cumulative incidence of progession of lesions with less than

60% reduction in lumen diameter progressing to more than 60%
reduction in lumen diameter was 30% at 1 year, 44% at 2 years,
and 48% at 3 years. Progression to total occlusion occurred only
in arteries with a baseline reduction in lumen diameter of more
than 60%. The cumulative incidence of progression to total
occlusion in patients with baseline stenosis of 60% or greater
was 4% at 1 year, 4% at 2 years, and 7% at 3 years. Blood
pressure control and serum creatinine were not predictors of
progression. The risk of renal parenchymal atrophy over time in
kidneys with ASO-RAD has also been described. (Table adapted
from Rimmer and Gennari [2]; with permission.)
FREQUENCY AND NATURAL HISTORY OF FIBROUS RENAL ARTERY DISEASES

Lesion
Intimal fibroplasia and
medial hyperplasia
Perimedial fibroplasia
Medial fibroplasia
Frequency, %*
Risk of progression
Threat to renal function
10
++++
++++
1025
7085
++++
++
++++
*Frequency relates to frequency of only the fibrous renal artery diseases.
FIGURE 3-4
Frequency and natural history of fibrous renal artery diseases. There are four types of fibrous
renal artery disease (fibrous dysplasias): medial fibroplasia, perimedial fibroplasia, intimal
fibroplasia, and medial hyperplasia. Although the true incidence of these specific types of
fibrous renal artery disease is not clearly defined, medial fibroplasia is the most common,
estimated to account for 70% to 85% of fibrous renal artery disease. The majority of patients
with medial fibroplasia are almost exclusively women who are diagnosed between the ages of
25 to 50 years. Although medial fibroplasia progresses to higher degrees of stenosis in about
one third of cases, complete arterial occlusion or ischemic atrophy of the involved kidney is
rare. Intervention on this type of fibrosis dysplasia is for relief of hypertension because the
threat of progressive medial fibroplasia to renal function is negligible. Perimedial fibroplasia is
the second most common type of fibrous

dysplasia, accounting for 10% to 25% of
fibrous renal artery lesions. This lesion also
occurs predominantly in women, is diagnosed
between the ages of 15 and 30, is frequently
bilateral and highly stenotic, and may progress
to total arterial occlusion. These patients
should undergo surgical renal revascularization
to relieve hypertension and to avoid loss of
renal function. Intimal fibroplasia and medial
hyperplasia (usually indistinguishable angiographically) are not common, accounting for
only 5% to 10% of fibrous renal artery
lesions. Intimal fibroplasia occurs primarily in
children and adolescents. Medial hyperplasia
is found predominantly in adolescents; angiographically it appears as a smooth linear
stenosis that may extend into the primary
renal artery branches. Medial hyperplasia, like
intimal fibroplasia, is a progressive lesion and
is associated with ipsilateral renal atrophy.
Surgical renal revascularization is recommended
for patients with either intimal fibroplasia or
medial hyperplasia to avoid lifelong antihypertensive therapy and to avert renal atrophy.
3.4
FIGURE 3-5
Arteriogram and schematic diagrams of
medial fibroplasia. A, Right renal arteriogram demonstrating weblike stenosis
with interposed segments of dilatation
(large beads) typical of medial fibroplasia
(string of beads lesion). B, Schematic
diagram of medial fibroplasia.
The lesion of medial fibroplasia characteristically affects the distal half of the main renal
artery, frequently extending into the branches,
is often bilateral, and angiographically gives
the appearance of multiple aneurysms (string
of beads). Histologically, this beaded lesion
is characterized by areas of proliferation of
fibroblasts of the media surrounded by
fibrous connective tissue (stenosis) alternating
with areas of medial thinning (aneurysms).
Inspection of the renal angiogram in panel A
indicates that the width of areas of aneurysmal dilatation is wider than the nonaffected
proximal renal artery, an angiographic clue
to medial fibroplasia. (Panel A from Pohl [1];
with permission.)
FIGURE 3-6
Arteriogram and schematic diagram of perimedial fibroplasia. A, Selective right renal
arteriogram shows a tight stenosis in the
mid portion of the renal artery with a small
string of beads appearance, typical of perimedial fibroplasia. B, Schematic diagram of
perimedial fibroplasia.
Perimedial fibroplasia, accounting for
10% to 25% of the fibrous renal artery diseases, is also observed almost exclusively in
women. The stenotic lesion occurs in the
mid and distal main renal artery or branches
and may be bilateral. Angiographically, serial
stenoses are observed with small beads, which
are smaller in diameter than the unaffected
portion of the renal artery. This highly
stenotic lesion may progress to total occlusion; collateral blood vessels and renal atrophy on the involved side are frequently
observed. Pathologically, the outer layer of
the media varies in thickness and is densely
fibrotic, producing a severe reduction in
lumen diameter (panel B). Renal artery dissection and/or thrombosis are common.
(Panel A from Pohl [1]; with permission.)
ATHEROSCLEROTIC RENAL ARTERY DISEASE VERSUS MEDIAL FIBROPLASIA

Atherosclerotic
Medial fibroplasia
Men and women

Age >5055 y
Women
Age 2040 y
Total occlusion common

Ischemic atrophy common
Total occlusion rare

Ischemic atrophy rare
Surgical intervention or angioplasty:

Mediocre cure rates of the hypertension
Less amenable to PTRA
Surgical intervention or angioplasty:

Good cure rates of the hypertension
More amenable to PTRA
FIGURE 3-8
A comparison of atherosclerotic renal artery disease and medial fibroplasia. The most
common types of renal artery disease (atherosclerotic renal artery disease [ASO-RAD] and
medial fibroplasia) are compared here. In general, ASO-RAD is observed in men and
women older than 50 to 55 years of age, whereas medial fibroplasia is observed primarily
in younger white women. Total occlusion of the renal artery and, hence, atrophy of the
3.5
FIGURE 3-7
Arteriogram and schematic diagram of
intimal fibroplasia. A, Selective right renal
arteriogram demonstrating a localized,
highly stenotic, smooth lesion involving the
distal renal artery, from intimal fibroplasia.
B, Schematic diagram of intimal fibroplasia.
Intimal fibroplasia occurs primarily in
children and adolescents and angiographically gives the appearance of a localized,
highly stenotic, smooth lesion, with poststenotic dilatation. It may occur in the proximal portion of the renal artery as well as
in the mid and distal portions of the renal
artery, is progressive, and is occasionally
associated with dissection or renal infarction. Pathologically, idiopathic intimal fibroplasia is due to a proliferation of the intimal
lining of the arterial wall. Intimal fibroplasia
of the renal artery may also occur as an
event secondary to atherosclerosis or as a
reactive intimal fibroplasia consequent to an
inciting event such as prior endarterectomy
or balloon angioplasty. (Panel A from Pohl
kidney beyond the stenosis are relatively
common with ASO-RAD, but ischemic
atrophy of the kidney ipsilateral to the medial
fibroplasia lesion is rare. Surgical intervention
or pecutaneous transluminal renal angioplasty
(PTRA) typically produce good cure rates for
the hypertension in medial fibroplasia and
these lesions are technically quite amenable to
PTRA. In contrast, ASO-RAD is, technically,
much less amenable to PTRA (particularly
ostial lesions), and surgical intervention or
PTRA produce mediocre-to-poor cure rates
of the hypertension. ASO-RAD and medial
fibroplasia may cause hypertension and
when the hypertension is cured or markedly
improved following intervention, the patient
may be viewed as having renovascular
hypertension. This sequence of events is
far more likely to occur in patients with
medial fibroplasia than in patients with
ASO-RAD. ASO-RAD and medial fibroplasia
involve both main renal arteries in approximately 30% to 40% of patients.
3.6
Pathophysiology of Renovascular Hypertension
Stenotic
kidney
Contralateral
kidney
Ischemia
Renin
Supressed renin
Pressure natriuresis
Angiotensin II
Vasoconstriction
Aldosterone
Intrarenal hemodynamics
Sodium retention
FIGURE 3-9
Schematic representation of renovascular hypertension. Renovascular
hypertension may be defined as the secondary elevation of blood
pressure produced by any of a variety of conditions that interfere
with the arterial circulation to kidney tissue and cause renal ischemia.
Almost always, renovascular hypertension is caused by obstruction
of the renal artery or its branches, and demonstration of causality
between the renal artery lesion and the hypertension is essential
to this definition.
This diagram shows the classic model of two-kidney, one

clip (2K,1C) Goldblatt hypertension, wherein one renal artery
is constricted and the contralateral kidney is left intact. In the
presence of hemodynamically sufficient unilateral renal artery
stenosis, the kidney distal to the stenosis is rendered ischemic,
activating the renin angiotensin system, and producing high
levels of angiotensin II, causing a vasoconstrictor type of
hypertension. Numerous studies have established the causal
relationship between angiotensin IImediated vasoconstriction
and hypertension in the early phase of this experimental model.
In addition, the high levels of angiotensin II stimulate the adrenal cortex to elaborate larger amounts of aldosterone such that
the stenotic kidney demonstrates sodium retention. This secondary aldosteronism also produces hypokalemia. The degree
of renal artery stenosis necessary to produce hemodynamically
significant reductions in perfusion, triggering renal ischemia
and activation of the renin angiotensin system, generally does
not occur until a reduction of 80% or more in both lumen diameter
and cross-sectional area of the renal artery takes place. Lesser
degrees of renal artery constriction do not initiate this sequence
of events.
This model of 2K,1C Goldblatt hypertension implies that
the contralateral (nonaffected) kidney is present, and that its
renal artery is not hemodynamically significantly narrowed.
As illustrated, the contralateral kidney demonstrates suppressed renin production and undergoes a pressure natriuresis,
presumably because of angiotensin IIinitiated vasoconstriction
and sodium retention, leading to systemic elevation of blood
pressure that then results in suppression of renin release and
enhanced excretion of sodium (pressure natriuresis) by the
contralateral kidney.
Clip
Phase
II
III
Blood pressure
Renin
Change in blood pressure
on removing clip
FIGURE 3-10
Sequential phases in two-kidney, one-clip (2K,1C) experimental renovascular hypertension. The schematic representation of renovascular
hypertension depicted in Figure 3-9 is an oversimplification. In
fact, the course of experimental 2K,1C hypertension may be divided
into three sequential phases. In phase I, renal ischemia and activation
of the renin angiotensin system are of fundamental importance,
and in this early phase of experimental hypertension, the blood
pressure elevation is renin- or angiotensin IIdependent. Acute
administration of angiotensin II antagonists, administration of
angiotensin-converting enzyme (ACE) inhibitors, removal of the
renal artery stenosis (ie, removal of the clip in the experimental
animal or removal of the stenotic kidney) promptly normalizes
blood pressure. Several days after renal artery clamping, renin levels
fall, but blood pressure remains elevated. This second phase of
experimental 2K,1C hypertension may be viewed as a pathophysiologic transition phase that, depending on the experimental model
and species, may last from a few days to several weeks. During this
transition phase (phase II), salt and water retention are observed as
a consequence of the effect of hypoperfusion of the stenotic kidney;
Two-kidney hypertension
Blood
pressure
Renin
Volume
High
Normal
One-kidney hypertension
Blood
pressure
Renin
Volume
Normal
High
3.7
augmented proximal tubular reabsorption of sodium and water

and angiotensin IIinduced stimulation of aldosterone secretion
contribute to this sodium and water retention. In addition, the high
levels of angiotensin II stimulate thirst, which further augments
expansion of the extracellular fluid volume. The expanded extracellular fluid volume results in a progressive suppression of peripheral
renin activity. During this transition phase, the hypertension is still
responsive to removal of the unilateral renal artery stenosis, to
angiotensin II blockade, or unilateral nephrectomy, although these
maneuvers do not normalize the blood pressure as promptly and
consistently as in the acute phase.
After several weeks, a chronic phase (phase III) ensues wherein
unclipping the renal artery of the experimental animal does not lower
the blood pressure. This failure of unclipping to lower the blood
pressure in this chronic phase (III) of 2K,1C hypertension is due to
widespread arteriolar damage to the contralateral kidney, consequent to prolonged exposure to high blood pressure and high levels
of angiotensin II. In this chronic phase of 2K,1C renovascular hypertension, extracellular fluid volume expansion and systemic vasoconstriction are the main pathophysiologic abnormalities. The pressure
natriuresis of the contralateral kidney blunts the extracellular
fluid volume expansion caused by the stenotic kidney; but as the
contralateral kidney suffers vascular damage from extended exposure
to elevated arterial pressure, its excretory function diminishes and
extracellular fluid volume expansion persists. In this third phase of
experimental 2K,1C hypertension, acute blockade of the renin
angiotensin system fails to lower blood pressure. Sodium depletion
may ameliorate the hypertension but does not normalize it. The
clinical surrogate of phase III experimental 2K,1C hypertension is
duration of hypertension. Widespread clinical experience indicates
that major improvements in blood pressure control or cure of the
hypertension following renal revascularization or even removal of
the kidney ipsilateral to the renal artery stenosis are rarely observed
in patients with a long duration (ie, >5 years) of hypertension.
(Adapted from Brown and coworkers [3]; with permission.)
FIGURE 3-11
Schematic representation of two types of experimental hypertension.
The discussion so far of the pathophysiology of renovascular
hypertension has focused on the two-kidney, one-clip model of
renovascular hypertension (two-kidney hypertension), wherein the
artery to the contralateral kidney is patent and the contralateral
nonaffected kidney is present. Elevated peripheral renin activity,
normal plasma volume, and hypokalemia are typically associated
with the elevated arterial pressure. There is another type of renovascular hypertension known as one-kidney hypertension,
wherein in the experimental model, one renal artery is constricted
and the contralateral kidney is removed. Although there is an initial
increase in renin release responsible for the early rise in blood pressure
in one-kidney hypertension as in two-kidney hypertension, the
absence of an unclipped contralateral kidney allows for sodium
retention early in the course of this one-kidney, one-clip (1K,1C)
model. Renin levels are suppressed to normal levels in conjunction
with high blood pressure which is maintained by salt and water
retention. Thus, extracellular fluid volume expansion is a prime
feature of one-kidney hypertension.
3.8
A. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR

HYPERTENSION (TWO-KIDNEY HYPERTENSION)*
Unilateral atherosclerotic renal arterial disease
Unilateral fibrous renal artery disease
Renal artery aneurysm
Arterial embolus
Arteriovenous fistula (congenital and traumatic)
Segmental arterial occlusion (traumatic)
Pheochromocytoma compressing renal artery
Unilateral perirenal hematoma or subcapsular hematoma (compressing renal parenchyma)
*Implies contralateral (nonaffected) kidney present.
B. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR

HYPERTENSION (ONE-KIDNEY HYPERTENSION)*
Stenosis to a solitary functioning kidney
Bilateral renal arterial stenosis
Aortic coarctation
Vasculitis (polyarteritis nodosa and Takayasus arteritis)
FIGURE 3-12
Lesions producing the syndrome of renovascular hypertension. A, Two-kidney
hypertension. The most common clinical
counterpart to two-kidney hypertension
is unilateral renal artery stenosis due to either
atherosclerotic or fibrous renal artery disease.
Unilateral renal trauma, with development
of a calcified fibrous capsule surrounding
the injured kidney causing compression of
the renal parenchyma, may produce renovascular hypertension; this clinical situation is
analogous to the experimental Page kidney,
wherein cellophane wrapping of one of two
kidneys causes hypertension, which is
relieved by removal of the wrapped kidney.
B, One-kidney hypertension. Clinical
counterparts of experimental one-kidney,
one-clip (one kidney) hypertension
include renal artery stenosis to a solitary
functioning kidney, bilateral renal arterial
stenosis, aortic coarctation, Takayasus
arteritis, fulminant polyarteritis nodosa,
atheroembolic renal disease, and renal
artery stenosis in a transplanted kidney.
In some parts of the world, eg, China and
India, Takayasus arteritis is a frequent
cause of renovascular hypertension.
*Implies total renal mass ischemic.
STEPS IN MAKING THE DIAGNOSIS

OF RENOVASCULAR HYPERTENSION
1. Demonstration of renal arterial stenosis by angiography
2. Determination of pathophysiologic significance of the stenotic lesion
3. Cure of the hypertension by intervention, ie, revascularization, percutaneous transluminal angioplasty, nephrectomy
FIGURE 3-13
Steps in making the diagnosis of renovascular hypertension (RVHT).
With the exception of oral contraceptive use and alcohol ingestion,
RVHT is the most common cause of potentially remediable secondary
hypertension. RVHT is estimated to occur with a prevalence of 1%
to 15%. Some hypertension referral clinics have estimated a prevalence of RVHT as high as 15%, whereas other prevalence data suggest
that less than 1% to 2% of the hypertensive population has RVHT.
Although elderly atherosclerotic hypertensive individuals often have

atherosclerotic renal artery disease, their hypertension is usually
essential hypertension, not RVHT. On balance, the prevalence of
RVHT in the general hypertensive population is probably no more
than 2% to 3%. The particular appeal of diagnosing RVHT centers
around its potential curability by an interventive maneuver such as
surgical revascularization, percutaneous transluminal renal angioplasty (PTRA), or renal artery stenting. Whether or not to use these
interventions for the goal of improving blood pressure depends on
the likelihood such intervention will improve the blood pressure.
The overwhelming majority of patients with RVHT will have this
syndrome because of main renal artery stenosis. Therefore, the first
step in making the diagnosis of RVHT is to demonstrate renal artery
stenosis by one of several imaging procedures and, eventually, by
angiography. The second step in establishing the probability that
the renal artery stenosis is instrumental in promoting hypertension
is to determine the pathophysiologic significance of the stenotic
lesion. Finally, the hypertension, presumed to be renovascular in
origin, is proven to be RVHT when the elevated blood pressure is
cured or markedly ameliorated by an interventive maneuver such as
surgical revascularization, PTRA, renal artery stent, or nephrectomy.
DIAGNOSIS OF RENAL ARTERIAL STENOSIS

Clinical clues
Diagnostic tests
Age of onset of hypertension <30 y or >55 y

Abrupt onset of hypertension
Acceleration of previously well-controlled hypertension
Hypertension refractory to an appropriate
three-drug regimen
Accelerated retinopathy
Systolic-diastolic abdominal bruit
Evidence of generalized atherosclerosis obliterans
Flash pulmonary edema
Acute renal failure with use of angiotensin-converting
enzyme inhibitors or angiotensin II receptor-blockers
Duplex ultrasonography
Radionuclide renography
Captopril renography
Captopril provocation test
Intravenous digital subtraction angiography
Rapid sequence IVP
Magnetic resonance angiography
Spiral CT angiography
CO2 angiography
Conventional (contrast) angiography
FIGURE 3-14
Diagnosis of renal artery stenosis. Clinical clues suggesting renal artery stenosis, some of
which suggest that the stenosis is the cause of the hypertension, are listed on the left. The
well-documented age of onset of hypertension in an individual under the age of 30 or over
age 55 years, particularly if the hypertension is severe and requiring three antihypertensive
drugs, is a strong clinical clue to renal artery stenosis and predicts that the stenosis is causing
the hypertension. The patient with a long history of mild hypertension, easily controlled with
one or two drugs, who, particularly in older age, develops severe and refractory hypertension,
is likely to have developed atherosclerotic renal artery stenosis as a contributor to underlying
3.9
longstanding essential hypertension. Grade III

hypertensive retinopathy, malignant hypertension, and flash pulmonary edema all
suggest renal artery stenosis with or without
renovascular hypertension. The observation
of a diastolic bruit in the abdomen of a young
white women suggests fibrous renal artery
disease and, further, is a reliable clinical clue
that the hypertension will be helped substantially by surgical renal revascularization or
percutaneous transluminal renal angioplasty.
The diagnostic tests listed along the right
side are used mainly to detect renal artery
stenosis (ie, the anatomic presence of disease). Captopril renography is also used
to predict physiologic significance of the
stenotic lesion. The popularity of these
diagnostic tests in detecting renal artery
stenosis varies from institution to institution; correlations with percent stenosis by
comparative angiography are widely variable. A substantial fall in blood pressure
following initiation of an angiotensin-converting enzyme inhibitor or angiotensin II
receptor blocker suggests RVHT. With the
exception of a diastolic abdominal bruit
and accelerated retinopathy, no clear-cut
physical findings definitely discriminate
patients with RVHT from the larger pool
of patients with essential hypertension.
FIGURE 3-15
Renal duplex ultrasound for diagnosis of renal artery stenosis. Duplex ultrasound scanning
of the renal arteries is a noninvasive screening test for the detection of renal artery stenosis.
It combines direct visualization of the renal arteries (B-mode imaging) with measurement
of various hemodynamic factors in the main renal arteries and within the kidney (Doppler),
thus providing both an anatomic and functional assessment. Unlike other noninvasive screening
tests (eg, captopril renography), duplex ultrasonography does not require patients to discontinue any antihypertensive medications before the test. The study should be performed
while the patient is fasting. The white arrow indicates the aorta and the black arrow the left
renal artery, which is stenotic. Doppler scans (bottom) measure the corresponding peak systolic
velocities in the aorta and in the renal artery. The peak systolic velocity in the left renal artery
was 400 cm/s, and the peak systolic velocity in the aorta was 75 cm/s. Therefore, the renalaortic ratio was 5.3, consistent with a 60% to 99% left renal artery stenosis. (From Hoffman
3.10
COMPARISON OF DUPLEX ULTRASOUND

WITH ARTERIOGRAPHY
Percent stenosis
by ultrasound
059
6099
100
Total
Percent stenosis by arteriogram

059
6079
8099
100
Total
62
1
0
63
0
31
1
32
1
67
1
69
1
0
22
23
64
99
24
187
Sensitivity, 0.98.
Specificity, 0.98.
Positive predictive value, 0.99.
Negative predictive value, 0.97.
DETERMINATION OF PATHOPHYSIOLOGIC
SIGNIFICANCE OF THE STENOTIC LESION
Duration of hypertension <35 y
Appearance of lesion on angiogram (>75% stenosis)
Systolic-diastolic bruit in abdomen
Renal vein renin ratio >1.5
Positive captopril provocation test or captopril renogram
Abnormal rapid sequence IVP
Hypokalemia
FIGURE 3-17
Determination of pathophysiologic significance of the stenotic
lesion. The second step in making the diagnosis of renovascular
hypertension (RVHT) is to determine the pathophysiologic significance of the stenotic lesion demonstrated by angiography. The
likelihood of cure of the hypertension by an interventive maneuver is greatly enhanced when one or more of the items listed here
are present. A positive captopril provocation test, abnormal rapid
sequence intravenous pyelogram (IVP), or positive captopril
FIGURE 3-16
Comparison of duplex ultrasound with arteriography. A total of
102 consecutive patients with both duplex ultrasound scanning of
the renal arteries and renal arteriography were prospectively studied.
All patients in this study had difficult-to-control hypertension,
unexplained azotemia, or associated peripheral vascular disease,
giving them a high pretest likelihood of renovascular hypertension.
Sixty-two of 63 arteries that showed less than 60% stenosis by formal
arteriography, were identified by duplex ultrasound scanning.
Twenty-two of 23 arteries with total occlusion on arteriography
were correctly identified by duplex ultrasound. Thirty-one of 32
arteries with 60% to 79% stenosis using arteriography were identified
as having 60% to 99% stenosis on duplex ultrasound and 67 of 69
arteries with 80% to 99% stenosis on arteriography were detected
to have 60% to 99% stenosis on ultrasound. A current limitation
of duplex ultrasound is the inability to consistently distinguish
between more than and less than 80% stenosis (considered to be
the magnitude of stenosis required for hemodynamic significance
of the lesion). Nevertheless, duplex ultrasound is currently highly
sensitive and specific in patients with a high likelihood of renovascular
disease in detecting patients with more or less than 60% renal artery
stenosis. Accessory renal arteries are difficult to identify by ultrasound and remain a limitation of this test. (Adapted from Olin
renogram not only suggest the anatomic presence of renal artery
stenosis but also imply that the stenosis is instrumental in producing the hypertension. Reductions of lumen diameter of less
than 70% to 80% generally do not initiate renal ischemia or activation of the renin angiotensin system; thus, before recommending a renal revascularization procedure, severe renal artery stenosis (>75% reduction in lumen diameter) should be observed on
the renal angiogram. A lateralizing renal vein renin ratio (a comparison of renin harvested from the renal vein ipsilateral to the
renal artery stenosis with the renin level from renal vein of the
contralateral kidney), particularly when renin production from
the contralateral kidney is suppressed, suggests that an intervention on the renal artery stenosis will cure or markedly ameliorate
the hypertension in about 90% of cases. Conversely, cure or
marked improvement in blood pressure following renal revascularization has been reported in nearly 50% of cases in the
absence of lateralizing renal vein renins. Hypokalemia, in the
absence of diuretic therapy, strongly suggests that the hypertension is renovascular in origin, consequent to secondary aldosteronism. The sensitivity of an IVP in detecting unilateral RVHT is
relatively poor (about 75%) and the overall sensitivity in detecting patients with bilateral renal artery disease is only about 60%.
Because RVHT has a low prevalence in the general population, a
negative IVP provides strong evidence (98% to 99% certainty)
against RVHT.
3.11
RENIN CRITERIA FOR CAPTOPRIL TEST THAT

DISTINGUISH PATIENTS WITH RVHT FROM
THOSE WITH ESSENTIAL HYPERTENSION
Stimulated PRA of 12 ng/mL/h or more
Absolute increase in PRA of 10 ng/mL/h or more
Percent increase in PRA
Increase in PRA of 150% if baseline PRA >3 ng/mL/h
Increase in PRA of 400% if baseline PRA <3 ng/mL/h
FIGURE 3-18
The captopril test: renin criteria that distinguish patients with
renovascular hypertension from those with essential hypertension.
The captopril provocation test evolved because the casual measurement of peripheral plasma renin activity (PRA) has been of little
value as a diagnostic screening test for renovascular hypertension

(RVHT). The notion that patients with high PRA, even in the
face of high urinary sodium excretion, might turn out to have
RVHT has not been supported by numerous clinical observations.
However, the short-term (60- to 90-minute) response of blood
pressure and PRA to an oral dose (25 to 50 mg) of captopril has
gained recent popularity as a screening test for presumed RVHT.
Preparation of patients for this test is vital; ideally patients
should discontinue their antihypertensive medications, maintain
a diet adequate in salt, and have good renal function. A baseline
blood pressure and PRA are obtained after which captopril is
administered; 60 minutes after captopril administration, a postcaptopril PRA is obtained along with repeat measurements of
blood pressure. Early reports with this test indicated a high sensitivity and specificity (95% to 100%) in identifying RVHT if all
three of the renin criteria listed here were met. Subsequent
reports have not been as encouraging such that the overall sensitivity of this captopril test is only about 70%, with a specificity
of approximately 85%. (Adapted from Muller and coworkers [6];
with permission.)
1.0
1.0
0.8
Relative acidity
Relative acidity
0.8
0.6
0.4
0.2
0.4
0.2
Bladder
Right kidney
Left kidney
Bladder
Right kidney
Left kidney
0
0
0.6
16
24
Time, min
32
40
48
FIGURE 3-19
Captopril renography. A, TcDPTA time-activity curves during
baseline. B, TcDPTA time-activity curves after captopril administration. These curves represent a captopril renogram in a patient
with unilateral left renal artery stenosis. This diagnostic test has been
used to screen for renal artery stenosis and to predict renovascular
hypertension. Captopril renography appears to be highly sensitive
and specific for detecting physiologically significant renal artery
stenosis. Scintigrams and time-activity curves should both be analyzed
to assess renal perfusion, function, and size. If the renogram following
captopril administration is abnormal (panel B, demonstrating delayed
time to maximal activity and retention of the radionuclide in the right
kidney), another renogram may be obtained without captopril for
comparison. The diagnosis of renal artery stenosis is based on
16
24
Time, min
32
40
48
asymmetry of renal size and function and on specific, captoprilinduced changes in the renogram, including delayed time to maximal
activity (11 minutes), significant asymmetry of the peak of each
kidney, marked cortical retention of the radionuclide, and marked
reduction in the calculated glomerular filtration rate of the kidney
ipsilateral to the stenosis. One must interpret the clinical and renographic data with caution, as protocols are complex and diagnostic
criteria are not well standardized. Nevertheless, captopril renography appears to be an improvement over the captopril provocation
test, with many reports indicating sensitivity and specificity from
80% to 95% in predicting an improvement in blood pressure
following intervention. (Adapted from Nally and coworkers [7];
with permission.)
3.12
Suggested work-up for renovascular hypertension

Index of clinical suspicion
Low (<1%)
PRA
Low
High (>25%)
Moderate (5%15%)
Normal
or high
Captopril test, or captopril renogram,

or stimulated renal vein renins,
or (?) duplex ultrasound
No further work-up
Negative
Positive
Arteriogram + renal
vein renins
FIGURE 3-20
Suggested work-up for renovascular hypertension. Because the prevalence of renovascular hypertension (RVHT) among hypertensive persons in general is approximately 2% or less, widespread
screening for renovascular disease is not justified. Despite the proliferation of diagnostic tests
now available to detect renal artery stenosis

and several tests designed to predict the
physiologic significance of the stenotic lesion,
the index of clinical suspicion for RVHT
remains the focal point of the work-up for
RVHT. A brief duration of moderately severe
hypertension is the most important clue
directing subsequent work-up for RVHT. If
the index of clinical suspicion (see Fig. 3-14)
is high, it is reasonable to proceed directly to
formal renal arteriography with renal vein
renin determination. Alternatively, in patients
highly suspected to have RVHT, a captopril
renogram followed by a renal arteriogram
may be recommended. Strong arguments
against RVHT include 1) long duration (more
than 5 years) of hypertension, 2) old age,
3) generalized atherosclerosis, 4) increased
serum creatinine, and 5) a normal serum
potassium concentration. For these patients,
particularly if the blood pressure is only minimally elevated or easily controlled with one or
two antihypertensive medications, further
work-up for RVHT is not indicated. (Adapted
from Mann and Pickering [8]; with permission.)
Ischemic Nephropathy
FIGURE 3-21
Aortogram in a 62-year-old white woman demonstrating subtotal occlusion of the left
main renal artery supplying an atrophic left kidney and high-grade ostial stenosis of the
proximal right renal artery from atherosclerosis. This patient presented in 1977 with a
recent appearance of hypertension and a blood pressure of 170/115 mm Hg. Three years
previously, when diagnosed with polycythemia vera, an IVP was normal. She was followed closely between 1974 and 1977 by her physician and was always normotensive
until the hypertension suddenly appeared. A repeat rapid sequence IVP demonstrated a
reduction in the size of the left kidney from 14 cm in height (1974) to 11.5 cm in height
(1977). The serum creatinine was 2.6 mg/dL. The renal arteriogram shown here indicates high-grade bilateral renal artery stenosis with the left kidney measuring 11.5 cm
in height, and the right kidney measuring 14.5 cm in height. Renal vein renins were
obtained and lateralized strongly to the smaller left kidney. The blood pressure was
well controlled with inderal and chlorthalidone. Right aortorenal reimplantation was
undertaken solely to preserve renal function. Postoperatively the serum creatinine fell to
1.5 mg/dL and remained at this level for the next 13 years. Blood pressure continued to
require antihypertensive medication, but was controlled to normal levels with inderal
and chlorthalidone.
3.13
12.0
11.0
10.0
9.0
8.0
Pt. 7
Pt. 8
7.0
6.0
Pt. 3
5.0
Pt. 6
4.0
3.0
Pt. 2
Pt. 1
Pt. 4
2.0
Pt. 3
1.0
0
Admission
Medical
therapy
Surgery or
angioplasty
FIGURE 3-22
Effects of medical therapy and surgery or angioplasty on serum
creatinine levels. This figure describes eight patients hospitalized
because of severe hypertension and renal insufficiency. With medical management of the hypertension (antihypertensive drug therapy), four of the eight patients developed substantial worsening of
their renal function as measured by serum creatinine; three of these
four patients demonstrated improvement following surgery or
angioplasty. The other four patients (patients one to four) did not
demonstrate a worsening serum creatinine level with medical therapy; but three of these four patients showed improved renal function following surgery or angioplasty. (Adapted from Ying and
B
FIGURE 3-23
Improved renal function demonstrated by intravenous pyelography
following left renal revascularization. A, preoperative IVP (5-minute
film) in a 65-year-old white man with a 15-year history of hypertension; serum creatinine 2.6 mg/dL. Note poorly functioning left kidney,
which measured 11.5 cm in height. B, post operative IVP (5-minute
film) obtained following left aortorenal saphenous vein bypass grafting
to the left kidney. Note the prompt function and increased height
(14.0 cm) of the revascularized left kidney versus the preoperative
IVP. (From Novick and Pohl [10]; with permission.)
The clinical story of the patient in Figure 3-21, the benefits of
surgical renal revascularization or pecutaneous transluminal renal
angioplasty (Fig. 3-22), and the radiographic evidence of improved
renal function after renal revascularization (Fig. 3-23) are examples
of ischemic nephropathy. Two definitions of ischemic nephropathy
are suggested herein: 1) clinically significant reduction in renal
function due to compromise of the renal circulation; and 2) clinically
significant reduction in glomerular filtration rate due to hemodynamically significant obstruction to renal blood flow, or renal failure
due to renal artery occlusive disease.
3.14
ATHEROSCLEROTIC RENAL ARTERY STENOSIS IN 395 PATIENTS

WITH GENERALIZED ATHEROSCLEROSIS OBLITERANS AND IN
PATIENTS WITH CORONARY ARTERY DISEASE
Patients, n
Percent of patients with >50% stenosis
109
21
189
76
76
817
38
33
39*
70
29
20
Abdominal aortic aneurysm

Aorto-occlusive disease
Lower extremity disease
Suspected renal artery stenosis
Coronary artery disease
*50% in diabetic patients.

Data from Vetrovec and coworkers [12].
Data from Harding [13].
CLINICAL PRESENTATIONS OF
ISCHEMIC RENAL DISEASE
Acute renal failure, frequently precipitated by a reduction in blood pressure
(ie, angiotensin-converting enzyme inhibitors plus diuretics)
Progressive azotemia in a hypertensive patient with known renal artery stenosis
treated medically
Progressive azotemia in a patient (usually elderly) with refractory hypertension
Unexplained progressive azotemia in an elderly patient
Hypertension and azotemia in a renal transplant patient
FIGURE 3-24
Atherosclerotic renal artery stenosis in
patients with generalized atherosclerosis
obliterans and in patients with coronary
artery disease (CAD). Atherosclerotic renal
artery stenosis is common in older patients
with and without hypertension simply as a
consequence of generalized atherosclerosis
obliterans. Approximately 40% of consecutively studied patients undergoing arteriography
for routine evaluation of abdominal aortic
aneurysm, aorto-occlusive disease, or lower
extremity occlusive disease have associated
renal artery stenosis (more than 50% unilateral
renal artery stenosis) and nearly 30% of
patients undergoing coronary angiography
may have incidentally detected unilateral
renal artery stenosis. Approximately 4%
to 13% of patients with CAD or peripheral
vascular disease have more than 75% bilateral
renal artery stenosis. Correlations of hypercholesterolemia and cigarette smoking with
renal artery atherosclerosis are not unequivocally clear, but they probably represent
risk factors for renal artery atherosclerosis
just as they represent risk factors for
atherosclerosis in other vascular beds.
(Adapted from Olin and coworkers [11];
with permission.)
FIGURE 3-25
Clinical presentations of ischemic renal disease. The clinical presentation of a patient likely to develop renal failure from atherosclerotic ischemic renal disease is that of an older (more than 50 years)
individual demonstrating progressive azotemia in conjunction with
antihypertensive drug therapy, risk factors for generalized atherosclerosis obliterans, known renal artery disease, refractory hypertension, and generalized atherosclerosis. Acute renal failure precipitated by a reduction in blood pressure below a critical perfusion
pressure, and particularly with the use of angiotensin convertingenzyme inhibitors (ACEI) or angiotensin II receptor blockers plus
diuretics, strongly suggests severe intrarenal ischemia from arteriolar nephrosclerosis and/or severe main renal artery stenosis.
Unexplained progressive azotemia in an elderly patient with clinical
signs of vascular disease with minimal proteinuria and a bland urinary
sediment also suggest ischemic nephropathy. (Adapted from
Jacobson [14]; with permission.)
FIGURE 3-26
Mild stenosis (less than 50%) due to atherosclerotic disease of the left main renal artery
(panel A) that has progressed to high-grade
(75% to 99%) stenosis on a later arteriogram (panel B). Underlying the concept
of renal revascularization for preservation
of renal function is the notion that atherosclerotic renal artery disease (ASO-RAD)
is a progressive disorder. The sequential
angiograms in Figures 3-26 and 3-27 show
angiographic progression of ASO-RAD over
time. In patients demonstrating progressive
renal artery stenosis by serial angiography, a
decrease in kidney function as measured by
serum creatinine and a decrease in ipsilateral
kidney size correlate significantly with progressive occlusive disease. Patients demonstrating more than 75% stenosis of a renal
artery are at highest risk for progression to
complete occlusion. (From Novick [15];
with permission.)
A
FIGURE 3-27
A, Normal right main renal artery and minimal atherosclerotic
irregularity of left main renal artery on initial (1974) aortogram.
B, Repeat aortography (1978) showed progression to moderate
3.15
B
stenosis of the right main renal artery (arrow) and total occlusion
of left main renal artery (arrow). (From Schreiber and coworkers
3.16
CLINICAL CLUES TO BILATERAL ATHEROSCLEROTIC

RENOVASCULAR DISEASE
Generalized atherosclerosis obliterans
Presumed renovascular hypertension
Unilateral small kidney
Unexplained azotemia
Deterioration in renal function with BP reduction and/or ACE inhibitor therapy
Flash pulmonary edema
FIGURE 3-28
Clinical clues to bilateral atherosclerotic renovascular disease.
The patient at highest risk for developing renal insufficiency from
renal artery stenosis (ischemic nephropathy) has sufficient arterial
stenosis to threaten the entire renal functioning mass. These highrisk patients have high-grade (more than 75%) arterial stenosis
to a solitary functioning kidney or high-grade (more than 75%)
bilateral renal artery stenosis. Patients with two functioning
kidneys with only unilateral renal artery stenosis are not at
significant risk for developing renal insufficiency because the
PREDICTORS OF KIDNEY SALVAGEABILITY
Kidney size >9 cm (laminography)

Function on either urogram or renal flow scan
Filling of distal renal arteries (by collaterals) angiographically, with total proximal occlusion
Glomerular histology on renal biopsy
FIGURE 3-29
Predictors of kidney salvageability. In evaluating patients as
candidates for renal revascularization to preserve or improve
renal function, some determination should be made of the
entire renal functioning mass is not threatened by large vessel

occlusive disease.
Clinical clues to the high-risk patient are similar to the clinical
presentations of ischemic renal disease shown in Figure 3-25. Nearly
75% of adults with a unilateral small kidney have sustained this
renal atrophy due to large vessel occlusive disease from atherosclerosis.
One third of these patients with a unilateral small kidney have
high-grade stenosis of the artery involving the contralateral normalsized kidney. Flash pulmonary edema is another clue to bilateral
renovascular disease or high-grade stenosis involving a solitary
functioning kidney. These patients, usually hypertensive and with
documented coronary artery disease and underlying hypertensive
heart disease, present with the abrupt onset of pulmonary edema.
Left ventricular ejection fractions in these patients are not seriously
impaired. Flash pulmonary edema is associated with atherosclerotic
renal artery disease and may occur with or without severe hypertension.
Renal revascularization to preserve kidney function or to prevent
life-threatening flash pulmonary edema may be considered in patients
with high-grade arterial stenosis to a solitary kidney or high-grade
bilateral renal artery stenosis. Pecutaneous transluminal renal
angioplasty (PTRA), renal artery stenting, or surgical renal revascularization may be employed. Patients with chronic total renal artery
occlusion bilaterally or in a solitary functioning kidney are candidates
for surgical renal revascularization, but are not candidates (from a
technical standpoint) for PTRA or renal artery stents.
potential for salvable renal function. Clinical clues suggesting
renal viability include 1) kidney size greater than 9 cm (pole-topole length) by laminography (tomography); 2) some function
of the kidney on either urogram or renal flow scan; 3) filling of
distal renal arteries (by collaterals) angiographically, when the
main renal artery is totally occluded proximally (see Fig. 3-30);
and 4) well-preserved glomeruli with minimal interstitial scarring
(see Fig. 3-31) on renal biopsy. Patients with moderately severe
azotemia, eg, serum creatinine more than 3-4 mg/dL, are likely
to have severe renal parenchymal scarring (see Fig. 3-32), which
renders improvement in renal function following renal revascularization unlikely. Exceptions to this observation are cases of
total main renal artery occlusion wherein kidney viability is
maintained via collateral circulation (see Figure 3-30). A kidney
biopsy may guide subsequent decision making regarding renal
revascularization for the goal of improving kidney function.
FIGURE 3-30
This abdominal aortogram reveals complete occlusion of the left main renal artery
(panel A) with filling of the distal renal
artery branches from collateral supply on
delayed films (panel B). The observation
of collateral circulation when the main
renal artery is totally occluded proximally
suggests viable renal parenchyma. (From
Novick and Pohl [10]; with permission.)
FIGURE 3-31
Renal biopsy of a solitary left kidney in a 67-year-old woman who
had been anuric and on chronic dialysis for 9 months. The biopsy
shows hypoperfused retracted glomeruli consistent with ischemia.
There is no evidence of active glomerular proliferation or glomerular
sclerosis. Note intact tubular basement membranes and negligible
interstitial scarring. Left renal revascularization resulted in recovery
of renal function and discontinuance of dialysis with improvement in
serum creatinine to 2.0 mg/dL. (From Novick [15]; with permission.)
3.17
FIGURE 3-32
Pathologic specimen of kidney beyond a main renal artery occlusion
in a patient with severe bilateral renal artery stenosis and a serum
creatinine of 4.5 mg/dL. The biopsy demonstrates glomerular sclerosis, tubular atrophy, and interstitial fibrosis. The magnitude of
glomerular and interstitial scarring predict irreversible loss of kidney
viability. (From Pohl [1]; with permission.)
FIGURE 3-33
Severe atherosclerosis involving the abdominal aorta, renal, and iliac arteries. This abdominal
aortogram demonstrates a ragged aorta, total occlusion of the right main renal artery, and
subtotal occlusion of the proximal left main renal artery. Such patients are at high-risk for
atheroembolic renal disease following aortography, selective renal arteriography, pecutaneous
transluminal renal angioplasty, renal artery stenting, or surgical renal revascularization.

Purple toe syndrome reflecting peripheral atheroembolic
disease in the patient in Figure 3-33 (ragged aorta), following
an abdominal aortogram.
3.18

FIGURE 3-35
Pathologic specimen of kidney demonstrating atheroembolic renal
disease (AERD). Microemboli of atheromatous material are readily
identified by the characteristic appearance of cholesterol crystal
inclusions that appear in a biconvex needle-shaped form. In routine
paraffin-embedded histologic sections, the cholesterol is not seen
because the methods used in preparing sections dissolve the crystals;
the characteristic biconvex clefts in the glomeruli (or blood vessels)
persist, allowing easy identification. Several patterns of renal failure
in patients with AERD are recognized: 1) insult (eg, abdominal
aortogram) leads to end-stage renal disease (ESRD) over weeks
to months; 2) insult leads to chronic stable renal insufficiency;
3) multiple insults (repeated angiographic procedures) lead to a
step-wise rise in serum creatinine eventuating in end-stage renal
failure; and 4) insult leading to ESRD over several weeks to
months with recovery of some renal function allowing for
discontinuance of dialysis.
FIGURE 3-36
Renal biopsy demonstrating severe arteriolar nephrosclerosis.
Arteriolar nephrosclerosis is intimately associated with hypertension.
The histology of the kidney in arteriolar nephrosclerosis shows
considerable variation in intensity and extent of the arteriolar
lesions. Thickening of the vessel wall, edema of the smooth muscle
cells, hypertrophy of the smooth muscle cells, and hyaline degeneration of the vessel wall may be apparent depending on the severity of
the nephrosclerosis. In addition to the vascular lesions of arteriolar
nephrosclerosis there are abnormalities of glomeruli, tubules, and
interstitial areas that are believed to be secondary to the ischemia
that results from arteriolar insufficiency. Arteriolar nephrosclerosis
is observed in patients with longstanding hypertension; the more
severe the hypertension, the more severe the arteriolar nephrosclerosis.
Arteriolar nephrosclerosis may also be seen in elderly normotensive
individuals and is frequently observed in elderly patients with generalized atherosclerosis or essential hypertension.
Atherosclerosis
Nephrosclerosis
Atheroembolism
FIGURE 3-37
Schematic representation of ischemic nephropathy. Patients with atherosclerotic renal artery
disease (ASO-RAD) often have coexisting renal parenchymal disease with varying degrees of
nephrosclerosis (small vessel disease) or atheroembolic renal disease. Whether or not the renal
insufficiency is solely attributable to renal artery stenosis, nephrosclerosis, or atheroembolic renal
disease is difficult to determine. The term ischemic nephropathy is more complex than being
simply due to atherosclerotic renal artery stenosis. In addition, in the azotemic patient with ASORAD, one should exclude other potential or contributing causes of renal insufficiency such as
obstructive uropathy, primary glomerular disease (suggested by heavy proteinuria), drug-related
renal insufficiency (eg, nonsteroidal anti-inflammatory drugs), and uncontrolled blood pressure.

4%
Miscellaneous
FIGURE 3-38
Distribution of endstage renal disease diagnoses. Atherosclerotic renal artery disease (ASORAD) has been claimed to contribute to the ESRD population. This diagram from the US
Renal Data System Coordinating Center 1994 report indicates that 29% of calendar year
1991 incident patients entered ESRD programs because of hypertension (HBP). No renovascular disease diagnosis is listed. Crude estimates of the percentage of patients entering
ESRD programs because of ASO-RAD range from 1.7% to 15%. Precise bases for making
these estimates are both unclear and confounded by the high likelihood of coexisting arteriolar nephrosclerosis, type II diabetic nephropathy, and atheroembolic renal disease. ASO-RAD
as a major contributor to the ESRD population is probably small on a percentage basis, occupying some portion of the ESRD diagnosis hypertension (HBP). For dialysis-dependent
patients with ASO-RAD, predictors of recovery of renal function following renal revascularization and allowing for discontinuance of dialysis (temporary or permanent) include 1) bilateral (vs unilateral) renal artery stenosis, 2) a relatively fast rate of decline of estimated
glomerular filtration rate (less than 6 months) prior to initiation of dialysis; and 3) mild-tomoderate arteriolar nephrosclerosis angiographically.
11%
Other
12%
CGN
5%
Urology
3%
Cyst
3.19
36%
DM
29%
High blood
pressure
Treatment of Renovascular Hypertension

and Ischemic Nephropathy
TREATMENT OPTIONS FOR RENOVASCULAR
HYPERTENSION AND ISCHEMIC NEPHROPATHY
Pharmacologic antihypertensive therapy
PTRA
Renal artery stents
Surgical renal revascularization
INCREASING COMORBIDITY IN PATIENTS

UNDERGOING RENOVASCULAR SURGERY
Comorbidity, %
Condition
Angina
Prior MI
CHF
Cerebrovascular disease
Diabetes
Claudication
*P <0.001.
19701980
19801993
21.4
16.3
12.2
11.2
7.1
35.7
29.9
27.0
23.7*
24.8*
18.1*
56.4*
FIGURE 3-39
Treatment options for renovascular hypertension and ischemic
nephropathy. The main goals in the treatment of renovascular hypertension or ischemic nephropathy are to control the blood pressure,
to prevent target organ complications, and to avoid the loss of renal
function. Although the issue of renal function may be viewed as
mutually exclusive from the issue of blood pressure control, uncontrolled hypertension may hasten a decline in renal function, and
renal insufficiency may produce worsening hypertension. Even in the
presence of excellent blood pressure control, progressive arterial
stenosis might worsen renal ischemia and promote renal atrophy and
fibrosis. Therapeutic options include pharmacologic antihypertensive
therapy, percutaneous transluminal renal angioplasty (PTRA), renal
artery stents, and surgical renal revascularization. Pharmacologic antihypertensive therapy is covered in more detail separately in this Atlas.
FIGURE 3-40
Comorbidity in patients undergoing renovascular surgery. Patients
presenting for renovascular surgery or endovascular renal revascularization are at high-risk for complications during intervention
because of age, and frequently associated coronary, cerebrovascular,
or peripheral vascular disease. As the population ages, the percentage
of patients being considered for interventive maneuvers on the
renal artery has increased significantly. Approximately 30% of
patients currently undergoing interventive approaches to renal
artery disease have angina, or have had a previous myocardial
infarction. Congestive heart failure, cerebrovascular disease (eg, carotid
artery stenosis), diabetes mellitus, and claudication are frequent
comorbid conditions in these patients. Their aortas are often laden
with extensive atherosclerotic plaque (Fig. 3-33), making angiographic
investigation or endovascular renal revascularization hazardous.
(Adapted from Hallet and coworkers [17]; with permission.)
3.20
DIMINISHED OPERATIVE MORBIDITY AND MORTALITY FOLLOWING SURGICAL

REVASCULARIZATION FOR ATHEROSCLEROTIC RENOVASCULAR DISEASE
Preoperative screening and correction of coronary and carotid artery disease
Avoidance of operation on severely diseased aorta
Unilateral revascularization in patients with bilateral renovascular disease
FIGURE 3-41
Diminished operative morbidity and mortality following surgical revascularization for
atherosclerotic renovascular disease. Operative morbidity and mortality in patients undergoing surgical revascularization have been minimized by selective screening and/or correction of significant coexisting coronary and/or carotid artery disease before undertaking
elective surgical renal revascularization for atherosclerotic renal artery disease. Screening
tests for carotid artery disease include carotid ultrasound and carotid arteriography.
Screening tests for coronary artery disease include thallium stress testing, dipyridamole
stress testing, dobutamine echocardiography, and coronary arteriography. Aortorenal
bypass with saphenous vein grafting is

a frequently used surgical approach in
patients with nondiseased abdominal aortas.
Severe atherosclerosis of the abdominal
aorta may render an aortorenal bypass or
renal endarterectomy technically difficult
and potentially hazardous to perform.
Effective alternate bypass techniques include
splenorenal bypass for left renal revascularization, hepatorenal bypass for right renal
revascularization, ileorenal bypass, bench
surgery with autotransplantation, and use
of the supraceliac or lower thoracic aorta
(usually less ravaged by atherosclerosis).
Simultaneous aortic replacement and renal
revascularization are associated with an
increased risk of operative mortality in
comparison to renal revascularization alone.
Some surgeons advocate unilateral renal
revascularization in patients with bilateral
renovascular disease.
FIGURE 3-42
Schematic diagram of alternate bypass
procedures. A, Hepatorenal bypass to
right kidney. B, Splenorenal bypass to left
kidney. C, Ileorenal bypass to left kidney.
D, Autotransplantation.
3.21
FIGURE 3-43
Percutaneous transluminal renal angioplasty (PTRA) of the renal artery.
A, High-grade (more than 75%) nonostial atherosclerotic stenosis of the
left main renal artery in a patient with a solitary functioning kidney (right
renal artery totally occluded). Note gradient of 170 mm Hg across the
stenotic lesion. B, Balloon angioplasty of the left main renal artery was
successfully performed with reduction in the gradient across the stenotic
lesion from 170 mm Hg pre-PTRA to 15 mm Hg post-PTRA. Repeat
aortogram 3 years later demonstrated patency of the left renal artery.
PTRA of the renal artery has emerged as an important interventional modality in the management of patients with renal
artery stenosis. PTRA is most successful and should be the initial
interventive therapeutic maneuver for patients with the medial
fibroplasia type of fibrous renal artery disease (eg, Fig.3-5A).
Excellent technical success rates have also been attained for
nonostial atherosclerotic lesions of the main renal artery, as
shown here.
FIGURE 3-44
High-grade atherosclerotic renal artery
stenosis at the
ostium of the right
main renal artery in
a 68-year-old man
with a totally
occluded left main
renal artery. Several
attempts at balloon
dilatation were
unsuccessful. Over
the subsequent 10
days, severe renal
insufficiency developed (serum creatinine increasing from
2.0 to 12.0 mg/dL)
requiring dialysis.
Renal function never
improved and the
patient remained
on dialysis.
FIGURE 3-45
Palmaz stent, expanded. Because percutaneous transluminal renal
angioplasty (PTRA) has suboptimal long-term benefits for atherosclerotic ostial renal artery stenosis, endovascular stenting has gained
wide acceptance. Renal artery stenting may be performed at the time
of the diagnostic angiogram, or at some time thereafter, depending
on the physicians preference and the risk to the patient of repeated
angiographic procedures. From a technical standpoint, indications
for renal artery stenting include 1) as a primary procedure for ostial
atherosclerotic renal artery disease (ASO-RAD), 2) technical difficulties in conjunction with attempted PTRA, 3) post-PTRA dissection,
4) post-PTRA abrupt occlusion, and 5) restenosis following PTRA.
It is unclear what the long-term patency and restenosis rates will be
for renal artery stenting for ostial disease. Preliminary observations
suggest that the 1-year patency rate for stents is approximately twice
that for PTRA.
3.22

FIGURE 3-46
Abdominal aortogram in a 63-year-old male, 6 months following placement of a Palmaz
stent. Note wide patency of the left main renal artery.
A. SURGICAL REVASCULARIZATION VERSUS PTRA

FOR ATHEROSCLEROTIC RENAL ARTERY DISEASE
Lesion
Nonostial
(20%)
Ostial
(80%)
Successful PTRA, %
Successful surgical
revascularization, %
8090
90
2530
90
FIGURE 3-47
Surgical revascularization vs percutaneous transluminal renal
angioplasty (PTRA) for renal artery disease. A, Success rates for
atherosclerotic renal artery disease (ASO-RAD). B, Success rates
for fibrous renal artery disease. Success of either PTRA or surgical renal revascularization is viewed in terms of technical success and clinical success. For PTRA, technical success reflects
a lumen patency with less than 50% residual stenosis (ie, successful establishment of a patent lumen). For surgical revascularization, technical success is the demonstration of good blood
flow to the revascularized kidney determined during surgery, or
postoperatively by DPTA renal scan or other immediate postoperative imaging procedures. Technical success with either PTRA
or surgical revascularization is rarely defined by postoperative
angiography. Clinical success may be defined as improved
blood pressure or improvement in kidney function, and/or resolution of flash pulmonary edema. Technical and clinical successes do not necessarily occur together because technical success
may be apparent, but without improvement in blood pressure
or renal function.
B. SURGICAL REVASCULARIZATION VERSUS

PTRA FOR FIBROUS RENAL ARTERY DISEASE
Lesion
Successful PTRA, %
Successful surgical
revascularization, %
Main
(50%)
Branch
(50%)
8090
90
NA
90
The percent success for PTRA and surgical revascularization

depicted above are estimates, and reflect primarily technical success
for both nonostial and ostial lesions in ASO-RAD. Technical success
rates for surgical revascularization are high, approximating 90%,
with little difference in the technical success rates between ostial
and nonostial lesions. For PTRA, technical success rates are much
higher for nonostial lesions. There is a high rate of restenosis at 1
year (50% to 70%) for ostial ASO-RAD, which has promoted the
use of renal artery stents for these lesions.
The success rates of surgical renal revascularization and PTRA
for stenosis of the main renal artery in fibrous renal artery disease
are comparable, approximately 90%. Hypertension is more predictably improved with surgical revascularization and PTRA in
fibrous renal artery disease in comparison with ASO-RAD. Technical
success rates with surgical renal revascularization are high for
branch fibrous renal artery disease, but long-term technical and
clinical success rates are not available for PTRA of branch lesions
due to fibrous dysplasia. NAnot available. (Adapted from Pohl
COMPLICATIONS OF TRANSLUMINAL
ANGIOPLASTY OF THE RENAL ARTERIES
Contrast-induced ARF (mild or severe)
Atheroembolic renal failure
Rupture of the renal artery
Dissection of the renal artery
Thrombotic occlusion of the renal artery
Occlusion of a branch renal artery
Balloon malfunction (may lead to inability to remove balloon)
Balloon rupture
Puncture site hematoma, hemorrhage, or vessel tear
Median nerve compression (axillary approach)
Renal artery spasm
Mortality (1%)
FIGURE 3-48
Complications of transluminal angioplasty of the renal arteries.
The more common complications of PTRA are contrast-induced
acute renal failure (ARF) and atheroembolic renal failure.
Dissection of the renal artery, occlusion of a branch renal artery,
and occasionally thrombotic occlusion of the main renal artery
may occur. In experienced hands, rupture of the renal artery is
rare. Minor complications relate primarily to the puncture site.
When the axillary approach is used (because of severe iliac and
lower abdominal aortic atherosclerosis), median nerve compression
may transpire. Some of these complications of percutaneous transluminal renal angioplasty, particularly atheroembolic renal failure
and/or contrast-induced acute renal failure (ARF) may also be
observed with renal artery stent procedures.
3.23
FACTORS TO CONSIDER IN SELECTION OF TREATMENT

FOR PATIENTS WITH RENAL ARTERY DISEASE
Is renal artery disease causing hypertension?
Severity of hypertension
Specific type of renal artery disease and threat to renal function
General medical condition of patient
Relative efficacy and risk of medical antihypertensive therapy, PTRA,
renal artery stenting, surgical revascularization
FIGURE 3-49
Selection of treatment for patients with renal artery disease. In
selecting treatment options for patients with renal artery disease,
there are several factors to consider: what is the likelihood that
the renal artery disease is causing the hypertension? For patients
with fibrous renal artery disease the likelihood is high; for patients
with atherosclerotic renal artery disease (ASO-RAD), the likelihood for a cure of hypertension is small. The more severe the
hypertension, the greater the inclination to intervene with either
surgery or balloon angioplasty. For children, adolescents, and
younger adults, most of whom will have fibrous renal artery disease, intervention is usually recommended to avoid lifelong antihypertensive therapy. Cardiovascular comorbidity is high for
patients with ASO-RAD and appropriate caution in approaching
these patients is warranted, weighing the relative efficacy and risk
of medical antihypertensive therapy, percutaneous transluminal
renal angioplasty (PTRA), renal artery stenting, and surgical
revascularization. Local experience and expertise of the treating
physicians must be considered as well in selection of treatment
options for these patients.
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Adrenal Causes of
Hypertension
Myron H. Weinberger
he adrenal gland is involved in the production of a variety of

steroid hormones and catecholamines that influence blood
pressure. Thus, it is not surprising that several adrenal disorders
may result in hypertension. Many of these disorders are potentially
curable or responsive to specific therapies. Therefore, identifying
adrenal disorders is an important consideration when elevated blood
pressure occurs suddenly or in a young person, is severe or difficult to
treat, or is associated with manifestations suggestive of a secondary
form of hypertension. Because these occurrences are relatively rare, it
is necessary to have a high index of suspicion and understand the
pathophysiology on which the diagnosis and treatment of these problems
is based.
Three general forms of hypertension that result from excessive production of mineralocorticoids, glucocorticoids, or catecholamines are reviewed
in the context of their normal production, metabolism, and feedback
systems. The organization of this chapter provides the background for
understanding the normal physiology and pathophysiologic changes
on which effective screening and diagnosis of adrenal abnormalities are
based. Therapeutic options also are briefly considered. Primary aldosteronism, Cushings syndrome, and pheochromocytoma are discussed.
CHAPTER
4.2
Adrenal Hypertension
PHYSIOLOGIC MECHANISMS IN ADRENAL HYPERTENSION
Disorder
Cause
Pathophysiology
Pressure mechanism
Autonomous hypersecretion
of aldosterone (hypermineralocorticoidism)

expansion, hypokalemia
(?), alkalosis
Cushings syndrome
Hypersecretion of cortisol
(hyperglucocorticoidism)
Pheochromocytoma
Hypersecretion of
catecholamines
Increased renal sodium and

water reabsorption,
increased urinary
excretion of potassium
and hydrogen ions
Increased activation of
mineralocorticoid
receptor (?), increased
angiotensinogen (renin
substrate) concentration
Vasoconstriction, increased
heart rate
FIGURE 4-1
The causes and pathophysiologies of the
three major forms of adrenal hypertension
and the proposed mechanisms by which
blood pressure elevation results.

expansion (?), increased
angiotensin II (vasoconstriction and increased
peripheral resistance)
Increased peripheral
resistance, increased
cardiac output
Histology of the Adrenal

FIGURE 4-2
Histology of the adrenal. A cross section of the normal adrenal
before (left) and after (right) stimulation with adrenocorticotropic
hormone (ACTH) [1]. The adrenal is organized into the outer
adrenal cortex and the inner adrenal medulla. The outer adrenal
cortex is composed of the zona glomerulosa, zona fasciculata, and
zona reticularis. The zona glomerulosa is responsible for production of aldosterone and other mineralocorticoids and is chiefly
under the control of angiotensin II (see Figs. 4-3 and 4-5). The
zona fasciculata and zona reticularis are influenced primarily by
ACTH and produce glucocorticoids and some androgens (see Figs.
4-3 and 4-19). The adrenal medulla produces catecholamines and
is the major source of epinephrine (in addition to the organ of
Zuckerkandl located at the aortic bifurcation) (see Fig. 4-25.)
Capsule
Zona
glomerulosa
Zona
fasciculata
Zona
reticularis
Medulla
Normal human
suprarenal gland
Human suprarenal
gland after
administration
of crude ACTH
Adrenal Causes of Hypertension
4.3
Adrenal Steroid Biosynthesis

17Hydroxylase
CH3
C=O
HO
Pregnenolone
CH3
O
C=O
OH
HO
17-Hydroxypregnenolone
HO
Dehydroepiandrosterone
3 -OH-Dehydrogenase: 5 4 Isomerase
CH3
CH3
C=O
C=O
OH
O
17-Hydroxypregnenolone
Pregnenolone
21-Hydroxylase
OH2OH
CH2OH
C=O
C=O
OH
O
11-Deoxycorticosterone
11-Deoxycortisol
11-Hydroxylase
CH2OH
HO
HO
O
Corticosterone
18-Hydroxylase
18-OH-Dehrydrogenase
CH2OH
HO
CH2OH
C=O
OHC C=O
Aldosterone
Cortisol
Zona
glomerulosa
only
C=O
OH
O
4 Androstene 3,17-dione
FIGURE 4-3
Adrenal steroid biosynthesis. The sequence of
adrenal steroid biosynthesis beginning with
cholesterol is shown as are the enzymes
responsible for production of specific steroids
[2]. Note that aldosterone production normally occurs only in the zona glomerulosa
(see Fig. 4-2). (From DeGroot and coworkers
4.4
ACTH
PRA
Aldosterone
Cortisol
Morning
6 AM
Noon
6 PM
Morning
FIGURE 4-4
Circadian rhythmicity of steroid production and major stimulatory
factors. Aldosterone and cortisol and their respective major stimulatory
factors, plasma renin activity (PRA) and adrenocorticotropic hormone
(ACTH), demonstrate circadian rhythms. The lowest values for all of
these components are normally seen during the sleep period when the
need for active steroid production is minimal. ACTH levels increase
early before awakening, stimulating cortisol production in preparation for the physiologic changes associated with arousal. PRA increases abruptly with the assumption of the upright posture, followed by
an increase in aldosterone production and release. Both steroids
demonstrate their highest values through the morning and early afternoon. Cortisol levels parallel those of ACTH, with a marked decline
in the afternoon and evening hours. Aldosterone demonstrates a
broader peak, reflecting the postural stimulus of PRA.
Kidney
Perfusion pressure
Kidney
Juxtaglomerular
apparatus
Perfusion pressure
Sodium content
Sodium content
6
Juxtaglomerular
apparatus
9
12
Renin
Renin
Angiotensin II

8
Sodium reabsorption
Adrenal complex
Aldosterone
Zona glomerulosa
10
Angiotensin II
11
Sodium reabsorption
Adrenal complex
Aldosterone
Zona glomerulosa
13
14
Normal
K+
ACTH
K+
ACTH
FIGURE 4-5
Control of mineralocorticoid production. A, Control of aldosterone production under normal circumstances.
A decrease in renal perfusion pressure or tubular sodium content (1) at the level of the juxtaglomerular apparatus
and macula densa of the kidney triggers renin release (2). Renin acts on its substrate angiotensinogen to generate
angiotensin I, which is converted rapidly by angiotensin-converting enzyme to angiotensin II. Angiotensin II
then induces peripheral vasoconstriction to increase perfusion pressure (6) and acts on the zona glomerulosa
of the adrenal cortex (3) (see Fig. 4-2) to stimulate production and release of aldosterone (4). Potassium and
adrenocorticotropic hormone (ACTH) also play a minor role in aldosterone production in some circumstances.
Aldosterone then acts on the cells of the collecting duct of the kidney to promote reabsorption of sodium (and
passively, water) in exchange for potassium and hydrogen ions excreted in the urine. This increased secretion
promotes expansion of extracellular fluid volume and an increase in renal tubular sodium content (5) that further
suppresses renin release, thus closing the feedback loop (servomechanism). B, Abnormalities present in primary
aldosteronism. Autonomous hypersecretion of aldosterone (7) leads to increased extracellular fluid volume
expansion and increased renal tubular sodium content. These elevated levels are a result of increased renal
sodium and water

reabsorption (8) at the
expense of increased
potassium and hydrogen
ion excretion in the
urine. The increase in
sodium and volume then
increase systemic blood
pressure and renal
perfusion pressure and
sodium content (9),
thereby suppressing
further renin release
(10) and angiotensin II
production (11). Thus,
in contrast to the normal situation depicted
in panel A, the levels of
angiotensin II are highly
suppressed and therefore
do not contribute to an
increase in systemic
blood pressure (12). In
primary aldosteronism,
ACTH (13) has a dominant modulatory role in
influencing aldosterone
production and hypokalemia, resulting from
increased urinary potassium exchange for
sodium, which has a
negative effect on aldosterone production (14).
4.5
Aldosteronism
TYPES OF PRIMARY ALDOSTERONISM
Types
SCREENING TESTS FOR PRIMARY ALDOSTERONISM
Relative frequency, %
Solitary adrenal adenoma

Bilateral adrenal hyperplasia
Unilateral adrenal hyperplasia
Glucocorticoid-remediable aldosteronism
Bilateral solitary adrenal adenomas
Adrenal carcinoma
Test
Serum potassium 3.5 mEq/L
Plasma renin activity 4 ng/mL/90 min
Urinary aldosterone 20 g/d
Plasma aldosterone 15 ng/dL
Plasma aldosteroneplasma renin
activity ratio 15
Plasma aldosteroneplasma renin
activity ratio 30
65
30
2
<1
<1
<1
FIGURE 4-6
Types of primary aldosteronism. (Data from Weinberger and
coworkers [3].)
Sensitivity, %
75
>99
70
90
99.8
96
Specificity, %
20
4060
60
60
98
100
FIGURE 4-7
Screening tests for primary aldosteronism. Serum potassium levels
range from 3.5 to normal levels of patients with primary aldosteronism. Most hypertensive patients with hypokalemia have secondary
rather than primary aldosteronism. The plasma aldosterone-to-plasma renin activity (PRA) ratio (disregarding units of measure) is the
most sensitive and specific single screening test for primary aldosteronism. However, because of laboratory variability, normal ranges
must be developed for individual laboratory values. A random
peripheral blood sample can be used to obtain this ratio even while
the patient is receiving antihypertensive medications, when the
effects of the medications on PRA and aldosterone are considered.
(Data from Weinberger and coworkers [3,4].)
LOCALIZING TESTS FOR PRIMARY ALDOSTERONISM

Test
Adrenal computed tomographic scan
Adrenal isotopic scan
Adrenal venography
Adrenal magnetic resonance imaging
Adrenal venous blood sampling with
adrenocorticotropic hormone infusion
Sensitivity, %
Specificity, %
50
50
70
?
>92
60
65
80
?
>95
FIGURE 4-8
Localizing tests for primary aldosteronism. Adrenal venous blood
sampling with determination of both aldosterone and cortisol
concentrations during adrenocorticotropic hormone stimulation
provides the most accurate way to identify unilateral hyperaldosteronism. This approach minimizes artefact owing to episodic
steroid secretion and to permit correction for dilution of adrenal
venous blood with comparison of values to those in the inferior
vena cava. (see Fig. 4-12). (Data from Weinberger and coworkers [3].)
A
FIGURE 4-9
Normal and abnormal adrenal isotopic scans. A, Normal scan.
Increased bilateral uptake of I131-labeled iodo-cholesterol of normal adrenal tissue is shown above the indicated renal outlines.
4.6

B, Intense increase in isotopic uptake by the left adrenal (as viewed
from the posterior aspect) containing an adenoma.
B
FIGURE 4-10
Adrenal venography in primary aldosteronism. A, Typical leaflike pattern of the normal right adrenal venous drainage. B, In
contrast, marked distortion of the normal
venous anatomy by a relatively large (3-cmdiameter) adenoma of the left adrenal.
Most solitary adenomas responsible for primary aldosteronism are smaller than 1 cm
in diameter and thus usually cannot be seen
using anatomic visualizing techniques.
Normal
Plasma aldosterone, ng/dL
60
Adenoma
Hyperplasia
50
40
30
20
10
0
8 AM
Supine
Noon
Upright
8 AM
Supine
8 AM
Supine
Noon
Upright
Noon
Upright
FIGURE 4-11
Changes in plasma aldosterone with upright posture. AC, Depicted are individual data
for persons showing temporal and postural changes in plasma aldosterone concentration
in normal persons (panel A), and in patients with primary aldosteronism owing to a solitary
adrenal adenoma (panel B) or to bilateral adrenal hyperplasia (panel C). Blood is sampled
at 8 AM, while the patient is recumbent, and again at noon after 4 hours of ambulation.
In normal persons the increase in plasma

renin activity associated with upright posture
results in a marked increase in plasma aldosterone at noon compared with that at 8 AM
(see Fig. 4-4). In adenomatous primary
aldosteronism, the plasma renin activity is
markedly suppressed and does not increase
appreciably with upright posture. Moreover,
aldosterone production is modulated by
adrenocorticotropic hormone (which decreases
from high levels at 8 AM to lower values at
noon (see Fig. 4-4). Thus, these patients
typically demonstrate lower levels of aldosterone at noon than they do at 8 AM. In
patients with bilateral adrenal hyperplasia,
the plasma renin activity tends to be more
responsive to upright posture and aldosterone production also is more responsive
to the renin-angiotensin system. Thus, postural increases in aldosterone usually are
seen. Exceptions to these changes occur in
both forms of primary aldosteronism, however, making the postural test less sensitive
and specific [3].
4.7
AC
TH
TH
AC
TH
AC
AC
TH
A
C
A
C
A
C
A
C
A
C
Bilateral aldosteronism
FIGURE 4-12
Adrenal venous blood sampling during infusion of adrenocorticotropic hormone (ACTH) [3]. A, Bilateral aldosteronism. A schematic
representation of the findings in primary aldosteronism owing to
bilateral adrenal hyperplasia is shown on the left. When blood is
sampled from both adrenal veins and the inferior vena cava during
ACTH infusion, the aldosterone-to-cortisol ratio is similar in both
adrenal effluents and higher than that in the inferior vena cava. In
such cases, medical therapy (potassium-sparing diuretic combinations
such as hydrochlorothiazide plus triamterene, amiloride, or spirolactone and calcium channel entry blockers) usually is effective. B,
Unilateral aldosteronism. On the right is depicted the findings in a
patient with a unilateral right adrenal lesion. This lesion can be
diagnosed by an elevated aldosterone-to-cortisol ratio in right adrenal
A
C
Unilateral aldosteronism
venous blood compared with that of the left adrenal and the inferior
vena cava. Even if the venous effluent cannot be accurately sampled
from one side (as judged by the levels of cortisol during ACTH
infusion), when the contralateral adrenal venous effluent has an
aldosterone-to-cortisol ratio lower than that in the inferior vena
cava, it can be inferred that the unsampled side is the source of
excessive aldosterone production (unless there is an ectopic source).
In such cases, surgical removal of the solitary adrenal lesion usually
results in normalization of blood pressure and the attendant metabolic
abnormalities. Medical therapy also is effective but often requires
high doses of Aldactone (GD Searle & Co., Chicago) (200 to 800
mg/d), which may be intolerable for some patients because of side
effects. Aaldosterone; Ccortisol.
4.8

A section of a typical adrenal adenoma in primary aldosteronism
pathology. A relatively large (2-cm-diameter) adrenal adenoma
with its lipid-rich (bright yellow) content is shown.
180
FIGURE 4-14
Glucocorticoid-remediable aldosteronism. AC, Seen are the effects
of dexamethasone and spironolactone on blood pressure in a father
(panel A) and two sons, one aged 6 years (panel B) and the other
aged 8 years (panel C). Blood pressure levels are shown before and
after treatment with dexamethasone (left) or spironolactone (right) [5].
Note that the maximum blood pressure reduction with dexamethasone
required more than 2 weeks of treatment. Similarly, the maximum
response to spironolactone was both time- and dose-dependent.
Father
160
140
120
100
80
mg
200
100
60
A
Son 1
Blood pressure
160
Dexamethasone
Spironolactone
140
120
100
80
60
200
100
40
Son 2
160
140
120
100
80
60
200
100
40
3
4
Weeks
4 6
Months
Urinary aldosterone,
g/ 24 h
20
15
10
5
20
15
10
Dexamethasone
1.0
50
0.8
0.6
0.4
0.2
Serum potassium, mEq/L
A
Plasma renin activity, ng AI/mL- 3hr
25
25
Plasma aldosterone,
ng/100 mL
Plasma cortisol, g/ 100 mL
Changes with dexamethasone
40
30
20
10
7
6
5
4
3
Weeks
FIGURE 4-15
Humoral changes in glucocorticoid-remediable aldosteronism with dexamethasone. AE, Depicted are the changes
in plasma cortisol (panel A), urinary aldosterone (panel B), plasma renin activity (PRA) (panel C), plasma aldosterone (panel D), and serum potassium (panel E) before and after dexamethasone administration in the patients
in Figure 4-14. Note that before dexamethasone administration, serum cortisol was in the normal range and was
markedly suppressed after treatment. Urinary aldosterone was completely normal and plasma aldosterone was
Glomerulosa
Glomerulosa
AII
AII
Aldosterone
Aldosterone
ACTH
Aldosterone
ACTH
Cortisol
Chimeric
Aldos
Fasciculata
Fasciculata
Aldosterone
Cortisol
+
Aldosterone
+
18OH cortisol
+
18OXO cortisol
4.9
elevated in only one

patient before dexamethasone administration. The
diagnosis was made by
demonstrating that
the plasma aldosterone
concentration failed to
suppress normally after
intravenous saline infusion (2 L/4 h) [6]. After
dexamethasone administration, both plasma and
urinary aldosterone levels
decreased markedly
(except for one occasion
when it is suspected that
the patient did not comply with dexamethasone
therapy). PRA, which was
markedly suppressed
before treatment,
increased with dexamethasone. Note also
that serum potassium
levels were normal in
two of the three patients
before treatment with
dexamethasone but
increased with therapy
in all three [5]. All of
these changes reverted to
control baseline values
when dexamethasone
therapy was discontinued.
FIGURE 4-16
Normal and chimeric aldosterone synthase
in glucocorticoid-remedial aldosteronism
(GRA). A, Normal relationship between the
stimuli and site of adrenal cortical steroid
production. Aldosterone synthase normally
responds to angiotensin II (AII) in the zona
glomerulosa, resulting in aldosterone synthesis and release (see Figs. 4-2 and 4-3). B, In
GRA, a chimeric aldosterone synthase gene
results from a mutation, which stimulates
production of aldosterone and other steroids
from the zona glomerulosa under the control
of adrenocorticotropic hormone (ACTH)
(Fig. 4-17). Thus, when ACTH production is
suppressed by steroid administration, aldosterone production is reduced.
4.10

FIGURE 4-17
Mutation of the (11-OHase) chimeric aldosterone synthase gene
[8]. The unequal crossing over between aldosterone synthase and
11-hydroxylase genes resulting in the mutated gene responsible for
glucocorticoid-remedial aldosteronism is described.
11OHase
5'
3'
5'
3'
Unequal crossing over
5'
3'
Aldosterone synthase
5'
3'
5'
3'
5'
3'
5'
3'
Chimeric gene
11OHase
Cushings Syndrome

Physical characteristics of Cushings syndrome. A, Side profile of a patient with Cushings
syndrome demonstrating an increased cervical fat pad (so-called buffalo hump), abdominal
obesity, and thin extremities and petechiae (on the wrist). The round (so-called moon)
facial appearance, plethora, and acne cannot be seen readily here. B, Violescent abdominal
striae in a patient with Cushings syndrome. Such striae also can be observed on the inner
parts of the legs in some patients.
4.11
Pituitary
Pituitary
Pituitary
CRF
()
()
()
Cortisol
ACTH
Cortisol
ACTH
Cortisol
ACTH
Adrenal cortex
(zona fasciculata
zona reticularis)
FIGURE 4-19
Normal pituitary-adrenal axis. Corticotropinreleasing factor (CRF) acts to stimulate the
release of adrenocorticotropic hormone
(ACTH) from the anterior pituitary. ACTH
then stimulates the adrenal zona fasciculata
and zona reticularis to synthesize and release
cortisol (see Figs. 4-2 and 4-3). The increased
levels of cortisol feed back to suppress additional release of ACTH. As shown in Figure
4-4, ACTH and cortisol have circadian
patterns.
Adrenal cortex
(zona fasciculata
zona reticularis)
Adrenal cortex
(zona fasciculata
zona reticularis)
FIGURE 4-20
Pituitary Cushings disease. Pituitary Cushings
disease results from excessive production of
adrenocorticotropic hormone (ACTH), typically owing to a benign adenoma. Excess
ACTH stimulates both adrenals to produce
excessive amounts of cortisol and results in
bilateral adrenal hyperplasia. The increased
cortisol production does not suppress ACTH
release, however, because the pituitary tumor
is unresponsive to the normal feedback suppression of increased cortisol levels. The
diagnosis usually is made by demonstration
of elevated levels of ACTH in the face of
elevated cortisol levels, particularly in the
afternoon or evening, representing loss of
the normal circadian rhythm (see Fig. 4-4).
Radiographic studies of the pituitary (computed tomographic scan and magnetic resonance imaging) will likely demonstrate the
source of increased ACTH production. When
the pituitary is the source, surgery and irradiation are therapeutic options.
FIGURE 4-21
Adrenal Cushings syndrome. Adrenal
Cushings syndrome typically is caused by
a solitary adrenal adenoma (rarely by carcinoma) producing excessive amounts of
cortisol autonomously. The increased levels
of cortisol feed back to suppress release of
adrenocorticotropic hormone (ACTH) and
corticotropin-releasing factor. The finding
of very low ACTH levels in the face of
elevated cortisol values and a loss of the
circadian pattern of cortisol confirm the
diagnosis (see Fig. 4-4). Additional anatomic
studies of the adrenal (computed tomographic
scan and magnetic resonance imaging) usually
disclose the source of excessive cortisol production. Surgical removal usually is effective.
4.12
Cushing's syndrome: ectopic etiology
SCREENING TESTS FOR CUSHINGS SYNDROME
Ectopic
Tumor
Test
Pituitary
Elevated PM serum cortisol

Elevated urinary 17-hydroxy corticosteroids
Elevated urinary free cortisol
Sensitivity, %
Specificity, %
75
>90
>95
60
60
>95
()
Cortisol
ACTH
ACTH
FIGURE 4-23
Screening tests for Cushings syndrome. Whereas elevated evening
plasma cortisol levels typically indicate abnormal circadian rhythm,
other factors such as stress also can cause increased levels late in
the day. Urinary levels of 17-hydroxy corticosteroids may be
increased in association with obesity. In such cases, repeat measurement after a period of dexamethasone suppression may be required
to distinguish this form of increased glucocorticoid excretion from
Cushings syndrome. The measurement of urinary-free cortisol is
the most sensitive and specific screening test.
Adrenal cortex
(zona fasciculata
zona reticularis)
FIGURE 4-22
Ectopic etiology of Cushings syndrome. Rarely, Cushings syndrome may be due to ectopic production of adrenocorticotropic
hormone (ACTH) from a malignant tumor, often in the lung. In
such cases, hypercortisolism is associated with increased levels of
ACTH-like peptide; however, no pituitary lesions are found.
Patients with ectopic Cushings syndrome often are wasted and
have other manifestations of malignancy.
FIGURE 4-24
Algorithm for differentiation of Cushings syndrome. The first step in the differentiation
of Cushings syndrome after diagnosing hypercortisolism is measurement of plasma
adrenocorticotropic hormone (ACTH) levels. Typically, these should be reduced after
the morning hours (see Fig. 4-4). In pituitary Cushings disease and ectopic forms
of Cushings syndrome, elevated values are
observed, especially in the afternoon and
evening. The next step in differentiation is
an anatomic evaluation of the pituitary.
When no abnormality is found, the next
step is a search for a malignancy, typically
in the lung. The finding of low ACTH levels points to the adrenal as the source of
excessive cortisol production, and anatomic
studies of the adrenal are indicated. CT
computed tomography; MRImagnetic
resonance imaging.
4.13
Catecholamines
FIGURE 4-25
Synthesis, actions, and metabolism of catecholamines. Depicted
is the synthesis of catecholamines in the adrenal medulla [9].
Epinephrine is only produced in the adrenal and the organ of
Zuckerkandl at the aortic bifurcation. Norepinephrine and dopamine
can be produced and released at all other parts of the sympathetic
nervous system. The kidney is the primary site of excretion of
catecholamines and their metabolites, as noted here. The kidney

also can contribute catecholamines to the urine. The relative
contributions of norepinephrine and epinephrine to biologic
events is noted by the plus signs. BMRbasal metabolic rate;
CNScentral nervous system; NEFAnonesterified fatty acids;
VMAvanillylmandelic acid.
4.14
Pheochromocytoma
Blood pressure taken at
2-min intervals
5-min intervals
150
100
240
230
220
210
190
180
170
160
140
130
120
110
90
80
70
60
40
30
20
10
50
200
250
Calibrate
8:30
10
5:00
7:45
10
11
PM
PM
AM
AM
AM
AM
AM
AM
12
Noon
1
PM
During the attack:

Blood pressure, 192/100 mm Hg
Pulse 108
Respirations, 24
FIGURE 4-26
Paroxysmal blood pressure pattern in pheochromocytoma.
Note the extreme variability of blood pressure in this patient
with pheochromocytoma during ambulatory blood pressure
monitoring [9]. Whereas most levels were within the normal

Neurofibroma associated with pheochromocytoma. Neurofibromas
are sometimes found in patients with pheochromocytoma. These
lesions are soft, fluctuant, and nontender and can appear anywhere
on the surface of the skin. These lesions can be seen in profile in
Figure 4-28.
range, episodic increases to levels of 200/140 mm Hg were

observed. Such paroxysms can be spontaneous or associated
with activity of many sorts. (Adapted from Manger and Gifford
FIGURE 4-28
Caf au lait lesions
in a patient with
pheochromocytoma.
These light-browncolored (coffeewith-cream-colored)
lesions, sometimes
seen in patients with
pheochromocytoma,
usually are larger
than 3 cm in the
largest dimension.
In this particular
patient, neurofibromas also are present
and can be seen in
profile.
4.15
DISORDERS ASSOCIATED WITH

PHEOCHROMOCYTOMA
FIGURE 4-29
Disorders associated with pheochromocytoma. In addition to the neurofibromas and
caf au lait lesions depicted in Figures 4-27 and 4-28, several other associated abnormalities have been reported in patients with pheochromocytoma. (From Ganguly et al. [9];
with permission.)
Cholelithiasis
Neurofibromas
Caf au lait lesions
Multiple endocrine neoplasia, types II and III
Von Hippel-Lindau syndrome
(hemangioblastoma and angioma)
Mucosal neuromas
Medullary thyroid carcinoma
COMMON SYMPTOMS
AND FINDINGS IN
PHEOCHROMOCYTOMA
Patients, %
Symptoms
Severe headache
Perspiration
Palpitations, tachycardia
Anxiety
Tremulousness
Chest, abdominal pain
Nausea, vomiting
Weakness, fatigue
Weight loss
Dyspnea
Warmth, heat intolerance
Visual disturbances
Dizziness, faintness
Constipation
Finding
Hypertension:
Sustained
Paroxysmal
Pallor
Retinopathy:
Grades I and II
Grades III and IV
Abdominal mass
Associated multiple endocrine
adenomatosis
82
67
60
45
38
38
35
26
15
15
15
12
7
7
61
24
44
40
53
9
6
FIGURE 4-30
Common symptoms
and findings in pheochromocytoma. Note
that severe hypertensive retinopathy,
indicative of intense
vasoconstriction,
frequently is
observed. (Adapted
from Ganguly
et al. [10].)
SCREENING AND DIAGNOSTIC TESTS

IN PHEOCHROMOCYTOMA
Test
Elevated 24-h urinary catecholamines,
vanillylmandelic acid, homovanillic
acid, metanephrines
Abnormal clonidine suppression test
Elevated urinary sleep norepinephrine
Sensitivity, %
Specificity, %
85
80
75
>99
85
>99
FIGURE 4-31
Screening and diagnostic tests in pheochromocytoma. Drugs, incomplete urine collection, and episodic secretion of catecholamines can
influence the tests based on 24-hour urine collections in a patient
with a pheochromocytoma. The clonidine suppression test is fraught
with false-negative and false-positive results that are unacceptably
high for the exclusion of this potentially fatal tumor. The sleep
norepinephrine test eliminates the problems of incomplete 24-hour
urine collection because the patient discards all urine before retiring;
saves all urine voided through the sleep period, including the first
specimen on arising; and notes the elapsed (sleep) time [10]. The sleep
period is typically a time of basal activity of the sympathetic nervous
system, except in patients with pheochromocytoma (see Fig. 4-32).
4.16
Sleep urinary norepinephrine excretion, g
1000
Patient I
Patient II
Patient III
Patient IV
Patient V
Patient VI
100
FIGURE 4-32
Nocturnal (sleep) urinary norepinephrine. The values for urinary
excretion of norepinephrine are shown for normal persons and
patients with essential hypertension as mean plus or minus SD
[10]. Values for patients with pheochromocytoma are indicated by
symbols. Note that the scale is logarithmic and the highest value
for patients with normal or essential hypertension was less than 30
g, whereas the lowest value for a patient with pheochromocytoma
was about 75 g. Most patients with pheochromocytomas had values an order of magnitude higher than the highest value for
patients with essential hypertension.
Maximum for normal

Maximum for hypertensive
10
Hypertensive
mean + SD
Normal
mean + SD
LOCALIZATION OF PHEOCHROMOCYTOMA
Test
Abdominal plain radiograph
Intravenous pyelogram
Adrenal isotopic scan
(meta-iodobenzoylguanidine)
Adrenal computed tomographic scan
Sensitivity, %
Specificity, %
40
60
85
50
75
85
>95
>95
FIGURE 4-33
Localization of pheochromocytoma. Once the diagnosis of
pheochromocytoma has been made it is very important to localize
the tumor preoperatively so that the surgeon may remove it with a
minimum of physical manipulation. Computed tomographic scan
or MRI appears to be the most effective and safest techniques for
this purpose [10]. The patient should be treated with -adrenergic
blocking agents for 7 to 10 days before surgery so that the contracted
extracellular fluid volume can be expanded by vasodilation.
FIGURE 4-34
Intravenous pyelogram in pheochromocytoma. Note the
displacement of the
left kidney (right) by
a suprarenal mass.
FIGURE 4-35
AD, Computed tomographic scans in four patients with pheochromocytoma [10]. The black arrows identify the adrenal tumor in
A
FIGURE 4-36 (see Color Plates)
A and B, Pathologic appearance of pheochromocytoma before
(panel A) and after (panel B) sectioning. This 3.5-cm-diameter
4.17
these four patients. Three patients have left adrenal tumors, and in
one patient (panel B) the tumor is on the right adrenal.
B
tumor had gross areas of hemorrhage noted by the dark areas
visible in the photographs.
4.18
References
1.
Netter FH: Endocrine system and selected metabolic diseases. In Ciba

Collection of Medical Illustrations, vol. 4; 1981:Section III, Plates 5, 26.
2.
DeGroot LJ, et al.: Endocrinology, edn 2. Philadelphia: WB Saunders;

1989:1544.
3.
Weinberger MH, Grim CE, Hollifield JW, et al.: Primary aldosteronism: diagnosis, localization and treatment. Ann Intern Med 1979,
90:386395.
4.
Weinberger MH, Fineberg NS: The diagnosis of primary aldosteronism

and separation of subtypes. Arch Intern Med 1993, 153:21252129.
5.
Grim CE, Weinberger MH: Familial, dexamethasone-suppressible

normokalemic hyperaldosteronism. Pediatrics 1980, 65:597604.
6.
Kem DC, Weinberger MH, Mayes D, Nugent CA: Saline suppression

of plasma aldosterone and plasma renin activity in hypertension. Arch
Intern Med 1971, 128:380386.
7: Lifton RP, Dluhy RG, Powers M: Hereditary hypertension caused by

chimeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet 1992, 2:6674.
8. Lifton RP, Dluhy RG, Powers M: A glucocorticoid-remediable aldosterone synthase gene causes glucocorticoid-remediable aldosteronism
and human hypertension. Nature 1992, 355:262265.
9. Manger WM, Gifford RW Jr: Pheochromocytoma. New York:
Springer-Verlag; 1977:97.
10. Ganguly A, Henry DP, Yune HY, et al.: Diagnosis and localization of
pheochromocytoma: detection by measurement of urinary norepinephrine during sleep, plasma norepinephrine concentration and computed
axial tomography (CT scan). Am J Med 1979, 67:2126.
Insulin Resistance
and Hypertension
Theodore A. Kotchen
esistance to insulin-stimulated glucose uptake is associated with

increased risk for cardiovascular disease [1]. Risk factors for
cardiovascular disease tend to cluster within individuals, and
insulin resistance may be the link between hypertension and dyslipidemia.
Depending on the populations studied and methodologies used for
defining insulin resistance, approximately 25% to 40% of nonobese
nondiabetic patients with hypertension are insulin-resistant [2]. Insulin
resistance also has been observed in genetic and acquired animal models
of hypertension. A constellation of insulin resistance, reactive hyperinsulinemia, increased triglycerides, decreased high-density lipoprotein
cholesterol, and hypertension was designated as syndrome X by
Reaven in 1988 [3].
Although a number of putative mechanisms have been proposed, it
is unclear whether insulin resistance or reactive hyperinsulinemia, or
both, actually cause hypertension. The recent observations that insulinsensitizing agents attenuate the development of hypertension lend
credence to this hypothesis [4]. As discussed subsequently, however,
these agents may lower blood pressure by different mechanisms.
Whatever mechanism may be involved, the observation that a single
agent may have the capacity to both increase insulin sensitivity and
lower blood pressure is potentially of considerable clinical significance.
Noninsulin-dependent diabetes mellitus represents an extreme of
insulin resistance. Among diabetics, a two- to threefold increased
prevalence of hypertension exists. Hypertension is associated with a
fourfold increase in mortality among patients with noninsulin-dependent diabetes, and antihypertensive drug therapy has a beneficial
impact on both macrovascular and microvascular disease [5]. Despite
the potential concern that diuretics may augment insulin resistance,
diabetic patients benefit from antihypertensive therapy with diuretics.
The renal protective effect of antihypertensive drugs varies among
different classes of agents. Angiotensin-converting enzyme inhibitors
decrease proteinuria and retard the progression of renal insufficiency
in diabetic patients with normal blood pressure and hypertension.
CHAPTER
5.2
This benefit is independent of an effect on blood pressure

and may be related specifically to the capacity of these agents
to dilate the efferent renal arteriole. Results of studies evaluating the effects of calcium antagonists on the progression of
diabetic nephropathy are varied. Some studies suggest that
Men
7.0
dihydropyridine calcium antagonists accelerate the progression of diabetic nephropathy, particularly in the short term.
Additional studies are required to evaluate the antihypertensive potential of insulin-sensitizing agents in patients with
noninsulin-dependent diabetes.
Women
Total cholesterol, mmol/L
5054 y
6.5
4049 y
6.0
3039 y
B. NATIONAL HEALTH AND NUTRITION

EXAMINATION SURVEY II
4049 y
3039 y
5.5
2029 y
1. Persons with blood pressure >140/90 mm Hg or taking medication for hypertension:

40% have cholesterol >240 mg/dL
2. Persons with blood cholesterol >240 mg/dL:
46% have blood pressure >140/90 mm Hg
2029 y
5.0
70
80
90
100
70
80
90
Diastolic blood pressure, mm Hg
100
FIGURE 5-1
Hyperlipidemia and hypertension. A, Epidemiologic studies document an association between serum cholesterol and blood pressure
in men and women. B, Based on data from the National Health
Epidemiologic + clinical association

Hereditary + acquired mechanisms
Obesity
Insulin-resistance
Hyperinsulinemia
Glucose tolerance
Diabetes type II
Dyslipidemia, hypertension
and Nutrition Examination Survey II, persons with hypertension

have a high prevalence of hyperlipidemia and vice versa [6].
(Panel A from Bonna and Thelle [7]; with permission.)
B. HYPERTENSION AND
INSULIN RESISTANCE
Type II diabetes mellitus
Obesity
Essential hypertension
Salt sensitive (?)
Experimental hypertension
Dahl-salt-sensitive rats
Spontaneously hypertensive rats
FIGURE 5-2
Insulin resistance and hypertension.
A, Genetic and nutritional factors contribute to insulin resistance and resultant
hyperinsulinemia. In addition to obesity
and type II diabetes, hyperlipidemia and
hypertension also may be associated with
insulin resistance. Insulin resistance may
account for the association of hyperlipidemia with hypertension. B, Insulin resistance is associated with hypertension in a
number of clinical and experimental settings. (Panel A from Ferrari and
Weidmann [8]; with permission.)
5.3
Insulin Resistance and Hypertension
120
*
80
Control group
40
Plasma insulin, U/mL
0
60
40
20
0
0
30
60
Time, min
90
120
FIGURE 5-3
Insulin resistance
based on glucose
and insulin responses
to glucose load. In
response to an oral
glucose load of 75 g,
compared with persons with normal
blood pressure,
patients with hypertension tend to have
higher plasma glucose
and insulin levels.
These data suggest
that patients with
hypertension are
insulin resistant.
(From Ferrannini
and coworkers [9];
with permission.)
10
Glucose, mmol/L
Hypertensive patients
1 mmol/l = 0.0555 mg/dL
8
6
Salt-sensitive
Salt-resistant
4
0
30
400
200
30
Count
60
90
Time, min
120
150
FIGURE 5-4
Salt sensitivity.
Persons who have
salt-sensitive hypertension tend to
be more insulinresistant than are
those who are saltresistant. That is,
patients who are saltsensitive have higher
plasma glucose and
insulin responses to
a glucose load than
do those who are
salt-resistant.
(From Bigazzi and
coworkers [10];
with permission.)
FIGURE 5-5
Insulin sensitivity. Insulin sensitivity also
may be assessed using the euglycemic insulin
clamp technique. The frequency distribution
for insulin-mediated glucose disposal during
euglycemic insulin clamping (M value) differs
in persons with normal blood pressure and
those with hypertension. The percentage of
persons with hypertension considered
insulin-resistant depends on the definition
of insulin resistance. In this study, 27% of
patients with hypertension were classified
as being insulin-resistant based on an M value
over two SDs above the mean for persons
with normal blood pressure. (From Lind
10
8
6
4
2
0
4
150
1 pmol/L = 7.175 U/mL
12
120
Hypertensive subjects
Control subjects
90
600
16
14
60
800
Insulin, pmol/L
Plasma glucose, mg/100 mL
140
10
12
14
M value at clamp, mg/kg/min
SYNDROME X AND
ASSOCIATED CONDITIONS
Hypertension
Hyperinsulinemia
Increased triglycerides
Decreased high-density lipoprotein cholesterol
Increased low-density lipoprotein cholesterol
Decreased plasminogen activator
Increased plasminogen activator inhibitor
Increased blood viscosity
Increased uric acid
Increased fibrinogen (?)
FIGURE 5-6
As originally defined, syndrome X includes hypertension, hyperinsulinemia, increased
plasma triglycerides, and decreased HDL cholesterol. The syndrome also may be
associated with clustering of additional cardiovascular disease risk factors.
5.4
Obesity
Vascular
growth
Antinatriuresis
Increased 1
adrenegic
receptors
Endothelial injury
Increased endothelial superoxide

anion production
Increased degradation of nitric oxide
Hyperglycemia
Hyperlipidemia
Impaired endotheliumdependent vasodilation
FIGURE 5-8
Metabolic consequences of insulin
resistance. These
consequences also
may affect peripheral vascular resistance.
Hypercholesterolemia
may result in vascular
endothelial injury
and, hence, impaired
vasodilation.
Hypercholesterolemia
(low-density lipoprotein, lipoprotein (a))
FIGURE 5-7
Hypertension associated with insulin resistance. It is unclear whether hyperinsulinemia associated with insulin resistance causes hypertension, although a number of
potential mechanisms have been proposed.
Genetic predisposition
Resistance to
insulin-stimulated
glucose uptake
Compensatory
hyperinsulinemia
Increased
sympathetic nervous
system activity
Nutrition
High glucose
Decreased nitric
oxide production
Protein kinase C
activation
Increased
sodium-hydrogen
antiport activity
FIGURE 5-9
Results of high glucose concentrations.
High glucose concentrations may
inhibit nitric oxide
production and alter
ion transport in vascular smooth muscle
cells, favoring vasoconstriction.
Impaired endothelium-dependent vasodilation
Sulfonylureas
R1
Biguanides
R1
R2
SO2 NH C NH R2
Thiazolidinediones
N C NH C NH2
CH2
R1 O
NH
NH
O
C1
O
C NH CH2CH2
H 3C
SO2 NH C NH
H 3C
O
NH
N
N C NH C NH2
NH
CH3CH2
CH2CH2 O
CH2
NH
O
Glyburide
Metformin
Pioglitazone
Systolic blood pressure,

mm Hg
O
NH
FIGURE 5-11
Pioglitazone in the treatment of hypertension in rats. A, Systolic
blood pressures in Dahl-salt-sensitive rats treated with either vehicle or
pioglitazone (a thiazolidinedione) for 3 weeks. Pioglitazone attenuated
development of hypertension in this animal model. Weight gain did
not differ in the two groups.
160
Control
Pioglitazone
140
120
100
80
0
FIGURE 5-10
Effects of chemically
distinct oral hypoglycemic agents on
blood pressure.
Sulfonylureas stimulate
endogenous insulin
secretion and do not
lower blood pressure.
In contrast, biguanides
and thiazolidinediones
increase insulin sensitivity
without stimulating
endogenous insulin
secretion, and drugs in
these classes lower
blood pressure.
10
12
Day
14
16
18
20
22
5.5
B. HEMODYNAMIC MEASUREMENTS IN DAHL-SALT-SENSITIVE RATS
Control group
Group treated with pioglitazone
MODELS IN WHICH
THIAZOLIDINEDIONES LOWER
BLOOD PRESSURE
Mean intra-arterial
pressure, mm Hg
Cardiac index,
mL/min/100 g
Total peripheral resistance,

mm Hg/mL/min/100 g
129 1
121 3*
51.4 1.6
59.11.7*
2.50 0.07
2.07 0.07*
*P<0.05

B, Direct intra-arterial pressure and cardiac index (thermodilution) in these same chronically
instrumented, conscious pioglitazone-treated and control rats. Compared with control animals, rats treated with pioglitazone had lower mean arterial pressure, higher cardiac index,
and lower total peripheral resistance. Thus, attenuation of hypertension by pioglitazone is due
to a reduction of peripheral resistance. (From Dubey and coworkers [11]; with permission.)
AGENTS THAT INCREASE INSULIN SENSITIVITY, DECREASE PLASMA LIPID

CONCENTRATIONS, AND LOWER BLOOD PRESSURE IN ANIMAL MODELS
AND PRELIMINARY STUDIES IN HUMANS
Thiazolidinediones
Metformin
Humans (?)
Vanadyl sulfate
Fructose-fed rats
Etomoxir
Clofibrate
Fenfluramine derivatives
Fructose-fed rats
Humans
Mean arterial pressure, mm Hg
200
Dahl-S rat
1-Kidney, 1-clip rat
Obese Zucker rat
Fructose-fed rat
L-NNAtreated rat
SHR
Obese rhesus monkey
Watanabe hyperlipidemic rabbit
Obese human
FIGURE 5-12
Thiazolidinediones lower blood pressure in
several models of experimental hypertension and in obese humans.
FIGURE 5-13
Agents that increase insulin sensitivity,
decrease plasma lipid concentrations, and
lower blood pressure in animal models and
preliminary studies in humans.
Lovastatin/pravastatin
Human (?)
EFFECT OF CHOLESTEROL REDUCTION ON BLOOD PRESSURE RESPONSE

TO MENTAL STRESS IN PATIENTS WITH NORMAL BLOOD PRESSURE AND
HIGH CHOLESTEROL
180
160
140
120
100
80
Clofibrate Vehicle Clofibrate Vehicle
Dahl-S
Placebo group
Group treated with lovastatin
Systolic blood pressure
Diastolic blood pressure
Baseline
Stress
Baseline
Stress
122
119
141
133*
69
67
78
75
Dahl-R
FIGURE 5-14
Clofibrate in prevention of hypertension in
rats. Clofibrate prevents the development of
hypertension in Dahl salt-sensitive rats.
This agent does not affect blood pressure in
Dahl salt-resistant rats. (From Roman and
FIGURE 5-15
In humans with normal blood pressure who have high serum cholesterol concentrations,
treatment with lovastatin lowers serum cholesterol and attenuates the systolic blood
pressure response to mathematics-induced stress. (From Sung and coworkers [13];
with permission.)
5.6

FIGURE 5-16
Insulin-sensitizing and lipid-lowering agents may lower blood
pressure by a number of different mechanisms. Different agents
may act through different mechanisms.
ANTIHYPERTENSIVE MECHANISMS OF
INSULIN-SENSITIZING AGENTS
Block agonist-induced calcium ion entry into vascular smooth muscle cells
Inhibit agonist-mediated vasoconstriction
Inhibit growth of vascular smooth muscle cells
Augment endothelium-dependent vasodilation
Direct effect
Metabolic effect
Natriuresis
Increase 20-hydroxy-eicosatetraenoic acid production
Increase renal medullary blood flow
0.95
R172 #18 + 20 ng/mL PDGF
0.90
0.95
Intracellular [Ca2+]i
0.90
0.85
0.80
350
0.85
0.80
0.75
(59)
* P<0.05
200
150
0.70
0.65
50
0.65
0.60
(286) (290)
0
0 100 200 300 400 500 600 700 800
250
100
Time, s
Control
Metformin
(73)
300
0.70
0.75
0 100 200 300 400 500 600 700 800
Arginine vasopressin
R172 #3141 + 2 ug/mL ciglitazone

+ 20 ng/mL PDGF
Basal
450
Time, s
FIGURE 5-17
Use of ciglitazone to abolish calcium concentration elevation. Ciglitazone, a thiazolidinedione,
abolishes agonist-stimulated sustained elevations of intracellular calcium concentrations.
Shown are time-dependent plots of changes in intracellular calcium (in arbitrary units;
[Ca2+]i) induced by platelet-derived growth factor (PDGF) in human gliobastoma cells
with and without preincubation with ciglitazone. A, Addition of PDGF to control cells is
indicated by the vertical line. B, An identical experiment conducted on cells pretreated with
ciglitazone. The capacity of this agent to shorten the duration of agonist-stimulated
increases in intracellular calcium may result in attenuation of both growth of vascular
smooth muscle cells and vasoconstriction. (From Pershadsingh and coworkers [14];
with permission.)
Peak
400
Thrombin
(213)
350
(231)
Delta
* P<0.05
300
[Ca2+]i(nM)
Intracellular [Ca2+]i
1.00
[Ca2+]i(nM)
1.05
250
*
200
150
(286) (290)
100
50
0
Basal
Peak
Delta
FIGURE 5-18
Use of metformin to attenuate intracellular
calcium concentration elevation. Metformin
is a biguanide that attenuates agonist-stimulated increases of intracellular calcium concentrations in vascular smooth muscle. (From
Bhalla and coworkers [15]; with permission.)
Cell number (x104)
28
24
Insulin
20
Insulin + pioglitazone
(days 06)
16
12
8
Insulin + pioglitazone
0.4% FCS
0
0
6
8
10
Days in culture
12
FIGURE 5-19
Effect of pioglitazone on insulin-induced proliferation of arterial
smooth muscle cells. Inhibition of insulin-stimulated vascular
hyperplasia and hypertrophy is one potential mechanism by which
insulin-sensitizing and lipid-lowering agents may decrease peripheral
resistance. Two kinds of evidence suggest that thiazolidinediones
inhibit the growth of vascular smooth muscle cells in vitro. Shown
here, pioglitazone inhibits insulin-stimulated proliferation of vascular
smooth muscle cells. Pioglitazone also inhibits 3H-thymidine incorporation in vascular smooth muscle cells (Fig. 5-19). FCSfetal
calf serum. (From Dubey and coworkers [11]; with permission.)
14
FIGURE 5-20
Effect of pioglitazone on 3H-thymidine incorporation in vascular smooth muscle cells.
3H-thymidine incorporation is stimulated by insulin, fetal calf serum (FCS), and epidermal
growth factor (EGF). Pioglitazone inhibits 3H-thymidine incorporation stimulated by each
of these mitogens. Similar observations have been made with pravastatin and lovastatin.
(From Dubey and coworkers [11]; with permission.)
120
100
80
60
40
Insulin = 1 mU/mL
EGF = 100 mg/mL
5% FCS
20
H-Thymidine incorporation,
% of control
5.7
0
0.001
0.01
0.1
10
100
Pioglitazone concentration, uM
Control
Pioglitazone
40
50
Percent of change
Percent of change
50
30
20
10
40
30
20
FIGURE 5-21
Decreases in mean arterial pressure in rats treated with pioglitazone and control Dahl-salt-sensitive rats in response to graded
infusions of norepinephrine and angiotensin II. In vivo, pressor
responses to norepinephrine and angiotensin are II attenuated in
Dahl-salt-sensitive rats treated with pioglitazone [16]. (From
Kotchen and coworkers [16]; with permission.)
10
0
0
Norepinephrine x 108 (log M)
Control
Pioglitazone
100 200 300 400 500

Norepinephrine,
ng/kg/min
2
1
0
Control
Insulin Pioglitazone Insulin

+
pioglitazone
100 200 300 400 500

Angiotensin II,
ng/kg/min
FIGURE 5-22
Half-maximal values for norepinephrine-induced contraction in aortic strips preincubated
with insulin, pioglitazone, or both. In vitro, pressor responsiveness of aortic strips to norepinephrine-induced contraction is inhibited by preincubation with insulin plus pioglitazone
[16]. The half-maximal value is increased for strips incubated with insulin plus pioglitazone
(ie, higher concentrations of norepinephrine are required to achieve half-maximal contraction)
but not in strips incubated with insulin alone or pioglitazone alone.
5.8

FIGURE 5-23
Impaired endothelium-dependent vascular
relaxation and insulin resistance. Insulin
resistance is associated with impaired
endothelium-dependent vascular relaxation,
which is a defect that may be corrected by
insulin-sensitizing agents. One approach to
evaluating vascular endothelial function is
to measure vascular relaxation in response
to acetylcholine. EDRFendothelium
derived relaxing factor.
Substance P
Bradykinin
Acetylcholine
B
Sodium
P
Gq protein
M
nitroprusside
Endothelium
Gi protein
Nitric oxide
L-arginine synthase Nitric oxide
EDRF-nitric oxide
5
60
4
3
2
1
0
Control
Insulin Pioglitazone Insulin

+
pioglitazone
FIGURE 5-24
Half-maximal values for acetylcholineinduced vasodilation in aortic strips preincubated with insulin, pioglitazone, or both. In
the presence of insulin, pioglitazone augments
endothelium-dependent vasodilation. In vitro,
the half-maximal values for acetylcholineinduced vasodilation is less in aortic strips
incubated with insulin plus pioglitazone (ie,
the strips are more responsive to acetylcholine)
than in control strips or strips incubated
with insulin alone or pioglitazone alone [16].
BENEFITS OF CONTROL OF
HYPERTENSION AND DIABETES
Hypertension
Decreased nephropathy
Decreased retinopathy
Decreased stroke, myocardial infarction
Drug specific (?)
Diabetes (type I)
Decreased nephropathy
Decreased retinopathy
Decreased neuropathy
Protein, pmol/min/mg
Acetylcholine x 107 (log M)
Smooth muscle
50
20-Hydroxy-eicosotetraenoic acid
* P<0.05
Control, n = 9
Clofibrate, n = 12
*
2 Cl
+
Na
+
K
40
30
20
10
(+)
20-HETE
+
PLC
3 Na
All
bradykinin
vasopressin
+
Ca2
2K
Cl
0
Cortex Outer medulla
Na K Ca2 Mg2
AA
PLA
Liver
FIGURE 5-25
Effect of clofibrate on 20-hydroxy-eicosatetraenoic (20-HETE) production in Dahlsalt-sensitive rats. Insulin stimulates sodium
reabsorption in the proximal tubule.
Consequently, lowering plasma insulin concentrations by increasing insulin sensitivity
would potentially result in less sodium
retention. In addition, clofibrate induces
renal P-450 fatty acid w-hydroxylase activity
and, hence, increases metabolism of arachidonic acid to 20-HETE. (From Roman and
FIGURE 5-26
20-Hydroxy-eicosotetraenoic acid inhibits
chloride transport in the thick ascending
limb of the loop of Henle. This inhibition
results in a natriuretic effect in the
Dahl-salt-sensitive rat. This may be the
mechanism by which clofibrate prevents
hypertension in this animal model.
FIGURE 5-27
Benefits of hypertension control and blood glucose controls are well established in diabetic
patients. Noninsulin-dependent diabetes mellitus represents an extreme of insulin
resistance, and hypertension is a major contributor to the cardiovascular complications
of diabetes. Despite the potential concern that diuretics increase insulin resistance, overall
cardiovascular disease morbidity and mortality are reduced in diabetic patients with
hypertension by antihypertensive therapy with regimens that include diuretics.
5.9

mL/min/1-73 m2
Mean arterial blood

pressure, mm Hg
Start of antihypertensive treatment
125
115
105
95
105
GFR: 0.94
(mL/min/mo)
95
85
GFR: 0.29
(mL/min/mo)
GFR: 0.10
(mL/min/mo)
75
65
55
Albuminuria,
g/min
1250
750
250
2 1 0
FIGURE 5-28
Course of diabetic
nephropathy during
effective antihypertensive treatment in
patients with overt
diabetic nephropathy. Effective antihypertensive therapy
with regimens that
include diuretics
also decreases the
rate of progression
of renal failure
(both the glomerular
filtration rate and
albumin excretion)
in patients with diabetic nephropathy.
(From Parving and
coworkers [17];
with permission.)
50
45
40
35
30
25
20
15
10
5
0
Insulin sensitivity Renal protection

Diuretics
-Blockers
1-Blockers
Calcium ion antagonists
Dihydropyridines
Others
+
?
0
0
0
Increase
-?
+?
0.5
Percent risk reduction = 48.5% (1669)

P = 0.007
Risk reduction = 50.5%

P = 0.006
0.4
0.3
0.2
Placebo
0.1
Captopril
0.0
0.5
Increase
Decrease
Decrease
Increase
FIGURE 5-29
Different antihypertensive agents have different effects on insulin
sensitivity, and in diabetic patients, on renal function. Question
mark indicates inconsistent study results; plus sign indicates a
protective effect; minus sign indicates no protection.
Placebo
Captopril
0.0
Agent
Proportion with event
Percent doubling of baseline creatinine
Time, y
EFFECT OF ANTIHYPERTENSIVE AGENTS ON

INSULIN SENSITIVITY AND RENAL FUNCTION
IN DIABETIC PATIENTS
1.0
1.5
2.0
2.5
Years of follow-up
3.0
3.5
4.0
FIGURE 5-30
Cumulative incidence of events in patients with diabetic nephropathy
in captopril and placebo groups. A, Time to doubling of serum creatinine. B, Time to end-stage renal disease or death. In type I diabetic
patients with nephropathy and either normal blood pressure or hypertension, treatment with angiotensin-converting enzyme inhibitors
2
3
Years from randomization
4.5
decreases proteinuria and retards the rate of progression of renal

insufficiency. The cumulative incidence of doubling of serum creatinine concentrations over time and development of end-stage renal
disease are less in patients treated with captopril than in those treated with placebo. (From Lewis and coworkers [18]; with permission.)
5.10
CHANGES OF MEAN BLOOD PRESSURE, PROTEINURIA, AND GLOMERULAR FILTRATION RATE IN TREATMENT WITH
DIFFERENT ANTIHYPERTENSIVE AGENTS IN PATIENTS WITH INSULIN-DEPENDENT DIABETES MELLITUS AND
NONINSULIN-DEPENDENT DIABETES MELLITUS WHO HAVE MICROALBUMINURIA OR MACROALBUMINURIA
Treatment type
Placebo
Conventional (diuretics and -blockers)
Calcium antagonists:
All except nifedipine and nitrendipine
Nifedipine
Nitrendipine
Patients, n
MBP, %
UProt, %
GFR, %
244
213
489
-2
-10
-16
+39
-20
-52
-8
-9
-1
63
63
39
-16
-12
-17
-42
+2
-48
+2
-48
+30
FIGURE 5-31
Despite similar control of hypertension, different classes of antihypertensive agents have different effects on renal function in patients with
diabetic nephropathy. GFRglomerular filtration rate; MBPmean

blood pressure; Uproturine protein. (From Bretzel [19]; with permission.)
References
1. Kotchen TA, Kotchen JM, OShaughnessy IM: Insulin and hypertensive cardiovascular disease. Curr Opin Cardiol 1996, 11:483489.
2. Lind L, Berne C, Lithell H: Prevalence of insulin resistance in essential
hypertension. J Hypertens 1995, 17:14571462.
3. Reaven GM: Role of insulin resistance in human disease. Diabetes
1988, 37:15951607.
4. Kotchen TA: Attenuation of hypertension by insulin-sensitizing
agents. Hypertension 1996, 28:219223.
5. Nadig V, Kotchen TA: Insulin sensitivity, blood pressure and cardiovascular disease. Cardiol Rev 1997, 5:213219.
6. National High Blood Pressure Education Program and National
Cholesterol Education Program: Working Group Report on
Management of Patients with Hypertension and High Blood
Cholesterol. National Institutes of Health Publication No. 90-2361.
National Institutes of Health, 1990.
7. Bonna KH, Thelle DJ: Association between blood pressure and serum
lipids in a population: the Tromso study. Circulation 1991,
83:13051324.
8. Ferrari P, Weidmann P: Insulin, insulin sensitivity and hypertension.
J Hypertens 1990, 8:491500.
9. Ferrannini E, Buzzigoli E, Bonadonna R, et al.: Insulin resistance in
essential hypertension. N Engl J Med 1987, 317:350357.
10. Bigazzi R, Bianchi S, Baldari G, et al.: Clustering of cardiovascular
risk factors in salt-sensitive patients with essential hypertension: role
of insulin. Am J Hypertens 1996, 9:2432.
11. Dubey RK, Zhang HY, Reddy SR, et al.: Pioglitazone attenuates
hypertension and inhibits growth in renal arteriolar smooth muscle in
rats. Am J Physiol 1993, 265:R726R732.
12. Roman RJ, Ma Y-H, Frohlich B, et al.: Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. Hypertension
1993, 21:985988.
13. Sung BH, Izzo JL, Wilson MF: Effects of cholesterol reduction on BP
response to mental stress in patients with high cholesterol. Am J
Hypertens 1997, 10:592599.
14. Pershadsingh H, Szollosi J, Benson S, et al.: Effects of ciglitazone on
blood pressure and intracellular calcium metabolism. Hypertension
1993, 21:10201023.
15. Bhalla RC, Toth KF, Tan EQ, et al.: Vascular effects of metformin:
possible mechanisms for its antihypertensive action in the spontaneously hypertensive rat. Am J Hypertens 1996, 9:570576.
16. Kotchen TA, Zhang HY, Reddy S, et al.: Effect of pioglitazone on
vascular reactivity in vivo and in vitro. Am J Physiol 1996,
260:R660R666.
17. Parving H-H, Andersen AR, Smidt UM, et al.: Effect of antihypertensive
treatment on kidney function in diabetic nephropathy. Br Med J 1987,
294:14431447.
18. Lewis EJ, Hunsicker LG, Bain RP, et al.: The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. N Engl J Med
1993, 329:14561462.
19. Bretzel RG: Effects of antihypertensive drugs on renal function in patients
with diabetic nephropathy. Am J Hypertens 1997, 10:208S217S.
The Role of Hypertension

in Progression of
Chronic Renal Disease
Lance D. Dworkin
Douglas G. Shemin
ypertension is a cause and consequence of chronic renal disease. Data from the United States Renal Data System
(USRDS) identifies systemic hypertension as the second most
common cause of end-stage renal disease, with diabetes mellitus being
the first. Renal failure in patients with hypertension has many causes,
including functional impairment secondary to vascular disease and
hypertensive nephrosclerosis. Even in those in whom hypertension is
not the primary process damaging the kidney, elevations in systemic
blood pressure may accelerate the rate at which kidney function is
lost. This accelerated loss of kidney function occurs particularly in
patients with glomerular diseases and clinically evident proteinuria.
Hypertension may damage the kidney by several mechanisms. Because
autoregulation of glomerular pressure is impaired in chronic renal disease, elevations in systemic blood pressure also are associated with
increased glomerular capillary pressure. Glomerular hypertension results
in increased protein filtration and endothelial damage, causing increased
release of cytokines and other soluble mediators that promote replacement of normal kidney tissue by fibrosis. An important factor contributing to progressive renal disease is activation of the renin-angiotensin system, which not only tends to increase blood pressure but also promotes
cell proliferation, inflammation, and matrix accumulation.
Numerous studies in experimental animals suggest that antihypertensive drugs can slow the progression of chronic renal disease. Drugs
that inhibit the renin-angiotensin system may be more effective than
are other agents in retarding renal disease progression.
For many reasons, the effects of angiotensin II receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors may not
CHAPTER
6.2
be identical. Calcium channel blockers also are beneficial in

some settings; however, this effect is critically dependent on
the degree of blood pressure reduction.
The relationship between hypertension and progression of
chronic renal disease has been examined in a number of clinical
trials. Individuals with systemic hypertension are at increased
risk for developing end-stage renal disease. The rate at which
kidney function is lost increases in patients with poorly controlled systemic hypertension. Antihypertensive therapy can
slow the rate of loss of kidney function in patients with diabetic and nondiabetic renal disease. Studies suggest that ACE
inhibitors are particularly useful in patients with hypertension
and proteinuria of over 1g/24 h. Calcium channel blockers also
may slow the progression of renal disease; however, whether all
classes of calcium channel blockers have equivalent renal protective effects is uncertain.
Patients with hypertension and chronic renal disease should
be treated aggressively. A 24-hour urine collection determines
the extent of proteinuria. The patient who excretes more than
1 g/24 h of protein or who has diabetes mellitus should receive
an ACE inhibitor. The target in this group of patients is to
reduce the blood pressure to lower than 120/80 mm Hg. Most
often, reaching this goal requires the use of combinations of
antihypertensive agents, diuretics, or calcium channel blockers.
Patients who excrete less than 1 g/24 h of protein may be treated
according to standard recommendations with diuretics, beta
blockers, ACE inhibitors, or other agents. The target blood
pressure for this group of patients is lower than 130/85 mm Hg.
Hypertension and Kidney Damage

Partial loss
of function
Fibrosis
apoptosis
Compensatory
growth
Renin AII
activation
Afferent
vasodilation
Systemic
hypertension
Release of
cytokines and
growth factors
Increased
wall tension
Capillary
injury
Proteinuria
Glomerular
hypertension
FIGURE 6-1
Hypothesis identifying systemic hypertension as a central factor contributing to the progression of chronic renal disease. After partial loss of kidney function resulting from an undefined primary renal disease, a number of secondary processes develop that promote progressive kidney failure. Activation of the renin-angiotensin system is a common event in patients
with chronic renal disease. In these patients, renin levels are either elevated or at least not
appropriately suppressed for the degree of

volume expansion, elevation in blood pressure, or both. Activation of the reninangiotensin system and the relative salt and
water excess contribute to the development
of systemic hypertension in most patients
with chronic renal disease. Systemic hypertension and a decrease in preglomerular vascular resistance lead to an increase in
hydraulic pressure within the glomerular
capillaries. Glomerular hypertension has a
number of adverse effects, including
increased protein filtration, which promotes
release of cytokines and growth factors by
mesangial cells and downstream tubular
epithelial cells. A partial loss of kidney function also is a potent stimulus for compensatory renal growth. Glomerular hypertrophy and hypertension combine to increase
capillary wall tension, promoting endothelial cell activation and injury, again causing
release of cytokines and growth factors and
recruitment of inflammatory cells. These
mediators stimulate processes such as apoptosis, causing loss of normal kidney cells
and increased matrix production, which
leads to glomerular and interstitial fibrosis
and scarring. As additional nephrons are
damaged secondarily the cycle is repeated
and amplified, causing progression to endstage renal failure. AIIantiotensin II.
The Role of Hypertension in Progression of Chronic Renal Disease
FIGURE 6-2
Imaginary autoregulation curves in normal and diseased kidneys.
Plotted on the y-axis are renal plasma flow (RPF), glomerular
filtration rate (GFR), and glomerular capillary hydraulic pressure
(PGC) with undefined units. Ordinarily, RPF, GFR, and PGC remain
relatively constant over a wide range of perfusion pressures within
the physiologic range, from approximately 80 to 140 mm Hg.
Because autoregulatory ability is impaired in the kidneys of persons
with chronic renal disease, these patients who develop systemic
hypertension also are likely to have glomerular hypertension.
PGC, RPF, or GFR
Typical autoregulatory response in

normal kidneys
RPF, GRF, and PGC vary with
perfusion pressure in chronic
renal failure
40
60
80
100
120
6.3
140
160
180
Renal perfusion pressure, mm Hg
PGC = PGC
RE
MAP
MAP
RA
Baseline
RE
RA
Increased perfusion pressure
PGC < PGC
MAP
RE
RA
MAP
Baseline
FIGURE 6-3
Mechanism of autoregulation of glomerular capillary pressure in a
single glomerulus from a normal kidney. A, Baseline. B, Increased
perfusion pressure. Glomerular pressure is determined by three factors: mean arterial pressure (MAP) or perfusion pressure, and the
relative resistance of both the afferent and efferent arterioles. The
initial response to an increase in MAP is an increase in afferent
arteriolar resistance (RA), preventing transmission of the elevated
systemic pressure to the glomerular capillaries. Efferent arteriolar
resistance (RE) also may decline. This decrease decompresses the
glomerulus, helping to limit the increase in glomerular capillary
hydraulic pressure (PGC), and maintains constant renal plasma flow.
RE
RA
Increased perfusion pressure
FIGURE 6-4
Mechanism of failure of autoregulation in a glomerulus from a
damaged kidney. A, Baseline. B, Increased perfusion pressure.
To compensate for a partial loss of function, surviving glomeruli
undergo adaptive changes to increase the filtration rate. These
include a reduction in afferent (RA) and efferent (RE) arteriolar
resistances, tending to increase renal plasma flow and the glomerular filtration rate. In this setting, an increase in mean arterial pressure (MAP) is transmitted directly to the glomerular capillaries,
resulting in glomerular capillary hypertension, increased protein
filtration, and hemodynamically mediated capillary injury. PGC
glomerular capillary hydraulic pressure.
6.4
Effects of Antihypertensive Agents

on Experimental Kidney Injury
60
Results of the linear regression analysis

Effects of going from low to high dose of
triple therapy
40
Change in sclerosis, %
20
0
-20
-40
UnxSHR
RemnantHD
RemnantLD
Docsalt
NSN
-60
-80
-100
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
Change in PGC, mm Hg
FIGURE 6-5
Effects of triple therapy on glomerular pressure and injury.
Relationship between the change in glomerular capillary hydraulic
pressure (PGC) and the extent of glomerular injury (sclerosis) in
400
No treatment
Enalapril
Low dose triple therapy
High dose triple therapy
Glomerular injury score
350
300
250
200
150
100
50
0
80
100
120
140
160
180
200
Overall averaged systolic blood pressure at final 8 week, mm Hg
five separate studies. In these studies, rats with experimental renal

disease were given similar antihypertensive agents. Studies were
conducted in several different animal models of hypertension and
renal disease, including the following: uninephrectomized spontaneously hypertensive rats (Unx SHR); rats with a remnant kidney
given either relatively high-dose (remnant-HD) or low-dose (remnant-LD) drug therapy; rats with desoxycorticosteronesaltinduced hypertension (Doc-salt); and rats with nephrotoxic
serum nephritis (NSN), an immune-mediated form of glomerular
disease (NSN) [15]. In all these studies, untreated rats were compared with those receiving a combination of three antihypertensive
agents (triple therapy), including hydralazine, reserpine, and a thiazide diuretic. In rats with remnant kidneys, separate studies
examined the effects of low or high doses of these agents. A close
correlation was revealed between the degree of reduction in
glomerular capillary pressure produced by triple therapy and subsequent development of glomerular sclerosis. The data are consistent with the hypothesis that antihypertensive agents lessen
glomerular injury by reducing glomerular capillary pressure. In the
studies in rats with remnant kidneys, only a relatively high dose of
the drugs was effective in reducing pressure and injury, suggesting
that aggressive antihypertensive therapy is more likely to slow
progression of renal disease. This finding is particularly true for
antihypertensive combinations that include direct vasodilators,
such as the triple-therapy regimen. By dilating the afferent arteriole, regimens such as these tend to further impair autoregulation
of glomerular pressure in the setting of chronic renal disease.
(From Weir and Dworkin [6]; with permission.)
FIGURE 6-6
Correlation between systolic blood pressure and glomerular injury
in rats with remnant kidneys. In these rats, blood pressure was continuously monitored by implanting a blood pressure sensor in the
abdominal aorta connected telemetrically to a receiver. The timeaveraged blood pressure in rats with remnant kidneys that were
untreated or given the angiotensin-converting enzyme inhibitor
enalapril or triple therapy (combination of hydralazine, reserpine,
and a thiazide diuretic) was correlated with morphologic evidence of
glomerular injury. A close correlation was found between the average blood pressure and extent of glomerular injury that developed in
these rats. It is proposed that, because of impaired autoregulation in
chronic renal disease, elevations in systemic blood pressure are associated with glomerular hypertension in these rats. The higher the systemic pressure, the higher the glomerular pressure is predicted to be
and the more glomerular injury is observed. These data provide
additional evidence that systemic hypertension produces glomerular
injury by causing elevation in glomerular pressure, and that antihypertensive therapy reduces injury by reducing glomerular capillary
pressure. (From Griffen and coworkers [7]; with permission.)
Tension=pressure x radius
RGC
RGC
PGC
PGC
T
T
6.5
FIGURE 6-7
The wall tension hypothesis. A, Normal. B, Chronic renal failure.
After a partial loss of kidney function, compensatory adaptations
within surviving nephrons include renal vasodilation. Vasodilation
leads to an increase in glomerular capillary pressure and compensatory renal growth associated with an increase in the radius of the
glomerular capillaries. According to the LaPlace equation, wall tension in a blood vessel is equal to the product of the transmural pressure and the radius of the vessel. In a surviving glomerular capillary
of a damaged kidney, therefore, wall tension increases not only
because of the increase in glomerular pressure but also because of
an increase in capillary radius. Elevations in wall tension contribute
to progressive renal disease by damaging the endothelial and epithelial cells lining the glomerular capillaries. By reducing wall tension,
maneuvers that decrease either glomerular pressure or glomerular
capillary radius are predicted to be beneficial. PGCglomerular
capillary hydraulic pressure; RGCglomerular capillary radius;
Ttension. (From Dworkin and Benstein [8]; with permission.)
FIGURE 6-8
Scanning electron micrographs of vascular
casts of glomeruli from normal or uninephrectomized rats. A, A glomerulus from
a rat having had a sham operation, showing
a uniform capillary pattern. (Panels BD
display casts from uninephrectomized rats.)
B, A uniform pattern with most capillaries
being approximately the same size. C and
D, Nonuniform patterns in which individual
capillary loops (indicated by asterisks) are
markedly dilated. In dilated capillary loops,
wall tension is elevated and capillary wall
damage is most likely to occur. The segmental nature of the capillary dilation may
explain why glomerular sclerosis that eventually develops in remnant kidneys is also
focal in early stages of the disease process.
(Panels AD 320.) (From Nagata and
6.6
Role of the Renin Angiotensin System

Release of cytokines
and growth factors
Increased protein
filtration
Hyperplasia and
hypertrophy
A II
Systemic and glomerular

hypertension
FIGURE 6-9
The central role of angiotensin II(AII) in promoting progressive kidney failure. Based on studies in which the renin-angiotensin system
has been blocked and renal injury ameliorated, it has been suggested that activation of this system is a crucial factor promoting progressive kidney failure. Increased activity of the renin-angiotensin
system also may help explain the association between hypertension
and progression of renal disease. AII may promote renal injury by

several mechanisms. Activation of the renin-angiotensin system is
one mechanism leading to an increase in systemic blood pressure,
the result of peripheral vasoconstriction. Glomerular hypertension
results not only from the increase in systemic blood pressure but
also because of the ability of AII to constrict efferent arterioles, contributing to an increase in glomerular pressure. Glomerular hypertension damages the glomerular capillary wall and promotes injury
by multiple mechanisms (see Fig. 6-1). An increase in glomerular
pressure tends to increase protein filtration directly. In addition,
evidence suggests that AII alters the permeability of the glomerular
capillary wall to macromolecules, directly increasing protein filtration. By activating mesangial and epithelial cells, proteinuria itself
is a factor promoting progressive kidney failure. Evidence also exists
that AII directly stimulates production of various growth factors
and cytokines by kidney cells, including fibrogenic cytokines such as
transforming growth factor-beta and platelet-derived growth factor.
Release of these factors has been linked to the development of
glomerular sclerosis and interstitial fibrosis. AII also stimulates proliferation and growth of kidney cells that contribute to progression
of renal disease.
80
60
40
60
40
20
20
0
0
Remnant
AC
EI
Triple
Remnant
AC
EI
Triple
30
Proteinuria, g/24
h
120
100
20
80
60
10
40
20
0
Remnant
AC
EI
Triple
Remnant
AC
EI
0
Triple
Glomerular injury, %
100
80
120
FIGURE 6-10
Angiotensin-converting enzyme (ACE)
inhibitors and low-dose triple therapy. The
effects of ACE inhibitors are compared with
those of low-dose triple therapy on systemic
and glomerular pressure, proteinuria, and
morphologic evidence of glomerular injury
in rats with remnant kidneys. Both ACE
inhibitors and triple therapy caused similar
reductions in mean arterial pressure in rats
with remnant kidneys; however, glomerular
pressure declined only in the group treated
with ACE inhibitors, by approximately
10 mm Hg. ACE inhibitorinduced reductions in systemic and glomerular pressure
were associated with a reduction in proteinuria and morphologic evidence of glomerular
injury. The data suggest that ACE inhibitors
are superior to low-dose triple therapy in preventing glomerular injury in chronic renal
disease. The data support the importance of
increased glomerular pressure as a determinant of glomerular injury. ACE inhibitors
may be more effective than are other agents,
specifically because of their ability to reduce
glomerular pressure. It should be noted, however, that significant reductions in glomerular
pressure and injury may be achieved even
with the triple-therapy regimen when significantly higher doses than those used in the
current study are administered (see Figs. 6-5
and 6-6). Asterisk indicates P < 0.05 versus
remnant. (Data from Anderson and
coworkers [10].)
6.7
volume flux
0.1
0.01
selective
pores
0.1
0.01
0.001
Fractional
Large
Large nonselective
pores
nonselective
pores
0.001
0.0001
0.0005
0.0001
0.0005
30
at CA=0
1
Fractional volume flux at CA=0
Small
Small selective
pores
40
50
60
Effective pore radius, A
FIGURE 6-11
Effect of renal vein constriction on glomerular protein filtration. The
role of angiotensin II (AII) in modulating macromolecular clearance
across the glomerular capillary wall has been examined by Yoshioka
and coworkers [11]. These authors used a model of renal vein
constriction to increase glomerular pressure and markedly increase
protein filtration. They calculated the volume flux through the small
selective pores (effective pore radius, 4050 ) within the glomerular
capillary wall and through the large nonselective pores. A, Volume
fluxes under control conditions (hatched bars) and during renal vein
30
40
50
60
Effective
pore radius,
constriction (open bars). Renal vein constriction causes an increase

in filtration through large nonselective pores, which accounts for
increased protein filtration. B, Effects of renal vein constriction
were again examined, alone (open bars) and during administration
of the AII receptor antagonist saralasin (hatched bars). Saralasin
reduced volume flux through the large pores, indicating that
increased endogenous AII action was largely responsible for
proteinuria during renal vein constriction. (From Yoshioka and
Local activation of the renin-angiotensin system and production of fibrogenic cytokines in
experimental chronic renal disease. In situ
reverse transcriptase was performed in rats
with remnant kidneys to examine the level of
gene expression for angiotensinogen and transforming growth factor-beta (TGF-beta). Rats
still had not developed widespread morphologic evidence of glomerular injury 24 days after
subtotal nephrectomy. A, At this point in time
(arrows), staining for angiotensinogen messenger RNA (mRNA) was observed along the
wall of a dilated capillary loop (CL) and in an
adjacent cluster of mesangial cells. B, TGFbeta mRNA was present in an identical pattern
in a contiguous section (arrows). C and D,
Staining for angiotensinogen (panel C) and
TGF-beta (panel D) is examined in kidneys
from rats treated with the angiotensin receptor
antagonist losartan from the time of nephrectomy. Administration of losartan markedly
reduced expression of both factors in remnant
kidneys. The findings are consistent with the
hypothesis that endothelial injury is associated
with increased angiotensinogen production
and local activation of the renin-angiotensin
system, leading to increased expression of TGFbeta and progressive glomerular fibrosis. (From
Lee and coworkers [12]; with permission.)
6.8
**
* P< 0.05 vs cells treated

with A II alone
** P< 0.01 vs unstimulated
controls
90
fg RANTES/ 104 cells
80
15
**
70
60
*
50
40
Migrated monocytes
100
* P<0.05 vs control medium

** P<0.05 vs A II medium without
antibody
*
10
**
5
30
0
20
Control
A II
CGP
CGP+
A II
PD
PD +
A II
los
los +
A II
FIGURE 6-13
Angiotensin II (AII) may be a proinflammatory molecule. The effect
of AII on production of the chemokine RANTES was examined in
cultured glomerular endothelial cells. A, Effects of AII on secretion
of RANTES by cultured glomerular endothelial cells. AII markedly
stimulated RANTES secretion. Of note is that AII-induced RANTES
secretion was prevented by incubation with the AT2 receptor antagonists SCP-42112A (CGP) or PD 1231777 (PD) but not by the AT1
receptor antagonist losartan (los). These finding suggest AT2 receptors mediate the increase in secretion of RANTES. B, Results of a
chemotactic assay for human monocytes. Migration of monocytes
Renin-angiotensin systems
Angiotensinogen
Bradykinin
Substance P
Enkephalin
b
m
G
Ab
A II
diu
t Ig
ES A
-6 M
TE S
me
NT
goa
N
0
l
A
A
1
a
R
A II
+
m
ii-R
ant
EM
ant
nor
DM
+m
m+
m+
u
u
i
i
m
d
d
u
di
me
me
me
A II
trol
A II
Con
m
trol
Con
10
Renin
Angiotensin I
CAGE
Cathepsin G
Tonin
ACE
Inactive
fragments
Angiotensin II
Other
proteases
Angiotensin III and IV
tPA
Cathepsin G
Tonin
ediu
was assessed using a modified Boyden chamber. Migration of monocytes

was stimulated by conditioned medium from glomerular endothelial cells
that were exposed to AII. This effect was blocked by incubation of the
medium with an anti-RANTES antibody but not by control serum.
The anti-RANTES antibody alone was also without effect, as was AII
in the absence of conditioned media. The findings are consistent with
the hypothesis that AII promotes glomerular inflammation by binding
to AT2 receptors, promoting RANTES secretion and infiltration of
inflammatory monocytes and macrophages. fgfemtograms. (From
Wolf and coworkers [13]; with permission.)
FIGURE 6-14
Renin-angiotensin systems. For many reasons the effects of
angiotensin-converting enzyme (ACE) inhibitors and angiotensin
II (AII) type 1 AT1 receptor antagonists on the progression of
chronic renal disease may not be identical. In the classic pathway, renin cleaves angiotensinogen to form AI, which is further
cleaved by ACE to form biologically active AII. ACE inhibitors
inhibit the renin-angiotensin system by reducing the activity of
ACE and decreasing AII formation. ACE also catalyzes other
important pathways, however, including the breakdown of
vasodilator substances such as bradykinin, substance P, and
enkephalin. Increased levels of these substances might account
for some of the biologic effects of ACE inhibition. Levels of
these substances would not increase after administration of an
AT1 receptor antagonist. In contrast, inhibition of the reninangiotensin system by ACE inhibitors may be incomplete
because other proteases may catalyze to conversion of angiotensinogen to AII (on the right). CAGE chymostatin-sensitive
angiotensin IIgenerating enzyme; t-PAtissue plasminogen
activator. (Adapted from Dzau and coworkers [14].)
Vasoconstriction
AT 1
Aldosterone
Growth
Angiotensin II
Proteases
Clearance
Apoptosis
Angiotensin III and IV
Vasodilation AT 4
AT 2
FIGURE 6-15
Subclasses of angiotensin receptors. Another theoretic reason the
actions of angiotensin-converting enzyme (ACE) inhibitors and
angiotensin II (AII) receptor antagonists may differ. All of the AII
receptor antagonists currently available for clinical use selectively block
the AT1 receptor. This receptor appears to transduce most of the wellknown effects of AII, including vasoconstriction, stimulation of cell
growth, and secretion of aldosterone. Increasingly, however, potentially
important actions of other angiotensin receptors are being discovered.
For example, AT2 receptors may be involved in regulation of apoptosis
and modulation of inflammation by way of secretion of RANTES (see
Fig. 6-13) [13,15]. AT4 receptors bind other angiotensins preferentially
and may promote endothelially mediated vasodilatation [16]. Activity
of all pathways is reduced after administration of ACE inhibitors,
whereas only AT1 receptormediated events are blocked by drugs currently available. Whether these differences will have important consequences for progression of renal disease is currently unknown.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS VERSUS

ANGIOTENSIN II ANTAGONISTS IN EXPERIMENTAL RENAL DISEASE
Angiotensin II antagonists equivalent to
Angiotensin II antagonists inferior to

Remnant kidney
Passive Heymann nephritis
Chronic rejection
Two-kidney, one-clip hypertension
Streptozocin-induced diabetes
Puromycin aminonucleoside
Munich-Wistar Furth/Ztm rat
Uninephrectomized spontaneously hypertensive rats

Obese Zucker rats
Passive Heymann nephritis
MAP
PGC
Reduction, %
0
-20
-40
-60
-80
Nifedipine
Felodipine
Amlodipine
PROT
SCLER
6.9
FIGURE 6-16
Shown are results of studies comparing the
effects of angiotensin II (AII) receptor antagonists and angiotensin-converting enzyme
(ACE) inhibitors on experimental renal injury.
AII receptor antagonists were as effective as
were ACE inhibitors in the remnant kidney
model; streptozotocin-induced diabetic rats;
the puromycin aminonucleoside model of
progressive glomerular sclerosis, preventing
interstitial fibrosis associated with obstructive
uropathy; and an inherited model of glomerular sclerosis, the Munich-Wistar Furth/Ztm
rat [1721]. In contrast, AII receptor antagonists were somewhat less effective than were
ACE inhibitors in several other animal models of chronic renal disease, including
uninephrectomized spontaneously hypertensive rats, obese Zucker rats, and the passive
Heymann nephritis model of membranous
glomerulonephritis [2224]. Clinical trials are
necessary to determine whether these classes
of drugs will be equally effective in preventing
progressive renal disease in humans.
FIGURE 6-17
Three calcium channel blockers and their effects in experimental animals. The results of several studies examining the effects of three different dihydropyridine calcium channel blockers on hemodynamics
and injury in the uninephrectomized spontaneously hypertensive rat
model of progressive glomerular sclerosis are summarized. The three
drugs produced graded declines in mean arterial pressure (MAP),
with nifedipine causing the greatest and amlodipine the least reduction in systemic pressure. Micropuncture determinations of glomerular capillary hydraulic pressure (PGC) revealed that only nifedipine
and felodipine caused glomerular pressure to decline significantly.
These drugs reduced both the protein excretion rate (PROT) and
morphologic evidence of glomerular injury (SCLER). The data are
consistent with the hypothesis that antihypertensive agents ameliorate
renal damage by reducing glomerular pressure and that, for calcium
channel blockers, significant reductions in PGC occur only when drug
administration causes a marked decline in systemic pressure. (From
Dworkin [25,26]; with permission.)
6.10
The Effect of Hypertension on Renal Disease

100
ROLE OF HYPERTENSION IN CHRONIC RENAL DISEASE
90
Contributors to disease progression
80
Renal artery stenosis or occlusion

Hypertensive nephrosclerosis
Diabetes mellitus
Glomerulonephritis
Tubulointerstitial disease (?)
Adult-onset polycystic kidney disease (?)
70
FIGURE 6-18
The impact of hypertension on the incidence of end-stage renal
disease (ESRD) is vastly underestimated if one considers only
those patients in whom systemic hypertension is the primary
process resulting in loss of kidney function. The group of
patients in whom ESRD is attributed to hypertension undoubtedly includes persons with renal disease of several causes. Some
of these causes are occlusive disease of the main renal arteries as
a result of atherosclerotic disease, atheroembolic disease of the
kidneys, and hypertensive nephrosclerosis. The exact incidence
of these processes within the hypertensive population with
chronic renal disease is unknown. Even more commonly, poorly
controlled systemic hypertension accelerates the rate of loss of
kidney function in many patients in whom the primary cause of
renal injury is another process altogether. This fact is particularly true in patients with glomerular diseases such as diabetic
nephropathy and chronic glomerulonephritis [27,28]. Whether
systemic hypertension also contributes to loss of kidney function
in patients with tubulointerstitial or cystic disease of the kidney
is less certain [29].
Volume/ total body sodium

excess
Stimulation of
renin-angiotensin
system
Augmented
sympathetic
tone
Hypertensive persons, %
Cause
60
50
40
30
20
10
0
0
10
20
30
40
50
60
Mean GFR, mL/min/1.73m
70
80
90
FIGURE 6-19
Hypertension prevalence corresponds with decreased glomerular
filtration rate (GFR). Hypertension is common in glomerular,
tubular, vascular, and interstitial renal disease and becomes
increasingly prevalent as renal function declines. In almost 200
patients screened for the Modification of Diet in Renal Disease
study, the prevalence of hypertension increased as the GFR
decreased and hypertension was almost universal as the GFR
approached 10 mL/min [29].
FIGURE 6-20
Multifactorial mechanisms for hypertension in clinical renal disease. An increased
intravascular volume, owing to decreased renal excretion of sodium and water as the
glomerular filtration rate declines, is probably the primary cause. Activation of sympathetic tone and involvement of the renin-angiotensin system, which is inappropriately
stimulated in the setting of volume expansion, have been demonstrated in renal failure.
Decreased activity of nitric oxide and other vasorelaxants and increased activity of
endothelin and other endogenous vasoconstrictors also are probably contributory.
6.11
1.0
(53)
(30)
80
(18)
60
0.8
(17)
40
Probability of survival
Free of renal failure, %
100
(7)
(2)
Normotensive (n=79)
Hypertensive (n=69)
20
0
0
10
Free of renal endpoints, %
80
P<0.001
60
40
<120 mm Hg
>120 mm Hg
0
0
1
Time, y
NBP after age 35
0.4
0.2
FIGURE 6-21
Consistent relationship between hypertension and progressive
renal disease. Analysis of the Modification of Diet in Renal
Disease study, which involved patients with a heterogeneous miscellany of renal diagnoses, showed that the degree of elevation
of the mean arterial blood pressure correlated with the decline in
the glomerular filtration rate [30]. This finding has been confirmed in cohorts of patients with the same renal disease. In
immunoglobulin A (IgA) nephropathy, eg, the presence of high
blood pressure at diagnosis is a strong predictor for development
of end-stage renal disease. In this study by Radford and coworkers [31] of 148 patients with IgA nephropathy, 69 patients with
hypertension had a much higher risk of proceeding to renal failure than did the 79 patients who were normotensive.
100
HBP before age 35
15
Time since biopsy, y
Systolic blood pressure
0.6
0
0
10
20
30
40
50
Age, y
60
70
80
90
FIGURE 6-22
Relationship between hypertension and renal failure. Johnson and
Gabow [32] studied over one thousand patients with autosomal dominant polycystic kidney disease. These authors demonstrated that the time
of renal survival was much shorter for patients with hypertension compared with patients whose blood pressure was normal (see Fig. 6-21).
Renal survival was defined as the time period before the need for dialysis. HBPhigh blood pressure; NBPnormal blood pressure.
FIGURE 6-23
Hypertension accelerates progression of renal failure in children and adults. For 2 years,
Wingen and coworkers [33] followed almost 200 children and adolescents with renal disease, aged 2 to 18 years. Here, renal survival is defined as stability of the creatinine clearance rate. Compared with patients with systolic blood pressures lower than 120 mm Hg,
those with systolic blood pressures higher than 120 mm Hg had more rapid development
of renal death. Renal death was defined as a decrease in the creatinine clearance rate by
10 mL/min/1.73 m2.
6.12
4.0
Optimal
Normal but not optimal
High normal
Stage 1 hypertension
Stege 4 hypertension
ESRD due to any cause, %
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Years since screening
FIGURE 6-24
There long has been controversy over whether hypertension
alone, without renal disease, can cause renal failure, especially in
whites. Recent convincing epidemiologic evidence, however, links
Deteriorating
renal
function
Stable
renal
function
Stable
renal
function
16%
Controlled
diastolic blood pressure
<90 min Hg
12%
Uncontrolled
diastolic blood pressure
<90 min Hg
Blood pressure
0
Decline in GFR mL/min
Deteriorating
renal
function
Low BP group
Usual BP group
3
6
9
12
15
B3
F4
F12
F20
Time, mo
F28
F36
hypertension to later development of renal failure. In over

300,000 men screened for the Multiple Risk Factor Intervention
Trial, Klag and coworkers [34] showed that a single blood pressure measurement was strongly correlated with the risk of endstage renal disease (ESRD) later in life. Even men with high-normal blood pressures (defined as a systolic pressure of 130 to 139
mm Hg or a diastolic blood pressure of 85 to 89 mm Hg) were at
a statistically significant greater risk for ESRD than were men
with blood pressures under 120/80 mm Hg. This risk increases
sequentially with the higher stage of hypertension. This study
used definitions of hypertension discussed in the Fifth Report of
the Joint National Committee on Detection, Evaluation and
Treatment of High Blood Pressure (JNC-5). Stage I hypertension
is defined as a systolic pressure of 140 to 159 mm Hg and a diastolic pressure of 90 to 99 mm Hg. Stage II hypertension is
defined as a systolic pressure of 160 to 179 mm Hg and a diastolic pressure of 100 to 109 mm Hg. Stage III hypertension is a
systolic pressure of 180 to 209 mm Hg and a diastolic pressure of
110 to 119 mm Hg. Stage IV hypertension is a systolic pressure
of 210 mm Hg or higher and a diastolic blood pressure of 120
mm Hg or greater. The highest relative risk for renal failure was
among persons with stage III or IV hypertension.
FIGURE 6-25
Hypertension and impact on progression of renal disease caused by
hypertension. In a study of 94 patients with essential hypertension
and an initially normal serum creatinine concentration, Rostand
and coworkers [35] showed that hypertension control apparently
had little impact on progression of renal disease. When patients
were divided into those with diastolic blood pressures higher and
lower than 90 mm Hg, the percentage whose renal function deteriorated was equivalent in both groups. Blacks were at especially
high risk; 23% of black patients with diastolic blood pressures
below 90 mm Hg had worsened renal function over time, compared with 11% of white patients with diastolic blood pressures
lower than 90 mm Hg.
FIGURE 6-26
Lower-than-usual blood pressure (BP) target. The Modification of
Diet in Renal Disease study [36] also prospectively examined the
effect of a lower-than-usual BP target in a larger cohort of patients
with renal insufficiency. Patients were randomized to two target
BPs: a usual mean arterial pressure (MAP) target of 107 mm Hg,
corresponding to a BP of 140/90 mm Hg; or a low MAP target of
92 mm Hg, corresponding to a BP of 125/75 mm Hg. The changes
in the glomerular filtration rate (GFR) in the two groups over a 3year follow-up period are depicted. (The y-axis depicts the changes
in GFR, and the x-axis represents months. For example, F36 means
36 months after initiation of the study.) Patients in the two groups
had statistically equivalent declines in GFR. Over the last 6 months
of the study, however, a trend toward greater stabilization in renal
function occurred in the group randomized to the lower target.
6.13
FIGURE 6-27
Two patient groups in the study of diet in
renal disease. The Modification of Diet in
Renal Disease (MDRD) study involved two
patient groups. The group in which patients
had moderate renal dysfunction (glomerular
filtration rate [GFR] between 25 and 55
mL/min) was called Study 1. The other group,
which included patients who had more severe
renal dysfunction (with a GFR between 13
and 24 mL/min) was called Study 2. The
effects of the lower blood pressure (BP) target
on patients with proteinuria in Studies 1 and
2 are shown. The y-axis divides patients in
Studies 1 and 2 into three groups, depending
on urinary protein excretion. The x-axis represents the rate of GFR decline. In the subset
of patients in the MDRD trial in both Studies
1 and 2 who had massive proteinuria (protein
over 3 g/24 h), the lower blood pressure had
an especially salutary effect: the decline in
GFR was much slower [37].
Patients randomized to low BP target

Patients randomized to the usual BP target
Mean rate of GFR decline, mL/min/y
Study 1
Study 2
12
n=420
n=101
n=54
n=136
<1
1<3
<1
n=63
n=32
1<3
12
Baseline urinary protein, g/d
Renal survival
100
1.00
90
0.95
80
0.90
0.85
0.80
Proteinuria: <1g/24h
mean BP: <107 mm Hg
0.75
mean BP: >107 mm Hg
0.70
mean BP: <107 mm Hg
0.65
mean BP: >107 mm Hg
70
60
50
40
30
20
10
-12
0.60
Group A
0
12
18
Time, mo
24
30
FIGURE 6-28
Proteinuria as a marker for progressive renal disease. Nephrotic
proteinuria may be a more important and independent marker for
progression of renal disease than is hypertension. That is, patients
in whom massive proteinuria and hypertension coexist have the
worst renal prognosis. In a study of over 400 patients with renal
insufficiency followed over 2 years, Locatelli and coworkers [38]
found that patients who had both a mean blood pressure (BP)
higher than 107 mm Hg and protein excretion of 1 to 3 g/24 h had
the lowest rates of renal survival.
-6
12
18
24
30
36
Group B
Evolution of creatinine clearance
FIGURE 6-29
The effect of reduction of proteinuria on the stabilization of renal
function. The observations that the potentially correctable factors of
hypertension and proteinuria predict the decline of renal function lead
to the hypothesis that antihypertensive agents in the angiotensin-converting enzyme (ACE) inhibitor class may be especially important in
treatment of hypertension in renal disease. Praga and coworkers [39]
investigated 46 patients with nondiabetic renal disease and massive
proteinuria treated with the ACE inhibitor captopril. These authors
found that proteinuria was decreased by about half. In patients with
the greatest reduction in proteinuria (group A), a greater stabilization
of renal function occurred over time when compared with those
(group B) whose reduction in proteinuria was less.
6.14
50
1.6
40
Ramipril
35
1.4
Placebo
30
Mean rate of GFR, mL/min/mo
Percentage with doubling

of baseline creatinine
45
25
20
P=0.007
15
10
Captopril
5
0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Placebo
1.2
1.0
0.8
0.6
Years of follow-up
0.4
FIGURE 6-30
Large study of patients with diabetes mellitus and renal disease
randomly assigned to captopril or placebo. Lewis and coworkers
[40] have studied the use of the angiotensin-converting enzyme
inhibitor captopril in patients with type I diabetes mellitus who
have diabetic nephropathy and proteinuria. Captopril provides
strong protection against progression of renal disease. Those
patients treated with captopril had a significant decrease in proteinuria and a slower rate of disease progression, as defined by
the time to doubling of the serum creatinine, as compared with
patients randomized to placebo.
0.2
0
Country Year
IT
Zucchelli et al. [43]
DEN
Kamper et al. [44]
Brenner (Unpublished data) USA
Toto (Unpublished data) USA
HOL
van Essen et al. [45]
Hannedouche et al. [46] FR
AUS
Bannister et al. [47]
Himmelmann et al. [48] SW
AUS
Becker et al. and
Ihle et al. [49,50]
EUR
Maschio et al. [51]
1992
1992
1993
1993
1994
1994
1994
1995
1996
121
70
112
124
103
100
51
260
70
1996 583
Overall
0.5 1
n=20
FIGURE 6-31
Study of patients with renal disease not associated with diabetes
randomly assigned to ramipril or placebo. A study structured similarly to that in Figure 6-30 examined the use of the angiotensinconverting enzyme inhibitor ramipril in over 150 patients with
nondiabetic renal disease [41]. The primary conclusion of the study
is summarized. Blood pressure and proteinuria decreased more significantly in the patients treated with ramipril. This group had significantly lower rates of decline in glomerular filtration rate (GFR)
over time. This effect was increasingly striking as the baseline level
of proteinuria increased and was most pronounced in patients with
a urinary protein excretion of over 7 g per 24 hours.
Patients, n
0.01 0.02 0.05 0.1 0.2
n=36
Baseline urinary protein excretion, 1g/24h
Favors ACE inhibitors Favors other drugs

Reference
n=61
Relative risk for ESRD
10
20 50 100
FIGURE 6-32
Meta-analysis of over 1500 patients with
renal insufficiency. A recent meta-analysis
examined randomized studies comparing
an angiotensin-converting enzyme inhibitor
(ACE) to other antihypertensive agents
[42]. None of the individual studies
showed that the relative risk for development of end-stage renal disease (ESRD)
was statistically lower in patients treated
with ACE inhibitors. The pooled relative
risk, incorporating data from all the studies, however, was lower in the cohort
groups treated with ACE inhibitors.
6.15
100
Glomerular
basement
membrane
80
No change in
proteinuria
Renal survival, %
Podocytes
60
40
Captopril
Nifedipine
20
Decreased
proteinuria
0
0
12
18
24
30
36
42
Time, mo
Dihydropyridine
calcium channel blockers
Nifedipine
Amlodipine
Felodipine
Isradipine
Nisolodipine
Non-dihydropyridine
Diltiazem
Verapamil
FIGURE 6-33
Calcium channel blockers. Calcium channel blockers are prescribed
widely to patients with normal renal function and affect renal protein excretion variably. The general consensus is that the nondihydropyridine calcium channel blockers diltiazem and verapamil
decrease proteinuria, whereas the dihydropyridine agents have minimal or minor effects on proteinuria.
FIGURE 6-34
The effect of calcium channel blockers on preservation of renal function. Most studies of angiotensin-converting enzyme (ACE) inhibitors
versus other agents did not examine calcium channel blockers. In a
paper by Zucchelli and coworkers [43], patients with nondiabetic
renal diseases and hypertension initially were treated with adrenergic
antagonists, diuretics, and vasodilators. These patients were then randomized to treatment with the dihydropyridine calcium entry antagonist nifedipine or to the ACE inhibitor enalapril. The rate of decline
in renal function was most rapid in the pre-randomization phase in
patients treated with conventional antihypertensive agents, mostly
adrenergic antagonists. The rate of decline then slowed after randomization. No significant difference in rates of decline was seen in
patients treated with nifedipine compared with those treated with
captopril. (From Zucchelli and coworkers [43]; with permission.)
Creatinine clearance, mL/min/1.73 m2
60
Lisinopril
NDCCBs
40
Atenolol
20
Lisinopril
NDCCBs
Atenolol
1998
18
18
16
1989
18
18
16
1990
18
18
16
1991
18
17
15
1992
16
16
13
1993
16
15
11
1994
15
15
11
FIGURE 6-35
The effect of angiotensin-converting
enzyme inhibitors and other antihypertensive agents on stabilization of renal function in noninsulin-dependent diabetes.
Bakris and coworkers [52] studied patients
with noninsulin-dependent diabetes mellitus, hypertension, proteinuria, and presumed diabetic nephropathy. These patients
were randomized to treatment with the
angiotensin-converting enzyme inhibitor
lisinopril; the beta-blocker atenolol; or a
nondihydropyridine calcium channel blocker (NDCCB), either verapamil or diltiazem.
The primary conclusion of the study is summarized. The change in glomerular filtration rate as a function of time is depicted in
groups of patients receiving lisinopril, calcium channel blockers, or atenolol. The creatinine clearance rate declined in all three
groups. However, the slope of the decline
was significantly greater in the group treated with atenolol and not significantly different between the groups treated with
lisinopril and the calcium entry antagonist.
6.16

120
115
Mean BP, mm Hg
110
105
100
Atenolol
Amiodipine
Enalapril
95
90
0
Baseline GFR1
GFR2
RV
FV3
FV6
Time, mo
FIGURE 6-36
Race and ethnicity in choice of antihypertensive agents. Racial and
ethnic differences also may be important in determining the choice
of antihypertensive agent to delay progression of chronic renal disease. Blacks are at much higher risk than are whites for progression of renal disease. In addition, a more aggressive antihypertensive program may be beneficial to blacks. In the Modification of
Diet in Renal Disease study, a trend toward a more gradual decline
in renal function in blacks randomized to the low mean blood
pressure target was seen [36]. Blacks tend to have a better blood
pressure response to administration of diuretics than do whites. In
a large study of patients with normal renal function, blacks also
responded well to calcium channel blockers [53]. The AfricanAmerican Study of Kidney Disease and Hypertension (AASK), currently in progress, is examining the hypothesis that a lower-thanusual blood pressure goal will have a renal protective effect in
renal disease with hypertension. A preliminary finding from the
study is depicted. The study randomized blacks with hypertension
to the beta-blocker atenolol, the dihydropyridine calcium channel
blocker amlodipine, or the angiotensin-converting enzyme
enalapril. In the initial 6 months of the study, the mean arterial
blood pressure decreased most significantly in the short term with
amlodipine [54]. GFRglomerular filtration rate.
Management of Hypertension in Clinical Renal Disease

Blood pressure:> 130/185 mm HG or higher with renal disease
Blood pressure: 130/85 mm Hg or higher with renal disease
Proteinuria: 1g/24h or less
Proteinuria: 1G/24h or more
Diabetic or primary glomerular disease
Begin ACE inhibitor
Target blood pressure: 125/75 mm Hg or lower
If hyperkalemia or acute renal failure

develops, evaluate possible causes
If no other precipitant, decrease ACE inhibitor dose
Add diuretic, calcium channel blocker
A
FIGURE 6-37
Treatment of patients with renal disease and high-normal or elevated
blood pressure (BP). A, All patients should have a measurement of
24-hour protein excretion. If the protein excretion is over 1 g/24 h, an
angiotensin-converting enzyme (ACE) inhibitor should be started. The
goal of hypertension control in patients with azotemia who have massive proteinuria should be a blood pressure of 125/75 mm Hg or lower.
It is unlikely that an ACE inhibitor alone will be able to decrease the
blood pressure to this level before hyperkalemia or hemodynamically
mediated acute renal failure intervenes. A diuretic and medications from
other classes, such as a calcium channel blocker, should then be added.
Yes
No
Treatment with ACE inhibitor

Target blood pressure:
125/75 mm Hg or lower
Treatment with diuretic,

ACE inhibitor, or
calcium channel
blocker
B, When protein excretion is less than 1 g/24 h, the blood pressure should be lowered to at least 130/85 mm Hg. No conclusive
evidence exists to support the use of one antihypertensive agent
or class of agents over another. However, in patients at risk for
progressive proteinuria (eg, diabetic patients with microalbuminuria), ACE inhibitors should be used. Given the importance of
sodium retention in the hypertension in renal disease, a loop
or thiazide diuretic is a reasonable initial treatment. An ACE
inhibitor or calcium channel blocker should be added as a
second-line agent.
6.17
References
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6.18
41. Gruppo Italiano di Studi Epidemiologici in Nefrologia: Randomised

placebo-controlled trial of effect of ramipril on decline in glomerular
filtration rate and risk of renal failure in proteinuric, non-diabetic
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45. van Essen GG, Apperloo AJ, Sluiter WJ, et al.: Is ACE inhibition
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46. Hannedouche T, Landais P, Goldfarb B, et al.: Randomized controlled
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49. Becker GJ, Whitworth JA, Ihle BU, et al.: Prevention of progression
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52. Bakris GL, Copley JB, Vicknair N, et al.: Calcium channel blockers
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53. Materson BJ, Reda DJ, Cushman WC, et al.: Single-drug therapy for
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Kidney Dis 1997, 29:720728.
Pharmacologic Treatment
of Hypertension
Garry P. Reams
John H. Bauer
his chapter reviews the currently available classes of drugs used

in the treatment of hypertension. To best appreciate the complexity of selecting an antihypertensive agent, an understanding
of the pathophysiology of hypertension and the pharmacology of the
various drug classes used to treat it is required. A thorough understanding of these mechanisms is necessary to appreciate more fully the
workings of specific antihypertensive agents. Among the factors that
modulate high blood pressure, there is considerable overlap. The drug
treatment of hypertension takes advantage of these integrated mechanisms to alter favorably the hemodynamic pattern associated with
high blood pressure.
CHAPTER
7.2
Pathogenesis of Hypertension
Pathogenesis of hypertension
Autoregulation
B LO O D PR E SSUR E = C AR D I AC O U T P U T
PE R IPHER AL VA SCUL AR RE SISTAN CE

H y p er tens i o n = I n c re a s e d CO
and/or
I n c re a s e d P V R
Preload
Fluid volume
Functional
constriction
Sympathetic
nervous overactivity
Reninangiotensin
excess
Structural
hypertrophy
Volume
redistribution
Renal
sodium
retention
Excess
sodium
intake
Contractility
Decreased
filtration
surface
Genetic
alteration
Stress
FIGURE 7-1
Pathogenesis of hypertension. Mean arterial pressure (MAP) is the
product of cardiac output (CO) and peripheral vascular resistance
Cell
membrane
alteration
Hyperinsulinemia
Genetic
alteration
Obesity
Endotheliumderived
factors
(PVR). There are a large number of control mechanisms involved

in every type of hypertension. (From Kaplan [1]; with permission.)
FIGURE 7-2
Blood pressure changes and diet. Many hypertensive patients appear to be sodium sensitive,
as first suggested by studies in 19 hypertensive subjects who were observed after normal
(109 mmol/d), low (9 mmol/d), and high (249 mmol/d) sodium intake [2]. This figure
shows the percent increase in mean blood pressure in salt-sensitive (SS) and nonsalt-sensitive (NSS) patients with hypertension when their diet was changed from low sodium to
high sodium. Vertical lines indicate mean standard deviation. (From Kawasaki et al. [2];
with permission.)
Increase, %
20
10
0
SS
NSS
Mean arterial pressure
20
19
18
17
16
15
6.0
33 %
4%
20 %
5.5
5%
5.0
16
14
12
10
Cardiac output,
L/min
70
65
60
55
50
Total peripheral
resistance,
mm Hg/L/min
13
12
11
10
40
35
30
25
20
15
Arterial pressure,
mm Hg
Pressure gradient Mean circulatory

for venous
filling pressure,
return, mm Hg
mm Hg
Blood volume,
L
Extracellular fluid
volume, L
Pharmacologic Treatment of Hypertension
150
140
130
120
110
100
60 %
20 %
35 %
44 %
40 %
5%
38 %
11 %
Set-point elevated
45 %
22.5 %
8
Days
12
16
7.3
FIGURE 7-3
Cardiac output. An increase in cardiac output has been suggested
as a mechanism for hypertension, particularly in its early borderline phase [3,4]. Sodium and water retention have been theorized
to be the initiating events. Sequential changes following salt loading are depicted [3]. The resultant high cardiac output perfuses the
peripheral tissues in excess of their metabolic requirements, resulting in a normal autoregulatory (vasoconstrictor) pressure. The
early phase of high cardiac output and normal peripheral vascular
resistance gradually changes to the characteristic feature of the
sustained hypertensive state: normal cardiac output and high
peripheral vascular resistance. Shown here are segmental changes
in the important cardiovascular hemodynamic variables in the first
few weeks following the onset of short-term salt-loading hypertension. Note especially that the arterial pressure increases ahead of
the increase in total peripheral resistance. (From Guyton and
7.4
200
HR beats min1
SAP
180
TPRI dyn s cm5 m2
4000
150
100
3000
2000
140
60
1000
70
10
120
DAP
100
CI L min1 m2
MAP
SI mL stroke1 m2
BP, mm Hg
160
50
30
500
1000
VO2 mL min1 m2
500
1000
VO2 mL min1 m2
FIGURE 7-4
Peripheral vascular resistance. Most established cases of hypertension
are associated with an increase in peripheral vascular resistance [5].
These alterations may be related to a functional constriction, the
type observed under the influence of circulating or tissue-generated
vasoconstrictors, or may be a result of structural alterations in the
blood vessel. Solid line indicates values at start of the study [9];
500
1000
VO2 mL min1 m2
dashed line indicates results after 10 years; dotted line indicates results
after 20 years. BPblood pressure; CIcardiac index; DAPdiastolic
arterial blood pressure; HRheart rate; MAPmean arterial pressure;
SAPsystolic arterial blood pressure; SIstroke index; TPRItotal
peripheral resistance index; VO2oxygen consumption. (From LundJohansen [5]; with permission.)
7.5
Classes of Antihypertensive Drugs and Their Side Effects

FIGURE 7-5
Classes of antihypertensive drugs. There are 12 currently available
classes of antihypertensive agents.
CLASSES OF ANTIHYPERTENSIVE DRUGS

Diuretics: benzothiadiazides, loop, and potassium-sparing
-adrenergic and 1/-adrenergic antagonists
Central 2-adrenergic agonists
Central/peripheral adrenergic neuronal-blocking agent
Peripheral 1-adrenergic antagonists
Moderately selective peripheral 1-adrenergic antagonist
Peripheral adrenergic neuronal blocking agents
Direct-acting vasodilators
Calcium antagonists
Tyrosine hydroxylase inhibitor
Angiotensin II receptor antagonists
BP
PV
ISF
CO
CO
TPR
TPR
Rx
PRA
Time
No Rx
FIGURE 7-6
Hemodynamic response to diuretics. Diuretics reduce mean arterial
pressure by their initial natriuretic effect [6]. Acutely, this is achieved
by a reduction in cardiac output mediated by a reduction in plasma
and extracellular fluid volumes [7]. Initially, peripheral vascular
resistance is increased, mediated in part by stimulation of the reninangiotensin system. During sustained diuretic therapy, cardiac output
returns to pretreatment levels, probably reflecting restoration of
plasma volume. Chronic blood pressure control now correlates with
a reduction in peripheral vascular resistance. BPblood pressure;
COcardiac output; ISFinterstitial fluid; PRAplasma renin
activity; PVplasma volume; Rxtreatment; TPRtotal peripheral
resistance. (Adapted from Tarazi [7].)
7.6
A. DIURETICS: BENZOTHIADIAZIDES (PARTIAL LIST) AND RELATED DIURETICS

Generic (trade) name
First dose, mg
Hydrochlorothiazide (G)
(Hydrodiuril, Microzide)
Chlorthalidone (G)
(Hygroton)
Indapamide
(Lozol)
Metolazone
(Mykrox)*;
(Zaroxolyn)
Usual dose
Maximum dose
Duration of action, h
12.5
12.550 mg QD
100
612
12.5
12.550 mg QD
100
4872
1518
1224
1224
1.25
2.55.0 mg
0.5
2.5
0.51.0
2.510 mg QD
1
20
First dose, mg
Usual dose
Maximum dose
0.5
0.52 mg bid
10
46
25
2550 mg bid
200
68
20
20120 mg bid
600
68
550 mg bid
100
68
*Marketed only for treatment of hypertension.

(G)generic available.
B. DIURETICS: LOOP
Bumetanide (G)
(Bumex)
Ethacrynic Acid
(Edecrin)
Furosemide (G)
(Lasix)
Torsemide
(Demadex)
C. DIURETICS: POTASSIUM-SPARING DIURETICS

Spironolactone (G)
(Aldactone)
Amiloride (G)
(Midamor)
Triamterene (G)
(Dyrenium)
First dose, mg
Usual dose
Maximum dose
25
501 00 mg QD
400
510 mg QD
20
50
50-100 mg bid
300
4872
24
79
FIGURE 7-7
AC. Diuretics: benzothiadiazides and related agents, loop diuretics,
and potassium-sparing agents. A partial list of benzothiadiazides
and their related agents is given [6]. With the exception of indapamide and metolazone, their dose-response curves are shallow;
they should not be used when the glomerular filtration rate is
less than 30 mL/min/1.73 m2. The second group listed is loop
diuretics. Because of their steep dose-response curves and natriuretic potency, they are especially useful when the glomerular
filtration rate is less than 30 mL/min/1.73 m2. The third group
is the potassium-sparing diuretics. The major therapeutic use of
these drugs is to attenuate the loss of potassium induced by the
other diuretics.
7.7

Lumen
Blood
Lumen
Blood
Na
DCT
diuretics
Na
3Na
Cl
2K
3Na
Na channel
blockers
DCT
2K
PC
PT
DT
Blood
Lumen
HCO3
Na
3Na
H
CAI
H2CO3
CA
H2O + CO2
Lumen
2K
Blood
HCO3
H2CO3
CA
H2O + CO2
Loop
diuretics
CAI
Na
K
2Cl
3Na
2K
CD
PT
TAL
LH
FIGURE 7-8
Mechanisms of action of diuretics. This figure depicts the
major sites and mechanisms of action of diuretic drugs [8].
The diuretic/natriuretic action of benzothiadiazide-type diuretics
is predicated on their gaining access to the luminal side of the
distal convoluted tubule and inhibiting Na+ - Cl- cotransport
by competing for the chloride site.
The diuretic/natriuretic action of loop diuretics is
predicated on their gaining access to the luminal side of
the thick ascending limb of the loop of Henle and inhibiting
Na+ - K+ -2Cl- electroneutral cotransport by competing for
the chloride site.
The diuretic/natriuretic action of potassium-sparing diuretics is

predicated on their gaining access to the luminal side of the principal
cells located in the late distal tubule and cortical collecting duct and
blocking luminal sodium channels. Because Na+ uptake is blocked,
the lumen negative voltage is reduced, inhibiting K+ secretion. The
potassium-sparing diuretic spironolactone does this indirectly by
competing with aldosterone for its cytosolic receptor. CAcarbonic
anhydrase; CAIcarbonic anhydrase inhibitor; CDcollecting duct;
DCTdistal convoluted tubule; DTdistal tubule; LHloop of
Henle; PCprincipal cell; PTproximal tubule; TALthick ascending limb. (From Ellison [8]; with permission.)
7.8
THE SIDE EFFECT PROFILE OF DIURETIC THERAPY

Side effects
Thiazide-type diuretic
Azotemia
Hypochloremia, hypokalemia, metabolic alkalosis
Hypomagnesemia
Hyponatremia
Hypercalcemia
Hyperuricemia
Carbohydrate intolerance
Hyperlipidemia
Increased total triglyceride
Increased total cholesterol
Loop-type diuretics
Ototoxicity
Hypocalcemia
Potassium-sparing diuretics
Hyperkalemia
Decreased sexual function, gynecomastia, menstrual
irregularity, hirsutism
Renal stone
Mechanisms
Enhanced proximal fluid and urea reabsorption secondary
to volume depletion
Increased delivery of sodium to distal tubule facilitating Na+K+ and Na+-H+ exchange; increased net acid excretion;
increased urinary flow rate; secondary aldosteronism
Increase fractional Mg2+ excretion by inhibiting reabsorption in ascending limb of loop of Henle
Impaired free water clearance
(distal cortical diluting segment)
May reflect an increased protein-bound fraction secondary
to volume depletion
Impair enhanced proximal fluid and urate reabsorption
secondary to volume depletion
Hypokalemia impairing insulin secretion; decreased
insulin sensitivity
May be due to extracellular fluid depletion
High plasma concentration of furosemide or

ethacrynic acid
Increase fractional excretion of calcium by interfering with
reabsorption in loop of Henle
Blocks potassium excretion
Spironolactone only; lower circulatory testosterone levels
by increasing metabolic clearance and/or preventing
compensatory rise in testicular androgen production
Triamterene only
FIGURE 7-9
The side effect profile of diuretic therapy.
The complications of diuretic therapy are
typically related to dose and duration of
therapy, and they decrease with lower
dosages. This table lists the most common
side effects of diuretics and their proposed
mechanism of action [6].
Adrenal gland
Heart CO
E
NE
Effector cell
Kidney
-blockers
1
BP
Blood
vessels TPR
+
NE
7.9
FIGURE 7-10
-adrenergic antagonists. -adrenergic antagonists attenuate sympathetic activity through competitive antagonism of catecholamines
at both 1- and 2-adrenergic receptors [6,9]. In the absence of
partial agonist activity (PAA), the acute systemic hemodynamic
effects are a decrease in heart rate and cardiac output and an increase
in peripheral vascular resistance proportional to the degree of cardiodepression; blood pressure is unchanged. Chronically, there is a gradual
decrease in blood pressure proportional to the fall in peripheral
vascular resistance, which is dependent on the degree of cardiac
sympathetic drive. -adrenergic antagonists with sufficient partial
agonist activity to maintain heart rate and cardiac output may not
evoke acute reflex vasoconstriction: Blood pressure falls proportional to the decrease in peripheral resistance (see Fig. 7-11) [10].
BPblood pressure; COcardiac output; Eepinephrine; NE
norepinephrine; TPRtotal peripheral resistance.
MAP, %
Sympathetic
neuron
FIGURE 7-11
Hemodynamic changes associated with -adrenergic blockade. Time course of hemodynamic changes after treatment with a -adrenergic blocker devoid of partial agonist activity (PAA) (solid line) as compared with hemodynamic changes after administration of a
-adrenergic blocker with sufficient PAA to replace basal sympathetic tone (eg, pindolol)
(broken line). MAPmean arterial pressure. (From Man int Veld and Schalekamp [10];
with permission.)
100
90
Cardiac output, %
80
100
90
80
Vascular resistance, %
130
120
110
100
90
80
Time (hours to days)
7.10
A. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: NON-SELECTIVE (1 AND 2)

ADRENERGIC ANTAGONISTS THAT LACK PARTIAL AGONIST ACTIVITY
Nadolol (G)
(Corgard)
Propranolol (G)
(Inderal)
(Inderal LA)
Timolol (G)
(Blockadren)
First dose, mg
Usual daily dose, mg
Maximum daily dose, mg
40
40240 QD
320
>24
40
80
40120 bid
80240 QD
480
480
>12
>12
10
1030 bid
60
>12
Ggeneric available.
B. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: NON-SELECTIVE

(1 AND 2) ADRENERGIC ANTAGONISTS WITH PARTIAL AGONIST ACTIVITY
Pindolol (G)
(Visken)
Carteolol
(Cartrol)
Penbutolol
(Levatol)
First dose, mg
5
2.5
10
60
12
10
24
40
24
1030 bid
2.510 QD
1020 QD
Ggeneric available.
C: DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-SELECTIVE

ADRENERGIC ANTAGONISTS THAT LACK PARTIAL AGONIST ACTIVITY
Atenolol (G)
(Tenormin)
Metoprolol Tartrate (G)
(Lopressor)
Metoprolol Succinate
(Toprol-XL)
Betaxolol
(Kerlone)
Bisoprolol
(Zebeta)
First dose, mg
50
50100 QD
200
24
50
50150 bid
400
12
50
100300 QD
400
12
1020 QD
40
>24
520 QD
40
12
Ggeneric available.
FIGURE 7-12
Dosing schedules for -adrenergic antagonists. A, Nonselective adrenergic antagonists that lack partial agonist activity. B, Nonselective
-adrenergic antagonists with partial agonist activity. C, 1-selective

adrenergic antagonists that lack partial agonist activity.
7.11
D. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-SELECTIVE

ADRENERGIC ANTAGONISTS WITH WEAK PARTIAL AGONIST ACTIVITY
Acebutolol
(Sectrol)
First dose, mg
200
400800 QD
1200
24
E. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS:

1-NONSELECTIVE -ADRENERGIC ANTAGONISTS LABETALOL (G)
Labetalol (G)
(Normodyne)
(Trandate)
Carvedilol
(Coreg)
First dose, mg
100
6.25

100-600 bid
6.25-25 bid
Ggeneric available.

D, 1-selective adrenergic antagonists with weak partial agonist
activity. E, 1-nonselective -adrenergic antagonists.
2400
12
50
7.12
PHARMACOKINETICS OF -ADRENERGIC ANTAGONISTS
Nadolol
Propranolol
Propranolol LA
Timolol
Pindolol
Carteolol
Penbutolol
Atenolol
Metoprolol tartrate
Metoprolol succinate
Betaxolol
Bisoprolol
Acebutolol
Labetalol
Carvedilol
Solubility
Absorption
Hydrophilic
Lipophilic
Lipophilic
Lipophilic
Lipophilic
Hydrophilic
Lipophilic
Hydrophilic
Lipophilic
Lipophilic
Lipophilic
Equal
Lipophilic
Lipophilic
Lipophilic
30%40%
>90%
>90%
>90%
>90%
>90%
>90%
5060%
>90%
>90%
>90%
>90%
70%
>90%
>90
First-pass hepatic
metabolism
Peak
concentration, h
<10%
60%
80%
50%
<10%
<10%
<10%
<10%
50%
50%
<10%
20%
30%
60%
7080%
24
13
6
12
12
13
23
24
12
7
1.56
24
24
12
12
Active metabolite
Plasma
half-life, h
Dose reduction
in renal failure
None
Yes
Yes
None
None
Yes
Yes
None
None
None
None
None
Yes
None
Yes
2024
34
10
34
34
56
5
67
37
37
1422
912
34
34
710
Yes
No
No
No
Yes
Yes
Yes
Yes
No
No
Yes
Yes
Yes
No
No
FIGURE 7-13
Pharmacokinetics of -adrenergic antagonists.
THE SIDE EFFECT PROFILE OF -ADRENERGIC ANTAGONISTS

Side effects
Mechanisms
Bronchospasm
Bradycardia
Congestive heart failure; decrease in
exercise tolerance
Claudication
Constipation, dyspepsia
Blockade of 2-adrenergic receptors; increased airway resistance

Blockade of atrial 1/2-adrenergic receptors; decrease in heart rate
Blockade of ventricular 1-adrenergic receptors
Blockade of peripheral vascular 2-adrenergic receptors
Blockade of gastrointestinal 1/2-adrenergic receptors; decreased motility and relaxation of sphincter tone
Blockade of CNS 1/2-adrenergic receptors
Central nervous system manifestations

(sleep disturbances, depression)
Sexual dysfunction (impotence,
decrease libido)
Impaired glucose tolerance
Unknown
Prolonged insulin-induced
hypoglycemia
Hepatocellular necrosis
Withdrawal syndrome
Unstable angina
Myocardial infarction
Dyslipidemia
Increased total triglycerides
Decreased high-density lipoproteins
cholesterol
Labetalol only, idiosyncratic reaction

Acute overshoot in heart rate with increased myocardial oxygen demand
due to increase in number and/or sensitivity of -adrenergic receptors
during chronic blockade
Increased -adrenergic tone; reduced lipoprotein lipase activity
Impaired 2-adrenergicmediated islet cell insulin secretion; increase

hepatic glucose, and/or decrease insulin-stimulated glucose disposal
Block epinephrine-mediated counterregulatory mechanisms
FIGURE 7-14
The side effect profile of -adrenergic
antagonists. The side effect profile of betablockers is related to the specific blockade
of 1 or 2 receptors. This table lists the
more common side effects and their proposed mechanism(s) of action [6,9].
7.13

Phsysiologic effect of central
2-adrenergic agonists
-Methyldopa
guanfacine
guanabenz
Clonidine
Stimulates
Stimulates
Central 2
adrenoceptor
I1-Imidazoline
receptor
NTS
RVLM
Nucleus
tractus
solitarii
FIGURE 7-15
Central 2-adrenergic agonists. Central 2-adrenergic agonists cross the blood-brain barrier
and stimulate 2-adrenergic receptors in the vasomotor center of the brain stem [6,9].
Stimulation of these receptors decreases sympathetic tone, brain turnover of norepinephrine,
and central sympathetic outflow and activity of the preganglionic sympathetic nerves. The
net effect is a reduction in norepinephrine release. The central 2-adrenergic agonist clonidine
also binds to imidazole receptors in the brain; activation of these receptors inhibits central
sympathetic outflow. Central 2-adrenergic agonists may also stimulate the peripheral 2adrenergic receptors that mediate vasoconstriction; this effect predominates at high plasma
drug concentrations and may precipitate an increase in blood pressure. The usual physiologic
effect is a decrease in peripheral resistance and slowing of the heart rate; however, output
is either unchanged or mildly decreased. Preservation of cardiovascular reflexes prevents
postural hypotension.
Rostral
ventrolateral
medulla
Inhibition of central
sympathetic activity
Blood pressure
reduction
CENTRAL 2-ADRENERGIC ANTAGONISTS

First dose, mg
Usual daily dose
Maximum daily dose
-Methyldopa (G) (Aldomet)

Clonidine (G) (Catapres)
Clonidine TTS (Catapres-TTS)
Guanabenz (Wytensin)
Guanfacine (Tenex)
250
0.1
2.5 mg (TTS-1)
4
1
2501000 mg bid
0.10.6 mg bid/tid
2.57.5 mg (TTS1 to TTS3) qwk
416 mg bid
13 mg QD
3000
2.4
15 mg (TTS-3x2) 9 wk
64
3
Duration of action
2448 h
68 h
7d
12 h
36 h
Ggeneric available; TTStransdermal patch.
FIGURE 7-16
Central 2-adrenergic agonists. -Methyldopa is a methyl-substituted
amino acid that is active only after decarboxylation and conversion
to -methyl-norepinephrine. The antihypertensive effect results from
accumulation of 2-adrenergic receptors, displacing and competing with
endogenous catecholamines. Methyldopa is absorbed poorly
(<50%); peak plasma concentrations occur in 2 to 4 hours. It is
metabolized in the liver and excreted in the urine mainly as the inactive
O-sulfate conjugate. The plasma half-life of methyldopa (1 to 2 hours)
and its metabolites is prolonged in patients with renal insufficiency;
dose reduction is required.
Clonidine, an imidazoline derivative, acts by stimulating either
central 2-adrenergic receptors or imidazole receptors. Clonidine may
be administered orally or by a transdermal delivery system (TTS).
When given orally, it is absorbed well (>75%); peak plasma concentrations occur in 3 to 5 hours. Clonidine is metabolized mainly
in the liver; fecal excretion ranges from 15% to 30%, and 40% to
60% is excreted unchanged in the urine. In patients with renal
insufficiency, the plasma half-life (12 to 16 hours) may be extended

to more than 40 hours; dose reduction is required. When clonidine
is administered transdermally, therapeutic plasma levels are achieved
within 2 to 3 days.
Guanabenz, a guanidine derivative, is highly selective for central
2-adrenergic receptors. It is absorbed well (>75%); peak plasma
levels are reached in 2 to 5 hours. Guanabenz undergoes extensive
hepatic metabolism; less than 2% is excreted unchanged in the urine.
The plasma half-life (approximately 6 hours) is not prolonged in
patients with renal insufficiency.
Guanfacine is a phenylacetyl-guanidine derivative with a longer
plasma half-life than guanabenz. It is absorbed well (>90%); peak
plasma concentrations are reached in 1 to 4 hours. The drug is
primarily metabolized in the liver. Guanfacine and its metabolites
are excreted primarily by the kidneys; 24% to 37% is excreted as
unchanged drug in the urine. The plasma half-life (15 to 17 hours)
is not prolonged in patients with renal insufficiency [6,9].
7.14

FIGURE 7-17
The side effect profile of central 2-adrenergic agonists. The side
effect profile of these agents is diverse [6,9].
THE SIDE EFFECT PROFILE OF CENTRAL

2-ADRENERGIC AGONISTS
Side effects
Mechanisms
Sedation/drowsiness
Stimulation of 2-adrenergic receptors in

the brain
Centrally mediated inhibition of
cholinergic transmission
Reduced central dopaminergic inhibition
of prolactin release (methyldopa only)
Long-term tissue toxicity
(methyldopa only)
Xerostoniia (dry mouth)

Gynecomastia in men, galactorrhea
in women
Drug fever, hepatotoxicity, positive
Coombs test with or without
hemolytic anemia
Sexual dysfunction, depression,
decreased mental acuity
Overshoot hypertension
Restlessness
Insomnia
Headache
Tremor
Anxiety
Nausea and vomiting
A feeling of impending doom
Stimulation of 2-adrenergic receptor

in the brain
Acute excessive sympathetic discharge
in the face of chronic downregulation
of central 2-adrenergic receptors in
an inhibitory circuit during chronic
treatment when treatment is stopped
Indicates blockade
Brain stem
Preganglionic
neuron
Ganglion
NE
Postganglionic
adrenergic
nerve ending
NE
NE
NE
2
Vascular smooth muscle cells
FIGURE 7-18
Central and peripheral adrenergic neuronal blocking agents.
Rauwolfia alkaloids act both within the central nervous system and
in the peripheral sympathetic nervous system [6,9]. They effectively
deplete stores of norepinephrine (NE) by competitively inhibiting
the uptake of dopamine by storage granules and by preventing the
incorporation of norepinephrine into the protective chromaffin
granules; the free catecholamines are destroyed by monoamine
oxidase. The predominant pharmacologic effect is a marked
decrease in peripheral resistance; heart rate and cardiac output
are either unchanged or mildly decreased.
7.15
CENTRAL PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENT

Reserpine (G) (Serpasil)
First dose, mg
Duration of action
0.1
0.1.25 QD
0.5
23 wk
FIGURE 7-19
Central and peripheral adrenergic neuronal blocking agents. Reserpine
is the most popular rauwolfia product used. It is absorbed poorly
(approximately 30%); peak plasma concentrations occur in 1 to 2
hours. Catecholamine depletion begins within 1 hour of drug
administration and is maximal in 24 hours. Catecholamines are
restored slowly. Chronic doses of reserpine are cumulative. Blood
THE SIDE EFFECT PROFILE OF RESERPINE

Side effects
Mechanisms
Altered CNS function

Inability to concentrate
Decrease mental acuity
Sedation
Sleep disturbance
Depression
Nasal congestion/rhinitis
Increased GI motility,
increased gastric acid secretion
Increased appetite/weight gain
Sexual dysfunction
Impotence
Decreased libido
Depletion of serotonin and/or

catecholamine
pressure is maximally lowered 2 to 3 weeks after beginning therapy.

Reserpine is metabolized by the liver; 60% of an oral dose is recovered
in the feces. Less than 1% is excreted in the urine as unchanged drug.
The plasma half-life (12 to 16 days) is not prolonged in patients
with renal insufficiency.
Indicates blockade
Peripheral
adrenergic
nerve ending
NE
NE
NE
NE
NE
Cholinergic effects
Cholinergic effects
NE
Unknown
Unknown
NE
2
FIGURE 7-20
The side effect profile of the central and peripheral adrenergic neuronal
blocking agents [10,13]. Reserpine is contraindicated in patients with a
history of depression or peptic ulcer disease. CNScentral nervous
system; GIgastrointestinal.
1
FIGURE 7-21
Peripheral 1-adrenergic antagonists. 1-Adrenergic antagonists
induce dilation of both resistance (arterial) and capacitance (venous)
vessels by selectively inhibiting postjunctional 1-adrenergic receptors
[6,9]. The net physiologic effect is a decrease in peripheral resistance;
reflex tachycardia and the attendant increase in cardiac output do
not predictably occur. This is due to their low affinity for prejunctional
2-adrenergic receptors, which modulate the local control of norepinephrine release from sympathetic nerve terminals by a negative
feedback mechanism (see Fig. 7-22) [11]. NEnorepinephrine.
7.16
Varicosity
Vesicle
containing NA
Nerve impulse
induces
exocytotic NA release +
Presynaptic
-receptor
Sympathetic
C-fiber
Presynaptic
-receptor
Synaptic
cleft
Postganglionic
sympathetic neuron
NA
Varicosities
Synaptic
cleft
Postsynaptic
-receptor
Effector
cell
Response
NA
Postsynaptic
- receptors
Target
organ
FIGURE 7-22
Adrenergic synapse. Nerve activity releases
the endogenous neurotransmitter noradrenaline (NA) and also adrenaline from the
varicosities. Noradrenaline and adrenaline
reach the postsynaptic -adrenoceptors (or
-adrenoceptors) on the cell membrane of
the target organ by diffusion. On receptor
stimulation, a physiologic or pharmacologic
effect is initiated. Presynaptic 2-adrenoceptors on the membrane (enlarged area), when
activated by endogenous noradrenaline as
well as by exogenous agonists, inhibit the
amount of transmitter noradrenaline released
per nerve impulse. Conversely, the stimulation
of presynaptic 2-receptors enhances noradrenaline release from the varicosities. Once
noradrenaline has been released, it travels
through the synaptic cleft and reaches both
- and -adrenoceptors at postsynaptic
sites, causing physiologic effects such as
vasoconstriction or tachycardia. (Adapted
from Van Zwieten [11].)
PERIPHERAL 1-ADRENERGIC ANTAGONISTS

First dose, mg
Prazosin (G) (Minipress)

Terazosin (Hytrin)
Doxazosin (Cardura)
1
1
1
2-6 bid/tid
2-5 QD/bid
2-4 QD
20
20
16
Duration of action
6-12 w
12-24 h
24 h
Ggeneric available.
FIGURE 7-23
Peripheral 1-adrenergic antagonists. Prazosin is a lipophilic
highly selective 1-adrenergic antagonist. It is absorbed well
(approximately 90%) but undergoes variable first-pass hepatic
metabolism. Peak plasma concentrations occur in 2 to 3 hours.
It is extensively metabolized by the liver and predominantly
excreted in the feces. The plasma half-life of prazosin (2 to
4 hours) is not prolonged in patients with renal insufficiency.
Terazosin is a water-soluble quinazoline analogue of prazosin
with about one third of its potency. It is completely absorbed
and undergoes minimal first-pass hepatic metabolism. Peak
plasma concentrations occur in 1 to 2 hours. It is extensively
metabolized by the liver and predominantly excreted in the

feces. The plasma half-life of terazosin (approximately 12 hours)
is not prolonged in patients with renal insufficiency.
Doxazosin is also a water-soluble quinazoline analogue of
prazosin, with about half its potency. It is absorbed well but
undergoes significant first-pass hepatic metabolism; bioavailability is approximately 65%. Peak concentrations occur in
2 to 3 hours. It is extensively metabolized by the liver and
primarily eliminated in the feces. The plasma half-life of doxazosin (approximately 22 hours) is not prolonged in patients
with renal insufficiency [6,9].
150
Lying
Standing
Placebo
Mean BP, mm Hg
140
130
120
110
100
140
Day 0
Prazosin, 2 mg
130
Mean BP, mm Hg
120
110
100
90
80
70
60
50
140
Day 1
Prazosin, 2 mg
Mean BP, mm Hg
130
120
110
100
90
80
Day 4
0700
0900
1100
1300
Time, h
1500
1700
7.17
FIGURE 7-24
The side effect profile of the peripheral 1-adrenergic antagonists.
1-Adrenergic antagonists are associated with relatively few side
effects [6,9]; the most striking is the first-dose effect [12]. It
occurs 30 to 90 minutes after the first dose and is dose dependent.
It is minimized by initiating therapy in the evening and by careful
dose titration. The first-dose effect is exaggerated by fasting,
upright posture, volume contraction, concurrent -adrenergic
antagonism, or excessive catecholamine activity (eg, pheochromocytoma). (From Graham and coworkers [12]; with permission.)
7.18

FIGURE 7-25
Moderately selective peripheral 1-adrenergic antagonists.
Phenoxybenzamine is a moderately selective peripheral 1-adrenergic
antagonist [6,9]. It is 100 times more potent at 1-adrenergic
receptors than at 2-adrenergic receptors. Phenoxybenzamine binds
covalently to -adrenergic receptors, interfering with the capacity
of sympathomimetic amines to initiate action at these sites.
Phenoxybenzamine also increases the rate of turnover of norepinephrine (NE) owing to increased tyrosine hydroxylase activity,
and it increases the amount of norepinephrine released by each
nerve impulse owing to blockade of presynaptic 2-adrenergic
receptors [11]. The net physiologic effect is a decrease in peripheral
resistance and increases in heart rate and cardiac output. Postural
hypotension may be prominent, related to blockade of compensatory
responses to upright posture and hypovolemia. The degree of
vasodilation is dependent on the degree of adrenergic vascular tone.
Indicates blockade
Peripheral
adrenergic
nerve ending
NE
NE
NE
NE
NE
NE
NE
2
1
MODERATELY SELECTIVE PERIPHERAL 1-ADRENERGIC ANTAGONIST

Phenoxybenzamine (Dibenzyline)
First dose, mg
Maximum of action, mg
Duration of action
10
20-40 bid
120
34 d
FIGURE 7-26
Moderately selective peripheral 1-adrenergic antagonists.
Phenoxybenzamine is the only drug in its class. Absorption is variable
and incomplete (20% to 30%). Peak blockade occurs in 3 to 4
hours. Its plasma half-life is 24 hours. The duration of action is
approximately 3 to 4 days. Phenoxybenzamine is primarily used in

the management of preoperative or inoperative pheochromocytoma.
Efficacy is dependent on the degree of underlying excessive -adrenergic
vascular tone [6,9].
THE SIDE EFFECT PROFILE OF PHENOXYBENZAMINE

Side effects
Mechanisms
Nasal congestion
Miosis
Sedation
Weakness, lassitude
-adrenergic receptor blockade

Unknown
Impairment of compensatory vasoconstriction producing
orthostatic hypotension
Sexual dysfunction
Inhibition of ejaculation
Tachycardia
Indicates blockade
NE
NE
NE
NE
FIGURE 7-27
The side effect profile of phenoxybenzamine. The common side
effects are listed [6,9].
Uninhibited effects of epinephrine, norepinephrine and

direct or reflex sympathetic nerve stimulation on the heart
Peripheral
adrenergic
nerve ending
7.19
2
FIGURE 7-28
Peripheral adrenergic neuronal blocking agents. Peripheral adrenergic
neuronal blocking agents are selectively concentrated in the adrenergic nerve terminal by an active transport mechanism, or norepinephrine pump [6,9]. They act by interfering with the release of
norepinephrine (NE) from neuronal storage sites in response to nerve
stimulation and by depleting norepinephrine from nerve endings.
Acutely, cardiac output is reduced, caused by diminished venous
return and by blockade of sympathetic -adrenergic effects on the
heart; peripheral resistance is unchanged. Following chronic therapy,
peripheral resistance is decreased, along with modest decreases in
heart rate and cardiac output.
7.20
PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENTS

Guanethidine (Ismelin)
Guanadrel (Hylorel)
First dose, mg
Duration of action
10
5
2575 QD
1050 bid
150
150
721 d
414 h
FIGURE 7-29
Peripheral adrenergic neuronal blocking agents. Guanethidine is
the prototype peripheral adrenergic neuronal blocking agent.
Absorption is incomplete and variable; only 3% to 30% is absorbed
over 12 hours. Peak plasma levels are reached in 6 hours. The drug
rapidly leaves the plasma for extravascular storage sites, including
sympathetic neurons. Guanethidine is eliminated with a plasma
half-life of 4 to 8 days, a time course that corresponds with its antihypertensive effect. Approximately 24% of the drug is excreted
unchanged in the urine; the remainder is metabolized by the liver
into more polar, less active, metabolites that are excreted in the
urine and feces. When therapy is initiated or the dosage is changed,
three half-lives (approximately 15 days) are required to accumulate
87.5% of a steady-state level. By administering loading doses of

guanethidine at 6-hour intervals (the nearly maximal effect from a
single oral dose), blood pressure can be lowered in 1 to 3 days. In
patients with severe renal insufficiency, drug excretion is decreased;
dose reduction is required.
Guanadrel is a guanethidine derivative with a short therapeutic
half-life. Absorption is greater than 85%; peak plasma concentrations are reached in 1 to 2 hours. Guanadrel is metabolized by the
liver. Elimination occurs through the kidney; approximately 40%
of the drug is excreted unchanged in the urine. In patients with
renal insufficiency, the plasma half-life (10 to 12 hours) is prolonged; dose reduction is required [6,9].
THE SIDE EFFECT PROFILE OF PERIPHERAL

ADRENERGIC-NEURONAL BLOCKING AGENTS
Side effects
Mechanisms
Decrease renal function (GFR)

Fluid retention/weight gain
Decreased renal perfusion; effect is magnified in the upright position

Decreased filtered load and fractional excretion of sodium; diuretic should be
used in combination
Postural hypotension accentuated by hot weather, alcohol ingestion, and/or
physical exercise
Unopposed parasympathetic activity, increasing gastrointestinal motility
Inhibition of bladder neck closure, unknown
Dizziness/weakness
Syncope
Intestinal cramping/diarrhea
Sexual dysfunction
Retrograde ejaculation
Impotence
Decreased libido
Sinus bradycardia
Atrioventricular block
Bronchospasm
Interferes with cardiac sympathetic compensating reflexes

Catecholamine depletion aggravates airway resistance
Decreased cardiac output
FIGURE 7-30
The side effect profile of peripheral adrenergic neuronal blocking agents. The specific
side effects of this class are related to either
excessive sympathetic blockade or a relative
increase in parasympathetic activity. GFR
glomerular filtration rate.
7.21
Plasma
membrane
VGC
Leak
ROC
Altered calcium
metabolism (?)
Ca2+
VGC
Ca2+
Ca2+
Ca2+
SR
Ca2+
SR
FIGURE 7-31
Direct-acting vasodilators. Direct-acting vasodilators may have an
effect on both arterial resistance and venous capacitance vessels;
however, the currently available oral drugs are highly selective for
resistance vessels [6,9]. Their specific mechanism of vascular relaxation and reason for selectivity are unknown. By altering cellular calcium metabolism, they interfere with the calcium movements responsible for initiating or maintaining a contractile state. The net physiologic effect is a decrease in peripheral vascular resistance
associated with increases in heart rate and cardiac output. These
increases in heart rate and cardiac output are related directly to
sympathetic stimulation and indirectly to the baroreceptor reflex
response. ROCreceptor-operated channel; SRsarcoplasmic
reticulum; VGCvoltage-gaited channels.
Activation of
Myofilaments
Contraction of vascular
smooth muscle
Hypertension
DIRECT-ACTING VASODILATORS
Hydralazine (G) (Apresoline)
Minoxidil (G) (Loniten)
First dose, mg
10
5
50100 bid/tid
1020 QD/bid
300
80
1012
75
Ggeneric available.
FIGURE 7-32
Direct-acting vasodilators. Hydralazine is the prototype of directacting vasodilators. Absorption is more than 90%. Peak plasma
levels occur within 1 hour but may vary widely among individuals.
This is because hydralazine is subject to polymorphic acetylation;
slow acetylators have higher plasma levels and require lower drug
doses to maintain blood pressure control compared with rapid
acetylators. Bioavailability for slow acetylators ranges from 30%
to 35%; bioavailability for rapid acetylators ranges from 10% to
16%. Hydralazine undergoes extensive hepatic metabolism; it is
mainly excreted in the urine in the form of metabolites or as
unchanged drug. The plasma half-life is 3 to 7 hours. Dose reduction
may be required in the slow acetylator with renal insufficiency.
Minoxidil is a substantially more potent direct-acting vasodilator

than hydralazine. Absorption is greater than 95%. Peak plasma levels
occur within 1 hour. Following a single oral dose, blood pressure
declines within 15 minutes, reaches a nadir between 2 and 4 hours,
and recovers at an arithmetically linear rate of 30% per day.
Approximately 90% is metabolized by conjugation with glucuronic
acid and by conversion to more polar products. Known metabolites,
which are less pharmacologically active than minoxidil, are excreted
in the urine. The plasma half-life of minoxidil is approximately 4
hours; dose adjustments are unnecessary in patients with renal insufficiency. Minoxidil and its metabolites are removed by hemodialysis
and peritoneal dialysis; replacement therapy is required [6,9].
7.22

Side effects of direct-acting vasodilators
Heart rate
VASODILATORS
Myocardial
contractility
Sympathetic
function
Venous
capacitance
Peripheral
vascular
resistance
Peripheral
vascular
resistance
Plasma
renin
activity
Arterial
pressure
Cardiac
output
PROPRANOLOL
Circulating
angiotensin
Aldosterone
secretion
DIURETICS
Plasma and
extracellular
fluid volume
Sodium
excretion
Plasma
membrane
ROC
VGC
Ca2+
Ca2+
Ca2+
Ca2+
Myofilaments
SR
Ca2+
SR
VGC
FIGURE 7-33
The side effect profile of direct-acting
vasodilators. The most common and most
serious effects of hydralazine and minoxidil
are related to their direct or reflex-mediated
hemodynamic actions, including flushing,
headache, palpitations, anginal attacks, and
electrocardiographic changes of myocardial
ischemia [6,9]. These effects may be prevented by concurrent administration of a
-adrenergic antagonist. Sodium retention
with expansion of extracellular fluid volume
is a significant problem. Large doses of
potent diuretics may be required to prevent
fluid retention and the development of
pseudotolerance [13]. (From Koch-Weser
Repeated administration of hydralazine
can lead to a reversible syndrome that
resembles disseminated lupus erythematosus.
The incidence is dose dependent; it rarely
occurs in patients receiving less than 200
mg/day. Hypertrichosis is a common troublesome but reversible side effect of minoxidil;
it develops during the first 3 to 6 weeks of
therapy in approximately 80% of patients.
FIGURE 7-34
Calcium antagonists. The calcium antagonists share a common
antihypertensive mechanism of action: inhibition of calcium ion
movement into smooth muscle cells of resistance arterioles through
L-type (long-lasting) voltage-operated channels [6,9]. The ability of
these drugs to bind to voltage-operated channels, causing closure of
the gate and subsequent inhibition of calcium flux from the extracellular to the intracellular space, inhibits the essential role of calcium as an intracellular messenger, uncoupling excitation to contraction. Calcium ions may also enter cells through receptor-operated
channels. The opening of these channels is induced by binding neurohumoral mediators to specific receptors on the cell membrane.
Calcium antagonists inhibit the calcium influx triggered by the
stimulation of either -adrenergic or angiotensin II receptors in a
dose-dependent manner, inhibiting the influence of -adrenergic agonist and angiotensin II on vascular smooth muscle tone. The net
physiologic effect is a decrease in vascular resistance.
Although all the calcium antagonists share a basic mechanism of
action, they are a highly heterogeneous group of compounds that
differ markedly in their chemical structure, pharmacologic effects
on tissue specificity, pharmacologic behavior side-effect profile, and
clinical indications [6,9,14]. Because of this, calcium antagonists
have been subdivided into several distinct classes: phenylalkamines,
dihydropyridines, and benzothiazepines. ROCreceptor-operated
channel; SRsarcoplasmic reticulum; VGCvoltage-gaited channels.
7.23
A. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: PHENYLALKAMINE DERIVATIVE

Verapamil (G) (Isoptin, Calan)
Verapamil SR (Isoptin SR, Calan SR)
Verapamil SRpellet (Veralan)
Verapamil COER-24 (Covera HS)
First dose, mg
80
90
120
180
Usual dose, mg
80120 tid
90240 bid
240480 QD
180480 qhs
480
480
480
480
8
1224
24
24
Ggeneric available.
B. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: DIHYDROPYRIDINE DERIVATIVES

Amlodipine (Norvasc)
Felodipine (Plendil)
Isradipine (DynaCirc)
Isradipine CR (DynaCirc CR)
Nicardipine SR (Cardine SR)
Nifedipine Caps (G) (Procardia)
Nifedipine ER (Adalat CC)
Nifedipine GITS (Procardia XL)
Nisoldipine (Sular)
First dose, mg
Usual dose, mg
5
5
2.5
5
30
10
30
30
20
510 QD
51 0 QD
2.5-5 bid
520 QD
3060 bid
1030 tid/qid
3090 QD
3090 QD
2040 QD

10
20
20
20
120
120
120
120
60
24
24
12
24
12
46
24
24
24
Ggeneric available.
C. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: BENZODIAZEPINE DERIVATIVE

Diltiazem (G) (Cardizem)
Diltiazem SR (Cardizem SR)
Diltiazem CD (Cardizem CD)
Diltiazem XR (Dilacor XR)
Diltiazem ER (Tiazac)
First dose, mg
60
180
180
180
180
Usual dose, mg
60120 tid/qid
120240 bid
240480 QD
180480 QD
180480 QD
Ggeneric available.
FIGURE 7-35
AC. Dosing schedules for calcium antagonists: phenylalkamine derivatives,
dihydropyridine derivatives, and benzothiazepine derivatives.

480
480
480
480
480
8
12
24
24
24
7.24
PHARMACOKINETICS OF CALCIUM ANTAGONISTS

Absorption, %
First-pass hepatic
Peak concentration
Verapamil
>90
70%80%
Amlodipine
Felodipine
Isradipine
>90
>90
>90
Minimal
Extensive
Extensive
Nicardipine
Nifedipine
>90
>90
Extensive
20%30%
Nisoldipine
Diltiazem
>85
>80
Extensive
50%
12 h (tablet)
5 h (SR caplet)
79 h (SR pellet)
11 h (COER)
612 h
2.55 h
12 h (tablet)
718 h (CR)
14 h (SR)
<30 min (cap)
2.55 h (ER)
6 h GITS)
612 h
23 h (tablet)
611 h (SR)
1014 h (CD)
46 h (XR)
7 h (ER)
Route of elimination Active metabolite Plasma half-life, h Dose reduction

Liver
Yes
412 (tablet)
12 (SR pellet)
No
Liver
Liver
Liver
No
No
No
3050
1116
8
No
No
No
Liver
Liver
No
No
No
No
Liver
Liver
Yes
Yes
89
2
24
24
712
46
57
58
510
410
No
Yes
FIGURE 7-36
Pharmacokinetics of the calcium antagonists: phenylalkamine derivatives,
dihydropyridine derivatives, and benzothiazepine derivatives.
THE SIDE EFFECTS PROFILE OF CALCIUM ANTAGONISTS

Side effects
Mechanism
Dihydropyridine
Headache, flushing, palpitation, edema
Phenylalkylamine
Constipation
Bradycardia, AV block congestive heart failure
Benzodiazepine
Bradyarrhythmia, AV block congestive heart failure
Potent peripheral vasodilator

Negative inotropic, dromotropic, chronotropic effects
Negative inotropic, dromotropic, chronotropic effects
FIGURE 7-37
The side effect profile of calcium antagonists
[10,13,18]. AVatrioventricular.
7.25

ACE inhibition and angiotensin II type I receptor antagonists: mechanisms for decrease in peripheral vascular resistance
+
Angiotensinogen
(renin substrate)
1
Non-renin enzymes
AT1
receptor
Non-ACE enzymes
Renin
Angiotensin I
(decapeptide)
Remodeling,
vascular smooth
muscle
Blood
pressure
Sympathetic activity
(central and peripheral)
Baroreceptor
sensitivity
Inactive
fragments
Bradykinin
Vasoconstriction,
vascular smooth
muscle
ACE
Aldosterone
release
Angiotensin II
(octapeptide)
Functions::
Renal tubular
sodium reabsorption
AT2 receptor
? Function
Nitric oxide
Prostaglandin E2
Prostaglandin I2
FIGURE 7-38
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II
type I receptor antagonists. Angiotensin-converting enzyme
inhibitors and angiotensin II type I receptor antagonists lower
blood pressure by decreasing peripheral vascular resistance; there
is usually little change in heart rate or cardiac output [6,9,15].
Mechanisms proposed for the observed decrease in peripheral

resistance are shown [15]. Sites of pharmacologic blockade in the
renin angiotensin system: 1) renin inhibitors, 2) ACE inhibitors,
3) angiotensin II type I receptor antagonists, 4) angiotensin II
type II receptor antagonists.
7.26
A. DOSING SCHEDULES FOR SULFHYDRYL-CONTAINING ACE INHIBITOR

First dose, mg
Usual dose, mg
Maximum dose, mg
Captopril (G) (Capoten)
12.5
12.550 bid/tid
150
612
Maximum dose, mg
B. DOSING SCHEDULES FOR CARBOXYL-CONTAINING ACE INHIBITORS

First dose, mg
Benazepril (Lotensin)
Enalapril (Vasotec)
Lisinopril (Prinivil,Zestril)
Moexipril (Univasc)
Quinapril (Accupril)
Ramipril (Altace)
Trandolapril (Mavik)
10
5
10
7.5
510
2.5
1
Usual dose, mg
1020 QD
510 QD/bid
2040 QD
7.515 QD/bid
2040 QD
2.520 QD/bid
24 QD
40
40
40
30
40
40
8
24
1224
24
24
24
24
24
C. DOSING SCHEDULES FOR PHOSPHINIC ACIDCONTAINING ACE INHIBITOR

Fosinopril (Monopril)
First dose, mg
Usual dose, mg
Maximum dose, mg
10
2040 QD/bid
40
24
Ggeneric available.
FIGURE 7-39
AC. Classification of and dosing schedule for angiotensin-converting
enzyme (ACE) inhibitors. Angiotensin-converting enzyme inhibitors
differ in prodrug status, ACE affinity, potency, molecular weight and
conformation, and lipophilicity [6,9]. They are generally classified

into one of three main chemical classes according to the ligand of
the zinc ion of ACE: sulfhydryl, carboxyl, or phosphinic acid.
7.27
PHARMACOKINETICS OF ACE INHIBITORS
Captopril
Benazepril
Enalapril
Lisinopril
Moexipril
Quinapril
Ramipril
Trandolapril
Fosinopril
Absorption, %
Prodrug
Peak concentration
(active component), h
Route of elimination
Plasma half-life, h
Dose reduction
(renal disease)
6075
37
5575
25
> 20
60
5060
70
36
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
1
12
34
68
12
2
24
410
3
Kidney
Kidney/liver
Kidney
Kidney
Kidney
Kidney
Kidney/liver
Kidney/liver
Kidney/liver
2
1011
11
12
29
25
1317
1624
12
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
FIGURE 7-40
Pharmacokinetics of angiotensin-converting enzyme (ACE) inhibitors: sulfhydrylcontaining, carboxyl-containing, and phosphinic acidcontaining.
THE SIDE EFFECTS PROFILE OF ACE INHIBITORS

Side effects
Mechanisms
Cough, angioedema Laryngeal edema

Lightheadedness, syncope
Potentiation of tissue kinins

Excessive hypotension in patients with high basal peripheral vascular resistance
high renin states, like volume contraction, impaired cardiac output
Decreased aldosterone; potassium-containing salt substitutes and
supplements should be avoided
Extreme hypotension with impaired efferent arteriolar autoregulation
Hyperkalemia
Acute renal failure
FIGURE 7-41
The side effect profile of angiotensin-converting enzyme (ACE) inhibitors. ACE
inhibitors are well tolerated; there are few
side effects [6,9].
7.28
Arterial
pressure, mm Hg
Renal artery
stenosis
230
FIGURE 7-42
Angiotensin-converting enzyme (ACE) inhibition in acute renal failure.
ACE inhibitors may produce functional renal insufficiency in patients
with essential hypertension and hypertensive nephrosclerosis, in
patients with severe bilateral renal artery stenosis, or in patients
with stenosis of the renal artery of a solitary kidney. The postulated
mechanism for this effect is diminished renal blood flow (decrease
in systemic pressure, compromising flow through a fixed stenosis)
in combination with diminished postglomerular capillary resistance
(ie, decrease in angiotensin IImediated efferent arteriolar tone). In
unilateral renal artery stenosis, a drop in the critical perfusion and
filtration pressures may result in a marked drop in single-kidney
glomerular filtration rate (GFR); however, the contralateral kidney
may show an increase in both effective renal plasma flow (ERPF)
and GFR due to attenuation of the intrarenal effects of angiotensin
II on vascular resistance and mesangial tone. Thus, total net
GFR may be normal, giving the false appearance of stability [16].
Although ACE inhibition may invariably decrease the GFR of the
stenotic kidney, it is unlikely to cause renal ischemia owing to
preservation of ERPF; GFR usually returns to pretreatment values
following cessation of therapy.
Shown is the effect of captopril (50 mg) on total clearances of
131I-sodium iodohippurate (ERPF) and 126I-thalamate (GFR) in 14
patients with unilateral renal artery stenosis and in 17 patients with
essential hypertension. The effects after 60 minutes of captopril on
systolic and diastolic intra-arterial pressure (P < 0.001) and of renin
were significant. (From Wenting and coworkers [16]; with permission.)
Essential
hypertension
190
150
110
Total glomerular
filtration rate,
mL/min
Total effective
renal plasma flow,
mL/min
70
440
360
280
110
100
90
80
Plasma renin, mU/L
1000
100
10
Captopril 50 mg
Captopril 50 mg
30
30
15 0
60 15 0
Time, min
60
Indicates blockade
Peripheral
adrenergic
nerve ending
Tyrosine
Tyrosine hydroxylase
Dihydroxyphenylalanine
NE
2
FIGURE 7-43
Tyrosine hydroxylase inhibitor. Metyrosine (-methyl-para-tyrosine)
is an inhibitor of tyrosine hydroxylase, the enzyme that catalyzes
the conversion of tyrosine to dihydroxyphenylalanine [6,9]. Because
this first step is rate limiting, blockade of tyrosine hydroxylase
activity results in decreased endogenous levels of circulating catecholamines. In patients with excessive production of catecholamines,
metyrosine reduces biosynthesis 36% to 79%; the net physiologic
effect is a decrease in peripheral vascular resistance and increases in
heart rate and cardiac output resulting from the vasodilation. The
degree of vasodilation is dependent on the degree of blockade of
adrenergic vascular tone. NEnorepinephrine.
7.29
TYROSINE HYDROXYLASE INHIBITOR

Metyrosine (Demser)
First dose, mg
Maximum dose, mg
250
25 qid
1000 qid
34
FIGURE 7-44
Tyrosine hydroxylase inhibitor. Metyrosine is the only drug in its
class. The initial recommended dose is 1 g/d, given in divided doses.
This may be increased by 250 to 500 mg daily to a maximum of
4 g/d. The usual effective dosage is 2 to 3 g/d. The maximum biochemical effect occurs within 2 to 3 days. In hypertensive patients in
whom there is a response, blood pressure decreases progressively
during the first days of therapy. In patients who are usually normotensive, the dose should be titrated to the amount that will
reduce circulating or urinary catecholamines by 50% or more.
THE SIDE EFFECTS PROFILE OF METYROSINE

Side effects
Mechanisms
CNS symptoms
Sedation
Extrapyramidal signs
Drooling
Speech difficulty
Tremor
Trismus
Parkinsonian syndrome
Psychic dysfunction
Anxiety
Depression
Disorientation
Confusion
Crystalluria, uroliathiasis
Diarrhea
Insomnia (temporary)
Depletion of CNS dopamine
Poor urine solubility

Direct irritant to bowel mucosa
Following drug withdrawal
Following discontinuation of therapy, the clinical and biochemical

effects may persist 2 to 4 days. Metyrosine is variably absorbed
from the gastrointestinal tract; bioavailability ranges from 45%
to 90%. Peak plasma concentrations are reached in 1 to 3 hours.
The plasma half-life is 3 to 4 hours. Metyrosine is not metabolized;
the unchanged drug is recovered in the urine. Drug dosage should
be reduced in patients with renal insufficiency. Metyrosine is exclusively used in the management of preoperative or inoperative
pheochromocytoma [6,9].
FIGURE 7-45
The side effect profile of metyrosine. The adverse reactions observed
with metyrosine are primarily related to the central nervous system
and are typically dose dependent [6,9]. Metyrosine crystalluria
(needles or rods), which is due to the poor solubility of the drug in
the urine, has been observed in patients receiving doses greater
than 4 g/d. To minimize this risk, patients should be well hydrated.
CNScentral nervous system.
7.30
ANGIOTENSIN II RECEPTOR ANTAGONISTS

First dose, mg
Usual dose, mg
Maximum dose, mg
50
80
150
50100 QD/bid
80160 QD
150300 QD
100
320
300
1224
24
24
Losartan (Cozaar)
Valsartan (Diovan)
Irbesaftan (Avapro)
FIGURE 7-46
Angiotensin II receptor antagonists. These drugs antagonize
angiotensin IIinduced biologic actions, including proximal sodium
reabsorption, aldosterone release, smooth muscle vasoconstriction,
vascular remodeling, and baroreceptor sensitivity. Antihypertensive
efficacy appears dependent on an activated renin-angiotensin system;
bilateral nephrectomy and volume expansion abolish their activity.
Losartan is a nonpeptide, specific angiotensin II receptor antagonist
acting on the antagonist AT1 subtype receptor. Peak response occurs
within 6 hours of dosing. It is readily absorbed; peak plasma concentrations are achieved within 1 hour. It has a relatively short terminal
half-life of 1.5 to 2.5 hours. Oral bioavailability is approximately
33%. Losartan undergoes extensive first-pass hepatic metabolism
to the predominant circulatory form of the drug Exp-3174. This
metabolite is 15 to 30 times more potent than losartan with a
THE SIDE EFFECTS PROFILE OF ANGIOTENSIN II

RECEPTOR ANTAGONISTS
Side effects
Mechanisms
Hyperkalemia
Blockade of angiotensin II
Reduced aldosterone secretion
Hypotension with impaired efferent anteriolar
autoregulation
Acute renal dysfunction
longer half-life (between 4 and 9 hours). The metabolite is cleared

equally by the liver and the kidney; there may be enhanced hepatic
clearance in renal insufficiency [15]. Dose reduction is not required
in patients with renal insufficiency.
Valsartan is a nonpeptide, specific angiotensin II antagonist acting
on the AT1 subtype receptor. Peak response occurs within 6 hours
of dosing. Peak plasma concentrations are reached 2 to 4 hours
after dosing. The average elimination half-life is about 6 hours.
Oral bioavailability is approximately 25%. Dose reduction is not
required in patients with renal insufficiency [15].
Irebsartan is a nonpeptide, specific angiotensin II antagonist acting
on the AT1 subtype receptor. Peak response occurs in 4 to 8 hours.
There is no active metabolite. Dose reduction is not required in
patients with renal insufficiency [15].
FIGURE 7-47
The side effect profile of angiotensin II receptor antagonists.
Angiotensin II receptor antagonists are well tolerated. In contrast
to the angiotensin-converting enzyme (ACE) inhibitors, cough and
angioedema are rarely (if at all) associated with this class of antihypertensive drug. Similar to ACE inhibitors, however, hyperkalemia
and acute renal failure may occur in patients at risk [15].
7.31
Prevention and Treatment of High Blood Pressure

JNC VI CLASSIFICATION OF HYPERTENSION
Category*
Optimal
Normal
High normal
Hypertension
Stage 1
Stage 2
Stage 3
Systolic (mm Hg)
Diastolic (mm Hg)
<120
<130
130139
and
and
or
<80
<85
8589
140/159
160/179
-180
or
or
or
90/99
100/109
110
*Not taking anithypertensive drugs and not acutely ill. When systolic and diastolic
blood pressures fall into different categories, the higher category should be selected to
classify the individuals blood pressure status. For example, 160/92 mm Hg should be
classified as stage 2 hypertension, and 174/120 mm Hg should be classified as stage 3
hypertension. Isolated systolic hypertension is defined as systolic blood pressure of 140
mm Hg or greater and diastolic blood pressure of less than below 90 mm Hg and
staged appropriately (eg, 170/82 mm Hg is defined as stage 2 isolated hypertension).
In addition to classifying stages of hypertension on the basis of average blood pressure
levels, clinicians should specify presence of target organ disease and additional risk
factors. This specifically is important for risk classification.
Optimal blood pressure with respect to cardiovascular risk is below 120/80 mm Hg.
Unusually low readings should be evaluated for clinical significance.
Based on the average of two or more readings taken at each of two or more visits
after an initial screening. JNCJoint National Committee.
FIGURE 7-48
Prevention and treatment of high blood pressure. The aim of antihypertensive therapy is risk reduction. Since the relationship
between blood pressure and cardiovascular risk is continuous, the
goal of treatment might be the maximum tolerated reduction in
blood pressure. There is controversy concerning what constitutes
hypertension and how far systolic or diastolic blood pressure
should be lowered, however. The Sixth Report of the Joint
National Committee on Detection, Evaluation, and Treatment of
High Blood Pressure (JNC VI) [17] provides a new classification of
hypertension and recommends that risk stratification be used to
determine if lifestyle modification or drug therapy with adjunctive
lifestyle modification be initiated according to the patients blood
pressure classification (see Fig. 7-50). Major risk factors include
smoking, dyslipidemia, diabetes mellitus, an age of 60 or older,
male sex or postmenopausal state for women, and a family history
of cardiovascular disease in women younger than 65 and in men
younger than 55. Target organ damage includes heart disease (left
ventricular hypertrophy, angina pectoris, prior myocardial infarction,
heart failure), stroke or transient ischemic attack, and nephropathy.
Prevention and management of hypertension-related morbidity and
mortality may best be accomplished by achieving a systolic blood
pressure below 140 mm Hg and a diastolic blood pressure below
90 mm Hg; lower if tolerable. Recently, more aggressive blood
pressure control has been advocated in patients with renal disease
and hypertension, particularly in those patients with a urinary protein
excretion of greater than 1 g/d. Blood pressure control in the range
of 125/80 mm Hg (mean arterial pressure of 108 mm Hg) has been
shown to slow the progression of renal disease [18,19]. This targeted
blood pressure control may therefore be advisable in the majority
of patients with hypertension. Regardless, each patient should be
treated according to their cerebrovascular, cardiovascular, or renal
risks; their specific pathophysiology or target organ damage; and
their concurrent disease states. A uniform blood pressure goal (target)
probably does not exist for all hypertensive patients, and lower
may not always be better.
7.32
JNC VI DECISION ANALYSIS FOR TREATMENT
Blood pressure stages

(mm Hg)
High normal
(130139/8589)
Stage 1
(140159/9099)
Stages 2 and 3
(>160/100)
Risk group A
(no risk factors, no
TOD/CCD)*
Risk group B
(at least 1 risk factor,
not including diabetes;
no TOD/ CCD)
Risk Group C
(TOD/CCD and/or
diabetes, with or without other risk factors)
Lifestyle modification
Drug therapy
(up to 12 months)
Drug therapy
(up to 6 months)
Drug therapy
Drug therapy
FIGURE 7-49
Decision analysis for treatment based on the
Sixth Report of the Joint National Committee
on Detection, Evaluation, and Treatment of
High Blood Pressure (JNC VI) [17].
Drug therapy
Lifestyle modification should be adjunctive therapy for all patients recommended for pharmacologic therapy.
*TOD/CCD indicates target organ disease/clinical cardiovascular disease.
For patients with multiple risk factors, clinicians should consider drugs as initial therapy plus lifestyle modifications.
For those with heart failure, renal insufficiency, or diabetes.
CRITERIA FOR INITIAL DRUG THERAPY

Reduce peripheral vascular resistance
No sodium retention
No compromise in regional blood flow
No stimulation of the renin-angiotensin-aldosterone system
Favorable profile with concomitant diseases
Once a day dosing
Favorable adverse effect profile
Cost effective (low direct and indirect cost)
FIGURE 7-50
Selection of initial drug therapy. The Sixth Report of the Joint
National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC VI) recommends that
either a diuretic or a -blocker be chosen as initial drug therapy,
based on numerous randomized controlled trials that show reduction
in morbidity and mortality with these agents [17]. Not all authorities
agree with this recommendation.
In selecting an initial drug therapy to treat a hypertensive patient,
several criteria should be met [6,9]. The drug should decrease
peripheral resistance, the pathophysiologic hallmark of all hypertensive
diseases. It should not produce sodium retention with attendant
pseudotolerance. The drug should neither stimulate nor suppress
the heart, nor should it compromise regional blood flow to target
organs such as the heart, brain, or the kidney. It should not stimulate
the renin-angiotensin-aldosterone axis. Drug selection should consider
concomitant diseases such as arteriosclerotic cardiovascular and
peripheral vascular disease, chronic obstructive pulmonary disease,
diabetes mellitus, hypertensive cardiovascular disease, congestive
heart failure, and hyperlipidemia. Drug dosing should be infrequent.
The drugs side effect profile, including its effect on physical state,
emotional well-being, sexual and social function, and cognitive
activity, should be favorable. Drug costs, both direct and indirect,
should be reasonable. It is readily apparent that no current class of
antihypertensive drug fulfills all these criteria.
7.33
CANDIDATES FOR INITIAL DRUG THERAPY OF MILD TO MODERATE HYPERTENSIVE DISEASE
Peripheral vascular resistance

Sodium homeostasis
Urinary sodium excretion
Pseudotolerance
Target organ function
Heart rate, cardiac output
Cerebral function
Renal function (GFR)
Renin-angiotensin-aldosterone
Plasma renin activity
Plasma angiotensin II
Plasma aldosterone
Concurrent disease efficacy
Coronary disease
Peripheral vascular disease
Obstructive airway disease
Diabetes mellitus
Dyslipidemia
Systolic dysfunction
ACE inhibitors
1-adrenergic
antagonists
Angiotensin II type I
receptor antagonists
1-adrenergic
antagonists
Thiazide-type
Calcium antagonists diuretics
Decrease
Decrease
Decrease
Decrease
Decrease
Decrease
Increase/no change
No change
No
May decrease
May increase
No
Increase/no change
No change
No
No change
No change
No
Increase/no change
No change
No
Increase
Decrease
No
No change
Preserve
No change/increase
May increase
Preserve
No change
No change
Preserve
No change
Decrease
Preserve
No change/decrease
Class specific
Preserve
No change/increase
No change
Preserve
No change
Increase
Decrease
Decrease/no change
No change
No change
No change
Increase
Increase
Decrease/no change
Decrease
Decrease
Decrease/no change
No change
No change
No change
Increase
Increase
Increase
No effect
No effect
No effect
May benefit
No effect
Benefit
No effect
No effect
No effect
No effect
Benefit
No effect
No effect
No effect
No effect
May benefit
No effect
Benefit
Benefit
May aggravate
May aggravate
May aggravate
May aggravate
May aggravate
Benefit
May benefit
No effect
No effect
No effect
No effect
No effect
No effect
No effect
May aggravate
Aggravate
Benefit
FIGURE 7-51
Options for monotherapy. Given the drugs that we have and their
pharmacologic profiles, what are the best classes for initial drug therapy?
Alphabetically, they include 1) angiotensin-converting enzyme (ACE)
inhibitors, 2) 1-adrenergic antagonists, 3) angiotensin II type I receptor
antagonists, 4) 1-adrenergic antagonists, 5) calcium antagonists, and
6) thiazide-type diuretics [6,9,15]. All these drugs, given as monotherapy,

are effective in lowering blood pressure in 50% to 60% of patients
with mild to moderate hypertension. 1-adrenergic antagonists, ACE
inhibitors, and angiotensin II receptor antagonists are less efficacious
in blacks than in whites.
7.34

Options for subsequent antihypertensive therapy
Not at goal blood pressure (<140/<90 mm Hg);

lower goal in patients with diabetes mellitus or renal disease
No response or troublesome side effects
Sustitute another drug from a different class
Inadequate response but well tolerated
Add a second agent from a different class

(diuretic if not already used)
Not a goal blood pressure
FIGURE 7-52
Options for subsequent antihypertensive
therapy. The majority of patients with mild
to moderate hypertension can be controlled
with one drug. If, after a 1- to 3-month
interval, the response to the initial choice of
therapy is inadequate, however, three
options for subsequent antihypertensive
drug therapy may be considered: 1) increase
the dose of the initial drug, 2) discontinue
the initial drug and substitute a drug from
another class, or 3) add a drug from another
class (combination therapy). Recommendations
from the Sixth Report of the Joint National
Committee on Detection, Evaluation, and
Treatment of High Blood Pressure (JNC VI)
are provided [17].
Continue adding agents from other classes

Consider referral to a hypertension specialist
COMBINATION THERAPIES
Mild to moderate (stage 1 or 2) hypertension
Addition of low-dose thiazide-type diuretic to:
ACE inhibitor
1-adrenergic antagonist
Angiotensin III receptor antagonist
Severe (Stage 3) hypertension
Classic triple drug therapy
Diuretic
Direct-acting vasodilator
ACE inhibitor plus calcium antagonist
1-adrenergic antagonist plus 1-adrenergic antagonist
1-adrenergic antagonist plus dihydropyridine
calcium antagonist
FIGURE 7-53
Combination therapies. If a second drug is required, the addition of a low-dose thiazidetype diuretic to a nondiuretic drug will usually enhance the effectiveness of the first drug
[6,9,17]. Newly developed formulations, using combinations of low doses of two agents
from different classes, are available and effective and may minimize the likelihood of a
dose-dependent adverse effect. The fixed doses used in these formulations were chosen to
control mild to moderate (JNC VI stage 1 or 2) hypertension. More severe (JNC VI stage 3)
cases of hypertension that are unresponsive to this therapeutic strategy may respond either
to a variety of combination therapies given together as separate formulations or to classic
triple-drug therapy (ie, diuretic, -adrenergic antagonist, and direct-acting vasodilator) [6,9].
ACEangiotensin-converting enzyme; JNCJoint National Committee.
JNC VI LIFE STYLE MODIFICATIONS

Lose weight if overweight
Limit alcohol intake to no more than 1 oz (30 mL) ethanol (eg, 24 oz [720 mL] beer,
10 oz [300 mL] wine, or 2 oz [60 mL] 100-proof whiskey) per day or 0.5 oz (15 mL)
ethanol per day for women and lighter weight people
Increase aerobic physical activity (30 to 45 minutes most days of the week)
Reduce sodium intake to no more than 100 mmol/d
(2.4 g sodium or 6 g sodium chloride)
Maintain adequate intake of dietary potassium (approximately 90 mmol/d)
Maintain adequate intake of dietary calcium and magnesium for general health
Stop smoking and reduce intake of dietary saturated fat and cholesterol for
overall cardiovascular health
CAUSES OF RESISTANT HYPERTENSION

Patients failure to adhere to drug therapy
Physicians failure to diagnose a secondary cause of hypertension
Renal parenchymal hypertension
Renovascular hypertension
Mineralocorticoid excess state (eg, primary aldosteronism)
Pheochromocytoma
Drug-induced hypertension (eg, sympathomimetic, cyclosporine)
Illicit substances (eg, cocaine, anabolic steroids)
Glucocortoid excess state (eg, Cushings syndrome)
Coarctation of the aorta
Hormonal disturbances (eg, thyroid, parathyroid, growth hormone, serotonin)
Neurologic syndromes (eg, Guillain-Barr syndrome, porphyria, sleep apnea)
Physicians failure to recognize an adverse drugdrug interaction
See Physicians Desk Reference
Physicians failure to recognize the development of secondary drug resistance
Sodium retention with pseudotolerance, secondary to diuretic resistance or excess
sodium intake
Increased heart rate, cardiac output secondary to drug-induced reflex tachycardia
Increased peripheral vascular resistance secondary to drug-induced stimulation of
the renin-angiotensin system
7.35
FIGURE 7-54
Follow-up in antihypertensive therapy. During follow-up visits,
pharmacologic therapy should be reconfirmed or readjusted. As a
rule, antihypertensive therapy should be maintained indefinitely.
Cessation of therapy in patients who were correctly diagnosed as
hypertensive is usually (but not always) followed by a return of
blood pressure to pretreatment levels. After blood pressure has
been controlled for 1 year and at least four visits, however, attempts
should be made to reduce antihypertensive drug therapy in a
deliberate, slow, and progressive manner; such step-down therapy
may be successful in patients following lifestyle modification [17].
Patients for whom drug therapy has been reduced or discontinued
should have regular follow-up, since blood pressure may increase
again to hypertensive levels. JNCJoint National Committee.
FIGURE 7-55
Resistant hypertension. Causes of failure to achieve or sustain control
of blood pressure with drug therapy are listed [6,9].
7.36
DIURETIC RESISTANCE
Problem
Mechanism
Solution
Limits active transport of diuretics

Reduced renal blood flow
Use of large doses of a diuretic and
into proximal tubular fluid, reducing
appropriate dosing interval to achieve
inhibitory effect at a more distal
a therapeutic tubular drug concentration
intraluminal membrane site
Reduced glomerular filtration rate Use loop diuretics with steep dose
Limits absolute amount of sodium
filtered
response curve and/or block multiple
sites of sodium reabsorption: loop
diuretic with thiazide-like diuretic
Secondary hyperaldosteronism
Sodium recaptured at late distal
Addition of a potassium-sparing diuretic
tubule and collecting duct
to above, to maintain urine
sodium/potassium ratio > 1
FIGURE 7-56
Diuretic resistance. Diuretic resistance may
result from patient noncompliance, impaired
bioavailability in an edematous syndrome,
impaired diuretic secretion by the proximal
tubule, protein binding in the tubule lumen
(eg, nephrotic syndrome), reduced glomerular
filtration rate, or enhanced sodium chloride
reabsorption [7,8]. Resultant fluid retention
will attenuate the effectiveness of most antihypertensive drugs. Renal mechanisms,
problems, and solutions are provided in this
table [6,8,9].
References
1. Kaplan NM: Clinical Hypertension, edn 6. Baltimore: Williams &
Wilkins; 1994:50.
2. Kawasaki T, Delea CS, Bartter FC, Smith H: The effect of high-sodium
and low-sodium intakes on blood pressure and other related variables
in human subjects with idiopathic hypertension. Am J Med 1978,
64:193198.
3. Guyton AC, Coleman TG, Yang DB, et al.: Salt balance and long-term
blood pressure control. Annu Rev Med 1980, 31:1527.
4. Julius S, Krause L, Schork NJ: Hyperkinetic borderline hypertension
in Tecumseh, Michigan. J Hypertens 1991, 9:7784.
5. Lund-Johansen P: Cetra haemodynamics in essential hypertension at
rest and during exercise: a 20-year follow-up study. J Hypertens 1989,
7(suppl 6): 552555.
6. Bauer JH, Reams GP: Mechanisms of action, pharmacology, and use
of antihypertensive drugs. In The Principles and Practice of Nephrology.
Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby;
1995:399415.
7. Tarazi RC: Diuretic drugs: mechanisms of antihypertensive action. In
Hypertension: Mechanisms and Management. The 26th Hahnemann
Symposium. Edited by Oneti G, Kim KE, Moer JH. New York: Grune
and Stratton; 1973:255.
8. Ellison DH: The physiologic basis of diuretic synergism: its role in
treating diuretic resistance. Ann Intern Med 1991, 114:886894.
9. Bauer JH, Reams GP: Antihypertensive drugs. In The Kidney, edn 5.
Edited by Brenner BM. Philadelphia: W.B. Saunders Co.; 1995:
23312381.
10. Man int Veld AJ, Schalekamp MADH: How intrinsic sympathomimetic
activity modulates the haemodynamic responses to -adrenoceptor
antagonists: a clue to the nature of their antihypertensive mechanism.
Br J Clin Pharmac 1982, 13:24552575.
11. Van Zwieten PA: Antihypertensive drug interacting with -and -adrenoceptors: a review of basic pharmacology. Drugs 1988, 35(suppl 6):619.
12. Graham RM, Thornell IR, Gain JM, et al.: Prazosin: the first dose
phenomenon. Br Med J 1976, 2:12931294.
13. Koch-Weser J: Vasodilation drugs in the treatment of hypertension.
Arch Intern Med 1974, 133:10171025.
14. Entel SI, Entel EA, Clozel J-P: T-type Ca2+ channels and pharmacological
blockade: potential pathophysiological relevance. Cardiovasc Drugs
Ther 1997, 11:723739.
15. Bauer JH, Ream GP: The angiotensin II type 1 receptor antagonists.
Arch Intern Med 1995, 155:13611368.
16. Wenting GJ, Tan-Tjiong HL, Derkx FMH, et al.: Split renal function
after captopril in unilateral renal artery stenosis. Br Med J 1974,
288:886890.
17. JNC VI: The Sixth Report of the Joint National Committee on
Detection, Evaluation, and Treatment of High Blood Pressure. Arch
Intern Med 1993, 153:154183.
18. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control,
proteinuria, and the progression of renal disease. Ann Intern Med
1995, 123:754762.
19. Hebert LA, Kusek JW, Greene T, et al.: Effects of blood pressure control on progressive renal disease in blacks and whites. Hypertension
1997, 30 (part 1):428435.
Hypertensive Crises
Charles R. Nolan
ost patients with hypertension remain asymptomatic for many

years, until complications from atherosclerosis, cerebrovascular
disease, or congestive heart failure supervene. In some patients,
this so-called benign course is punctuated by a hypertensive crisis.
Hypertensive crisis is defined as the turning point in the course of an
illness at which acute management of the elevated blood pressure
plays a decisive role in the eventual outcome [1]. The haste with which
blood pressure must be controlled varies with the type of hypertensive
crisis. If the patients outcome is to be optimal, however, the crucial
role of hypertension in the disease process must be identified and a
plan for management of the blood pressure successfully implemented.
The absolute level of the blood pressure clearly is not the most important
factor in determining the existence of a hypertensive crisis. For example,
in children, pregnant women, and other previously normotensive persons
in whom mild to moderate hypertension develops suddenly, a hypertensive crisis can occur at a level of blood pressure that normally is
well-tolerated by adults with chronic hypertension. Furthermore, a
crisis can occur in adults with mild to moderate hypertension with the
onset of acute end-organ dysfunction involving the heart or brain.
CHAPTER
8.2
HYPERTENSIVE CRISES
(Hypertensive neuroretinopathy present)
Benign (nonmalignant) hypertension with acute complications
(Acute organ system dysfunction without hypertensive neuroretinopathy)
Hypertensive encephalopathy (also common in malignant hypertension)
Acute hypertensive heart failure (also common in malignant hypertension)
Acute aortic dissection
Central nervous system catastrophe
Subarachnoid hemorrhage
Severe head trauma
Acute myocardial infarction or unstable angina
Active bleeding, including postoperative bleeding
Uncontrolled hypertension in patients requiring surgery
Severe postoperative hypertension
Postcoronary artery bypass hypertension
Postcarotid endarterectomy hypertension
Catecholamine excess states
Pheochromocytoma
Monoamine oxidase inhibitortyramine interactions
Miscellaneous hypertensive crises
Preeclampsia and eclampsia
Scleroderma renal crisis
Autonomic hyperreflexia in quadriplegic patients
FIGURE 8-1
Malignant hypertension is a clinical syndrome characterized by
marked elevation of blood pressure, with widespread acute arteriolar injury (hypertensive vasculopathy). Funduscopy reveals hypertensive neuroretinopathy with flame-shaped hemorrhages, cottonwool spots (soft exudates), and sometimes papilledema. Regardless
of the severity of blood pressure elevation, malignant hypertension
cannot be diagnosed in the absence of hypertensive neuroretinopathy. Thus, hypertensive neuroretinopathy is an extremely important
clinical finding, indicating the presence of a hypertension-induced
arteriolitis that may involve the kidneys, heart, and central nervous
system. In malignant hypertension, rapid and relentless progression
to end-stage renal disease occurs if effective blood pressure control
is not implemented. Mortality can result from acute hypertensive
heart failure, intracerebral hemorrhage, hypertensive encephalopathy, or complications of uremia. Malignant hypertension represents
a hypertensive crisis given that adequate control of blood pressure
clearly prevents these morbid complications. Even in patients with
so-called benign (nonmalignant) hypertension, in which hypertensive neuroretinopathy is absent, a hypertensive crisis may occur based
on the development of concomitant acute end-organ dysfunction.
Hypertensive crises caused by benign hypertension with acute
complications include hypertension in the setting of hypertensive
encephalopathy, acute hypertensive heart failure, acute aortic
dissection, intracerebral hemorrhage, subarachnoid hemorrhage,
severe head trauma, acute myocardial infarction or unstable angina,
and active bleeding. Poorly controlled hypertension in patients
requiring surgery increases the risk of intraoperative cerebral or
myocardial ischemia and postoperative acute renal failure. Severe
postoperative hypertension, including postcoronary artery bypass
hypertension and postcarotid endarterectomy hypertension, increases
the risk of postoperative bleeding, hypertensive encephalopathy,
pulmonary edema, and myocardial ischemia. The various
catecholamine excess states can cause a hypertensive crisis with
hypertensive encephalopathy or acute hypertensive heart failure.
Preeclampsia and eclampsia represent hypertensive crises unique to
pregnancy. Scleroderma renal crisis is a hypertensive crisis because
failure to adequately control blood pressure with a regimen that
includes a converting enzyme inhibitor results in rapid irreversible
loss of renal function. Hypertensive crises as a result of autonomic
hyperreflexia induced by bowel or bladder distention also can occur
in patients with quadriplegia. The sudden onset of hypertension in
this setting can lead to hypertensive encephalopathy or acute
pulmonary edema. Each hypertensive crisis is discussed in more
detail in the figures that follow.
Hypertensive Crises
HYPERTENSIVE SYNDROMES SOMETIMES

MISDIAGNOSED AS HYPERTENSIVE CRISES
Severe uncomplicated hypertension
(Severe hypertension without hypertensive neuroretinopathy or acute end-organ
dysfunction, formerly known as urgent hypertension)
Benign hypertension with chronic end-organ complications
Chronic renal insufficiency from primary renal parenchymal disease
Chronic congestive heart failure from systolic or diastolic dysfunction
Atherosclerotic coronary vascular disease (previous myocardial infarction, stable angina)
Cerebrovascular disease (history of transient ischemic attack or cerebrovascular accident)
8.3
FIGURE 8-2
Hypertensive syndromes sometimes misdiagnosed as hypertensive
crises. It should be noted that the finding of severe hypertension
does not always imply the presence of a hypertensive crisis. In
patients with severe uncomplicated hypertension (formally known
as urgent hypertension) in which severe hypertension is not accompanied by evidence of malignant hypertension or acute end-organ
dysfunction, eventual complications due to stroke, myocardial
infarction, or congestive heart failure tend to occur over months to
years, rather than hours to days. Long-term control of blood pressure
can prevent these eventual complications. However, a hypertensive
crisis cannot be diagnosed because no evidence exists that acute
reduction of blood pressure results in improvement in short- or
long-term prognosis. Moreover, the presence of chronic hypertensive
end-organ complications in a patient with nonmalignant hypertension
does not imply the existence of a hypertensive crisis requiring rapid
control of blood pressure. The category of benign hypertension
with chronic complications includes hypertensive patients with
chronic renal insufficiency due to underlying primary renal
parenchymal disease, chronic congestive heart failure as a result
of either systolic or diastolic dysfunction, atherosclerotic coronary
vascular disease (stable angina or previous myocardial infarction),
or chronic cerebrovascular disease (previous transient ischemic
attacks or cerebrovascular accident). Long-term inadequate blood
pressure control increases the risk of further deterioration of endorgan function in each of these conditions. However, no evidence
exists that rapid control of blood pressure is necessary to prevent further complications. Therefore, a true hypertensive crisis does not exist.
8.4
Pathophysiology of malignant hypertension

Renal parenchymal disease
Endocrine hypertension
Essential
hypertension
Severe
hypertension
Spontaneous
natriuresis
Critical level or
Rate of increase
Volume
depletion
Forced vasodilation
(sausage-string)
Catecholamines
Vasopressin
Renin/Angiotensin II
Low potassium
diet
Renal
ischemia
Decreased prostacyclin
Oral contraceptives
Cigarette smoking
Vascular damage
Denudation of epithelium
Endothelial permeability
Platelet adherence
PDGF release
Extravasation
Fibrinogen
Smooth muscle
proliferation
Fibrin deposition
Arteriolar wall
Deposition of
mucopolysaccharide
Necrosis of
smooth muscle
Musculomucoid intimal
hyperplasia
Fibrinoid
necrosis
Localized
intravascular
coagulation
Lumen
Narrowing of vascular lumen
Renal ischemia
Accelerated glomerular
obsolescence
Tubular
atrophy
Interstitial
fibrosis
FIGURE 8-3
Pathophysiology of malignant hypertension. The vicious cycle of malignant hypertension
is best demonstrated in the kidneys. This cycle also applies equally well to the vascular
beds of the retina, pancreas, gastrointestinal tract, and brain [1]. In this scheme, severe
hypertension is central. Hypertension may be either essential or secondary to any one of a
variety of causes. Because not all patients develop malignant hypertension despite equally
severe hypertension, the interaction between the level of blood pressure and the adaptive
capacity of the vasculature may be important. In this regard, chronic hypertension results
in thickening and remodeling of arteriolar

walls that may be an adaptive mechanism
to prevent vascular damage from the
mechanical stress of hypertension. However,
when the blood pressure increases suddenly
or increases to a critical level, these adaptive
mechanisms may be overwhelmed, resulting
in vascular damage. As a result of the
mechanical stress of increased transmural
pressure, focal segments of the arteriolar
vasculature become dilated, producing a
sausage-string pattern. Endothelial permeability increases in the dilated segments,
leading to extravasation of fibrinogen, fibrin
deposition in the media, and necrosis of
smooth muscle cells (fibrinoid necrosis).
Platelet adherence to damaged endothelium
with release of platelet-derived growth factor
induces migration of smooth muscle cells to
the intima where they proliferate (neointimal
proliferation) and produce mucopolysaccharide. These cells also produce collagen,
resulting in proliferative endarteritis,
musculomucoid hyperplasia, and eventually,
fibrotic obliteration of the vessel lumen.
Occlusion of arterioles leads to accelerated
glomerular obsolescence and end-stage
renal disease. Other factors may synergize
with hypertension to damage the arterial
vasculature. Renal ischemia leads to activation of the renin-angiotensin system that can
cause further elevation of blood pressure and
progressive vascular damage. Spontaneous
natriuresis early in the course of malignant
hypertension leads to volume depletion with
activation of the renin-angiotensin system or
catecholamines that further elevates blood
pressure. It also is possible that angiotensin
II may be directly vasculotoxic. Activation
of the clotting cascade within the lumen of
damaged vessels may lead to fibrin deposition
with localized intravascular coagulation.
Thus, microangiopathic hemolytic anemia is
a common finding in malignant hypertension.
Cigarette smoking and oral contraceptive
use may contribute to development of
malignant hypertension by decreasing
prostacyclin production in the vessel wall
and thereby inhibiting repair of hypertensioninduced vascular injury. Low dietary intake
of potassium may help promote vascular
smooth muscle proliferation and therefore
predisposes to the development of malignant hypertension in Blacks with severe
essential hypertension. PDGFplateletderived growth factor.
Hypertensive Crises
Vascular lesions in malignant hypertension

Fibrinoid necrosis
Proliferative endarteritis
Occlusion of vessels
Ischemia
Retinal
Hemorrhages
Cotton-wool
spots
Papilledema
CNS
Intracerebral
hemorrhage
Hypertensive
encephalopathy
Cardiac
Left ventricular
dysfunction
Renal
Glomerulosclerosis
Tubular atrophy
GI
Hemorrhage
Bowel necrosis
COMMON CAUSES OF MALIGNANT HYPERTENSION

Primary (essential) malignant hypertension*
Secondary malignant hypertension
Primary renal disease
Chronic glomerulonephritis*
Chronic pyelonephritis*
Analgesic nephropathy*
Immunoglobulin A nephropathy*
Radiation nephritis
Renovascular hypertension*
Oral contraceptives
Atheroembolic renal disease (cholesterol embolism)
Scleroderma renal crisis
Antiphospholipid antibody syndromes
Chronic lead poisoning
Endocrine hypertension
Aldosterone-producing adenoma (Conns syndrome)
Cushings syndrome
Congenital adrenal hyperplasia
Pheochromocytoma
*Most common causes of malignant hypertension.
FIGURE 8-5
Malignant hypertension is not a single disease entity but, rather, a
syndrome in which the hypertension can be either primary (essential)
or secondary to any one of a number of different causes [2]. Among
Black patients the underlying cause is almost always essential hypertension that has entered a malignant phase. The most common
secondary causes of malignant hypertension are primary renal
parenchymal disorders. Chronic glomerulonephritis is thought to
be the cause of malignant hypertension in up to 20% of cases. Unless
a history of an acute nephritic episode or long-standing hematuria or
proteinuria is available, the underlying glomerulonephritis may only
Pancreatic
Necrosis
Hemorrhage
8.5
FIGURE 8-4
Distribution of vascular lesions in malignant
hypertension. Malignant hypertension is
essentially a systemic vasculopathy induced
by severe hypertension. Fibrinoid necrosis and
proliferative endarteritis occur throughout the
body in numerous vascular beds, leading to
ischemic changes. In the retina, striate hemorrhages and cotton-wool spots develop.
The finding of hypertensive neuroretinopathy
is the clinical sine qua non of malignant
hypertension. Vascular lesions in the gastrointestinal tract (GI) can lead to hemorrhage
or bowel necrosis. Hemorrhagic pancreatitis
also can occur. Cerebrovascular lesions can
lead to cerebral infarction or intracerebral
hemorrhage. Hypertensive encephalopathy
also can develop as a result of failure of
autoregulation with cerebral overperfusion
and edema (Fig. 8-22). Vascular lesions also
can develop in the myocardium; however,
acute hypertensive heart failure is largely the
result of acute diastolic dysfunction induced
by the marked increase in afterload that
accompanies malignant hypertension (Figs. 824 and 8-25). CNScentral nervous system.
become apparent when a renal biopsy is performed. Recently,

immunoglobulin A (IgA) nephropathy has been reported as an
increasingly frequent cause of malignant hypertension. In one series
of 66 patients with IgA nephropathy, 10% developed malignant
hypertension [3]. Chronic atrophic pyelonephritis in children, often
a result of underlying vesicoureteral reflux, is the most common cause
of malignant hypertension [4]. In Australia, malignant hypertension
complicates up to 7% of cases of analgesic nephropathy [5].
Transient malignant hypertension responsive to volume expansion
has been reported in analgesic nephropathy. It has been suggested
that interstitial disease with salt-wasting is important in the pathogenesis by causing profound volume depletion with activation of
the renin-angiotensin axis. Malignant hypertension is both an early
and late complication of radiation nephritis that can occur up to
11 years after radiotherapy. Renovascular hypertension from either
fibromuscular dysplasia or atherosclerosis is a well-recognized
cause of malignant hypertension. In a series of 123 patients with
malignant hypertension, renovascular hypertension was found in
43% of Whites and 7% of Blacks [6]. Among women of childbearing
age, oral contraceptives can cause malignant hypertension [7]. In
the absence of underlying renal disease, with discontinuation of the
drug, long-term prognosis is excellent. Severe hypertension that
may become malignant is a common complication of atheroembolic
renal disease. In patients presenting with malignant hypertension in
the weeks to months after an arteriographic procedure, a careful
history and physical should be performed to look for evidence of
atheroembolism. Scleroderma renal crisis is the most life-threatening
complication of progressive systemic sclerosis. Scleroderma renal
crisis is characterized by hypertension that may enter the malignant
phase. Even in the absence of hypertensive neuroretinopathy suggesting malignant hypertension, the renal lesion in scleroderma
renal crisis is virtually indistinguishable from primary malignant
nephrosclerosis [8]. Patients with antiphospholipid antibody syndrome, either primary or secondary to systemic lupus erythematosus,
can develop malignant hypertension with renal insufficiency as
a result of thrombotic microangiopathy [9]. The endocrine causes
of hypertension only rarely lead to malignant hypertension.
Pheochromocytoma can cause hypertensive crises owing to hypertensive encephalopathy or acute hypertensive heart failure in the
absence of hypertensive neuroretinopathy (malignant hypertension).
8.6
Tertiary hyperaldosteronism after treatment

of malignant hypertension
Renal ischemia
Vascular
lesions heal
Activation
of reninangiotensin
axis
Antihypertensive
treatment with
resolution of malignant
hypertension
Renin levels
decrease rapidly
Bilateral adrenal hyperplasia
Resolves slowly over

1 year after control
of blood pressure
FIGURE 8-6
Tertiary hyperaldosteronism after treatment of malignant hypertension. The diagnosis of primary hyperaldosteronism must be made
with caution in patients with a history of malignant hypertension.
After successful treatment of malignant hypertension, plasma renin
activity rapidly normalizes, whereas aldosterone secretion may
remain elevated for up to a year. This phenomenon has been attributed to persistent adrenal hyperplasia induced by long-standing
hyperreninemia during the malignant phase [10]. During this phase
of tertiary hyperaldosteronism, despite suppressed renin activity,
hypokalemia, metabolic alkalosis, and aldosterone levels that are
not suppressible, mimic primary hyperaldosteronism. Adrenal
imaging studies reveal bilateral nodular adrenal hyperplasia. With
continued long-term control of blood pressure this hyperaldosteronism remits spontaneously.
Nonsuppressible aldosteronism
Renal potassium-wasting
with hypokalemia
Metabolic alkalosis
RENAL CHANGES IN HYPERTENSION

Retinal arteriosclerosis and arteriosclerotic retinopathy (benign hypertension)
Focal or diffuse arteriolar narrowing
Arteriovenous crossing changes
Broadening of the light reflex
Copper or silver wiring
Perivasculitis (parallel white lines around the arteries)
Solitary round hemorrhages
Hard exudates
Central or branch venous occlusion
Hypertensive neuroretinopathy (malignant hypertension)
Generalized arteriolar narrowing
Striate (flame-shaped) hemorrhage*
Cotton-wool spots*
Papilledema*
Star figure at the macula
*Features that distinguish hypertensive neuroretinopathy from retinal arteriosclerosis.
FIGURE 8-7
Funduscopic findings are pivotal in the diagnosis of malignant
hypertension. Keith and Wagener [11] graded retinal findings in
hypertensive patients as follows: grade I, arteriolar narrowing;
grade II, arteriovenous crossing changes; grade III, hemorrhages
and exudates; grade IV, the changes in grade III plus papilledema.
Although this classification of hypertensive retinopathy is of great
historical importance, its clinical utility has several limitations, eg,
it is extremely difficult to quantify arteriolar narrowing. In this
regard, a tendency exists for significant observer bias such that
patients with mild hypertension and questionable narrowing are
invariably assigned to grade I. More importantly, this classification
does not distinguish the retinal changes of benign and malignant
hypertension. For example, the clinical significance of a cottonwool spot appearing in the fundus of a young man with severe
hypertension (diagnostic of malignant hypertension) is quite different from the clinical significance of a hard exudate in the fundus of
a 60-year-old man with moderate hypertension. The prognostic
and therapeutic implications of these two types of exudates clearly
are different, although both would be classified as grade III. For
this reason, the Keith and Wagener classification has been supplanted by the more clinically useful classification of hypertensive
retinopathy shown here. This classification system draws a distinction between retinal arteriosclerosis with arteriosclerotic retinopathy, which is characteristic of benign hypertension, and hypertensive neuroretinopathy, which defines the existence of malignant
hypertension [12,13]. Retinal arteriosclerosis, which is characterized histologically by the accumulation of hyaline material in arterioles, occurs in elderly normotensive persons or in the setting of
long-standing benign hypertension. Funduscopic findings reflecting
retinal arteriosclerosis include arteriolar narrowing, arteriovenous
crossing changes, perivasculitis, and changes in the light reflex with
copper or silver wiring. Arteriosclerotic retinopathy manifests as
solitary round hemorrhages in the periphery of the fundus and
hard exudates. The finding of retinal arteriosclerosis is of no prognostic significance with regard to the risk of coronary atherosclerosis or cerebrovascular disease. The arteries visualized with the ophthalmoscope are technically arterioles with a diameter of 0.1 mm.
Hyaline arteriolosclerosis of the retinal vessels is a process entirely
distinct from the atherosclerotic process that affects larger muscular arteries. Thus, the finding of retinal arteriosclerosis cannot predict the presence of atherosclerosis of the coronary or cerebral vessels. This lack of clinical significance of retinal arteriosclerosis in
hypertensive patients contrasts dramatically with the importance
and prognostic significance of the finding of hypertensive neuroretinopathy. This finding is the clinical sine qua non of malignant
hypertension. The appearance of striate hemorrhages or cottonwool spots with or without papilledema closely parallels the development of fibrinoid necrosis and proliferative endarteritis in the
kidney and other organs. Thus, the presence of hypertensive neuroretinopathy predicts the development of end-stage renal disease,
or other life-threatening hypertensive complications, within a year
if adequate control of the blood pressure is not achieved.
Hypertensive Crises
8.7

Fundus photography of retinal arteriosclerosis in benign hypertension. Funduscopy in a
60-year-old man reveals the characteristic changes of retinal arteriosclerosis, including
arteriolar narrowing, mild arteriovenous crossing changes, copper wiring, and perivasculitis
(parallel white lines around blood columns). The striate hemorrhages, cotton-wool spots,
and papilledema characteristic of malignant hypertension are absent.

Fundus photography of arteriosclerotic retinopathy in benign hypertension. Funduscopy in
a 52-year-old woman with benign hypertension demonstrates a solitary round hemorrhage
characteristic of arteriosclerotic retinopathy.

Fundus photography of striate hemorrhages in hypertensive neuroretinopathy. Funduscopic
findings in a 53-year-old woman with secondary malignant hypertension as a result of
underlying immunoglobulin A nephropathy, demonstrating striate or flame-shaped
hemorrhages (arrows). The appearance of small striate hemorrhages often is the first
sign that malignant hypertension has developed. These hemorrhages are most commonly
observed in a radial arrangement around the optic disc. The retinal circulation is under
autoregulatory control such that under normal circumstances as blood pressure increases,
arterioles constrict to maintain constant retinal blood flow. The appearance of striate
hemorrhages implies that autoregulation has failed. Striate hemorrhages are a result of
bleeding from superficial capillaries in the nerve fiber bundles near the optic disc. These
capillaries originate directly from arterioles so that when autoregulation fails, the high
systemic pressure is transmitted directly to the capillaries. This process leads to breaks in
the continuity of the capillary endothelium. The resultant hemorrhages extend along nerve
fiber bundles parallel to the retinal surface. The hemorrhages often have a frayed distal
border owing to extravasation of blood between nerve fiber bundles.
8.8

Fundus photography of cotton-wool spots in hypertensive neuroretinopathy. Cotton-wool
spots (arrows) are the most characteristic feature of malignant hypertension. They usually
surround the optic disc and most commonly occur within three disc-diameters of the optic
disc. Cotton-wool spots result from ischemic infarction of retinal nerve fiber bundles owing
to arteriolar occlusion caused by proliferative arteriopathy in retinal vessels. Fluorescein
angiography demonstrates that cotton-wool spots are areas of retinal nonperfusion.
Embolization of pig retina with glass beads produces immediate neuronal cell edema followed
by accumulation of mitochondria and other subcellular organelles in ischemic nerve fibers.
It has been postulated that the normal axoplasmic flow of subcellular organelles is disrupted
by retinal ischemia such that accumulation of organelles in ischemic nerve fiber bundles
results in a visible white patch. Cotton-wool spots tend to distribute around the optic disc
because nerve fiber bundles are most dense in this region. The detection of cotton-wool spots
is a crucial clinical finding because they are the retinal manifestation of the malignant hypertension-induced systemic vasculopathy that also causes proliferative endarteritis and ischemia
in the kidney and other organs. (This is the same patient as in Fig. 8-10.)
Fundus photography of papilledema in hypertensive neuroretinopathy. Funduscopic findings in a 23-year-old Black man noted incidentally to be severely hypertensive during a
routine dental clinic visit. Papilledema of the optic disc is apparent, with surrounding cotton-wool spots and striated hemorrhages. The pathogenesis of papilledema in hypertensive
neuroretinopathy is unclear. Intracranial pressure is not always increased in patients with
malignant hypertension and papilledema. Papilledema has been produced experimentally
in Rhesus monkeys by occlusion of the long posterior ciliary artery that supplies the optic
nerve. As in cotton-wool spots, indeed papilledema may result from hypertensive vasculopathyinduced ischemia of nerve fiber bundles in the optic disc. Thus, in hypertensive
neuroretinopathy, papilledema essentially may represent a giant cotton-wool spot resulting
from ischemia of the optic nerve. When papilledema occurs in malignant hypertension, it
almost always is accompanied by striated hemorrhages and cotton-wool spots. When
papilledema occurs alone, the possibility of a primary intracranial process such as tumor
or cerebrovascular accident should be considered.
Fundus photography of far-advanced hypertensive neuroretinopathy. Funduscopy in this
30-year-old man with malignant hypertension demonstrates all the characteristic features
of hypertensive neuroretinopathy. These features include striate hemorrhages, cotton-wool
spots, papilledema, and a star figure at the macula.
Hypertensive Crises
10
No papilledema
Papilledema
Estimated survival
08
06
04
96
43
74
28
45
16
26
10
14
6
No. with papilledema

No. without papilledema
6
Years
10
8.9
FIGURE 8-14
Prognosis in accelerated hypertension versus malignant hypertension.
In the original Keith and Wagener [11] classification of hypertensive
retinopathy, malignant hypertension (grade IV) was defined by the
presence of papilledema, whereas the term accelerated hypertension
(grade III) was used when hemorrhages and exudates occurred in
the absence of papilledema. However, more recent studies indicate
that the prognosis is the same in hypertensive patients with striate
hemorrhages and cotton-wool spots whether or not papilledema is
present. In this regard, the World Health Organization has recommended that accelerated hypertension and malignant hypertension be
regarded as synonymous terms for the same disease. Demonstrated
are the effects of the presence or absence of papilledema on survival
among 139 hypertensive patients with hypertensive neuroretinopathy
(striated hemorrhages and cotton-wool spots) [14]. By multivariate
analysis, after controlling for age, gender, smoking habit, initial
serum creatinine concentration, and initial and achieved blood
pressure, the presence of papilledema did not influence prognosis.
(From McGregor [14] et al.; with permission.)

Micrograph of fibrinoid necrosis in malignant hypertension.
Fibrinoid necrosis of the afferent arterioles and interlobular arteries
has traditionally been regarded as the hallmark of malignant
hypertension. The characteristic finding is the deposition in the
arteriolar wall of a granular material that is a bright-pink color on
hematoxylin and eosin staining. On Masson trichrome staining, as
illustrated, the granular fibrinoid material is bright red (arrow).
The fibrinoid material usually is found in the media of the vessel;
however, deposition in the intima also may occur. Whole or fragmented erythrocytes may be extravasated into the arteriolar wall.
These hemorrhages account for the petechial hemorrhages that give
rise to the peculiar flea-bitten appearance of the capsular surface of
the kidney in malignant hypertension. Fibrinoid necrosis is thought
to result from the mechanical stress placed on the vessel wall by
severe hypertension. Forced vasodilation occurs when there is failure
of autoregulation of renal blood flow, which leads to endothelial
injury with seepage of plasma proteins into the vessel wall. Contact
of plasma constituents with smooth muscle cells activates the coagulation cascade, and fibrin is deposited in the wall. Fibrin deposits
then cause necrosis of smooth muscle cells (fibrinoid necrosis).
(Masson trichrome stain, original magnification 100.)
8.10
SPECTRUM OF CLINICAL RENAL INVOLVEMENT

IN MALIGNANT HYPERTENSION
Progressive subacute deterioration of renal function to end-stage renal disease
Transient deterioration of renal function with initial blood pressure control
Oliguric acute renal failure
Established renal failure

Micrograph of proliferative endarteritis in malignant hypertension
(musculomucoid intimal hyperplasia). In malignant nephrosclerosis,
the interlobular (cortical radial) arteries reveal characteristic lesions.
These lesions are variously referred to as proliferative endarteritis,
endarteritis fibrosa, musculomucoid intimal hyperplasia, or the
onionskin lesion. The typical finding is marked thickening of the
intima that obstructs the vessel lumen. In severely affected vessels
the luminal diameter may be reduced to the caliber of a single erythrocyte. Occasionally, complete obliteration of the lumen by a
superimposed fibrin thrombus occurs.
Traditionally, three patterns of intimal thickening have been
described [15]. (1) The onionskin pattern consists of pale layers of
elongated concentrically arranged myointimal cells along with delicate connective tissue fibrils that give rise to a lamellar appearance.
The media often appears as an attenuated layer stretched around
the expanded intima. (2) In the mucinous pattern, intimal cells are
sparse. Seen is an abundance of lucent, faintly basophilic-staining
amorphous material. (3) In fibrous intimal thickening, seen are few
cells with an abundance of hyaline deposits, reduplicated bands of
elastica, and coarse layers of collagen. The renal histology in Blacks
with malignant hypertension demonstrates a characteristic finding
in the larger arterioles and interlobular arteries known as musculomucoid intimal hyperplasia, with an abundance of cells and a small
amount of myxoid material (that is light blue in color on hematoxylin and eosin staining) between the cells [16, 17]. These various
intimal findings may represent progression over time from an initially cellular lesion to fibrosis of the intima. Electron microscopy
demonstrates that in each type of intimal thickening the most abundant cellular element is a modified smooth muscle cell. This cell is
called a myointimal cell. Proliferative endarteritis is thought to
occur as a result of phenotypic modulation of medial smooth muscle cells that dedifferentiate from the normal contractile phenotype
to acquire a more embryologic proliferative-secretory phenotype. It
has been proposed that the endothelial injury in malignant hypertension results in attachment of platelets with release of plateletderived growth factor (PDGF) that may induce the phenotypic
change in smooth muscle cells. PDGF stimulates chemotaxis of
medial smooth muscles to the intima, where they proliferate and
secrete mucopolysaccharide and later collagen and other extracellular matrix proteins, resulting in proliferative endarteritis, musculomucoid hyperplasia, and ultimately fibrous intimal thickening.
(Hematoxylin and eosin stain, original magnification 100.)
FIGURE 8-17
Malignant hypertension is a progressive systemic vasculopathy in
which renal involvement is a relatively late finding. In this regard,
patients with malignant hypertension can present with a spectrum
of renal involvement ranging from normal renal function with minimal
albuminuria to end-stage renal disease (ESRD) indistinguishable
from that seen in primary renal parenchymal disease. In patients
initially exhibiting preserved renal function, in the absence of adequate
blood pressure control, it is common to observe subacute deterioration of renal function to ESRD over a period of weeks to months.
Transient deterioration of renal function with initial control of
blood pressure is a well-documented entity in patients initially
exhibiting mild to moderate renal impairment. Occasionally,
patients with malignant hypertension initially exhibit oliguric acute
renal failure, necessitating initiation of dialysis within a few days of
hospitalization. Because erythrocyte casts sometimes appear in the
urine sediment, malignant nephrosclerosis initially may be misdiagnosed as a rapidly progressive glomerulonephritis or systemic vasculitis
[18]. Careful examination of the fundus for evidence of hypertensive
neuroretinopathy confirms the diagnosis of malignant hypertension.
Patients with malignant hypertension can also present with established renal failure. Often, it is impossible to determine clinically
whether a patient initially exhibiting hypertensive neuroretinopathy
and renal failure has primary malignant hypertension or secondary
malignant hypertension with underlying primary renal parenchymal
disease. The presence of normal-sized kidneys on ultrasonography
supports a diagnosis of primary malignant nephrosclerosis that
potentially is reversible with long-term blood pressure control.
However, a renal biopsy may be required for definitive diagnosis.
All patients with malignant hypertension should receive aggressive
antihypertensive therapy to prevent further renal damage, regardless
of the degree of renal impairment. Control of blood pressure in
patients with malignant hypertension and renal insufficiency often
causes further deterioration of renal function, especially when the
initial glomerular filtration rate (GFR) is less than 20 mL/min.
However, a fall in GFR is not a contraindication to intensive blood
pressure control aimed at normalization of blood pressure. Control
of hypertension protects other vital organs, such as the heart and
brain, whose function cannot be replaced. Moreover, with rigid
blood pressure control, renal function may eventually recover over
the ensuing months, even in patients with apparent ESRD owing to
primary malignant nephrosclerosis [19,20].
Hypertensive Crises
8.11

Micrograph of hyaline arteriolar nephrosclerosis in benign hypertension. It is important to draw a clear distinction between malignant hypertension and benign hypertension with regard to renal
histology and clinical renal involvement. In benign arteriolar
nephrosclerosis caused by benign hypertension, the characteristic
histologic lesion is hyaline arteriosclerosis. In hyaline arteriosclerosis there is expansion of the intima of afferent arterioles with hyaline material that stains a pale-pink color on periodic acidSchiff
staining (large arrow). Patchy (focal) ischemic atrophy of the
glomeruli usually is seen. Many glomeruli appear normal, whereas
some are completely hyalinized. Atrophic tubules (small arrows),
sometimes filled with amorphous material, may be seen in the
vicinity of ischemic glomeruli. The severity of the glomerular and
tubular changes generally reflect the extent of vascular involvement
with hyaline arteriosclerosis. On gross examination, the kidneys
are small with a granular-appearing capsular surface (contracted
granular kidney). The loss of renal mass primarily is due to a thinning of the cortex. In untreated malignant hypertension, relentless
progression to end-stage renal disease (ESRD) occurs within a year.
In contrast, in benign hypertension, without underlying renal disease or superimposed malignant hypertension, despite well-established folklore to the contrary, ESRD seldom develops [21,22]. In
benign hypertension, there is a usually a long asymptomatic phase,
with eventual complications resulting from cerebrovascular disease,
atherosclerotic disease, or congestive heart failure, in the absence
of significant renal impairment despite histologic evidence of
benign nephrosclerosis. In this regard, patients classified as having
ESRD owing to hypertensive nephrosclerosis typically exhibit
advanced disease initially, making the original process that initiated
the renal disease difficult to detect. Moreover, significant racial bias
may occur in the clinical diagnosis of the cause of ESRD [23].
Nephrologists presented with identical case histories of hypothetical patients with ESRD and hypertension in which the race is arbitrarily stated to be Black or White, tend to diagnose hypertensive
nephrosclerosis in Blacks and chronic glomerulonephritis in
Whites. It has been proposed that many of the patients presumed
clinically to have ESRD owing to benign hypertension, actually
have occult intrinsic renal disease with chronic glomerulonephritis,
unrecognized bilateral atherosclerotic renal artery stenosis with
ischemic nephropathy, atheroembolic renal disease, or episodes of
malignant hypertension that had gone undetected [21,22]. (Periodic
acidSchiff stain, original magnification 100.)
8.12
INDICATIONS FOR PARENTERAL THERAPY

IN MALIGNANT HYPERTENSION
Hypertensive encephalopathy
Rapidly failing vision
Pulmonary edema
Rapid deterioration of renal function
Acute pancreatitis
Gastrointestinal hemorrhage or acute abdomen from mesenteric vasculitis
Patients unable to tolerate oral therapy because of intractable vomiting
FIGURE 8-19
Malignant hypertension must be treated expeditiously to prevent
complications such as hypertensive encephalopathy, acute hypertensive
heart failure, and renal failure. The traditional approach to patients
with malignant hypertension has been the initiation of potent parenteral agents. Listed are the settings in which parenteral antihypertensive therapy is mandatory in the initial management of
malignant hypertension. Parenteral therapy generally should be
used in patients with evidence of acute end-organ dysfunction or
those unable to tolerate oral medications. Nitroprusside is the
treatment of choice for patients requiring parenteral therapy.
Diazoxide, employed in minibolus fashion to avoid sustained overshoot hypotension, may be advantageous in patients for whom
monitoring in an intensive care unit is not feasible. It generally is
safe to reduce the mean arterial pressure by 20% or to a level of
160 to 170 mm Hg systolic over 100 to 110 mm Hg diastolic. The
use of a short-acting agent such as nitroprusside has obvious
advantages because blood pressure can be stabilized quickly at a
higher level if complications develop during rapid blood pressure
reduction. When no evidence of vital organ hypoperfusion is seen
during this initial reduction, the diastolic blood pressure can be
lowered gradually to 90 mm Hg over a period of 12 to 36 hours.
Oral antihypertensive agents should be initiated as soon as possible to
minimize the duration of parenteral therapy. The nitroprusside
infusion can be weaned as the oral agents become effective. The
cornerstone of initial oral therapy should be arteriolar vasodilators
such as calcium channel blockers, hydralazine, or minoxidil. Usually,
-blockers are required to control reflex tachycardia, and a diuretic
must be initiated within a few days to prevent salt and water retention,
in response to vasodilator therapy, when the patients dietary salt
intake increases. Diuretics may not be necessary as a part of initial
parenteral therapy because patients with malignant hypertension
often present with volume depletion (Fig. 8-20).
Many patients with malignant hypertension definitely require initial
parenteral therapy. However, some patients may not yet have evidence
of cerebral or cardiac dysfunction or rapidly deteriorating renal
function and therefore do not require instantaneous control of blood
pressure. These patients often can be managed with an intensive oral
regimen, often with a -blocker and minoxidil, designed to bring
the blood pressure under control within 12 to 24 hours. After the
immediate crisis has resolved and the patients blood pressure has
been controlled with initial parenteral therapy, oral therapy, or
both, lifelong surveillance of blood pressure is mandatory. If blood
pressure control lapses, malignant hypertension can recur even
after years of successful antihypertensive therapy. Triple therapy
with a diuretic, -blocker, and a vasodilator often is required to
maintain satisfactory long-term blood pressure control.
Hypertensive Crises
Role of diuretics to treat malignant hypertension
Abrupt increase in blood pressure

Pressure-induced natriuresis and diuresis
Activation of the renin-angiotensin axis
Angiotensin IImediated vasoconstriction
Vicious
circle
8.13
FIGURE 8-20
Role of diuretics in the treatment of malignant hypertension.
Traditionally, it had been taught that patients with malignant
hypertension require potent parenteral diuretics in conjunction
with potent vasodilator therapy during the initial phase of management of malignant hypertension. However, evidence now exists to
suggest that parenteral diuretic therapy during the acute management
phase actually may be deleterious. In experimental animals, spontaneous natriuresis appears to be the initiating event in the transition
from benign to malignant hypertension, and treatment with volume
expansion leads to resolution of the malignant phase [24]. Rapid
weight loss often occurs in patients with malignant hypertension,
which is consistent with a pressure-induced natriuresis. In analgesic
nephropathy, profound volume depletion often accompanies malignant
hypertension, perhaps owing to tubular dysfunction with salt-wasting
[5]. In this setting, restoration of normal volume status actually
lowers blood pressure and leads to resolution of the malignant
phase. Thus, some patients with malignant hypertension may benefit
from a cautious trial of volume expansion. Volume depletion should
be suspected when there is exquisite sensitivity to vasodilator therapy
with a precipitous decrease in blood pressure at relatively low infusion
rates. Even patients with malignant hypertension complicated by
pulmonary edema may not be total-body salt and water overloaded.
Pulmonary congestion in this setting may result from acute hypertensive heart failure caused by an acute decrease in left ventricular
(LV) compliance precipitated by severe hypertension. In this setting,
pulmonary edema occurs owing to a high LV end-diastolic pressure
with normal LV end-diastolic volume (Fig. 8-24). Thus, the need
for diuretic therapy during the initial phases of management of
malignant hypertension depends on a careful assessment of volume
status. Unless obvious fluid overload is present, diuretics should
not be given initially. Overdiuresis may result in deterioration of
renal function owing to superimposed volume depletion. Moreover,
volume depletion may further activate the renin-angiotensin system
and other pressor hormone systems. Although vasodilator therapy
will eventually result in salt and water retention by the kidneys, an
increase in total body sodium content cannot occur unless the
patient is given sodium. Eventually, during long-term treatment
with oral vasodilators, the use of diuretics becomes imperative to
prevent fluid retention and adequately control blood pressure.
8.14
Pathogenesis and treatment of hypertensive encephalopathy

(hypertensive neuroretinopathy
present)
Sudden or severe nonmalignant

hypertension
(hypertensive neuroretinopathy absent)
Sudden onset or severe hypertension
Failure of autoregulation of cerebral blood flow

(breakthrough of autoregulation)
Forced vasodilation of cerebral arterioles
Endothelial damage
(increased permeability to
plasma proteins)
Cerebral hyperperfusion
(increased capillary
hydrostatic pressure)
Cerebral edema
(headache, vomiting, altered mental status, seizures)
Prompt blood pressure reduction with nitroprusside
New or progressive focal findings

(suspect primary central nervous
system process)
Dramatic clincal improvement

(diagnostic of hypertensive
encephalopathy)
FIGURE 8-21
Pathogenesis and treatment of hypertensive encephalopathy.
Hypertensive encephalopathy is a hypertensive crisis in which acute
cerebral dysfunction is attributed to sudden or severe elevation of
blood pressure [2527]. Hypertensive encephalopathy is one of the
most serious complications of malignant hypertension. However,
malignant hypertension (hypertensive neuroretinopathy) need not
be present for hypertensive encephalopathy to develop. Hypertensive
encephalopathy also can occur in the setting of severe or sudden
hypertension of any cause, especially if an acute elevation of blood
pressure occurs in a previously normotensive person, eg, from
postinfectious glomerulonephritis, catecholamine excess states, or
eclampsia. Under normal circumstances, autoregulation of the cerebral
microcirculation occurs, and therefore, cerebral blood flow remains
constant over a wide range of perfusion pressures. However, in the
setting of sudden severe hypertension, autoregulatory vasoconstriction fails and there is forced vasodilation of cerebral arterioles with
endothelial damage, extravasation of plasma proteins, and cerebral
hyperperfusion with the development of cerebral edema. This
breakthrough of cerebral autoregulation underlies the development
of hypertensive encephalopathy. In patients with chronic hypertension,
structural changes occur in the cerebral arterioles that lead to a shift
in the autoregulation curve such that much higher blood pressures
can be tolerated without breakthrough. This phenomenon may
explain the clinical observation that hypertensive encephalopathy
occurs at much lower blood pressure in previously normotensive
persons than it does in those with chronic hypertension. Clinical
features of hypertensive encephalopathy include severe headache,
blurred vision or occipital blindness, nausea, vomiting, and altered
mental status. Focal neurologic findings can sometimes occur. If
aggressive blood pressure reduction is not initiated, stupor, convulsions, and death can occur within hours. The sine qua non of
hypertensive encephalopathy is the prompt and dramatic clinical
improvement in response to antihypertensive drug therapy. When a
diagnosis of hypertensive encephalopathy seems likely, antihypertensive therapy should be initiated promptly without waiting for
the results of time-consuming radiographic examinations. The goal
of therapy, especially in previously normotensive patients, should
be reduction of blood pressure to normal or near-normal levels as
quickly as possible. Theoretically, cerebral blood flow could be
jeopardized by rapid reduction of blood pressure in patients with
chronic hypertension in whom the lower limit of cerebral blood
flow autoregulation is shifted to a higher blood pressure. However,
clinical experience has shown that prompt blood pressure reduction
with the avoidance of frank hypotension is beneficial in patients
with hypertensive encephalopathy [25]. Of the conditions in the
differential diagnosis of hypertension with acute cerebral dysfunction, only cerebral infarction might be adversely affected by the
abrupt reduction of blood pressure. Pharmacologic agents that
have rapid onset and short duration of action such as sodium
nitroprusside should be used so that the blood pressure can be
titrated carefully, with close monitoring of the patients neurologic
status. A prompt improvement in mental status with blood pressure
reduction confirms the diagnosis of hypertensive encephalopathy.
Conversely, when blood pressure reduction is associated with new
or progressive focal neurologic deficits, the presence of a primary
central nervous system event, such as cerebral infarction, should be
considered.
Hypertensive Crises
CAUSES OF HYPERTENSIVE ENCEPHALOPATHY

Malignant hypertension of any cause
Acute glomerulonephritis, especially postinfectious
Eclampsia
Catecholamine-induced hypertensive crises
Pheochromocytoma
Monoamine oxidase inhibitortyramine interactions
Abrupt withdrawal of centrally acting 2-agonists
Phenylpropanolamine overdose
Cocaine-hydrochloride or alkaloid (crack cocaine) intoxication
Phencyclidine (PCP) poisoning
Acute lead poisoning in children
High-dose cyclosporine for bone marrow transplantation in children
Femoral lengthening procedures
Scorpion envenomation in children
Acute renal artery occlusion from thrombosis or embolism
Atheroembolic renal disease (cholesterol embolization)
Recombinant erythropoietin therapy
Transplantation renal artery stenosis
Acute renal allograft rejection
Paroxysmal hypertension in acute or chronic spinal cord injuries
Postcoronary artery bypass or postcarotid endarterectomy hypertension
8.15
FIGURE 8-22
Hypertensive encephalopathy can complicate malignant hypertension of any cause. However, not all patients with hypertensive
encephalopathy have hypertensive neuroretinopathy, indicating the
presence of malignant hypertension. In fact, hypertensive
encephalopathy most commonly occurs in previously normotensive
persons who experience a sudden onset or worsening of hypertension. In acute postinfectious glomerulonephritis, the abrupt onset
of even moderate hypertension may cause breakthrough of
autoregulation of cerebral blood flow, resulting in hypertensive
encephalopathy. Eclampsia can be viewed as a variant of hypertensive encephalopathy that complicates preeclampsia. Moreover,
hypertensive encephalopathy is a common complication of catecholamine-induced hypertensive crises such as pheochromocytoma,
monoamine oxidase inhibitortyramine interactions, clonidine
withdrawal, phencyclidine (PCP) poisoning, and phenylpropanolamine overdose. Cocaine use also can induce a sudden
increase in blood pressure accompanied by hypertensive
encephalopathy. In children, acute lead poisoning, high-dose
cyclosporine for bone marrow transplantation, femoral lengthening
procedures, and scorpion envenomation may be accompanied by
the sudden onset of hypertension with hypertensive encephalopathy. Acute renal artery occlusion resulting from thrombosis or renal
embolism can induce hypertensive encephalopathy. Likewise,
atheroembolic renal disease (cholesterol embolization) can cause a
sudden increase in blood pressure complicated by encephalopathy.
Recombinant erythropoietin therapy occasionally results in
encephalopathy and seizures. This complication is unrelated to the
extent or rate of increase in hematocrit; however, it is associated
with a rapid increase in blood pressure, especially if the patient
was normotensive previously. Transplantation renal artery stenosis
or acute renal allograft rejection may cause sudden severe hypertension with encephalopathy. Hypertensive encephalopathy may
complicate acute or chronic spinal cord injury. Sudden elevation of
blood pressure occurs owing to autonomic stimulation by bowel or
bladder distention or noxious stimulation in a dermatome below
the level of the injury. Hypertensive encephalopathy also may complicate the rebound hypertension that follows coronary artery
bypass procedures or carotid endarterectomy.
8.16
120
5.0
90
100
60
30
NF
0
NS
Stroke work index, g m/m2
150
NS
LVEDP, mm Hg
200
100
30
15
0
0
NS
P<0.005
NS
A Baseline hemodynamics in acute hypertensive heart failure (AHHF) vs no failure (NF)
60
AHHF: baseline
AHHF: with nitroprusside
No failure: baseline
No failure: with nitroprusside
LVFP, mm Hg
50
40
30
20
10
0
NP
NP
50
120
160
LVEDV, mL/m2
200
240
Left ventricular compliance at baseline and with nitroprusside
FIGURE 8-23
Pathogenesis of acute hypertensive heart failure. Both malignant
hypertension and severe benign hypertension can be complicated by
acute pulmonary edema caused by isolated diastolic dysfunction. In
acute hypertensive heart failure the compromise of left ventricular (LV)
diastolic function occurs as a result of a decrease in LV compliance
caused by an increased workload imposed on the heart by the marked
elevation in systemic vascular resistance. Illustrated are the hemodynamic derangements in acute hypertensive heart failure in a study that
compared five patients with severe essential hypertension complicated
by acute pulmonary edema with a control group of five patients with
equally severe hypertension but no pulmonary edema [28]. Patients
P<0.005
40
9
NP
6
3
NP
30
20
10
NP
B NP
0
P<0.005
80
P<0.005
NS
LVEDV, mL/m2
45
40
100
60
75
150
Cardiac output, L/min
AHHF
2.5
AHHF
NF
200
LVEDP, mm Hg
200
Cardiac index, L/min/m2
Heart rate, beats/min
Mean arterial
pressure, mm Hg
MAP, mm Hg
NS
P<0.005
P<0.025
Hemodynamic parameters at baseline (B) and during nitroprusside (NP) infusion
in both groups had electrocardiographic evidence of LV hypertrophy

caused by long-standing hypertension.
A, Baseline hemodynamic measurements before treatment
revealed that the following measurements were the same in both
groups: mean arterial pressure (MAP), heart rate, cardiac index,
systemic vascular resistance, and stroke work index. Likewise, the
LV end-diastolic volume (LVEDV) was similar in both groups. In
fact, the only hemodynamic difference between the groups was a
significant elevation of LV filling pressure (LVFP) (pulmonary capillary wedge pressure) in the group with pulmonary edema. In acute
hypertensive heart failure the finding of elevated LV end-diastolic
pressures (LVEDPs), despite normal ejection fraction and cardiac
index, implies the presence of isolated diastolic dysfunction. The
increased LV end-diastolic pressure (LVEDP), despite similar
LVEDV, can only be explained by a decrease in LV compliance in
patients with acute hypertensive heart failure. B, The importance
of an acute decrease in LV compliance in the pathogenesis of acute
hypertensive heart failure (AHHF) was confirmed in these patients
by the hemodynamic response to vasodilator therapy. Sodium
nitroprusside infusion resulted in prompt resolution of pulmonary
edema in the group having AHHF, with the LVEDP decreasing
from a mean of 43 to 18 mm Hg. C, The decrease in filling pressure during nitroprusside therapy in patients with AHHF was not
caused by venodilation with decreased venous return because the
LVEDV actually increased during nitroprusside infusion. Thus, the
response to sodium nitroprusside therapy was mediated through a
decrease in systemic vascular resistance that led to an immediate
improvement in LV compliance and reduction in wedge pressure
despite an increase in LVEDV. These findings suggest that the proximate cause of AHHF is an elevation of the systemic vascular resistance that precipitates acute diastolic dysfunction (decreased LV
compliance) with elevated pulmonary capillary wedge pressure,
resulting in pulmonary edema. NS not significant. (Adapted from
Cohn and coworkers [28]; with permission.)
Hypertensive Crises
50
40
Nitroprusside
30
HF
20
AH
Left ventricular end-diastolic

pressure, mm Hg
60
No
10
rm
al
0
40
80
120
160
200
Left ventricular end-diastolic volume, mL/m2
240
8.17
FIGURE 8-24
Treatment of acute hypertensive heart failure. The left ventricular
(LV) end-diastolic pressure-volume relationships (compliance
curves) in acute hypertensive heart failure (AHHF) before and after
treatment with sodium nitroprusside are represented schematically.
In AHHF, the pressure-volume curve is shifted up and to the left,
reflecting an acute decrease in LV compliance caused by severe
systemic hypertension. In this setting, a higher than normal LV
end-diastolic pressure (LVEDP) is required to achieve any given
level of LV end-diastolic volume (LVEDV). Normal LV systolic
function (ejection fraction and cardiac output) is maintained but
at the expense of a very high wedge pressure that results in acute
pulmonary edema. Treatment with sodium nitroprusside causes
a reduction in the elevated systemic vascular resistance, with a
concomitant decrease in impedance to LV ejection. As a result, LV
compliance improves. Pulmonary edema resolves owing to a reduction in LVEDP, despite the fact that LVEDV actually increases during treatment. Sodium nitroprusside is the preferred drug for treatment of AHHF. There is no absolute blood pressure goal. The infusion should be titrated until signs and symptoms of pulmonary
edema resolve or the blood pressure decreases to hypotensive levels. Rarely is it necessary to lower the blood pressure to this extent,
however, because reduction to levels still within the hypertensive
range is usually associated with dramatic clinical improvement.
Although hemodynamic monitoring is not always required, it is
essential in patients in whom concomitant myocardial ischemia or
compromised cardiac output is suspected. After the hypertensive
crisis has been controlled and pulmonary edema has resolved, oral
antihypertensive therapy can be substituted as the patient is
weaned from the nitroprusside infusion. As in the treatment of
hypertensive patients with chronic congestive heart failure symptoms owing to isolated diastolic dysfunction, agents such as blockers, angiotension-converting enzyme inhibitors, or calcium
channel blockers may represent logical first-line therapy. These
agents directly improve diastolic function in addition to reducing
systemic blood pressure. In patients with malignant hypertension
or resistant hypertension, however, adequate control of blood pressure may require therapy with more than one drug. Potent directacting vasodilators such as hydralazine or minoxidil may be used
in conjunction with a -blocker to control reflex tachycardia and
a diuretic to prevent reflex salt and water retention.
8.18
Aortic dissection
Transverse
aortic arch
Descending
aorta
Ascending
aorta
Proximal
(Type A)
Distal
(Type B)
FIGURE 8-25
Aortic dissection. Classification of aortic dissection is based on the
presence or absence of involvement of the ascending aorta [29].
The dissection is defined as proximal if there is involvement of the
ascending aorta. The primary intimal tear in proximal dissection
may arise in the ascending aorta, transverse aortic arch, or descending
aorta. In distal dissections, the process is confined to the descending
aorta without involvement of the ascending aorta, and the primary
intimal tear occurs most commonly just distal to the origin of the
left subclavian artery. Proximal dissections account for approximately
57% and distal dissections 43% of all acute aortic dissections.
Acute aortic dissection is a hypertensive crisis requiring immediate
antihypertensive treatment aimed at halting the progression of the
dissecting hematoma. The three most frequent complications of
aortic dissection are acute aortic insufficiency, occlusion of major
arterial branches, and rupture of the aorta with fatal hemorrhage
(location of rupture-hemorrhage: ascending aortahemopericardium
with tamponade, aortic archmediastinum, descending thoracic
aortaleft pleural space, abdominal aorta retroperitoneum).
Patients with acute dissection should be stabilized with intensive
antihypertensive therapy to prevent life-threatening complications
before diagnostic evaluation with angiography. The initial therapeutic
goal is the elimination of pain that correlates with halting of the
dissection, and reduction of the systolic pressure to the 100 to 120
mm Hg range or to the lowest level of blood pressure compatible
with the maintenance of adequate renal, cardiac, and cerebral
perfusion [30]. Even in the absence of systemic hypertension the
blood pressure should be reduced. Antihypertensive therapy should
be designed not only to lower the blood pressure but also to decrease
the steepness of the pulse wave. The most commonly used treatment
regimens consist of initial treatment with intravenous -blockers
such as propranolol, metoprolol, or esmolol followed by treatment
with sodium nitroprusside. After control of the blood pressure,
angiography or transesophageal echocardiography, or both, should
be performed. The need for surgical intervention is determined based
on involvement of the ascending aorta. In proximal dissections, surgical therapy is clearly superior to medical therapy alone (70% vs
26% survival, respectively). In contrast, in patients with distal
dissection, intensive drug therapy alone leads to an 80% survival
rate compared with only 50% in patients treated surgically. The
explanation for the advantage of surgical therapy in proximal
dissection is probably that the risks of complications such as cerebral
ischemia, acute aortic insufficiency, and cardiac tamponade are
higher and managed more effectively with surgery. Because these
complications do not occur in distal dissection, in the absence of
occlusion of a major arterial branch or development of a saccular
aneurysm during long-term follow-up, medical therapy is preferred.
Patients with distal dissection tend to be elderly with more advanced
aortic atherosclerosis and therefore are at higher risk of complications
from operative intervention. (Adapted from Wheat [29];
with permission.)
Hypertensive Crises
Poorly controlled hypertension in surgical patients

Postpone elective surgery until
blood pressure adequately
controlled for 23 weeks
Administer blood pressure and

antianginal medications the
morning of surgery
Manage intraoperative
hypertension with
sodium nitroprusside
Manage postoperative
hypertension with nitroprusside
in patients with complications
or labetalol in patients
without complications
Carefully institute oral

antihypertensives at low-dose
and titrate based on orthostatic
blood pressure measurements
Inadequate preoperative
blood pressure control
(diastolic blood pressure >110 mm Hg
or mild to moderate hypertension
in patients with history of
cerebrovascular accident,
myocardial ischemia, heart
failure, or renal insufficiency
General
anesthesia
Decreased cardiac output (30%)
Decreased systemic vascular
resistance (27%)
Hypotension
(45% Decrease in mean
arterial pressure)
Increased risks of
Cerebral ischemia
Myocardial ischemia
Acute renal failure
Increased perioperative morbidity
and mortality
FIGURE 8-26
Poorly controlled hypertension in the patient requiring surgery.
Hypertension in the preoperative patient is a common problem.
Poor control of preoperative hypertension, with a diastolic blood
pressure higher than 110 mm Hg, is a relative contraindication to
elective surgery. In such patients, perioperative morbidity and mortality are increased because of a higher incidence of intraoperative
hypotension accompanied by myocardial ischemia and a heightened
risk of acute renal failure [31]. Malignant hypertension clearly
represents an excessive surgical risk and all but lifesaving emergency
surgery should be deferred until the blood pressure can be controlled
and organ function stabilized. Mild to moderate uncomplicated
hypertension with diastolic blood pressure less than 110 mm Hg
does not appear to increase the risk of surgery significantly and
therefore is not an absolute indication to postpone elective surgery.
However, patients with mild to moderate hypertension and preexisting complications such as ischemic heart disease, cerebrovascular
disease, congestive heart failure, or chronic renal insufficiency,
represent a subgroup with significantly increased perioperative risk.
In these patients, adequate preoperative control of blood pressure
8.19
is imperative [32]. Even though the blood pressure in patients with

severe or complicated hypertension usually can be controlled within
hours using aggressive parenteral therapy, such precipitous control
of blood pressure carries the risk of significant complications such
as hypovolemia, electrolyte abnormalities, and marked intraoperative
blood pressure lability. General anesthesia is accompanied by a 30%
decrease in cardiac output. In normotensive persons and patients
with adequately treated hypertension, anesthesia is not associated
with a decrease in systemic vascular resistance. Therefore, the
decrease in mean arterial pressure (MAP) is modest (2530%).
However, in patients with inadequate preoperative blood pressure
control, anesthesia is associated with a concomitant decrease in
systemic vascular resistance (SVR) of approximately 27%. The
combined decrease in cardiac output and SVR leads to a profound
decrease in MAP (45%) during anesthesia [33]. This intraoperative
hypotension predisposes to myocardial ischemia, cerebrovascular
accidents, and acute renal failure. Therefore, in patients with diastolic
blood pressure over 110 mm Hg or these other high-risk groups,
elective surgery should be postponed and blood pressure brought
under control for a few weeks before surgery, if possible. Ideally,
sustained adequate preoperative blood pressure control should be
the goal in all hypertensive patients [34]. In patients with adequately
treated hypertension, oral antihypertensive, and antianginal medications should be continued up to and including the morning of
surgery, administered with small sips of water. Because hypovolemia
increases the risk of intraoperative hypotension and postoperative
acute renal failure, diuretics should be withheld for 1 to 2 days
preoperatively except in patients with overt heart failure or fluid
overload. Adequate potassium repletion should be given to correct
hypokalemia well in advance of surgery. Continuation of -blockers
to within a few hours of surgery does not impair cardiac function
and has been shown to decrease the risks of dysrhythmia and
myocardial ischemia during surgery. In patients with complications
and a history of cardiovascular disease or heart failure, or after
coronary artery bypass surgery, postoperative hypertension should
be managed with short-acting agents such as nitroglycerin or
nitroprusside. In patients without complications, intermittent
intravenous infusions of labetalol may be useful for management
of mild to moderate postoperative hypertension until the preoperative
oral antihypertensive agents can be resumed. Many patients with
long-standing hypertension, even if severe, require much smaller
doses of antihypertensive medications in the early postoperative
course. Thus, the preoperative regimen should not be restarted
automatically. Measurement of orthostatic blood pressures should
be used as a guide to dosage adjustment during the postoperative
recovery period. In most instances, the need for antihypertensive
medications will gradually increase over a few days to weeks to
eventually equal the preoperative requirement.
8.20
Hypertensive crises after bypass surgery
Coronary artery bypass

graft surgery
Paradoxical hypertensive response
to intravascular volume depletion
Increased sympathetic tone owing to

activation or pressor reflexes from heart,
coronary arteries, or great vessels
Increased systemic vascular resistance
Systemic hypertension
Increased risk of postoperative

mediastinal bleeding
Increased impedance to
left ventricular ejection
Treat with nitroprusside

or intravenous nitroglycerin
(Fig. 8-21)
Acute diastolic dysfunction

(decreased left ventricular compliance)
Increased left ventricular end-diastolic pressure
Impaired subendocardial perfusion

causing myocardial ischemia
Acute hypertensive heart failure

with pulmonary edema
(Figs. 8-23 and 8-24)
FIGURE 8-27
Hypertensive crisis after coronary artery bypass surgery. Paroxysmal hypertension in the
immediate postoperative period is a frequent and serious complication of cardiac surgery
[35,36]. Paroxysmal hypertension is the most frequent complication of coronary artery
bypass surgery, occurring in 30% to 50% of patients. It occurs just as often in normotensive
patients as it does in those with a history of chronic hypertension. The increase in blood
pressure usually occurs during the first 4 hours after surgery. The hypertension results
from a dramatic increase in systemic vascular resistance (SVR) without a change in the
cardiac output and is most commonly mediated by an increase in sympathetic tone owing
to activation of pressor reflexes from the heart, great vessels, or coronary arteries. Hypervolemia, although often cited as a potential mechanism of postoperative hypertension, is a
rare cause of postbypass hypertension except in patients with renal failure. In fact, increased
SVR owing to marked sympathetic overreaction to volume depletion is a common, often
unrecognized, cause of severe postoperative hypertension [37]. Patients with this paradoxical
hypertensive response to hypovolemia are exquisitely sensitive to vasodilator therapy and
may develop precipitous hypotension with

even low-dose infusions of nitroglycerin or
nitroprusside. Hypertension in this setting
should be treated using careful volume
expansion with crystalloid solutions or
blood if required. Postcoronary artery
bypass hypertension represents a hypertensive
crisis because the heightened SVR increases
the impedance to left ventricular (LV) ejection
(afterload) that can result in an acute decrease
in ventricular compliance with elevation of
LV end-diastolic pressure (LVEDP) and acute
hypertensive heart failure with pulmonary
edema (Figs. 8-23 and 8-24). The increase
in LVEDP also impairs subendocardial
perfusion and can cause myocardial
ischemia. Moreover, the elevated blood
pressure increases the risk of mediastinal
bleeding in these recently heparinized patients.
The initial management of postbypass hypertension should focus on attempts to ameliorate reversible causes of sympathetic activation, including patient agitation on emergence
from anesthesia, tracheal or nasopharyngeal
irritation from the endotracheal tube, pain,
hypothermia with shivering, ventilator asynchrony, hypoxia, hypercarbia, and volume
depletion. If these general measures fail to
control the blood pressure, further therapy
should be guided by measurement of systemic
hemodynamics. Intravenous nitroglycerin or
nitroprusside is the drug of choice to provide
a controlled decrease in SVR and blood
pressure. Nitroglycerin may be the preferred
drug because it dilates intracoronary collateral
arteries [35,36]. Therapy with -blockers is
not indicated in this setting and may be
detrimental because these drugs impair cardiac
output and cause a further increase in SVR.
Labetalol also has been shown to cause a
significant reduction in cardiac output in
postbypass hypertension. Postbypass hypertension is usually transient and resolves by
6 to 12 hours postoperatively, so that the
vasodilatory therapy can be weaned. The
hypertension usually does not recur after
the initial episode in the immediate postoperative period.
Hypertensive Crises
Hypertensive crises after carotid endarterectomy

Carotid endarterectomy
Postoperative hypertension
(mechanism unknown)
Repair of high-grade
stenosis
Sudden increase in perfusion pressure

in arteriocapillary bed that was
previously protected from hypertension
Failure of autoregulation of cerebral blood flow

(breakthrough of autoregulation)
Overperfusion of cerebral circulation

Vessel rupture
(hemorrhage and infarction)
8.21
FIGURE 8-28
Hypertensive crisis after carotid endarterectomy. Hypertension in
the immediate postoperative period occurs in up to 60% of patients
after carotid endarterectomy [38]. A history of chronic hypertension,
especially if the blood pressure is poorly controlled preoperatively,
dramatically increases the risk of postoperative hypertension. The
mechanism of post-endarterectomy hypertension is unknown. The
incidence of hypertension is the same whether or not the carotid
sinus nerve is preserved. Hypertension after endarterectomy is a
hypertensive crisis because it is associated with increased risk of
intracerebral hemorrhage and increases the postoperative mortality
rate [39]. A mechanism for the development of postcarotid
endarterectomy cerebral hemorrhage owing to postoperative hypertension has been proposed. In patients with high-grade carotid
artery stenosis, the distal cerebral circulation has been relatively
protected from systemic hypertension. In this regard, the autoregulatory curve may be shifted to a lower threshold to compensate for
reduced perfusion pressure. After repair of the obstructing lesion, a
relative increase in perfusion pressure occurs in the cerebral arteriocapillary bed. In the setting of systemic hypertension the increased
blood flow and perfusion pressure may overwhelm the autoregulatory mechanisms. Overperfusion and rupture may then occur,
resulting in hemorrhagic infarction. Because poor preoperative blood
pressure control increases the risk of postoperative hypertension,
strict blood pressure control is essential before elective carotid
endarterectomy. Furthermore, intra-arterial pressure should be
monitored in the operating room and in the immediate postoperative
period. Ideally, the patient should be awake and extubated before
reaching the recovery room so that serial neurologic examinations
can be performed to assess for the development of focal deficits.
When the systolic blood pressure exceeds 200 mm Hg, an intravenous
infusion of sodium nitroprusside should be initiated to maintain
the systolic blood pressure between 160 and 200 mm Hg. The use
of a short-acting parenteral agent is imperative to avoid overshoot
hypotension and cerebral hypoperfusion.
8.22
Risks of antihypertensive therapy in acute cerebral infarction

Acute cerebral infarction
Reflex increase in
systemic blood pressure
Even with cautious blood
pressure reduction using
parenteral agents
Altered blood flow

autoregulation in the
ischemic penumbra
surrounding the infarct
Exaggerated response to
oral antihypertensives
Spontaneous resolution
within first week
Failure of autoregulation
with worsening ischemia
Extension of infarct
FIGURE 8-29
Risks of antihypertensive therapy in acute cerebral infarction. Cerebral
infarction results from partial or complete occlusion of an artery
by an atherosclerotic plaque or embolization of atherothrombotic
debris from a more proximal plaque. These atherothrombotic
infarcts typically involve the cerebral cortex, cerebellar cortex, or
pons; these infarcts are to be contrasted with hypertension-induced
lipohyalinosis of the small penetrating cerebral end-arteries that is
the principal cause of the small lacunar infarcts occurring in the
basal ganglia, pons, thalamus, cerebellum, and deep hemispheric
white matter. Hypertension occurs in up to 85% of patients with
acute cerebral infarction, even in previously normotensive persons
[40]. This early elevation of blood pressure probably represents a
physiologic response to brain ischemia. Because of the known benefits
of antihypertensive therapy with regard to stroke prevention, it
previously had been assumed that acute reduction of blood pressure
would also be of benefit in acute cerebral infarction. However, no
evidence exists to suggest that acute reduction of blood pressure is
beneficial in this setting. In fact, reports exist of worsening neurologic
status, apparently precipitated by emergency treatment of hypertension
in patients with cerebral infarction [41]. In the setting of acute cerebral
infarction, hypertension tends to be very labile and exquisitely sensitive

to hypotensive therapy. Thus, even modest doses of oral antihypertensive agents can lead to profound and devastating overshoot
hypotension with extension of the infarct [42]. An additional rationale
for not treating hypertension in the acute setting is based on evidence
that local autoregulation of cerebral blood flow is impaired in the
so-called ischemic penumbra, which surrounds the area of acute
infarction [43]. Without intact autoregulation, the regional blood
flow in this marginal zone of ischemia becomes critically dependent
on the perfusion pressure. Thus, the presence of mild to moderate
systemic hypertension may actually be protective, and acute reduction
of blood pressure may cause a regional reduction in blood flow
with extension of the infarct. Thus, in most cases of cerebral infarction
it is prudent to allow the blood pressure to seek its own level during
the first few days to weeks after the event. In most cases the hypertension tends to resolve spontaneously, without any specific therapy,
over the first week as brain function recovers. When hypertension
persists for more than 3 weeks after a completed infarction, reduction
of the blood pressure into the normal range with oral antihypertensives is appropriate. Although benign neglect of mild to moderate
hypertension is prudent in acute cerebral infarction, there may be
certain indications for active treatment of blood pressure. When
the diastolic blood pressure is sustained at over 130 mm Hg, cautious
reduction of blood pressure into the ranges of 160 to 170 mm Hg
systolic and 100 to 110 mm Hg diastolic may be appropriate. In
stroke patients requiring anticoagulation therapy, moderate control
of severe hypertension also should be considered. Cautious blood
pressure reduction is indicated when stroke is accompanied by other
hypertensive crises such as acute myocardial ischemia or acute
hypertensive heart failure. Stroke caused by carotid occlusion by a
proximal aortic dissection mandates aggressive blood pressure
reduction into the normal range to halt the dissection process. In
the setting of sudden severe hypertension, it may be difficult to
distinguish hypertensive encephalopathy with focal neurologic findings
from cerebral infarction. Because rapid reduction of blood pressure
is lifesaving in patients with hypertensive encephalopathy, a cautious
diagnostic trial of blood pressure reduction may be warranted (Fig. 821). If blood pressure reduction is deemed necessary in patients with
acute cerebral infarction, treatment should be initiated using small
doses of a short-acting parenteral agent such as sodium nitroprusside.
Use of oral or sublingual nifedipine is associated with excessive risk of
prolonged overshoot hypotension. Oral clonidine loading also is contraindicated because of the risk of hypotension and because sedative
side effects interfere with the assessment of mental status.
Hypertensive Crises
Hypertensive crises from intracerebral hemorrhage
Reflex increase in blood pressure

(Cushing's reflex)
Hypertension may
help maintain
blood flow in
ischemic areas
Cerebral hyperperfusion
with cerebral edema
Impairment of autoregulation of
blood flow in ischemic area
surrounding hematoma
(shift of lower limit of
autoregulation)
Increased risk of rebleeeding

(expansion of hematoma)
Sodium nitroprusside
Cautious blood pressure
reduction by no more than 20%
of presenting mean arterial
pressure (intra-arterial and
intracranial pressure monitoring
to ensure adequate cerebral
perfusion pressure)
FIGURE 8-30
Hypertensive crises due to intracerebral hemorrhage. Chronic hypertension is the major
risk factor for intracerebral hemorrhage. The most common sites of hemorrhage are the
small-diameter penetrating cerebral end-arteries in the basal ganglia, pons, thalamus, cerebellum, and deep hemispheric white matter. Lacunar infarcts arise from the same vessels
and are similarly distributed. Intracerebral hemorrhage characteristically begins abruptly
with headache and vomiting followed by steadily increasing focal neurologic deficits and
alteration of consciousness [44]. More than 90% of hemorrhages rupture through brain
parenchyma into the ventricles, producing bloody cerebrospinal fluid. Patients presenting
with intracerebral hemorrhage are invariably hypertensive. In contrast to cerebral infarction,
the hypertension does not tend to decrease spontaneously during the first week. The patients
condition worsens steadily over a period of minutes to days until either the neurologic deficit
stabilizes or the patient dies. When death occurs, most often it is due to herniation caused
by the expanding hematoma and surrounding edema. Treatment of hypertension in the setting
of intracerebral hemorrhage is controversial. An increase in intracranial pressure accompanied
by a reflex increase in systemic blood pressure almost always occurs. Because cerebral perfusion
pressure is a function of the difference between arterial pressure and intracranial pressure,
reduction of blood pressure could compromise cerebral perfusion. Moreover, as in cerebral
infarction, autoregulation is impaired in the area of marginal ischemia surrounding the
hemorrhage. In contrast, cerebral vasogenic edema may be exacerbated by hypertension.
Moreover, hypertension may increase the risk of rebleeding with expansion of the hematoma.
Thus, in deciding to treat hypertension in the setting of intracerebral hemorrhage, a precarious balance must be struck between beneficial reduction in cerebral edema on the one
hand, and deleterious reduction of cerebral blood flow on the other. Studies have shown
that the lower limit of autoregulation after intracerebral hemorrhage is approximately
80% of the initial blood pressure; therefore, a 20% decrease in mean arterial pressure
should be considered the maximal goal of blood pressure reduction during the acute stage
[45]. Antihypertensive therapy should be undertaken only in conjunction with intracranial
and intra-arterial pressure monitoring to allow for assessment of cerebral perfusion pressure.
The short duration of action of nitroprusside makes its use preferable over other agents
with a longer duration of action and the risk of sustained overshoot hypotension, despite
the theoretic concern that nitroprusside treatment could lead to an increase in intracranial
pressure by way of dilation of cerebral veins and arteries.
8.23
8.24
Hypertensive crisis with pheochromocytoma

Pheochromocytoma
Acute treatment with
nitroprusside or phentolamine
followed by -blockers
Episodic release of
catecholamines
Paroxysmal hypertension
Pressure-induced
natriuresis and diuresis
Intravascular volume
depletion
Intracerebral
hemorrhage
Acute hypertensive heart

failure with pulmonary edema
(Figs. 8-23 and 8-24)
(Fig. 8-21)
Increased risk of intraoperative

and postoperative hypotension
FIGURE 8-31
Hypertensive crisis with pheochromocytoma. In most patients, pheochromocytoma causes
sustained hypertension that sometimes becomes malignant as evidenced by the presence of
hypertensive neuroretinopathy. Paroxysmal hypertension is present in approximately 30%
of patients. Spontaneous paroxysms consist of severe hypertension, headache, profuse
diaphoresis, pallor, coldness of hands and feet, palpitations, and abdominal discomfort.
Paroxysmal hypertension in pheochromocytoma represents a hypertensive crisis because it
can lead to intracerebral hemorrhage, hypertensive encephalopathy, or acute hypertensive
heart failure with pulmonary edema. Prompt control of the blood pressure is mandatory to
prevent these life-threatening complications. Although the nonselective -blocker phentolamine
often is cited as the treatment of choice for pheochromocytoma-related hypertensive crises,
sodium nitroprusside is equally effective and easier to administer [46]. Only after blood
pressure has been controlled with nitroprusside or phentolamine can intravenous -blockers,
such as esmolol, labetalol, or propranolol, be used to control tachycardia or arrhythmias.
After resolution of the hypertensive crisis, oral antihypertensive agents should be instituted
as the parenteral agents are weaned. The nonselective -blocker phentolamine usually is
administered orally for 1 to 2 weeks before elective surgery. After adequate -blockade is
achieved, based on the presence of moderate orthostatic hypotension, oral -blocker therapy
can be initiated as needed to control tachycardia. Oral or intravenous -blockers should
never be administered before adequate -blockade. Doing so can precipitate a hypertensive
crisis as the result of intense -adrenergic vasoconstriction that is no longer opposed by
-adrenergic vasodilatory stimuli. Careful attention to volume status also is mandatory in
the preoperative period. Catecholamine-induced hypertension induces a pressure natriuresis with volume depletion. Moreover, alleviation of the chronic state of vasoconstriction by
-blockade results in increases in both arterial and venous capacitances. Preoperative volume
expansion, guided by measurement of central venous pressure or wedge pressure often is
advocated to reduce the risk of intraoperative hypotension [47]. During surgery, rapid and
wide fluctuations in blood pressure should be anticipated. Careful intraoperative monitoring
of intra-arterial pressure, cardiac output, wedge pressure, and systemic vascular resistance
is mandatory to manage the rapid swings in blood pressure. Despite adequate preoperative
-blockade with phenoxybenzamine, severe hypertension can occur during intubation or
intraoperatively as a result of catecholamine release during tumor manipulation. Sodium
nitroprusside is the treatment of choice for controlling acute hypertension owing to
pheochromocytoma during surgery. At the opposite end of the spectrum, profound intraoperative hypotension can occur. Hypotension or even frank shock can supervene after
isolation of tumor venous drainage from the circulation, with resultant abrupt decrease in
circulating catecholamine levels. Volume expansion is the treatment of choice for intraoperative and postoperative hypotension [46]. Pressors only should be employed when
hypotension is unresponsive to volume repletion.
Hypertensive Crises
Hypertension crises secondary to monoamine

oxidase inhibitortyramine interactions
Monoamine oxidase inhibitor therapy
Impaired degradation of intracellular amines

(epinephrine, norepinephrine, dopamine)
Accumulation of catecholamines in
nerve terminal storage granules
Increased circulating
tyramine level
Massive release of catecholamines
Ingestion of
tyramine-containing food
Hepatic monamine
oxidase inhibition
with decreased
oxidative metabolism
of tyramine
Tachyarrhythmias
Vasoconstriction
(increased systemic vascular resistance)
Severe paroxysm of hypertension
(Fig. 8-21)
Acute hypertensive heart failure

with pulmonary edema
(Figs. 8-24 and 8-25)
FIGURE 8-32
Hypertensive crises secondary to monoamine oxidase inhibitortyramine interactions.
Severe paroxysmal hypertension complicated by intracerebral or subarachnoid hemorrhage,
hypertensive encephalopathy, or acute hypertensive heart failure can occur in patients treated
with monoamine oxidase (MOA) inhibitors after ingestion of certain drugs or tyraminecontaining foods [48,49]. Because MAO is required for degradation of intracellular amines,
including epinephrine, norepinephrine, and dopamine, MAO inhibitors lead to accumulation
of catecholamines within storage granules in nerve terminals. The amino acid tyramine is a
potent inducer of neurotransmitter release from nerve terminals. As a result of inhibition
of hepatic MAO, ingested tyramine escapes oxidative degradation in the liver. In addition,
the high circulating levels of tyramine provoke massive catecholamine release from nerve
terminals, resulting in vasoconstriction and a paroxysm of severe hypertension. A hyperadrenergic syndrome resembling pheochromocytoma then ensues. Symptoms include severe
pounding headache, flushing or pallor, profuse diaphoresis, nausea, vomiting, and extreme
prostration. The mean increase in blood pressure is 55 mm Hg systolic and 30 mm Hg
diastolic [49]. The duration of the attacks varies from 10 minutes to 6 hours. Attacks can
be provoked by the ingestion of foods known to be rich in tyramine: natural or aged
cheeses, Chianti wines, certain imported beers, pickled herring, chicken liver, yeast, soy
sauce, fermented sausage, coffee, avocado, banana, chocolate, and canned figs.
Sympathomimetic amines in nonprescription cold remedies also can provoke neurotransmitter
release in patients treated with an MAO inhibitor. Either sodium nitroprusside or phentolamine
can be used to manage this type of hypertensive crisis. Because most patients are normotensive
before onset of the crisis the goal of blood pressure treatment should be normalization of
the blood pressure. After blood pressure control, intravenous -blockers may also be
required to control heart rate and tachyarrhythmias. Because the MAO inhibitortyramine
hypertensive crisis is self-limited, parenteral antihypertensive agents can be weaned without
institution of oral antihypertensive agents.
8.25
8.26
Mechanism of action and metabolism of nitroprusside

+
NO
CN-
CNFe++
CN-
CNCNNitroprusside
t1/2=34 min
Metabolized by
direct combination
with -SH groups
in erythrocytes
and tissues
Free cyanide
(CN-)
Thiocyanate
t1/2=1 wk
Combination of nitroso
group with cysteine
Renal excretion
Nitrosocysteine
Activation of
guanylate cyclase
cGMP accumulation in
vascular smooth muscle
Venodilation
(increased venous capacitance)
t1/2=23min
Metabolized by
cGMP-specific
phosphodiesterases
Dilation of arteriolar resistance vessels

(decreased systemic vascular resistance)
Decreased blood pressure
Afterload reduction
FIGURE 8-33
Mechanism of action and metabolism of nitroprusside. Sodium
nitroprusside is the drug of choice for management of virtually all
hypertensive crises, including malignant hypertension, hypertensive
encephalopathy, acute hypertensive heart failure, intracerebral
hemorrhage, perioperative hypertension, catecholamine-related
hypertensive crises, and acute aortic dissection (in combination
with a -blocker) [1,50]. Sodium nitroprusside is a potent intravenous
hypotensive agent with immediate onset and brief duration of action.
The site of action is the vascular smooth muscle. Nitroprusside has
no direct action on the myocardium, although it may affect cardiac
performance indirectly through alterations in systemic hemodynamics.
Nitroprusside is an iron (Fe) coordination complex with five cyanide
moieties and a nitroso (NO) group. The nitroso group combines with
cysteine to form nitrosocysteine and other short-acting S-nitrosothiols.
Nitrosocysteine is a potent activator of guanylate cyclase, thereby
causing cyclic guanosine monophosphate (cGMP) accumulation
and relaxation of vascular smooth muscle [51,52]. Nitroprusside
causes vasodilation of both arteriolar resistance vessels and venous
capacitance vessels. Its hypotensive action is a result of a decrease
in systemic vascular resistance. The combined decrease in preload
and afterload reduces myocardial wall tension and myocardial oxygen
demand. The net effect of nitroprusside on cardiac output and
heart rate depends on the intrinsic state of the myocardium. In
patients with left ventricular (LV) systolic dysfunction and elevated
LV end-diastolic pressure, nitroprusside causes an increase in stroke
volume and cardiac output as a result of afterload reduction and
heart rate may actually decrease in response to improved cardiac
performance. In contrast, in the absence of LV dysfunction, venodilation and preload reduction can result in a reflex increase in sympathetic tone and heart rate. For this reason, nitroprusside must be
used in conjunction with a -blocker in acute aortic dissection. The
hypotensive action of nitroprusside appears within seconds and is
immediately reversible when the infusion is stopped. The cGMP in
vascular smooth muscle is rapidly degraded by cGMP-specific phosphodiesterases. Nitroprusside is rapidly metabolized with a half-life
(t1/2) of 3 to 4 minutes. Cyanide is formed as a short-lived intermediate
product by direct combination with sulfhydryl (SH) groups in erythrocytes and tissues. The cyanide groups are rapidly converted to
thiocyanate by the liver in a reaction in which thiosulfate acts as a
sulfur donor. Thiocyanate is excreted by the kidneys, with a half-life
of 1 week in patients with normal renal function. Thiocyanate
accumulation and toxicity can occur when a high-dose or prolonged
infusion is required, especially in patients with renal insufficiency.
When these risk factors are present, thiocyanate levels should be
monitored and the infusion stopped if the level is over 10 mg/dL.
Thiocyanate toxicity is rare in patients with normal renal function
requiring less than 3 g/kg/min for less than 72 hours [50]. Cyanide
poisoning is a very rare complication, unless hepatic clearance of
cyanide is impaired by severe liver disease or massive doses of
nitroprusside (over 10 g/kg/min) are used to induce deliberate
hypotension during surgery [50].
FIGURE 8-34
Sodium nitroprusside remains the treatment of choice in virtually
all hypertensive crises requiring rapid blood pressure control with
Minutes
Direct venodilation at
low doses; combined
venodilation and
arteriolar dilation at
higher doses
Selective 1- and
noncardioselective
-blocker; arteriolar
and venous dilation
Nonselective -blocker
Direct arteriolar
vasodilation
24 h
Decrease sympathetic
nervous system activity via CNS 2 stimulation, decrease systemic
vascular resistance
24 h
Sympathetic dysfunction owing to central
and peripheral catecholamine dysfunction; decreased SVR,
decreased CO
Nitroglycerin
Phentolamine
Hydralazine
Methyldopa
parenteral therapy. However, other parenteral antihypertensive

agents may be useful in certain circumstances.
24 h
46 h
3060 min
5 min
550 min
Minutes
Advantages
Disadvantages
Side effects
28 h
46 h
39 h
1530 min
1618 h
Useful in
catecholaminerelated crises
Short duration of
action
Intramuscular:
Initial, 0.51.0 mg
24 mg over 3 h
24 mg over 312 h
Contraindicated in
pheochromocytoma,
heart failure, asthma,
heart block >1
degree, after coronary artery bypass
graft surgery
Nitroprusside equally
efficacious in
catecholaminerelated crises
Delayed onset
Nasal congestion,
Nonenot
CNS sedation,
recommended for of action,
unpredictable
bradycardia,
use in hypertenhypotensive effect exacerbates pepsive crises
tic ulcer disease,
depression
Contraindicated in
hypertensive
encephalopathy,
CNS catastrophe,
cumulative hypotensive response
Contraindicated in
hypertensive
encephalopathy,
CNS catastrophe
aortic dissection,
atherosclerotic
coronary vascular
disease
Tachycardia,
arrhythmias,
nausea, vomiting,
diarrhea, exacerbation of peptic
ulcer disease
Headache, angina
Contraindicated in
Delayed onset
IV bolus: 510 mg over
Proven efficacy
of action,
2030 min or continuand safety in
ous infusion 400 g/mL hypertensive crises unpredictable
hypotensive effect
solution Loading dose:
of pregnancy
200300 g/min for
3060 min Maintenance
infusion: 50150 g/min
Delayed onset
Sedation
IV of 250500 mg
Nonenot
over 68 h
recommended for of action,
unpredictable
use in hypertenhypotensive effect
sive crises
IV bolus: 15 mg
over 5 min
Fails to control BP Headache, nausea,

Theoretic advanin some patients
vomiting,
tages over nitropalpitations,
prusside in setting
abdominal pain
of myocardial
ischemia
-blockage can
Nausea, vomiting,
IV minibolus: Initial, 20
Continuous
worsen congestive paresthesias,
mg over 2 min Then
monitoring not
heart failure,
headache,
4080 mg over 10 min.
required
bronchospasm,
bradycardia
Maximum, 300 mg
heart block
15 min after infusion Continuous infusion:

stopped
Initially, 5 g/min
Increase by 5 g/min
over 35 min
insufficiency and
glaucoma;
potentiates
succinylcholine
Dilates intracoronary
collaterals
Comments
Discontinue if
23 min after infusion Continuous infusion:
Precise titration of Monitoring in ICU Nausea, vomiting,
required
apprehension.
stopped
Initial, 0.5 g/kg/min
BP. Consistently
thiocyanate level
Thiocyanate toxic- >10 mg/dL
Average, 3 g/kg/min
effective when
ity with prolonged
Maximum, 10 g/kg/min other drugs fail.
infusion, renal
Parenteral agent
insufficiency
of choice for
hypertensive crises
Sustained
Nausea, vomiting, Contraindicated in
424 h
IV minibolus: 50100 mg Long duration of
hypotension with
hyperglycemia,
IV given rapidly over
action. Constant
aortic dissection,
CNS and myocarmyocardial
510 min. Total dose,
monitoring not
cerebrovascular
ischemia, uterine
150600 mg
required after ini- dial ischemic can
disease, myocardial
occur. Reflex sym- atony
tial titration
ischemia
pathetic cardiac
stimulation
Dry mouth, blurred Tilt-bed enhances
510 min after infuContinuous infusion:
Blocks barorecep- Parasympathetic
blockade
vision, urinary
sion stopped
Initial, 0.5 mg/min
tor-mediated
effect; tachyphylaxis
retention, paralyt- after 2448 h;
Maximum, 5.0 mg/min
sympathetic
ic ileus, respiratocardiac stimulation
contraindicated
ry arrest
in respiratory
Method of
Duration of action administration
BPblood pressure; CNScentral nervous system; COcardiac output; ICUintensive care unit; IVintravenous; SVRsystemic vascular resistance.
Reserpine
1030 min
23 min
Minutes
Minutes
Ganglionic blockage
with venodilation and
arteriolar vasodilation
Trimethaphan
camsylate
Labetalol
1015 min
12 min
Direct arteriolar
vasodilation
Diazoxide
Minutes
Immediate
Onset of action Peak effect

Instantaneous
Mechanism of
action
Sodium
Direct arteriolar
nitroprusside
vasodilation and
venodilation
Drug
VARIOUS ANTIHYPERTENSIVE DRUGS FOR PARENTERAL USE IN THE MANAGEMENT OF MALIGNANT HYPERTENSION AND OTHER HYPERTENSIVE CRISES
Hypertensive Crises
8.27
8.28
200
Uncontrolled hypertensives (n=13)

Controlled hypertensives (n=9)
Normotensives (n=10)
150
100
79
72
74
10%
29%
12%
50
0
Baseline mean
arterial pressure
Lower limit of
autoregulation
45
6%
46 45
16% 12%
Lowest tolerated mean

arterial pressure
FIGURE 8-35
Risks of rapid blood pressure reduction in hypertensive crises. It
has been argued over the years that rapid reduction of blood pressure
in the setting of hypertensive crises may have a detrimental effect
on cerebral perfusion because the autoregulatory curve of cerebral
blood flow is shifted upward in patients with chronic hypertension.
Conversely, this upward shift protects the brain from hypertensive
encephalopathy in the face of severe hypertension. However, this
autoregulatory shift could be deleterious when the blood pressure
is reduced acutely because the lower limit of autoregulation is shifted
to a higher level of blood pressure. Theoretically, aggressive reduction
of the blood pressure in chronically hypertensive patients could
induce cerebral ischemia. Nonetheless, in clinical practice, moderately
controlled reduction of blood pressure in patients with hypertensive
crises rarely causes cerebral ischemia. This clinical observation may
be explained by the fact that even though the cerebral autoregulatory
curve is shifted in patients with chronic hypertension, a considerable
difference still exists between the initial blood pressure at presentation
and the lower limit of autoregulation. Illustrated are the differences
in the lower autoregulatory threshold during blood pressure reduction
with trimethaphan in patients with uncontrolled hypertension and
treated hypertension, and those in the control group [53]. At least
eight of the 13 patients with uncontrolled hypertension had hypertensive neuroretinopathy consistent with malignant hypertension.
The control groups included nine patients with a history of severe
hypertension in the past whose blood pressure was effectively
controlled at the time of study and a group of 10 normotensive
persons. Baseline mean arterial pressures (MAPs) in the three
groups were 145 17 mm Hg, 116 18 mm Hg, and 96 17 mm
Hg, respectively. The lower limit of blood pressure at which autoregulation failed was 113 17 mm Hg in persons with uncontrolled
hypertension, 96 17mm Hg in persons with treated hypertension,
and 73 9 mm Hg in normotensive persons. Although the absolute
level at which autoregulation failed was substantially higher in
patients with uncontrolled hypertension, the percentage reduction
in blood pressure from the baseline level required to reach the
autoregulatory threshold was similar in each group. The numbers
on the bars indicate the percentage reduction from the baseline
blood pressure required to reach the autoregulatory limit. Thus, a

reduction in MAP of approximately 20% to 25% was required in
each group to reach the threshold. This result indicates that a
considerable safety margin exists for blood pressure reduction
before cerebral autoregulation of blood flow fails, even in patients
with severe untreated hypertension. Moreover, symptoms of cerebral
ischemia did not develop until the blood pressure was reduced
substantially below the autoregulatory threshold because even in
the face of reduced blood flow, cerebral metabolism can be maintained and ischemia prevented by an increase in oxygen extraction
by the tissues. The lowest tolerated MAP, defined as the level at
which mild symptoms of brain hypoperfusion developed (ie, yawning,
nausea, and hyperventilation), was 65 10 mm Hg in patients with
uncontrolled hypertension, 53 18 mm Hg in persons with treated
hypertension, and 43 8 mm Hg in normotensive persons. The
numbers on the bars illustrate that these MAP values were approximately 45% of the baseline blood pressure level in each group.
Thus, symptoms of cerebral hypoperfusion did not occur until the
MAP was reduced by an average of 55% from the presenting level.
In the reported cases of neurologic sequelae sustained during rapid
reduction of blood pressure in patients with hypertensive crises, the
MAP was reduced by more than 55% of the presenting blood pressure. This frank hypotension was sustained for a period of hours to
days, mostly as a result of treatment with bolus diazoxide, which
has long duration of action [54]. The general guideline for acute
blood pressure reduction in the treatment of hypertensive crises is
reduction of systolic blood pressure to 160 to 170 mm Hg and
diastolic pressure to 100 to 110 mm Hg, which equates to MAPs
of 120 to 130 mm Hg. Alternatively, the initial goal of antihypertensive therapy can be a 20% reduction of the MAP from the
patients initial level at presentation. This level should be above the
predicted autoregulatory threshold. Once this goal is obtained the
patient should be evaluated carefully for evidence of cerebral
hypoperfusion. Further reduction of blood pressure can then be
undertaken in a controlled fashion based on the overall clinical
status of the patient. Of course, in previously normotensive persons
in whom hypertensive crises develop, such as patients with acute
glomerulonephritis complicated by hypertensive encephalopathy,
the autoregulatory curve should not yet be shifted. Therefore, the
initial goal of therapy should be normalization of blood pressure.
In terms of avoiding sustained overshoot hypotension in the treatment of hypertensive crises, the use of potent parenteral agents
with short duration of action, such as sodium nitroprusside or
intravenous nitroglycerin, has obvious advantages. If neurologic
sequelae develop during blood pressure reduction with these agents,
these sequelae can be reversed quickly by tapering the infusion and
allowing the blood pressure to stabilize at a higher level. Agents
with a long duration of action have an inherent disadvantage in
that excessive reduction of blood pressure cannot be reversed
easily. Thus, bolus diazoxide, labetalol, minoxidil, hydralazine,
converting enzyme inhibitors, calcium channel blockers, and
central 2-agonists should be used with extreme caution in patients
requiring rapid but controlled blood pressure reduction in the
setting of hypertensive crises. (Adapted from Strandgaard [53];
with permission.)
Hypertensive Crises
Severe uncomplicated hypertension

Severe hypertension
(diastolic blood pressure > 115 mm Hg)
Hypertensive neuroretinopathy present

(striate hemorrhages, cotton-wool spots
with or without papilledema)
Treat malignant hypertension
(Fig. 8-20)
Hypertensive neuroretinopathy absent
No acute end-organ
dysfunction
Acute end-organ
dysfunction
Treat as hypertensive crisis
(see preceding figures)
Severe uncomplicated
hypertension
Step 1
Patient education regarding the
chronic nature of hypertension
and importance of long-term
compliance and blood pressure
control to prevent complications
Step 2
Step 3
Evaluate reason for inadequate

blood pressure control and
adjust maintenance
antihypertensive drug regimen
Noncompliant
Arrange outpatient follow-up to

document adequate blood
pressure control over the ensuing
days to weeks and change drug
treatment regimen as required
Compliant with current

blood pressure regimen
"Ran out" of
medications
Drug
side effects
Cannot afford
drugs
Restart
Switch to drug
of another class
Switch to generic
thiazide diuretic
Add low-dose thiazide

diuretic to existing
monotherapy with CCB,
CEI, -blocker, 2-agonist
FIGURE 8-36
Severe uncomplicated hypertension. The benefits of acute reduction in blood pressure in the
setting of true hypertensive crises are obvious. Fortunately, true hypertensive crises are relatively
rare events that almost never affect hypertensive patients. Another type of presentation that is
much more common than are true hypertensive crises is that of the patient who initially
exhibits severe hypertension (diastolic blood pressure >115 mm Hg) in the absence of hypertensive neuroretinopathy or acute end-organ damage that would signify a true crisis. This entity,
known as severe uncomplicated hypertension, is very commonly seen in the emergency department or other acute-care settings. Of patients with severe uncomplicated hypertension, 60% are
entirely asymptomatic and present for prescription refills or routine blood pressure checks, or
are found to have elevated pressure during routine physical examinations. The other 40% of
patients initially exhibit nonspecific findings such as headache, dizziness, or weakness in the
absence of evidence of acute end-organ dysfunction. In the past, this entity was referred to as
urgent hypertension, reflecting the erroneous notion that acute reduction of blood pressure,
over a few hours before discharge from the acute-care facility, was essential to minimize the
risk of short-term complications from severe hypertension. Commonly employed treatment
regimens included oral clonidine loading or sublingual nifedipine. However, in recent years the
practice of acute blood pressure reduction in severe uncomplicated hypertension has been questioned [55,56]. In the Veterans Administration Cooperative Study of patients with severe hypertension, there were 70 placebo-treated patients who had an average diastolic blood pressure
of 121 mm Hg at entry. Among these untreated patients, 27 experienced morbid events at a
mean of 11 8 months of follow-up. However, the earliest morbid event occurred only after
2 months [57]. These data suggest that in patients with severe uncomplicated hypertension in
which severe hypertension is not accompanied by evidence of malignant hypertension or acute
end-organ dysfunction, eventual complications from stroke, myocardial infarction, or congestive
8.29
heart failure tend to occur over months to

years, rather than hours to days. Although
long-term control of blood pressure clearly can
prevent these eventual complications, a hypertensive crisis cannot be diagnosed because no
evidence exists that acute reduction of blood
pressure results in an improvement in short- or
long-term prognosis. Acute reduction of blood
pressure in patients with severe uncomplicated
hypertension with sublingual nifedipine or oral
clonidine loading was once the de facto standard of care. This practice, however, often was
an emotional response on the part of the treating physician to the dramatic elevation of
blood pressure or motivated by the fear of
medico-legal repercussions in the unlikely
event of a hypertensive complication occurring
within hours to days [55]. Although observing
and documenting the dramatic decrease in
blood pressure is a satisfying therapeutic
maneuver, there is no scientific basis for this
approach. At present, no literature exists to
support the notion that some goal level of
blood pressure reduction must be achieved
before the patient with severe uncomplicated
hypertension leaves the acute-care setting [58].
In fact, acute reduction of blood pressure often
is counterproductive because it can produce
untoward side effects that render the patient
less likely to comply with long-term drug
therapy. Instead, the therapeutic intervention
should focus on tailoring an effective welltolerated maintenance antihypertensive regimen with patient education regarding the
chronic nature of the disease process and the
importance of long-term compliance and medical follow-up. If the patient has simply run
out of medicines, reinstitution of the previously effective drug regimen should suffice. If the
patient is thought to be compliant with an
existing drug regimen, a sensible change in the
regimen is appropriate, such as an increase in
a suboptimal dosage of an existing drug or
the addition of a drug of another class. In
this regard, addition of a low dose of a thiazide diuretic as a second-step agent to existing monotherapy with converting enzyme
inhibitor (CEI), angiotensin II receptor blocker,
calcium channel blocker (CCB), -blocker, or
central 2-agonist often is remarkably effective. Another essential goal of the acute intervention should be to arrange suitable outpatient follow-up within a few days. Gradual
reduction of blood pressure to normotensive
levels over the next few days to a week should
be accomplished in conjunction with frequent
outpatient visits to modify the drug regimen
and reinforce the importance of lifelong compliance with therapy. Although less dramatic
than acute reduction of blood pressure in the
acute-care setting, this type of approach to the
treatment of chronic hypertension is more likely to prevent long-term hypertensive complications and recurrent episodes of severe uncomplicated hypertension.
8.30
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Diabetic Nephropathy:
Impact of Comorbidity
Eli A. Friedman
hroughout the industrialized world, diabetes mellitus is the

leading cause of end-stage renal disease (ESRD), surpassing
glomerulonephritis and hypertension. Both the incidence and
the prevalence of ESRD caused by diabetes have risen each year over
the past decade, according to reports from European, Japanese, and
North American registries of patients with renal failure. Illustrating
the dominance of diabetes in ESRD is the 1997 report of the United
States Renal Data System (USRDS), which noted that of 257,266
patients receiving either dialytic therapy or a kidney transplant in
1995 in the United States, 80,667 had diabetes [1], a prevalence rate
of 31.4%. Also, during 1995 (the most recent year for which summative data are available), of 71,875 new (incident) cases of ESRD,
28,740 (40%) patients were listed as having diabetes.
In America, Europe, and Japan, the form of diabetes is predominantly type II; fewer than 8% of diabetic Americans are insulinopenic,
C-peptide-negative persons with type I disease. It follows that ESRD
in diabetic persons reflects the demographics of diabetes per se [2]: 1)
The incidence is higher in women [3], blacks [4], Hispanics [5], and
native Americans [6]. 2) The peak incidence of ESRD occurs from the
fifth to the seventh decade. Consistent with these attack rates is the
fact that blacks older than the age of 65 face a seven times greater risk
of diabetes-related renal failure than do whites. Within our Brooklyn
and New York state hospital ambulatory hemodialysis units in
October 1997, 97% of patients had type II diabetes. Despite widespread thinking to the contrary, vasculopathic complications of diabetes, including hypertension, are at least as severe in type II as in type
I diabetes [7,8]. When carefully followed over a decade or longer,
cohorts of type I and type II diabetic individuals have equivalent rates
of proteinuria, azotemia, and ultimately ESRD. Both types of diabetes
show strong similarities in their rate of renal functional deterioration
[9] and onset of comorbid complications. Initial nephromegaly as well
as both glomerular hyperfiltration and microalbuminuria (previously
thought to be limited to type I) is now recognized as equally in type II [10].
CHAPTER
1.2
Systemic Diseases and the Kidney
Overview and Prevalence

DIABETIC NEPHROPATHY
Epidemiology
IDDM vs. NIDDM
Natural history
Intervention measures
ESRD options
Promising strategies
FIGURE 1-1
Diabetic neuropathy topics. People with diabetes and progressive kidney disease are more
difficult to manage than age- and gender-matched nondiabetic persons because of extensive,
often life-threatening extrarenal (comorbid) disease. Diabetic patients manifesting end-stage
renal disease (ESRD) suffer a higher death rate than do nondiabetic patients with ESRD
owing to greater incidence rates for cardiac decompensation, stroke, sepsis, and pulmonary
disease. Concurrent extrarenal diseaseespecially blindness, limb amputations, and cardiac
diseaselimits and may preempt their rehabilitation. For most diabetic patients with ESRD,
the difference between rehabilitation and heartbreaking invalidism hinges on attaining a
renal transplant as well as comprehensive attention to comorbid conditions.
Gradually, over a quarter century, understanding of the impact of diabetes on the kidney
has followed elucidation of the epidemiology, clinical course, and options in therapy available for diabetic individuals who progress to ESRD. For each of the discussion points listed,
improvement in patient outcome has been contingent on a simple counting (point prevalence) of the number of individuals under consideration. For example, previously the large
number of diabetic patients with ESRD were excluded from therapy owing to the belief that
no benefit would result. A reexamination of exactly why dialytic therapy or kidney transplantation failed in diabetes, however, was stimulated. IDDMinsulin dependent diabetes
mellitus; NIDDMnoninsulin-dependent diabetes mellitus.
FIGURE 1-2
Maintenance hemodialysis. In the United States, the large majority (more than 80%) of
diabetic persons who develop end-stage renal disease (ESRD) will be treated with maintenance hemodialysis. Approximately 12% of diabetic persons with ESRD will be treated
with peritoneal dialysis, while the remaining 8% will receive a kidney transplant. A typical
hemodialysis regimen requires three weekly treatments lasting 4 to 5 hours each, during
which extracorporeal blood flow must be maintained at 300 to 500 mL/min. Motivated
patients trained to perform self-hemodialysis at home gain the longest survival and best
rehabilitation afforded by any dialytic therapy for diabetic ESRD. When given hemodialysis at a facility, however, diabetic patients fare less well, receiving significantly less dialysis
than nondiabetic patients, owing in part to hypotension and reduced blood flow [11].
Maintenance hemodialysis does not restore vigor to diabetic patients, as documented by
Lowder and colleagues [12]. In 1986, they reported that of 232 diabetics on maintenance
hemodialysis, only seven were employed, while 64.9% were unable to conduct routine
daily activities without assistance [12]. Approximately 50% of diabetic patients begun on
maintenance hemodialysis die within 2 years of their first dialysis session. Diabetic
hemodialysis patients sustained more total, cardiac, septic, and cerebrovascular deaths
than did nondiabetic patients.
When initially applied to diabetic patients with ESRD in the 1970s, maintenance
hemodialysis was associated with a first-year mortality in excess of 75%, with inexorable
loss of vision in survivors. Until the at-first-unappreciated major contribution of type II
diabetes to ESRD became evident, kidney failure was incorrectly viewed as predominantly
limited to the last stages of type I (juvenile, insulin-dependent) diabetes. Illustrated here is
a blind 30-year-old man undergoing maintenance hemodialysis after experiencing 20 years
of type I diabetes. A diabetic renal-retinal syndrome of blindness and renal failure was
thought to be inevitable until the salutary effect of reducing hypertensive blood pressure
became evident. Without question, reduction of hypertensive blood pressure levels was the
key step that permitted improvement in survival and reduction in morbidity.
Diabetic Nephropathy: Impact of Cormorbidity
FIGURE 1-3
Statistical increase in diabetes. In the past 20 years, since the diabetic patient with endstage renal disease (ESRD) is no longer excluded from dialytic therapy or kidney transplantation, there has been a steady increase in the proportion of all patients with ESRD
who have diabetes. In the United States, according to the 1997 report of the United States
Renal Data System (USRDS) for the year 1995, more than 40% of all newly treated
(incident) patients with ESRD have diabetes. For perspective, the USRDS does not list
the actual incidence of a renal disease but rather tabulates those individuals who have
been enrolled in federally reimbursed renal programs. The distinction may be important
in that a relaxation in policy for referral of diabetic kidney patients would be indistinguishable from a true increase in incidence.
Diabetes
40%
28,740
43,135
All other
60%
Prevalence of diabetes, %
25
Country of origin
United States
20
18
15
PERCENTAGE OF PATIENTS WITH END-STAGE

RENAL DISEASE WITH TYPE II DIABETES
23
19
18
16
15
15
14
10
Country
Japan
Germany
United States Pima Indians
10
1.3
Percentage
99
90
95
0
Black Mexican Puerto
Rican
Japanese Filipinos Chinese
Koreans
FIGURE 1-4
Prevalence of diabetes mellitus in minority populations. Attack
rates (incidence) for diabetes are higher in nonwhite populations
than in whites. Type II diabetes accounts for more than 90% of all
patients with end-stage renal disease (ESRD) with diabetes. As
studied by Carter and colleagues [13], the effect of improved nutrition on expression of diabetes is remarkable. The American diet
not only induces an increase in body mass but also may more than
double the expressed rate of diabetes, especially in Asians. (From
Carter and coworkers [13]; with permission.)
Infrequent feeding
Insulin resistance
Overfeeding
Obesity
Fat in muscle
NIDDM
FIGURE 1-6
Thrifty gene. In addition to the artificial increase in incident
patients with end-stage renal disease (ESRD) and diabetes that followed relaxation of acceptance criteria, industrialized nations have
experienced a real increase in type II diabetes that correlates with
an increase in body mass attributed to overfeeding. Formerly
FIGURE 1-5
Percent of diabetic ESRD. Noted first in United States inner-city
dialysis programs, type II diabetes is the predominant variety noted
in those individuals undergoing maintenance hemodialysis. Our
recent survey of hemodialysis units in Brooklyn, New York, found
that 97% of the mainly African-American patients had type II diabetes. Thus, there has been a reversal of the previously held
impression that uremia was primarily a late manifestation of type I
diabetes. (From Ritz and Stefanski [14] and Nelson and coworkers
termed noninsulin-dependent diabetes mellitus (NIDDM) or

maturity-onset diabetes, the variety of diabetes observed in industrialized overfed populations is now classified as type II disease.
According to the Thrifty Gene hypothesis, the ability to survive
extended fasts in prehistoric populations that hunted to survive
selected genes that in time of excess caloric intake are expressed as
hyperglycemia, insulin resistance, and hyperlipidemia (type II diabetes). A study by Ravussin and colleagues of American and
Mexican Pima Indian tribes illustrates the effect of overfeeding on
a genetic predisposition to type II diabetes. Separated about 200
years ago, Indians with the same genetic makeup began living in
different areas with different lifestyles and diets. In the Arizona
branch of the Pimas, who were fed surplus food and restrained to a
reservation that restricted hunting and other activities, the prevalence of type II diabetes progressively increased to 37% in women
and 54% in men. In contrast, Pimas living in Mexico with shorter
stature, lower body mass, and lower cholesterol had a lower prevalence of type II diabetes (11% in women and 6% in men). (From
Shafrir [16] and Schalin-Jantti [17]; with permission.)
1.4
Type I and Type II Classified

Type II
Insulin requiring
Type II
decreased insulin
secretion/sensitvity
C-PEPTIDE CRITERIA
Type I
Type I
-cell destruction
FIGURE 1-7
Type I and type II compared. Differentiating
type I from type II diabetes may be difficult,
especially in young nonobese adults with
minimal insulin secretion. Furthermore,
with increasing duration of type II diabetes,
beta cells may decrease their insulin secretion, sometimes to the range diagnostic of
type I diabetes. Shown here is a modification of the schema devised by Kuzuya and
Matsuda [18] that suggests a continuum of
diabetes classification based on amount of
insulin secreted. Lacking in this construction
is the realization of the genetic determination of type I diabetes (all?) and the clear
hereditary predisposition (despite inconstant
genetic analyses) of many individuals with
type II diabetes. At present, classification of
diabetes is pragmatic and will likely change
with larger-population screening studies.
IGTimpaired glucose tolerance. (From
Kuzuya and Matsuda [18]; with permission.)
70
Proportion on insulin, %
IGT
60
60
50
40
33
30
20
Type I (90% concordence between clinical criteria

and C-peptide testing)
Basal C-peptide <0.17 pmol/mL
Increment above basal at 6 min <0.07 pmol/mL
13
10
0
05
510
1015
Years of NIDDM
FIGURE 1-8
Increasing insulin treatment in noninsulindependent diabetes mellitus (NIDDM). A
decision to treat diabetes with insulin does
not necessarily equate with establishing a
diagnosis of type I diabetes. Terms such as
insulin-requiring do not help because the
need for insulin is physician-determined and
will vary from clinician to clinician. After
10 to 15 years of metabolic regulation of
type II diabetes, treatment with insulin has
been initiated in more than half of individuals with this disorder. Even in patients with
type II diabetes treated with insulin, measured secretion of insulin may fall in the
normal range. (From Clauson and coworkers [19]; with permission.)
TERMINOLOGY IN DIABETIC NEPHROPATHY

Hyperfiltration
A supernormal glomerular filtration rate associated with hyperglycemia during the
early years of diabetes
Microalbuminuria
Urinary albumin excretion of 30 to 300 mg/day or 20 to 200 g/mina predictor of
nephropathy
Mesangial expansion
An increase in mesangial matrix often but not always associated with basement
membrane thickening
FIGURE 1-9
C-peptide criteria. Multiple strategies have
been proposed to distinguish type I from
type II diabetes. Each has limitations. Service
and colleagues [20] employed baseline and
stimulated C-peptide levels to differentiate
between the two. They found satisfactory
differentiation of type I from type II diabetes
with minimal overlap using the screening
levels shown. (From Service and coworkers
FIGURE 1-10
Terminology. Clarification of the course of both types of diabetes
was made possible by recognizing two functional perturbations:
microalbuminuria and glomerular hyperfiltration. Additionally,
early glomerular mesangial expansion was noted to be a constant
finding in diabetic nephropathy.
1.5
Clinical Features of Diabetic Kidney

FIGURE 1-11
Diabetic kidney characteristics. The diabetic kidney is about 140%
greater in length, width, and weight. Morphologic findings on histologic examination of the kidney in diabetes include increased size
of glomeruli and tubules. Physiologic assessment of renal function
is supernormal in diabetes, as shown by increases of about 150%
in renal plasma flow and glomerular filtration rate in initial phases
of diabetic nephropathy. In the induced-diabetic rat and in limited
observations of type I diabetes, establishing euglycemia will return
enlarged kidneys and abnormal renal function test results to normal, suggesting that hyperglycemia is the cause of nephromegaly.
B
FIGURE 1-12
Mesangial expansion. Expansion of the mesangium is depicted in
light and electron microscopic views of a kidney biopsy specimen
from a patient with type I diabetes with a urinary albumin concentration of 500 mg/dL. A, Electron microscopic view of a greatly
expanded mesangium in a glomerulus is shown. B, Less advanced
changes are seen on a silver stain. C, Progression to nodular intercapillary glomerulosclerosis is shown.
1.6
FIGURE 1-13
Glomerular basement membrane thickening. B and D, Glomerular
basement membrane thickening is a constant abnormality in diabetic
nephropathy, as seen in these photomicrographs from a biopsy specimen in type I diabetes. Note the loss of epithelial foot processes in
panel B. In panel D, a mesangial nodule (MN) is present. A and C,

Electron photomicrographs from a normal kidney. BMbasement
membrane; Ccapillary; Eepithelial cell; MNmesangial nodule;
Mmesangial cell.
FIGURE 1-14
Diabetic nephropathy is a microvasculopathy. Microaneurysms are
visible in the retina and occasionally in glomerular capillaries. A
microaneurysm in a biopsy specimen from a 42-year-old woman
with type I diabetes is shown.
FIGURE 1-15
Key pathologic findings. Nondiabetic renal disorders (eg, amyloidosis, cryoglobulinemia, nephrosclerosis) may simulate the nodular and
diffuse intercapillary glomerulosclerosis of diabetes (both type I and
type II). When associated with afferent and efferent arteriolosclerosis, nodular and diffuse intercapillary glomerulosclerosis is pathognomonic for diabetic nephropathy. Aafferent artery arteriosclerosis;
Ddiffuse intercapillary glomerulosclerosis; Eefferent artery arteriosclerosis; Nnodular intercapillary glomerulosclerosis.
FIGURE 1-16
Diabetic nodules. Diabetic nodules are characterized by clear centers with cells along the periphery of the nodule, as shown here in
a kidney biopsy specimen from a 44-year-old man with type II diabetes (hematoxylin and eosin stain).
1.7
FIGURE 1-17
Nodular size variability. Great variability in nodular size in diabetic
nodular glomerulosclerosis is usual, as illustrated in this totally
obliterated glomerulus obtained by biopsy from a 65-year-old
woman with type II diabetes (periodic acidSchiff stain).
>4
4.0
Urinary albumin, g/d
3.5
3.0
2.5
2.0
1.5
Clinical
nephropathy
1.0
0.5
0
0
12
15
18
Hyperglycemia, y
21
24
27
FIGURE 1-18
A and B, Progression of nephropathy. Microalbuminuria, the excretion
of minute quantities of albumin in the urine (more than 20 mg/day), is
a marker of subsequent renal deterioration in diabetic nephropathy.
B
Typically, proteinuria increases to the nephrotic range, leading to
edema of the extremities and subsequent anasarca, which are often
the presenting complaints in diabetic nephropathy.
1.8
180
Type 2 diabetes
Type 1 diabetes
10
160
140
Cumulative incidence
chronic renal failure, %
GFR, mL/min
(13)
Clinical
nephropathy
120
100
80
60
40
(69)
(205)
(447)
20
(1,377)
(1,832)
0
0
12
15
18
21
24
(112)
(75)
(49)
10
15
5
6
Time, y
25
30
35
FIGURE 1-20
Renal failure cumulative incidence. Before careful studies of the natural history of type II diabetes were reported, it was not appreciated
that diabetic nephropathy was a real endpoint risk. Older diabetic
individuals with a touch of sugar are now known to be subject to
the same microvascular and macrovascular complications that
afflict individuals with type I disease. Population studies indicate
that the rate of loss of glomerular filtration is superimposable in
type I and type II diabetes. Humphrey and colleagues [21] documented the development of end-stage renal disease in diabetic subjects in
Rochester, Minnesota. They showed that chronic renal failure was as
likely to develop at a superimposable rate in both diabetic subsets.
Numbers in parentheses indicate number of patients for each line.
(From Humphrey and coworkers [21]; with permission.)
Type I diabetic patients
20
Years from diagnosis of diabetes
FIGURE 1-19
Hyperfiltration. Almost immediately after the onset of hyperglycemia
(signaling the onset of diabetes), glomerular filtration rate (GFR)
increases to the limit of renal reserve function (hyperfiltration). Over
subsequent years of hyperglycemia, a steady decline in glomerular filtration rate ensues in the 20% to 40% of diabetic individuals destined
to manifest diabetic nephropathy. There is great variability in the rate
of decline of GFR, from as rapid as 20 mL/min/year to 1 to 2
mL/min/year (usually seen in aging). Projection of future loss of GFR
on the basis of the slope of the curve of prior decline in function contains errors as high as 37%. The importance of an inconstant and thus
unpredictable decline in GFR lies in interpretation of interventive studies designed to protect kidney function. Careful attention to both selection of sufficient untreated controls and a run-in period is vital.
(30)
(812)
(136)
27
Hyperglycemia, y
130
120
110
100
90
80
70
60
50
40
30
20
10
(12)
10
Type II diabetic patients
11
FIGURE 1-21
Creatinine clearance. Further evidence of the similarity in course of
diabetic nephropathy in type I (A) and type II (B) diabetes was presented in Ritz and Stefanskys study [22] of equivalent deterioration
130
120
110
100
90
80
70
60
50
40
30
20
10
5
6
Time, y
10
11
in creatinine clearance over the course of a decade in subjects with

either type of diabetes in Heidelberg, Germany. (From Ritz and
Stefanski [22]; with permission.)
1.9
14
Hyperfiltration
>4
3.5
3.5
3.0
3.0
Clinical
nephropathy
2.5
2.5
2.0
2.0
1.5
1.5
Clinical
nephropathy
1.0
1.0
12
0.5
0.5
Microalbuminuria
0
0
12
15 18
Hyperglycemia, y
24
Doubling of base-line creatinine, %
Placebo
P=0.007
20
15
Captopril
0
0.0
Placebo 202
Captopril 207
0.5
1.0
1.5
184
199
173
190
161
180
2.0
2.5
Follow-up, y
142
167
99
120
6
4
2
15
30
45
60
75
90
105 120
135
150 165
50
10
5
Window for
conservative
management
27
FIGURE 1-22
Diabetic nephropathy in types I and II. Whereas microalbuminuria
and glomerular hyperfiltration are subtle pathophysiologic manifestations of early diabetic nephropathy, transformation to overt clinical diabetic nephropathy takes place over months to many years. In
this figure, the curve for loss of glomerular filtration rate is plotted
together with the curve for transition from microalbuminuria to
gross proteinuria, affording a perspective of the course of diabetic
nephropathy in both types of diabetes. While not all microalbuminuric individuals progress to proteinuria and azotemia, the majority
are at risk for end-stage renal disease due to diabetic nephropathy.
GFRglomerular filtration rate.
45
40
35
30
25
10
0
21
4.0
Urinary albumin, g/d
GFR, mL/min
>4
4.0
3.0
3.5
4.0
75
82
45
50
22
24
FIGURE 1-23
Clinical recognition of diabetic nephropathy. The timing of renoprotective therapy in diabetes is a subject of current inquiry.
Certainly, hypertension, poor metabolic regulation, and hyperlipidemia should be addressed in every diabetic individual at discovery.
Discovery of microalbuminuria is by consensus reason to start
treatment with an angiotensin-converting enzyme inhibitor in
either type of diabetes, regardless of blood pressure elevation. As is
true for other kidney disorders, however, nearly the entire course of
renal injury in diabetes is clinically silent. Medical intervention
during this silent phase, however (comprising blood pressure
regulation, metabolic control, dietary protein restriction, and
administration of angiotensin-converting enzyme inhibitors), is
renoprotective, as judged by slowed loss of glomerular filtration.
FIGURE 1-24
Renoprotection with enzyme inhibitors. Streptozotocin-induced diabetic rats manifest slower progression to proteinuria and azotemia
when treated with angiotensin-converting enzyme inhibitors than
with other antihypertensive drugs. The consensus supports the view
that angiotensin-converting enzyme inhibitors afford a greater level of
renoprotection in diabetes than do other classes of antihypertensive
drugs. Large long-term direct comparisons of antihypertensive drug
regimens in type II diabetes are now in progress. In the study shown
here by Lewis and colleagues [23], treatment with captopril delayed
the doubling of serum creatinine concentration in proteinuric type I
diabetic patients. Trials of different angiotensin-converting enzyme
inhibitors in both types of diabetes confirm their effectiveness but not
their unique renoprotective properties in humans. For patients who
cannot tolerate angiotensin-converting enzyme inhibitors because of
cough, hyperkalemia, azotemia, or other side effects, substitution of
an angiotensin-converting enzyme receptor blocker (losartan) may be
renoprotective, although clinical trials of its use in diabetes are
uncompleted. (From Lewis and coworkers [23]; with permission.)
1.10
Microalbuminuric
Normoalbuminuric
10
70
AER, g/min
50
6
40
30
AER, g/min
60
20
2
Lisinopril
0
n
n
10
Placebo
0
6
12 18 24
0
6
12
Time from randomization, m
227 202 201 179

213 196 179 170
120
193 34
191 45
33
37
29
34
18
24
25
32
32
37
FIGURE 1-26
Restricting protein. Dietary protein restriction in limited trials in
small patient cohorts has slowed renal functional decline in type I
diabetes. Because long-term compliance is difficult to attain, the
place of restricted protein intake as a component of management
is not defined. A, Normal diet. B, Protein-restricted diet. Dashed
line indicates trend line slope. (From Zeller and colleagues [25];
with permission.)
Normal diet

mL/min/1.73 m2
100
80
60
40
20
0
0
10
20
30
40
50
40
50
Time, mo
120
Protein-restricted diet

mL/min/1.73 m2
100
80
60
40
20
0
0
FIGURE 1-25
Albumin excretion rate. In the recently completed Italian Euclid multicenter study, both microalbuminuric and normalbuminuric type I
diabetic patients showed benefit from treatment with lisinopril, an
angiotensin-converting enzyme inhibitor. Although microalbuminuria, with or without hypertension, is now sufficient reason to start
treatment with an angiotensin-converting enzyme inhibitor, the question of whether normalbuminuric, normotensive diabetic individuals
should be started on drug therapy is unanswered. AERalbumin
excretion rate. (From Euclid study [24]; with permission.)
10
20
30
Time, mo
1.11
125
80
Rate of change in AER, % /year
Rate of change in AER, % /year
100
75
50
25
60
40
20
0
0
10
12
14
10
Mean Hb A1, %
FIGURE 1-27
Metabolic regulation studies. Multiple studies of the strict metabolic
regulation of type I and type II diabetes all indicate that reduction of
hyperglycemic levels to near normal slows the rate of renal functional deterioration. In this study, the albumin excretion rate (AER)
another way of expressing albuminuriacorrelates directly with
Function
Pathology
Hyperfiltration
Mesangial expansion
Microalbuminuria
12
14
Mean Hb A1, %
hyperglycemia, as indicated by hemoglobin A1 (Hb A1) levels in

both type I (A) and type II (B) diabetes. As for other studies using
different markers, the courses of both types of diabetes over time
were found to be equivalent. (From Gilbert and coworkers [26];
with permission.)
FIGURE 1-28
Stages of nephropathy. The interrelationships between functional
and morphologic markers of the stages of diabetic nephropathy are
shown. Additional pathologic studies are needed to time with precision exactly when glomerular basement membrane (GBM) thickening and glomerular mesangial expansion take place. ESRDendstage renal disease.
GBM thickening
Proteinuria
Glomerulosclerosis
ESRD
DIABETIC NEPHROPATHY:
COMPLICATIONS
Rate of GFR Loss
Course of proteinuria
Nephropathology
Comorbidity
Progression to ESRD
FIGURE 1-29
Type I and II nephropathic equivalence. A
summation about the
equivalence of type I
and type II diabetes in
terms of nephropathy
is listed. Both types
have similar complications. ESRDendstage renal disease;
GFRglomerular
filtration rate.
Hyperglycemia
Normotension
Euglycemia
Protein restriction
Glomerulosclerosis
FIGURE 1-30
Major therapeutic
maneuvers to slow
loss of glomerular
filtration rate are
shown. Recent
recognition of the
adverse effect of
hyperlipidemia is
reason to include
dietary and, if necessary, drug treatment for elevated
blood lipid levels.
1.12
PROGRESSION OF COMORBIDITY
IN TYPE II DIABETES*
Complication
Retinopathy
Cardiovascular
Cerebrovascular
Peripheral vascular
Initial, %
Subsequent, %
50
45
30
15
100
90
70
50
COMORBIDITY INDEX
Persistent angina or myocardial infarction
Other cardiovascular problems
Respiratory disease
Autonomic neuropathy
Musculoskeletal disorders
Infections including AIDS
Liver and pancreatic disease
Hematologic problems
Spinal abnormalities
Vision impairment
Limb amputation
Mental or emotional illness
*Creatinine clearance declined from 81 mL/min over 74

(40119) mo.
Endpoint: dialysis or death.
FIGURE 1-31
Comorbidity in type II. In both type I and
type II diabetes, comorbidity, meaning
extrarenal disease, makes every stage of
progressive nephropathy more difficult to
manage. In the long-term observational
study in type II diabetes done by Bisenbach
and Zazgornik [27], the striking impact of
eye, heart, and peripheral vascular disease
was noted in a cohort over 74 months.
(From Bisenbach and Zazgornik [27];
with permission.)
Score 0 to 3: 0 = absent; 1 = mild; 2 = moderate;

3 = severe. Total = Index.
FIGURE 1-32
Comorbidity index. We devised a Comorbidity Index to facilitate initial and subsequent evaluations of patients over the
course of interventive studies. Each of 12
areas is rated as having no disease (0) to
severe disease (3). The total score represents
overall illness and can be both reproduced
by other observers and followed for years
to document improvement or deterioration.
FIGURE 1-34
Heart disease and renal transplants. A, Pretransplantation. B, Five years after kidney transplation. Experienced clinicians managing renal failure in diabetes rapidly reach the conclusion
that quality of life following successful kidney transplantation is far superior to that attained
during any form of dialytic therapy. In the most favorable series, as illustrated by a singlecenter retrospective review of all kidney transplants performed between 1987 and 1993, there
is no significant difference in actuarial 5-year patient or kidney graft survival between diabetic
and nondiabetic recipients overall or when analyzed by donor source. It is equally encouraging
that no difference in mean serum creatinine levels at 5 years was noted between diabetic and
nondiabetic recipients [28]. Remarkably superior survival following kidney transplantation
compared with survival after peritoneal dialysis and hemodialysis is documented in the 1997
HEART DISEASE
Hyperlipidemia
Hypertension
Volume overload
ACE inhibitor
Erythropoietin
FIGURE 1-33
Heart disease. Heart disease is the leading
cause of morbidity and death in both type I
and type II diabetes. Throughout the course
of diabetic nephropathy, periodic screening
for cardiac integrity is appropriate. We have
elicited symptomatic improvement in angina
and work tolerance by using erythropoietin
to increase anemic hemoglobin levels.
ACEangiotensin-converting enzyme.
report of the United States Renal Data System

(USRDS) [1]. Fewer than five in 100 diabetic patients with end-stage renal disease
(ESRD) treated with dialysis will survive 10
years, while cadaver donor and living
donor kidney allograft recipients fare far
better. Rehabilitation of diabetic patients
with ESRD is incomparably better following renal transplantation compared with
dialytic therapy. The enhanced quality of
life permitted by a kidney transplant is the
reason to prefer this option for newly evaluated diabetic persons with ESRD who are
younger than the age of 60. More than half
of diabetic recipients of a kidney transplant
in most series live at least 3 years: many
survivors return to occupational, school,
and home responsibilities.
Failure to continue monitoring of cardiac integrity may have disastrous results,
as in this relatively young type I diabetic
recipient of a cadaver renal allograft for
diabetic nephropathy Although her allograft maintained good function, coronary
artery disease progressed silently until a
myocardial infarction occurred We now
perform annual cardiac testing in all diabetic patients who have ESRD and are
receiving any form of treatment.
RETINOPATHY
Hyperglycemia
Hypertension
Volume overload
Photocoagulation
Erythropoietin
1.13
FIGURE 1-35
Retinopathy. Blindness due to the hemorrhagic and fibrotic changes of diabetic retinopathy
is the most dreaded extrarenal complication feared by diabetic kidney patients. The pathogenesis of proliferative retinopathy reflects release by retinal and choroidal cells of growth
(angiogenic) factors triggered by hypoxemia, which is caused by diminished blood flow. The
interrelationship among hyperglycemia, hypertension, hypoxemia, and angiogenic factors is
now being defined. There is reason to hope that specifically designed interdictive measures
may halt progression of loss of sight.
FIGURE 1-36
Retinopathic changes. Proliferative retinopathy, microcapillary
aneurysms, and dot plus blot hemorrhages are present in this funduscopic photograph taken at the time of initial renal evaluation of
a nephrotic 37-year-old woman with type I diabetes. After prescription of a diuretic regimen, immediate consultation with a
laser-skilled ophthalmologist was arranged.
A
FIGURE 1-37
Panretinal photocoagulation (PRP). A, PRP is the therapeutic
technique performed for proliferative retinopathy using an argon
laser to deliver approximately 1500 discrete retinal burns, avoiding the fovea and disk (IA<I). By reducing the amount of retina
to be perfused by 35%, PRP somehow lessens the stimulus to
release angiogenic factors, and proliferative retinopathy regresses.
B, Disappearance of hemorrhages and nearly complete regression
B
of proliferative retinopathy were attained with PRP, as shown in
this fundus, photographed 6 weeks after the one shown in panel
A. Vision stabilized, and sight has been retained through the past
6 years of observation. If applied before retinal traction and
detachment supervene, PRP is effective in preserving sight in
more than 90% of diabetic patients undergoing dialytic therapy
or kidney transplantation.
1.14
AMPUTATION
Inspection
Shoes
Socks
Nails
Prompt treatment

FIGURE 1-38
Amputation. After blindness, no comorbid complication limits rehabilitation in diabetic
kidney patients more than lower limb amputation. A combination of macrovascular and
microvascular disease in the limb, loss of pain perception due to sensory nephropathy, and
impaired resistance to infection converts any minor insult to the foot into a major threat
to the limb and life. Previously regarded as unavoidable in as many as 30% of patients
with end-stage renal disease treated with dialysis or kidney transplantation, programs that
emphasize prophylactic foot care as a component of preventive medicine have reduced the
incidence of limb amputation to about 5% after 3 years.
FIGURE 1-40
Charcots joint. Diabetic neuropathy may involve the proprioceptive nerves, removing limitation of joint stretching and resulting in
bone shifts and joint destruction, as seen in the Charcots joint
shown here. An insensitive deformed foot with a compromised
blood supply is at risk of ulceration, with slow or absent healing
after minor trauma.
FIGURE 1-39
Genesis of foot problems. The genesis of diabetic foot problems
includes peripheral neuropathy, peripheral vascular disease, impaired
vision (nail cutting), edema (heart and kidney), and slow wound
healing. A, Note the demarcated hair line indicative of peripheral
vascular insufficiency. B, The foot radiograph shows a Charcots
joint. (From Shaw and Boulton [29]; with permission.)
FIGURE 1-41
Ulcers. A collaborating podiatrist stationed within the renal clinic
adds a level of protection for diabetic kidney patients. Common
lesions, like this pressure ulcer overlying the head of the first
metatarsal, are managed easily with shoe pads that shift weightbearing. The recent introduction of genetically engineered human skin
holds promise for closing formerly unhealable diabetic foot ulcers.
CLINICAL STRATEGY
Main Collaborators
Consultants
Opththalmologist
Podiatrist
Cardiologist
Nutritionist
Nurse educator
Neurologist
Vascular surgeon
Endocrinologist
Gastroenterologist
Urologist
FIGURE 1-42
Team management of neuropathy. Proper
management of diabetic kidney patients
requires a skilled team including collaborating specialists. Depending on the qualifications of the patients primary physician,
other professionals are recruited as needed.
A nurse educator can ease the interface
between otherwise independent specialists.
Without such a team mentality, the diabetic
patient is often set adrift, forced to cope
with conflicting instructions and unneeded
repetition of tests. Especially helpful as renal
function declines toward end-stage renal disease, patient education facilitates the choice
of uremia therapy and, if appropriate, interaction with the renal transplant service.
NEPHROTIC SYNDROME
Precedes renal failure
May arrest or revert (15%)
Confused with cardiac failure
Intensifies risk to feet
Management: ACEi + metolazone + furosemide
ANASARCA
Hypoproteinemia (renal loss, liver disease)
Glycated albumin (more permeable)
Heart failure (coronary disease)
Management includes
Daily weight
Metolazone + furosemide
Cardiac compensation
AUTONOMIC NEUROPATHY
Cardiovascular (rate, QT, R-R)
Orthostatic hypotension
Gastroparesis
Cystopathy
Diarrhea, obstipation
FIGURE 1-43
Autonomic neuropathy. Autonomic neuropathy accompanies advanced diabetic
nephropathy. While an unvarying R-R
interval may have minimal clinical importance, diabetic cystopathy and reduced
bowel motility, including gastroparesis, may
seriously impede quality of life. Questioning
to discern the presence of travel-limiting
diarrhea, obstipation, and gastroparesis
should be included in each initial evaluation
of a diabetic kidney patient. (From Spallone
and Menzinger [30]; with permission.)
1.15
GASTROPARESIS IN DIABETIC
NEPHROPATHY
Prevalent in majority, often silent
Correlates with autonomic neuropathy
Symptoms not linked to delayed emptying
Management includes
Prokinetic agents: cisapride, erythromycin,
metoclopramide, domperidone
Serotoninergic (5-HT-3) antagonists
FIGURE 1-44
Gastroparesis. Incomplete and inconstant
gastric emptying due to diabetic autonomic
neuropathy (gastroparesis) may preempt
good glucose regulation because of an
inability to match insulin dosing with food
ingestion. The diagnosis can be established
by having the patient ingest a test meal
with a radioisotope tracer. Satisfactory drug
treatment for gastroparesis is usually able
to minimize the problem. (From Enck and
Frieling [31] and Savkan and coworkers
FIGURE 1-45
Nephrotic syndrome. Proteinuria in diabetic nephropathy typically progresses more than
3.5 g/day (nephrotic range), leading to hypoproteinemia, hyperlipidemia, and extracellular
fluid accumulation (nephrotic syndrome). Management of a nephrotic diabetic patient
includes minimizing protein loss using an angiotensin-converting enzyme inhibitor (ACEi)
and promoting diuresis with a combination of loop diuretics (furosemide) and thiazide
diuretics (metolazone). Distinction between congestive heart failure and nephrotic edema
requires assessment of cardiac function. (From Herbert et at. [33] and Gault and
Fernandez [34]; with permission.)
FIGURE 1-46
Anasarca. Anasarca is a long-term management problem in diabetic nephropathy. As renal
reserve decreases, the balance between volume overload and excessive diuresis may be difficult to maintain. Having the patient measure and record weight daily as a guide for each
days dose of diuretics (metolazone plus furosemide) is a workable strategy. Once the creatinine clearance falls below 10 mL/min, ambulatory dialysis may be the only means of
continuing life outside the hospital.
1.16
90
30
5
10
s
tic
be
D ia
15
Creatinine
clearance,
mL/min
75
45
60
FIGURE 1-47
Uremia therapy, conservative management.
Although enthusiastically favored in Canada
and Mexico, in the United States peritoneal
dialysis sustains the life of only about 12%
of diabetic patients with end-stage renal disease (ESRD) [1]. Continuous ambulatory
PLANNING FOR ESRD

Expose patient to treatment options
Establish vascular or peritoneal access
Encourage intrafamilial kidney donation
Schedule visit with transplant surgeon
Monitor creatinine, general well being
Err on side of early dialysis start
Nondiabetic
peritoneal dialysis (CAPD) affords the advantages of freedom from a machine, ability to be
performed at home, rapid training, minimal cardiovascular stress, and avoidance of heparin
[35]. Some enthusiasts believe CAPD to be a first choice treatment for diabetic patients
with ESRD [36]. Consistent with the authors view, however, is the report of Rubin and colleagues [37]. They found that in a largely black diabetic population, only 34% of patients
continued CAPD after 2 years, and at 3 years, only 18% remained on CAPD.
In fairness, comparisons of either mortality or comorbidity in patients receiving
hemodialysis versus peritoneal dialysis suffer from the limitations of starting with unequal
cohorts reflecting selection bias. Data subsets from the United States Renal Data System
(USRDS) report for 1997 [1] show that in diabetic patients, all cohorts have a higher risk
of death with CAPD than with hemodialysis. Furthermore, patients receiving peritoneal
dialysis in the United States have a 14% greater risk of hospitalization than do patients
undergoing hemodialysis [38]. Benefits of peritoneal dialysis, including freedom from a
machine and electrical outlets and ease of travel, stand against the disadvantages of
unremitting attention to fluid exchange, constant risk of peritonitis, and disappearing
exchange surface.
There are no absolute criteria for abandoning conservative management in favor of initiating maintenance hemodialysis or peritoneal dialysis. As a generalization, diabetic individuals with progressive renal disease decompensate with uremic symptoms earlier than
nondiabetic individuals. A decision to start dialysis is usually the culmination of unsuccessful efforts to regain compensation after episodic dyspnea due to volume overload or nausea and a reversed sleep pattern characteristic of renal failure. Sometimes, both physician
and patient appreciate that lassitude and decreasing activity in a catabolic patient signal
the need to begin dialysis.
FIGURE 1-48
Treatment for end-stage renal disease (ESRD). Ideally, treatment for ESRD should be selected without stress or urgency on the basis of prior thought and planning. Discussions with
representatives of patient self-help groups, such as the American Association of Kidney
Patients, and institutional transplant coordinators aid in communicating the information
required by patients to enable them to select from available options for uremia therapy.
Diabetic
4064 y
51.5%
Center hemo
71.5%
Center hemo
Transplant
13.0%
Transplant
36.3%
Center hemo
Home hemo
CAPD
CCPD
Transplant
FIGURE 1-49
Management with dialysis. As tabulated in the 1997 report of the
United States Renal Data System [1], diabetic patients with end-stage
renal disease (ESRD) are less likely than nondiabetic patients with
ESRD to receive a kidney transplant and are most often managed
with maintenance hemodialysis (center hemo). A greater proportion
of diabetic patients with ESRD are managed with continuous ambulatory peritoneal dialysis (CAPD) or machine-based continuous cyclic
peritoneal dialysis (CCPD) than are nondiabetic patients with ESRD.
1.17
Nondiabetic transplant
Nondiabetic dialysis
26.2
100
Diabetic transplant
Diabetic dialysis
100 94.9
91.2
80
Surviving, %
24.1
205.4
90.3
84.3
75.3
76.3
60
64.7
57.9
36.9
40
26.5
279.9
20.1
20
0
50
100
150
200
250
300
3.9
0
0
Deaths per 1000 Patient Years
10
Time after initiatling treatment, y
FIGURE 1-50
Survival rates of diabetics and nondiabetics. As tabulated in the
1997 report of the United States Renal Data System [1], there are
sharp differences in survival between diabetic and nondiabetic
patients with end-stage renal disease (ESRD) as well as between
treatment by dialysis versus kidney transplantation. The highest
death rate is suffered by diabetic dialysis patients (combined peritoneal dialysis and hemodialysis), while the best survival is experienced by nondiabetic renal transplant recipients. Selection bias in
choosing more fit ESRD patients for kidney transplantation while
leaving a residual pool of sicker patients for dialysis accounts for
some of the difference in mortality. Other variables, especially
extrarenal comorbidity, are probably more important in defining
the less favorable course in diabetes.
FIGURE 1-51
Survival rates of diabetic ESRD patients. After a decade of treatment,
the remarkable superiority of renal transplantation over dialysis
(combined peritoneal dialysis and hemodialysis, lower curve) is
starkly evident in these survival curves drawn from the 1997 report
of the United States Renal Data System [1]. Fewer than 1 in 20
diabetic patients with end-stage renal disease (ESRD) treated with
any form of dialysis will live a decade. In contrast, kidney transplantation from a living donor (upper curve) or a cadaver donor
(middle curve) permits substantive cohorts to survive.
42.4
Deaths per 1000 Patient Years
USRDS 1996
Ages 4564
Transplant
Hemodialysis
Peritoneal dialysis
40
30.9
30
21.5
19
20
15.1
14.5
10
8.7
7.5 7.5
6.3
2.4
1.4
6.8
4.5
3.7
2.0
1.8
0.4
1.6
0
MI Nondiab
MI Diab
CVA Nondiab
CVA Diab
FIGURE 1-52
Comorbidity in ESRD. Death of diabetic patients with end-stage
renal disease (ESRD) relates to comorbidity, as shown in this table
abstracted from the 1997 report of the United States Renal Data
System (USRDS) [1]. Representative subsets of patients with ESRD
with and without diabetes treated by peritoneal dialysis, hemodialysis, or renal transplantation are shown. Note that for each comorbid
Cancer Nondiab
Cancer Diab
3.0
1.6
0.1
+]
[K Nondiab
4.0
0.1
[K+] Diab
cause of death, rates are higher in patients receiving peritoneal dialysis than in those receiving hemodialysis and are lowest in renal transplant recipients. For undetermined reasons, deaths due to cancer are
less frequent in diabetic than in nondiabetic patients with ESRD.
CVAcerebrovascular accident; Diabdiabetes; K+potassium;
MImyocardial infarction.
COMPLICATIONS IN PATIENTS
RECEIVING HEMODIALYSIS
Inadequate vascular access
Steal, thrombosis/infection
Interdialytic hypotension
Progressive eye disease
Progressive vascular disease
Minimal rehabilitation
RECEIVING PERITONEAL DIALYSIS
Peritonitis
Tunnel infection
Abdominal/back pain
Retinopathy
Progressive vascular disease
Minimal rehabilitation
FIGURE 1-53
Complications prevalent in diabetic
hemodialysis patients.
FIGURE 1-54
Complications prevalent in diabetic peritoneal dialysis patients.
Infections: bacterial (AFB), fungal viral (CMV);

genitourinary, lung, skin, wound
Cancer: skin, lymphoma, solid organ
Drug induced: gout, cataracts
Allograft rejection: acute/chronic
Recurrent diabetic nephropathy
Progressive eye, vascular disease
FIGURE 1-55
Frequent complications reported in diabetic
kidney transplant recipients. AFBacid fast
bacteria; CMVcytomegalovirus.
Rehabilitation
100
OPTIONS IN DIABETES WITH ESRD
First-year survival
Survival >10 y
Diabetic complications
Rehabilitation
Patient acceptance
UNDERGOING KIDNEY
TRANSPLANTATION
CAPD/CCPD
Hemodialysis
Transplantation
75%
<5%
Progress
Poor
Fair
75%
<5%
Progress
Poor
Fair
>90%
>25%
Slow progression
Fair to excellent
Good to excellent
FIGURE 1-56
Options in diabetes with ESRD. Comparing outcomes of various options for uremia therapy in diabetic patients with end-stage renal disease (ESRD) is flawed by the differing criteria for selection for each treatment. Thus, if younger, healthier subjects are offered kidney
transplantation, then subsequent relative survival analysis will be adversely affected for the
residual pool treated by peritoneal dialysis or hemodialysis. Allowing for this caveat, the
table depicts usual outcomes and relative rehabilitation results for continuous ambulatory
peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), hemodialysis,
and transplantation.
Kidney transplant
Karnofsky score
1.18
Hemodialysis
50
Peritoneal dialysis
Withdrawal
0
Death
FIGURE 1-57
Karnofsky scores in rehabilitation. Graphic
depiction of rehabilitation in diabetic
patients with end-stage renal disease (ESRD)
as judged by Karnofsky scores. Few diabetic
patients receiving hemodialysis or peritoneal
dialysis muster the strength to resume fulltime employment or other gainful activities.
Originally devised for use by oncologists,
the Karnofsky score is a reproducible, simple means of evaluating chronic illness from
any cause. A score below 60 indicates marginal function and failed rehabilitation.
1.19
FIGURE 1-58
Complications of the hemodialysis regimen
are more frequent in diabetic than in nondiabetic patients. A, Axillary vein occlusion
proximal to an arteriovenous graft used for
dialysis access is shown. B, Balloon angioplasty proffers only temporary respite owing
to a high rate (70% in 6 months) of restenosis in diabetic patients. The value of an intraluminal stent prosthesis is being studied.
76.2
75
USRDS 1996
PD + Hemo
74
Surviving, %
72.6
74.4
LIFE PLAN FOR DIABETIC

NEPHROPATHY
73.1
Explore and endorse treatment goals
Enlist patient as key team member
Prepare patient for probable course
Prioritize ESRD options
70.9
70
68.9
67.7
65.9
66.2
66.4
65
1983
1984 1985
1986
1987
1988 1989
1990
1991
1992
1993
FIGURE 1-59
Improving one year survival with dialysis. The summative effect of multiple incremental improvements in management of diabetic patients with end-stage renal disease
(ESRD) is reflected in a continuing increase in survival. Shown here, abstracted from
the 1977 report of the United States Renal Data System (USRDS), is the increasing
first-year survival rates for hemodialysis (hemo) plus peritoneal dialysis (PD) patients
with diabetes.
FIGURE 1-60
Life plan. Given the concurrent involvement
of multiple consultants in the care of diabetic individuals with end-stage renal disease (ESRD), there is a need for a defined
strategy, here termed a Life Plan.
Switching from hemodialysis to peritoneal
dialysis (or the reverse) and deciding on a
midcourse kidney transplant are common
occurrences that ought not to provoke anxiety or stress. Reappraisal and reconstruction of the Life Plan should be performed
by patient and physician at least annually.
1.20
References
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mortality in NIDDM. Diabetes 1988, 37:14991504.
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diabetes duration, metabolic control and beta-cell function in a representative population of type 2 diabetic patients in Sweden. Diabet
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diabetes mellitus: a population-based study in Rochester, Minnesota.
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23. Lewis EJ, et al.: The effect of angiotensin-converting-enzyme inhibition
on diabetic nephropathy: the Collaborative Study Group. N Engl J
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25. Zeller K, et al.: Effect of restricting dietary protein on the progression
of renal failure in patients with insulin-dependent diabetes mellitus.
N Engl J Med 1991, 324:7884.
26. Gilbert RE, Tsalamandris C, Bach LA, et al.: Long-term glycemic control
and the rate of progression of early diabetic kidney disease. Kidney Int
1993, 44:855859.
27. Biesenbach G, Zazgornik J: High mortality and poor quality of life
during predialysis period in type II diabetic patients with diabetic
nephropathy. Ren Fail 1994, 16:263272.
28. Shaffer D, Simpson MA, Madras PN, et al.: Kidney transplantation in
diabetic patients using cyclosporine. Five-year follow-up. Arch Surg
1995, 130:287288.
29. Shaw JE, Boulton AJ: The pathogenesis of diabetic foot problems: an
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30 Spallone V, Menzinger G: Diagnosis of cardiovascular autonomic
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range proteinuria in type I diabetes: Collaborative Study Group.
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34. Gault MH, Fernandez D: Stable renal function in insulin-dependent
diabetes mellitus 10 years after nephrotic range proteinuria. Nephron
1996, 72:8692.
35. Lindblad AS, Nolph KD, Novak JW, Friedman EA: A survey of the
NIH CAPD Registry population with end-stage renal disease attributed
to diabetic nephropathy. J Diabet Complications 1988, 2:227-232.
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insulin dependent diabetic patients: ten years experience. Clin Nephrol
1984, 21:72-81
37. Rubin J, Hsu H: Continuous anbulatory peritoneal dialysis: ten years
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Vasculitis (Polyarteritis
Nodosa, Microscopic
Polyangiitis, Wegeners
Granulomatosis, HenochSchnlein Purpura)
J. Charles Jennette
Ronald J. Falk
he kidneys are affected by a variety of systemic vasculitides

[1,2]. This is not surprising given the numerous and varied types
of vessels in the kidneys. The clinical manifestations and even the
pathologic expressions of vasculitis often are not specific for a particular
diagnostic category of vasculitis. An accurate precise diagnosis usually
requires the integration of many different types of data, including clinical
signs and symptoms, associated diseases (eg, asthma, systemic lupus
erythematosus, rheumatoid arthritis, hepatitis virus, polymyalgia
rheumatica), vascular distribution (ie, types and locations of involved
vessels), histologic pattern of inflammation (eg, granulomatous versus
necrotizing), immunopathologic features (eg, presence and composition
of vascular immunoglobulin deposits), and serologic findings (eg,
cryoglobulins, hypocomplementemia, hepatitis B antibodies, hepatitis C
antibodies, antineutrophil cytoplasmic autoantibodies, antiglomerular
basement membrane [GBM] antibodies, antinuclear antibodies). Specific
diagnosis of a vasculitis is very important because the prognosis and
appropriate therapy vary substantially among different types of vasculitis.
A general overview of the major categories of vasculitis that affect
the kidneys is presented. The focus is primarily on polyarteritis
nodosa, Henoch-Schnlein purpura, Wegeners granulomatosis, and
microscopic polyangiitis.
CHAPTER
2.2
Overview
SELECTED CATEGORIES OF VASCULITIS
Large vessel vasculitis
Giant cell arteritis
Takayasu arteritis
Medium-sized vessel vasculitis
Polyarteritis nodosa
Kawasaki disease
Small vessel vasculitis
ANCA small vessel vasculitis
Microscopic polyangiitis
Churg-Strauss syndrome
Immune complex small vessel vasculitis
Henoch-Schnlein purpura
Cryoglobulinemic vasculitis
Lupus vasculitis
Serum sickness vasculitis
Infection-induced immune complex vasculitis
AntiGBM small vessel vasculitis
Goodpastures syndrome
Distribution of renal vascular involvement

Small vessel vasculitis
FIGURE 2-1
Many different approaches to categorizing vasculitis exist. We use
the approach adopted by the Chapel Hill International Consensus
Conference on the Nomenclature of Systemic Vasculitis [3]. The
Chapel Hill System divides vasculitides into those that have a
predilection for large arteries (ie, the aorta and its major branches),
medium-sized vessels (ie, main visceral arteries), and small vessels
(predominantly capillaries, venules, and arterioles, and occasionally, small arteries). However, there is so much overlap in the size of
the vessel involved by different vasculitides that other criteria are
very important for precise diagnosis, especially when distinguishing
among the different types of small vessel vasculitis. ANCAantineutrophil cytoplasmic antibody.
FIGURE 2-2
Predominant distributions of renal vascular involvement. This diagram
depicts the predominant distributions of renal vascular involvement
by large, medium-sized, and small vessel vasculitides [2]. Note that
all three categories may affect arteries, although arteries are least
often affected by the small vessel vasculitides and often are not
involved at all by this category of vasculitis. By the Chapel Hill
definitions, glomerular involvement (ie, glomerulonephritis) is
confined to the small vessel vasculitides, which provides a concrete
criterion for separating the diseases in this category from those in
the other two categories [3].
Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegeners Granulomatosis, Henoch-Schnlein Purpura)
RENAL INJURY CAUSED BY DIFFERENT

CATEGORIES OF VASCULITIS
Ischemia causing renovascular hypertension (uncommon)
Renal infarcts (frequent)
Hemorrhage (uncommon)
and rupture (rare)
ANCA small vessel vasculitis
Pauci-immune crescentic glomerulonephritis (common)
Arcuate and interlobular arteritis (occasional)
Medullary angiitis (uncommon)
Interstitial granulomatous inflammation (rare)
Immune complex small vessel vasculitis
Immune complex proliferative or membranoproliferative glomerulonephritis with or
without crescents (common)
Arteriolitis and interlobular arteritis (rare)
AntiGBM small vessel vasculitis
Crescentic glomerulonephritis (common)
Extraglomerular vasculitis (only with concurrent ANCA disease)
2.3
FIGURE 2-3
The type of renal vessel involved by a vasculitis determines the
resultant renal dysfunction. Large vessel vasculitides cause renal
dysfunction by injuring the renal arteries and the aorta adjacent to
the renal artery ostia. These injuries result in reduced renal blood
flow and resultant renovascular hypertension. Medium-sized vessel
vasculitis most often affects lobar, arcuate, and interlobular arteries, resulting in infarction and hemorrhage. Small vessel vasculitides most often affect the glomerular capillaries (ie, cause
glomerulonephritis), but some types (especially the antineutrophil
cytoplasmic antibody vasculitides) may also affect extraglomerular
parenchymal arterioles, venules, and capillaries. Anti-GBM disease
is a form of vasculitis that involves only capillaries in glomeruli or
pulmonary alveoli, or both. This category of vasculitis is considered in detail seperately in this Atlas.
Large Vessel Vasculitis

NAMES AND DEFINITIONS FOR
LARGE VESSEL VASCULITIS
Giant cell arteritis
Takayasu arteritis
Granulomatous arteritis of the aorta and its major branches,

with a predilection for the extracranial branches of the
carotid artery. Often involves the temporal artery. Usually
occurs in patients older than aged 50 years and often is
associated with polymyalgia rheumatica.
Granulomatous inflammation of the aorta and its major branches. Usually occurs in patients younger than aged 50 years.
FIGURE 2-4
The two major categories of large vessel vasculitis, giant cell (temporal) arteritis and Takayasu arteritis, are both characterized pathologically by granulomatous inflammation of the aorta, its major
branches, or both. The most reliable criterion for distinguishing
between these two disease is the younger age of patients with
Takayasu arteritis compared with giant cell arteritis [3]. The presence of polymyalgia rheumatica supports a diagnosis of giant cell
arteritis. Clinically significant renal disease is more commonly associated with Takayasu arteritis than giant cell arteritis, although
pathologic involvement of the kidneys is a frequent finding with
both conditions [4,5].
2.4
Medium-sized Vessel Vasculitis

NAMES AND DEFINITIONS FOR
MEDIUM VESSEL VASCULITIS
Kawasaki disease
Necrotizing inflammation of medium-sized or small arteries

without glomerulonephritis or vasculitis in arterioles,
capillaries, or venules.
Arteritis involving large, medium-sized, and small arteries,
and associated with mucocutaneous lymph node syndrome. Coronary arteries are often involved. Aorta and
veins may be involved. Usually occurs in children.
FIGURE 2-5
The medium-sized vasculitides are confined to arteries by the
definitions of the Chapel Hill Nomenclature System [3,6]. By
this approach the presence of evidence for involvement of vessels
smaller than arteries (ie, capillaries, venules, arterioles), such as
glomerulonephritis, purpura, or pulmonary hemorrhage, would
point away from these diseases and toward one of the small vessel
vasculitides. Both polyarteritis nodosa and Kawasaki disease cause
acute necrotizing arteritis that may be complicated by thrombosis
and hemorrhage. The presence of mucocutaneous lymph node syndrome distinguishes Kawasaki disease from polyarteritis nodosa.
FIGURE 2-6
Photograph of kidneys showing gross features of polyarteritis nodosa.
The patient died from uncontrollable hemorrhage of a ruptured
aneurysm that bled into the retroperitoneum and peritoneum. The
cut surface of the left kidney and external surface of the right kidney are shown. The upper pole of the left kidney has three large
aneurysms filled with dark thrombus. These aneurysms are actually
pseudoaneurysms because they are not true dilations of the artery
wall but rather are foci of necrotizing erosion through the artery
wall into the perivascular tissue. These necrotic foci predispose to
thrombosis with distal infarction, and if they erode to the surface
of a viscera they can rupture and cause massive hemorrhage. The
kidneys also have multiple pale areas of infarction with hemorrhagic rims, which are seen best on the surface of the right kidney.
FIGURE 2-7
Antemortem abdominal CAT scans showing polyarteritis nodosa
(AE). These are the same kidneys shown in Figure 2-6. Demonstrated
are echogenic oval defects in both kidneys corresponding to the
C
aneurysms (pseudoaneurysms), and a perirenal hematoma adjacent
to the right kidney (left sides of panels) that resulted from rupture
of one of the aneurysms.
2.5

Antemortem abdominal CAT scans showing
polyarteritis nodosa.

Micrograph of transmural fibrinoid necrosis of an arcuate artery in
acute polyarteritis nodosa. The fibrinoid necrosis results from lytic
destruction of vascular and perivascular tissue with spillage of plasma constituents, including the coagulation proteins, into the zone of
destruction. The coagulation system, as well as other mediator systems, is activated and fibrin forms in the zone of necrosis, thus producing the deeply acidophilic (bright red) fibrinoid material.
Marked perivascular inflammation is seen, which is the basis for the
archaic term for this disease, ie, periarteritis nodosa. Note that the
glomerulus is not inflamed. (Hematoxylin and eosin stain, 200.)
FIGURE 2-9
Micrograph of extensive destruction and sclerosis of an arcuate
artery in the chronic phase of polyarteritis nodosa. Severe necrotizing injury, probably with thrombosis as well, has been almost completely replaced by fibrosis. A few small residual irregular foci of
fibrinoid material can be seen. Extensive destruction to the muscularis can be discerned. Infarction in the distal vascular distribution
of this artery was present in the specimen. (Hematoxylin and eosin
stain, 150.)
2.6
Small Vessel Vasculitis

NAMES AND DEFINITIONS FOR SMALL VESSEL VASCULITIS
Henoch-Schnlein purpura
Cryoglobulinemic vasculitis
Churg-Strauss syndrome
Microscopic polyangiitis
Vasculitis with IgA-dominant immune deposits affecting small vessels, ie, capillaries,
venules, or arterioles. Typically involves skin, gut and glomeruli, and is associated with
arthralgias or arthritis.
Vasculitis with cryoglobulin immune deposits affecting small vessels, ie, capillaries,
venules, or arterioles, and associated with cryoglobulins in serum. Skin and glomeruli
are often involved.
Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis
affecting small to medium-sized vessels, eg, capillaries, venules, arterioles, and arteries.
Necrotizing glomerulonephritis is common.
Eosinophil-rich and granulomatous inflammation involving the respiratory tract and
necrotizing vasculitis affecting small to medium-sized vessels, and associated with
asthma and blood eosinophilia
Necrotizing vasculitis with few or no immune deposits affecting small vessels, ie, capillaries, venules, or arterioles. Necrotizing arteritis involving small and medium-sized
arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary
capillaritis often occurs.
FIGURE 2-10
The small vessel vasculitides have the highest frequency of clinically significant renal
involvement of any category of vasculitis.
This is not surprising given the numerous
small vessels in the kidneys and their critical roles in renal function. The renal vessels
most often involved by all small vessel vasculitides are the glomerular capillaries,
resulting in glomerulonephritis. Glomerular
involvement in immune complex vasculitis
typically results in proliferative or membranoproliferative glomerulonephritis, whereas
ANCA disease usually causes necrotizing
glomerulonephritis with extensive crescent
formation. Involvement of renal vessels
other than glomerular capillaries is rare in
immune complex vasculitis but common in
ANCA vasculitis.
Diagnostic categorization of small vessel

vasculitis with glomerulonephritis
Signs and symptoms of small vessel vasculitis
(eg, nephritis, purpura, mononeuritis multiplex,
pulmonary hemorrhage, abdominal pain, arthralgias, myalgias)
Pauci-immune crescentic
glomerulonephritis
on renal biopsy
Cryoglobulins
in blood
IgA nephropathy
on renal biopsy
Type 1 MPGN
on renal biopsy
No granulomatous
inflammation
or asthma
Granulomatous
inflammation
but no asthma
Granulomatous
inflammation, asthma,
and eosinophilia
Henoch-Schnlein
purpura
Cryoglobulinemic
vasculitis
Microscopic
polyangiitis
Wegener's
granulomatosis
Churg-Strauss
syndrome
FIGURE 2-11
Algorithm for differentiating among the major categories of small vessel vasculitis that affect the kidneys. In a patient
with signs and symptoms of small vessel vasculitis, the type of glomerulonephritis is useful for categorization.
Identification of IgA nephropathy is indicative of Henoch-Schnlein purpura. Type I membranoproliferative glomerulonephritis (MPGN) suggests cryoglobulinemia and/or hepatitis C infection, and pauci-immune necrotizing and crescentic glomerulonephritis suggest some form of ANCA-associated vasculitis [1,2]. The different forms of ANCA vasculitis
are distinguished by the presence or absence of certain features in addition to the necrotizing vasculitis, ie, granulomatous inflammation in Wegeners granulomatosis, asthma and blood eosinophilia in Churg-Strauss syndrome, and neither
granulomatous inflammation nor asthma in microscopic polyangiitis. Approximately 80% of patients with active
untreated Wegeners granulomatosis or microscopic polyangiitis have ANCA, but it is important to realize that a small
proportion of patients with typical clinical and pathologic features of these diseases do not have detectable ANCA.
2.7
APPROXIMATE FREQUENCY OF ORGAN SYSTEM INVOLVEMENT IN SMALL VESSEL VASCULITIS
Organ system
Renal
Cutaneous
Pulmonary
Gastrointestinal
Ear, nose, and throat
Musculoskeletal
Neurologic
Henoch-Schnlein
purpura, %
50
90
<5
60
<5
75
10
Cryoglobulinemic
vasculitis, %
55
90
<5
30
<5
70
40
FIGURE 2-12
All of the small vessel vasculitides share signs and symptoms of small
vessel injury in multiple different tissues; however, the frequency of
involvement varies among the different diseases [1]. Combined renal
and pulmonary involvement (pulmonary-renal syndrome) is most common in ANCA vasculitis, whereas combined renal and dermal involvement (dermal-renal syndrome) is most common in immune complex
vasculitis. The cutaneous involvement in small vessel vasculitides usu-
Microscopic
polyangiitis, %
90
40
50
50
35
60
30
Wegeners
granulomatosis, %
80
40
90
50
90
60
50
Churg-Strauss
syndrome, %
45
60
70
50
50
50
70
ally manifests as purpura caused by venulitis, but occasionally is more

nodular or necrotizing secondary to arteritis or granulomatous inflammation. Nodular cutaneous lesions, as well as neuropathies, abdominal pain, and musculoskeletal symptoms also can be caused by medium sized vessel vasculitis (eg, polyarteritis nodosa), and thus these clinical manifestations are not specific for a small vessel vasculitis; whereas
glomerulonephritis, purpura, or alveolar capillaritis are.
Henoch-Schnlein Purpura
FIGURE 2-13
Cutaneous purpura in a patient with Henoch-Schnlein purpura.
This clinical appearance could be caused by any of the small vessel
vasculitides, and thus is not specific for Henoch-Schnlein purpura. Henoch-Schnlein purpura is the most common small vessel
vasculitis in children [7]. In a young child with purpura, nephritis
and abdominal pain, the likelihood of Henoch-Schnlein purpura
is approximately 80%; however, in an older adult with the same
clinical presentation, the likelihood of Henoch-Schnlein purpura
is very low and the patient has an approximately 80% chance of
having an ANCA-associated vasculitis.
FIGURE 2-14
Skin biopsy from a patient with small vessel vasculitis demonstrating the typical dermal leukocytoclastic angiitis pattern of venulitis
that results in vasculitic purpura. This histologic lesion is nonspecific and can be a component of any of the small vessel vasculitides. Additional immunohistologic, serologic, and clinical observations are required to determine what is causing the leukocytoclastic
angiitis (Figs. 2-9 and 2-10). (Hematoxylin and eosin stain.)
2.8
FIGURE 2-15
Direct immunofluorescence microscopy demonstrating granular
IgA-dominant immune complex deposits in dermal vessels, which is
indicative of Henoch-Schnlein purpura. This procedure typically
would show vascular IgM, IgG, and C3 cryoglobulinemic vasculitis, and little or no staining for immunoglobulins in a specimen
from a patient with an ANCA vasculitis (a paucity of staining for
immunoglobulins in vessel walls indicates pauci-immune vasculitis).
FIGURE 2-16
Direct immunofluorescence microscopy demonstrating granular,
predominantly mesangial IgA-dominant immune complex deposits
in a glomerulus. This is indicative of some form of IgA nephropathy, including the form that occurs as a component of HenochSchnlein purpura.
FIGURE 2-17
Electron micrograph showing mesangial dense deposits representative of the pattern of deposition seen in patients with HenochSchnlein purpura glomerulonephritis. The dense deposits are
immediately beneath the paramesangial basement membrane.
FIGURE 2-18
Severe crescentic proliferative glomerulonephritis in a patient
with Henoch-Schnlein purpura and rapidly progressive glomerulonephritis (Masson trichrome stain). Approximately half of
patients with Henoch-Schnlein purpura have mild nephritis with
hematuria and proteinuria, but less than a quarter develop renal
insufficiency, and rapidly progressive glomerulonephritis is rare.
Less than 10% of patients have persistent renal disease that progresses to end-stage renal disease.
2.9
FIGURE 2-19
Fibrinoid necrosis obliterating the wall of an arteriole in a renal
biopsy specimen from a patient with Henoch-Schnlein purpura
(hematoxylin and eosin). Involvement of renal vessels other than
glomeruli is rare in Henoch-Schnlein purpura.
ANCA Small Vessel Vasculitis

C-ANCA staining pattern of ethanol-fixed normal human neutrophils in an indirect immunofluorescence assay of serum.
Approximately 90% of C-ANCA are specific for proteinase 3
(PR3-ANCA) in specific immunochemical assays, such as enzyme
immunoassay (EIA) [810].

P-ANCA staining pattern of ethanol-fixed normal human neutrophils in an indirect immunofluorescence assay of serum.
Approximately 90% of P-ANCA in patients with nephritis or vasculitis are specific for myeloperoxidase (MPO-ANCA) in specific
immunochemical assays, such as EIA. P-ANCA in patients with
other types of inflammatory disease, such as inflammatory bowel
disease are typically not specific for MPO. Using ethanol-fixed neutrophils as substrate, nuclear staining caused by anti-nuclear antibodies (ANA) cannot be distinguished confidently from nuclear
staining caused by P-ANCA. Using formalin-fixed neutrophils as
substrate, P-ANCA stain the cytoplasm but ANA do not. The difference in staining pattern between ethanol and formalin fixed cells
is due to the artifactual diffusion of solubilized cationic ANCAantigens to the nucleus during substrate preparation of the ethanolfixed cells, as opposed to immobilization of the antigens in the
cytoplasm by covalent crosslinking during formalin fixation.
2.10
Pauci-immune crescentic
glomerulonephritis
Microscopic
polyangiitis
Wegener's
granulomatosis
P-ANCA/MPO-ANCA
C-ANCA/PR3-ANCA
FIGURE 2-22
Approximate relative frequency of P-ANCA/MPO-ANCA versus CANCA/PR3-ANCA in patients with pauci-immune necrotizing and
crescent glomerulonephritis without systemic vasculitis (renal-limited vasculitis), microscopic polyangiitis, and Wegeners granulomatosis. Note that most patients with renal-limited disease have PANCA/MPO-ANCA, most patients with Wegeners granulomatosis
have C-ANCA/PR3-ANCA, and patients with microscopic polyangiitis do not have a major preponderance of either ANCA specificity.
FIGURE 2-24
Glomerulus from a patient with ANCA and a pauci-immune necrotizing and crescentic glomerulonephritis showing a large circumferential crescent and segmental lysis of glomerular basement membranes (combined Jones silver and hematoxylin and eosin stain).
Also note the adjacent tubulointerstitial inflammation, which often
is pronounced in ANCA disease. This pattern of glomerular injury
can be seen with any of the ANCA-small vessel vasculitides.

Early segmental fibrinoid necrosis and infiltration by neutrophils in
an ANCA-positive patient with Wegeners granulomatosis (Masson
trichrome stain). There also is fibrin (red/fuchsinophilic material) in
Bowmans space, which is a precursor event to crescent formation.

Direct immunofluorescence microscopy demonstrating intense
staining of a crescent and adjacent segmental glomerular fibrinoid
necrosis with an antiserum specific for fibrin in a renal biopsy from a
patient with ANCA small vessel vasculitis. There was no staining of
glomeruli in this specimen with antisera specific for IgG, IgA, or IgM.
2.11
FIGURE 2-26
Chronic ANCA-associate glomerulonephritis with effacement of
the architecture of a glomerulus by extensive sclerosis. Bowmans
capsule has been destroyed and there is periglomerular fibrosis and
chronic inflammation.
FIGURE 2-27
Necrotizing arteritis involving an interlobular artery in a renal
biopsy specimen from a patient with ANCA-positive microscopic
polyangiitis (hematoxylin and eosin). There is focal transmural fibrinoid necrosis with intense perivascular inflammation. This pattern of arteritis is nonspecific, and could be seen, for example, in a
patient with polyarteritis nodosa, microscopic polyangiitis, or
Wegeners granulomatosis. The presence of ANCA or glomerulonephritis in the patient would exclude polyarteritis nodosa.
FIGURE 2-28
Direct immunofluorescence microscopy demonstrating intense
staining of the fibrinoid necrosis in the wall of an interlobular
artery with an antiserum specific for fibrin in a renal biopsy from a
patient with microscopic polyangiitis.
FIGURE 2-29
Medullary leukocytoclastic angiitis involving vasa recta in a patient
with Wegeners granulomatosis (hematoxylin and eosin). When this
process is severe, papillary necrosis may result. The frequency of
this process is unknown because the medulla often is not sampled
in renal biopsy specimens.
2.12
FIGURE 2-30
Poorly defined focus of necrotizing granulomatous inflammation
in the cortex in a renal biopsy obtained from a patient with
ANCA-positive Wegeners granulomatosis (hematoxylin and eosin).
Granulomatous inflammation is only very rarely observed in renal
biopsy specimens.
FIGURE 2-31
Necrotizing granulomatous inflammation in a wedge biopsy of
lung from a patient with Wegeners granulomatosis (hematoxylin
and eosin). Note the scattered large multinucleated giant cells on
the left side and the extensive necrosis and neutrophilic infiltration
on the right side. The granulomatous inflammation of acute
Wegeners granulomatosis has much more neutrophilic infiltration
and liquefactive necrosis than most other forms of granulomatous
inflammation, which is why the lesions in the lung tend to cavitate,
and why the lesions in the nose and sinuses tend to destroy bone.
P-ANCA
(MPO-ANCA)
disease
Systemic small
vessel vasculitis
(eg, MPA)
Pulmonary
renal
vasculitic
syndrome
FIGURE 2-32
Hemorrhagic alveolar capillaritis in a wedge biopsy from the lung
of a patient with microscopic polyangiitis (hematoxylin and eosin).
Note the neutrophils within alveolar capillaries and the massive
hemorrhage into the air spaces. This pattern of injury can be seen
in both microscopic polyangiitis and Wegeners granulomatosis.
The pulmonary hemorrhage of anti-GBM disease usually does not
have conspicuous neutrophils in alveolar capillaries.
Glomerulonephritis
alone
Wegener's
granulomatosis
Anti-GBM
disease
C-ANCA
(PR3-ANCA)
disease
FIGURE 2-33
Categorization of patients with crescentic glomerulonephritis with
respect to both the immunopathologic category of disease (immune
complex versus anti-GBM versus ANCA) and the clinicopathologic
expression (glomerulonephritis alone versus Wegeners granulomatosis versus Goodpastures syndrome versus other small vessel vasculitis) [11]. Note that most patients with ANCA have some expression
of systemic vasculitis rather than glomerulonephritis alone. Most
patients with Wegeners granulomatosis have C-ANCA/PR3-ANCA
but some have P-ANCA/MPO-ANCA. Also note that some patients
with anti-GBM and some patients with immune complex disease
also are ANCA positive. (Adapted from Jennette [11]).
2.13
References
1.
Jennette JC, Falk RJ: Small vessel vasculitis. N Engl J Med 1997,
337:15121523.
7. Dillon MJ, Ansell BM: Vasculitis in children and adolescents. Rheum

Dis Clin North Am 1995, 21:11151136.
2.
Jennette JC, Falk RJ: The pathology of vasculitis involving the kidney.
Am J Kidney Dis 1994, 24:130141.
3.
Jennette JC, Falk RJ, Andrassy K, et al.: Nomenclature of systemic

vasculitides: the proposal of an international consensus conference.
Arthritis Rheum 1994, 37:187192.
8. Gross WL, Schmitt WH, Csernok E: ANCA and associated diseases:

immunodiagnostic and pathogenetic aspects. Clin Exp Immunol
1993, 91:112.
4.
Klein RG, Hunder GG, Stanson AW, et al.: Larger artery involvement
in giant cell (temporal) arteritis. Ann Intern Med 1975, 83:806812.
5.
Arend WP, Michel BA, Bloch DA, et al.: The American College of
Rheumatology 1990 criteria for the classification of Takayasu arteritis.
Arthritis Rheum 1990, 33:11291134.
6.
Lhote F, Guillevin L: Polyarteritis nodosa, microscopic polyangiitis, and

Churg-Strauss syndrome. Rheum Dis Clin North Am 1995, 21:911947.
9. Kallenberg CGM, Brouwer E, Weening JJ, Cohen Tervaert JW:

Anti-neutrophil cytoplasmic antibodies: current diagnostic and
pathophysiologic potential. Kidney Int 1994, 46:115.
10. Jennette JC, Falk RJ: Anti-neutrophil cytoplasmic autoantibodies:
discovery, specificity, disease associations and pathogenic potential.
Adv Pathol Lab Med 1995, 8:363377.
11. Jennette JC: Anti-neutrophil cytoplasmic autoantibody-associated
disease: a pathologists perspective. Am J Kidney Dis 1991,
18:164170.
Amyloidosis
Robert A. Kyle
Morie A. Gertz
he word amyloid was first coined in 1838 by Schleiden, a German

botanist, to describe a normal constituent of plants. Virchow [1]
observed the similarity of the staining properties of the amyloid to
those of starch and named it amyloid.
All forms of amyloid appear homogeneous when viewed under a light
microscope and are pale pink when stained with hematoxylin-eosin. Under
polarized light, amyloid stained with Congo red dye produces the characteristic apple-green birefringence. The modification of alkaline Congo red
dye by Puchtler and Sweat [2] is used most often. The amorphous hyalinelike appearance of amyloid is misleading because it is a fibrous protein. On
electron microscopy, amyloid deposits are composed of rigid, linear, nonbranching fibrils 7.5- to 10-nm wide and of indefinite length. The fibrils
aggregate into bundles. The deposits occur extracellularly and ultimately
lead to damage of normal tissue.
In primary amyloidosis (AL) the fibrils consist of the variable portions of
monoclonal () or () immunoglobulin light chains or, very rarely, heavy
chains. In secondary amyloidosis (AA) the fibrils consist of protein A, a nonimmunoglobulin. In familial amyloidosis (AF) the fibrils are composed of
mutant transthyretin (prealbumin) or, rarely, fibrinogen or apolipoprotein.
In senile systemic amyloidosis the fibrils consist of normal transthyretin. The
amyloid fibrils associated with long-term dialysis (A 2M dialysis arthropathy) consist of 2-microglobulin.
Amyloid P component is a glycoprotein composed of 10 identical glycosylated polypeptide subunits, each with a molecular weight of 23,500
and arranged as two pentamers. The liver produces human serum amyloid
P (SAP) component. SAP is present in healthy persons and shows 50% to
60% homology with C-reactive protein. SAP is bound to the amyloid fibrils; it is not an integral part of the fibrillar structure. It is found in all types
of amyloid, including the vessel walls in patients with Alzheimers disease.
The physiologic function of SAP and its pathologic role in amyloidosis are
unknown. Glycosaminoglycans are present in amyloid deposits. Their role
also is unknown. Catabolism or breakdown of the fibrils is an important
factor in pathogenesis; however, little is known of the process [3].
No obvious predisposing condition is associated with primary amyloidosis.
Secondary amyloidosis is associated with an inflammatory process, malignancy,
and many other conditions. No monoclonal protein exits in the serum or urine.
CHAPTER
3.2
Microscopic Appearance and Classification

Blood vessel from a bone marrow biopsy specimen indicating primary amyloidosis. The specimen was stained with Congo red dye
and viewed with a polarizing light source, producing the characteristic apple-green birefringence. In more than half of patients,
results of bone marrow testing are positive for amyloidosis. (From
Kyle [4]; with permission.)
FIGURE 3-2
Electron photomicrograph showing the fibrillar character of
amyloidosis. The fibrils are 7.5- to 10-nm wide and of indefinite length. The fibrils are deposited extracellularly, are insoluble, and generally resist proteolytic digestion. They ultimately
lead to disorganization of tissue architecture and loss of normal
tissue elements.
CLASSIFICATION OF AMYLOIDOSIS
Amyloid type
Classification
Major protein component
Primary amyloidosis (AL)

Secondary amyloidosis (AA)
Familial amyloidosis (AF)
Primary, including multiple myeloma

Secondary
Familial
Neuropathic: Portugal, Sweden, Japan, and
other countries
Cardiopathic: Denmark and Appalachia in
the United States
Nephropathic: familial Mediterranean fever
Senile cardiac
Dialysis arthropathy
or light chain
Protein A
Senile systemic amyloidosis (AS)

Dialysis amyloidosis (AD)
Transthyretin mutant (prealbumin)

Transthyretin mutant (prealbumin)
Protein A
Transthyretin normal (prealbumin)
2-microglobulin
FIGURE 3-3
Classification of amyloidosis. The fibrils in primary amyloidosis consist of monoclonal
or light chains. Rarely, monoclonal heavy chains are responsible. The major component of
the amyloid fibril in secondary amyloidosis is protein A. It has a molecular weight of 8.5 kD
and contains 76 amino acids. It is derived

from serum amyloid A, which is an acutephase protein. The level of serum amyloid
A is increased in patients with rheumatoid
arthritis and Crohns disease. In familial
amyloidosis the Portuguese, Swedish, and
Japanese variants are characterized by substitution of methionine for valine at residue 30
(Met-30) in the transthyretin molecule. This
mutation is characterized by the development
of peripheral neuropathy. Cardiomyopathy
from a transthyretin mutation has been
reported in Denmark (Met-111) and in the
Appalachian area of the United States
(Ala-60). Familial renal amyloid from a
mutation of the fibrinogen -chain (Leu-554
or Glu-526) or mutations of lysozyme have
been reported. Amyloidosis associated with
familial Mediterranean fever consists of protein A. Senile systemic amyloidosis involving
the heart results from the deposition of normal transthyretin. Long-term dialysis often
results in systemic amyloidosis from 2microglobulin deposition.
3.3
Amyloidosis
SYSTEMIC AMYLOIDOSIS
Amyloid type
Amyloid stains
Primary (AL)
Secondary (AA)
FMF
Associated with long-term
hemodialysis
Familial (AF)
Senile systemic (AS)
Congo red
or
Serum amyloid A
2-microglobulin
Transthyretin (prealbumin)
+
+
+
+
+
-
+
+
-
+
+
+
+
FIGURE 3-4
Systemic amyloidosis. Types of proteins constituting the amyloid
fibrils. In primary amyloidosis the fibrils consist of monoclonal or
light chains. In secondary amyloidosis the fibrils consist of protein A.
Systemic amyloidosis associated with long-term hemodialysis consists
Secondary (AA), 3.5%

(5)
Familial, 3.5% (5)

Senile, 2% (2)
Localized, 8% (11)
Primary (AL), 83%

(112)
of 2-microglobulin. The amyloid fibrils consist of mutated transthyretin

or, rarely, fibrinogen or lysozyme in familial amyloidosis. Senile
systemic amyloidosis is characterized by the deposition of normal
transthyretin in the heart. (From Kyle and Gertz [5]; with permission.)
FIGURE 3-5
Distribution of forms of amyloidosis seen in patients at the Mayo Clinic in 1996. Of the
135 patients with amyloidosis, 83% had the primary form. Familial, secondary, and senile
amyloidosis accounted for less than 10% of patients. Localized amyloid is limited to the
involved organ and never becomes systemic. In localized amyloidosis, the fibrils consist of
an immunoglobulin light chain; however, the patients do not have a monoclonal protein in
their serum or urine. Most localized amyloidosis occurs in the respiratory tract, genitourinary tract, or skin.
n=135
Primary Systemic Amyloidosis

FIGURE 3-6
Pattern of primary systemic amyloidosis in patients during an 11year study at the Mayo Clinic. From 1981 to 1992, of the 474
patients seen within 30 days of diagnosis the median age was 64
years. Only 1% were younger than 40 years, and males were
affected more often than were females. (From Kyle and Gertz [5];
with permission.)
50
Patients, %
40
Male: 69% (n=327)

Female: 31% (n=147)
Median age: 64 y (n=474)
Age range: 3290 y
37
30
23
22
20
10
10
0
7
1
<40
4049
5059
6069
Age, y
7079
80
3.4
70
Range: 4200 lb
Median: 23 lb
62
60
With symptoms, %
52
50
40
30
20
15
10
0
Fatigue
Weight loss
Purpura
Symptoms
FIGURE 3-7
Symptoms of primary systemic amyloidosis in patients during an
11-year study at the Mayo Clinic. Weakness or fatigue and weight
loss were the most frequent initial symptoms seen within 30 days
of diagnosis. Weight loss occurred in more than half of patients.
The median weight loss was 23 lb; five patients lost more than
100 lb each. Purpura, particularly in the periorbital and facial
areas, was noted in about one sixth of patients. Gross bleeding was
reported initially in only 3%. Skeletal pain was a major symptom
in only 5% and usually was related to lytic lesions or fractures
associated with multiple myeloma. Dyspnea, pedal edema, paresthesias, light-headedness, and syncope were noted. (From Kyle and
Gertz [5]; with permission.)
Bone pain
FIGURE 3-8
Macroglossia in a man with primary systemic amyloidosis.
Macroglossia occurs initially in about 10% of patients. Note the
imprint of the teeth on the dorsum of the tongue. This patient
was unable to close his mouth and complained of drooling.
Macroglossia may cause obstruction of the airway, sometimes
necessitating a tracheostomy. (From Kyle [4]; with permission.)
FIGURE 3-9
Nodules causing
occlusion of the
auditory canal in a
patient with primary
systemic amyloidosis.
The external auditory canal may be
occluded completely
by nodules of amyloid. This condition
frequently produces
deafness, which
may be the initial
symptom. (From
Gertz and Kyle [6];
with permission.)
FIGURE 3-10
Shoulder pad sign in a woman with primary systemic amyloidosis.
Infiltration of the periarticular tissues with amyloid may produce this
sign. The shoulder pad sign causes pain and limitation of motion and
is very difficult to treat. (From Kyle [4]; with permission.)
3.5
Amyloidosis
FIGURE 3-11
Hypertrophic form of primary systemic amyloidosis in a 39-year-old man with prominent
and firm muscles. Despite the muscular appearance, results of a biopsy revealed displacement of muscle fibers with amyloid. Patients often exhibit stiffness or limitation of movement. (From Kyle and Greipp [7]; with permission.)
FIGURE 3-12
Signs of primary systemic amyloidosis in patients during an 11-year
study at the Mayo Clinic. The liver was palpable in about one fourth
of patients seen within 30 days of diagnosis. Hepatomegaly is due to
infiltration of amyloid or congestion from heart failure. The spleen is
palpable in only 5% of patients and rarely extends more than 5 cm
below the left costal margin. Lymphadenopathy occurs infrequently.
(Adapted from Kyle and Gertz [5]; with permission.)
30
Patients, %
25
24
20
15
10
9
5
5
0
Liver palpable
Spleen palpable Lymphadenopathy

Signs of primary amyloidosis
Macroglossia
HEMOGLOBIN AND PLATELET VALUES WITHIN 30 DAYS OF DIAGNOSIS

OF PRIMARY SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 19811992
2.0
20%
n=473
Factor
Hemoglobin, g/dL (<10 g/dL in 11%)
Platelets, 109/L (>500 109/L in 9%)
Median
Range
12.9
288
6.618.6
4953
FIGURE 3-13
Hemoglobin and platelet values within 30 days of diagnosis of primary systemic amyloidosis.
Anemia was not a prominent feature. When present, it usually is due to multiple myeloma, renal
insufficiency, or gastrointestinal bleeding. Thrombocytosis was relatively common; in 9% of
patients the platelet count was over 500 109/L. Functional hyposplenism from amyloid
replacement of the spleen may occur [8]. Hyposplenism is manifested by the presence of HowellJolly bodies and occurs in about one fourth of patients. (Adapted from Kyle and Gertz [5].)
1.31.9
25%
<1.2
55%
Median: 1.1
Range: 0.414.6
FIGURE 3-14
Serum creatinine (mg/dL) in patients at
diagnosis of primary systemic amyloidosis.
Renal insufficiency was present in almost
half of patients. Proteinuria was present in
about 75% of patients.
3.6
Polyclonal
1%
Hypogammaglobulinemia
20%
band
10%
IgM 5%
IgD 1%
6.0
20%
only
9%
Negative
28%
only
15%
band
38%
Normal
31%
n=463
IgA
10%
IgG
32%
<1.0
45%
3.05.9
16%
n=430
Median:1.2 g/d
Range: 0.124.1 g/d
1.02.9
19%
n=443
FIGURE 3-15
Results of serum protein electroplasmaphoresis in patients at diagnosis of
primary systemic amyloidosis. The serum
protein electrophoretic pattern showed
hypogammaglobulinemia in 20% of
patients. Only half of patients had a localized band or spike in the or areas of the
electrophoretic pattern. The median size of
the M spike was 1.4 g/dL. In the remaining
patients the pattern was normal.
S+, U
16%
S, U
11%
23%
50%
Negative
27%
FIGURE 3-16
Serum monoclonal (M-) protein in patients at
diagnosis of primary systemic amyloidosis in
an 11-year study at the Mayo Clinic.
Immunoelectrophoresis or immunofixation of
the serum showed an M-protein in 72% of
patients. IgG was most common, followed by
IgA. Twenty-four percent of patients had monoclonal immunoglobulin light chains in the
serum (Bence Jones proteinemia). (Adapted
from Kyle and Gertz [5]; with permission.)
n=429
S, U+
17%
FIGURE 3-17
Urine total protein values in patients at
diagnosis of primary systemic amyloidosis
in an 11-year study at the Mayo Clinic.
More than one third of patients exhibited
24-hour urine total protein values of 3.0
g/d or more. Over half of patients had a
urine protein value of more than 1 g/d. The
electrophoretic pattern showed mainly
albumin. (Adapted from Kyle and Gertz
S+, U+
56%
n=408
FIGURE 3-18
Urine monoclonal (M-) protein in patients
at diagnosis of primary systemic amyloidosis
Almost three fourths of patients had monoclonal light chains in their urine on immunoelectrophoresis or immunofixation. In
contrast to the type of protein found in multiple myeloma, is twice as common as is .
The 24-hour total amount of monoclonal
(M-) protein in the urine was less than 0.5
g/d in more than half of patients. (From
Kyle and Gertz [5]; with permission.)
FIGURE 3-19
Serum (S) and urine (U) proteins in
patients with primary systemic amyloidosis
Immunoelectrophoresis or immunofixation
of serum and appropriate concentrations in
urine showed a monoclonal protein in nearly
90% of patients. In the absence of monoclonal protein, one must search for a monoclonal population of plasma cells in the bone
marrow or perform immunohistochemical
staining to identify the type of amyloid.
(From Kyle and Gertz [5]; with permission.)
FIGURE 3-20
Enlarged kidney in primary systemic amyloidosis. Involvement of the kidneys is the
most common presenting feature. The kidney is frequently normal in size, but in some
instances small kidneys have been found.
Amyloidosis
3.7
100
Survival, %
80
60
40
20
0
0
Years after dialysis

Photomicrograph showing a renal biopsy specimen stained with
Congo red dye taken from a patient with primary systemic amyloidosis. Note the homogeneous deposition of amyloid in the glomerulus. Results of kidney biopsy are positive in about 95% of patients.
FIGURE 3-22
Survival analysis of patients with primary systemic amyloidosis.
The median survival from the onset of dialysis was 8.2 months in
37 patients. No difference exists between patients treated with
hemodialysis and those treated with peritoneal dialysis. Biopsy
results were used to make the diagnosis in 211 patients. The most
important predictors of which patients would ultimately require
dialysis were the 24-hour urinary protein loss and serum creatinine
values at the time of diagnosis. None of the patients who had a
normal serum creatinine value and a urine protein value of less
than 2 g/d at diagnosis required dialysis during follow-up. Of the
37 patients who received dialysis, 31 died, and 21 of the 31 died as
a result of extrarenal progression of their systemic amyloidosis.
Half of the deaths were caused by cardiac amyloidosis [9].
FIGURE 3-23
Gross specimen of a liver in primary systemic amyloidosis. The
liver is grossly enlarged.
FIGURE 3-24
Photomicrograph showing extensive amyloid deposition in the liver
in primary systemic amyloidosis.
3.8
ALKALINE PHOSPHATASE, ASPARTATE AMINOTRANSFERASE, AND BILIRUBIN VALUES WITHIN 30 DAYS OF

DIAGNOSIS OF PRIMARY SYSTEMIC AMYLOIDOSIS,
MAYO CLINIC, 19811992
PROTHROMBIN TIME, CAROTENE, AND B12 VALUES

WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY
SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 19811992
Factor
Factor
Normal value
Values above normal, n (%)
Alkaline phosphatase
250 U/L
Aspartate aminotransferase
30 U/L
>250 (26)
500 (11)
>30 (34)
100 (3)
>1.1 (11)
5 (1)
Total bilirubin
1.1 mg/dL
FIGURE 3-25
Alkaline phosphatase, aspartate aminotransferase, and bilirubin
values within 30 days of diagnosis of primary systemic amyloidosis. The serum alkaline phosphatase level was increased in one
fourth of 474 patients at the time of diagnosis. The aspartate
aminotransferase value was increased in one third of patients but
rarely reached 100 U/L. Hyperbilirubinemia was an infrequent
finding but when present was associated with short survival [5].
(Adapted from Kyle and Gertz [5].)
Patients, %
Prothrombin time >13 s

Carotene <48 g/dL
Serum B12 <150 pg/mL
16
6
3
FIGURE 3-26
Prothrombin time, carotene, and vitamin B12 values within 30 days
of diagnosis of primary systemic amyloidosis. The prothrombin
time was increased in one sixth of patients at the time of diagnosis.
It has been shown that prolongation of thrombin time occurs in
40% of patients [10]. A deficiency in factor X occurs in 15% but
is not associated with bleeding. Malabsorption as manifested by a
low carotene or serum B12 level occurs infrequently. (Adapted from
Kyle and Gertz [5].)
PERCENTAGE OF BONE MARROW PLASMA CELLS

WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 19811992
FIGURE 3-27
Bone marrow aspirate specimen from a patient with primary systemic
amyloidosis. This specimen contains an increase in plasma cells.
Plasma cells, % (median = 7%)
Patients, % (n = 391)
5
69
1019
20
44
16
22
18
FIGURE 3-28
Percentage of bone marrow plasma cells within 30 days of diagnosis of primary systemic amyloidosis. Almost half of patients had
5% or fewer plasma cells in the bone marrow at the time of diagnosis. About one fifth of patients had bone marrow plasmacytosis
of 20% or more. Multiple myeloma must be considered in this setting. The plasma cells are monoclonal or . (From Kyle and
Gertz [5]; with permission.)
3.9
Amyloidosis
FIGURE 3-29
Radiograph showing
marked cardiac
enlargement in a
patient with primary
systemic amyloidosis.
Overt congestive heart
failure is present in
about one sixth of
patients at the time
of diagnosis. Pleural
effusion is common.
FIGURE 3-30
Electrocardiogram in a patient with primary systemic amyloidosis,
showing low voltage in the limb leads or loss of anterior septal
forces that mimics the findings in myocardial infarction. However,
ischemic heart disease is not present. Arrhythmias may include atrial
fibrillation, junctional tachycardia, premature ventricular complexes,
or heart block.
20 mm
11%
1519 mm
36%
Survival, %
11 mm
24%
100
P=0.0003
75
< 15 mm (n=64)
50
25
1214 mm
29%
n=121
FIGURE 3-31
Echocardiogram of a patient with primary
systemic amyloidosis showing marked
thickness of the ventricular wall. Results on
echocardiogram are abnormal in two thirds
of patients at the time of diagnosis. LVleft
ventricle; RVright ventricle. (From Gertz
and Kyle [3]; with permission.)
FIGURE 3-32
Septal thickness on echocardiography in
patients with primary systemic amyloidosis.
Almost half of patients had septal thickness
of 15 mm or more on echocardiography at
the time of diagnosis. Only 24% had no
increased septal thickness.
15 mm (n=57)
0
0
3
Time, y
FIGURE 3-33
Analysis of the association between septal
thickness and survival in patients with primary systemic amyloidosis in an 11-year
study at the Mayo Clinic. An increase in
septal thickness is associated with shorter
survival. Patients with a septal thickness of
15 mm or more had a median survival of
7 months, whereas in those with a septal
thickness less than 15 mm the median survival was 26 months. (From Kyle and Gertz
3.10

FIGURE 3-34
Cross section of the heart showing marked thickening of the left
ventricular wall and septum in primary systemic amyloidosis. The
ventricular cavity is greatly reduced in volume. (From Gertz and
Kyle [3]; with permission.)
40
Patients, %
30
FIGURE 3-35
Analysis of previously unexplained syndromes in patients with primary systemic amyloidosis at the time of diagnosis in an 11-year
study at the Mayo Clinic. Nephrotic syndrome or renal failure was
present in 28% of patients, congestive heart failure (CHF) in 17%,
and carpal tunnel syndrome in 21%. Peripheral neuropathy and
orthostatic hypotension also were common features. The possibility
of primary systemic amyloidosis must be considered in every
patient who has monoclonal protein in the serum or urine and who
has unexplained nephrotic syndrome, CHF, sensorimotor peripheral neuropathy, carpal tunnel syndrome, hepatomegaly, or malabsorption. (Adapted from Kyle and Gertz [5]; with permission.)
At diagnosis
During follow-up
n=474
2
5
0.5
20
0.5
1.5
10
0
28
17
21
Nephrotic/
renal failure
(142)
CHF
Carpal
tunnel
(102)
(104)
17
11
Peripheral Orthostatic
neuropathy hypotension
(58)
(81)
Symptoms (number of patients)
100
Positive, %
80
60
94
90
86
Skin
Sural
nerve
(21)
83
82
80
100
97
75
56
40
20
0
Abdominal Bone Rectum Kidney Carpal

ligament
fat
marrow
(20)
(212)
(394)
(194)
(81)
Liver
(32)
Small
intestine
(23)
Presence of amyloid in tissue (number of patients)
(19)
Heart
(16)
FIGURE 3-36
Diagnosis of primary systemic amyloidosis
based on the presence of amyloid in tissue
The initial diagnostic procedure should be
an abdominal fat aspirate [11]. The diagnosis will be confirmed in 80% of patients.
Experience in the staining technique and
interpretation of the fat aspirate is important
before routine use. A bone marrow aspirate
and bone marrow biopsy specimen should
be obtained to determine the degree of plasmacytosis, and results of amyloid stains are
positive in more than half of patients. Either
the abdominal fat aspirate or bone marrow
biopsy specimen is positive in 90% of
patients. When amyloid is still suspected and
the test results of these tissues are negative,
one should proceed to performing a rectal
biopsy, which is positive in approximately
80% of patients. The specimen must include
the submucosa. When the test results for
these sites are negative, tissue should be
obtained from an organ with suspected
involvement. (From Kyle and Gertz [5];
with permission.)
3.11
Amyloidosis
100
Nephrotic/renal failure (n=114)

Congestive heart failure (n=80)
Orthostatic hypotension (n=41)
Survival, %
75
Peripheral neuropathy (n=40)

Total (n=474)
50
25
0
0

Aspirate of subcutaneous abdominal fat from a patient with primary systemic amyloidosis. The specimen shows the characteristic
apple-green birefringence when stained with Congo red dye and
viewed with a polarizing light source.
4
Time, y
FIGURE 3-38
Analysis of median survival in patients with primary systemic amyloidosis in an 11-year study at the Mayo Clinic. The median survival of 474 patients seen within 1 month of diagnosis was 13.2
months. The median duration of survival was 4 months for the
80 patients who exhibited congestive heart failure on presentation.
(From Kyle and Gertz [5]; with permission.)
FIGURE 3-39
Causes of death in patients with primary systemic amyloidosis in an 11-year study at the
Mayo Clinic. Of the 285 patients who died, death was attributed to cardiac involvement
from congestive heart failure or arrhythmias in 48%. The actual percentage of cardiacrelated deaths was probably higher because some patients whose death was attributed to
primary amyloidosis almost certainly had terminal cardiac arrhythmia. (Adapted from
Kyle and Gertz [5]; with permission.)
Infection
8%
Renal
6%
Other
8%
Cardiac
48%
Unknown
13%
"Primary
amyloidosis"
17%
n=285
100
Arm
MP
MPC
C
Patients, %
80
60
Months
18
17
8.5
P<0.001
40
20
0
0
5
6
Survival, y
10
FIGURE 3-40
Survival curves in patients with primary systemic amyloidosis. Because
amyloid fibrils consist of monoclonal immunoglobulin light chains,
treatment with alkylating agents that are effective against plasma cell
neoplasms is warranted. We treated 220 patients who had positive
results on biopsy. The patients were randomized to receive colchicine
(C, 72 patients), melphalan and prednisone (MP, 77), or melphalan,
prednisone, and colchicine (MPC, 71). Patients were stratified according to their chief clinical manifestations: renal disease (105 patients),
cardiac involvement (46), peripheral neuropathy (19), or other (50).
The median duration of survival after randomization was 8.5 months
in the colchicine group; 18 months in the group assigned to melphalan
and prednisone; and 17 months in the group assigned to melphalan,
prednisone, and colchicine (P < 0.001). In patients who had a reduction in serum or urine monoclonal protein at 12 months, the overall
duration of survival was 50 months; whereas among those without a
reduction in monoclonal protein at 12 months, the duration of survival was 36 months (P < 0.003). Thirty-four patients (15%) survived
for 5 years or longer. (Adapted from Kyle et al. [12]; with permission.)
3.12

FIGURE 3-41
Other therapy for primary amyloidosis. High-dose dexamethasone
has been reported to be beneficial in treating patients with primary
systemic amyloidosis [13]. More intensive therapy consisting of
high-dose chemotherapy followed by rescue with peripheral stem
cells shows promise [14]. The introduction of 4-iodo-4-deoxydoxorubicin, which has an affinity for amyloid fibrils, may be an
important treatment option [15].
OTHER THERAPY FOR PRIMARY AMYLOIDOSIS

High-dose dexamethasone
Stem cell transplantation
4-iodo-4-deoxydoxorubicin
Secondary Amyloidosis
CAUSES OF SECONDARY AMYLOIDOSIS
Cause
PRESENTING CLINICAL FEATURES

OF SECONDARY AMYLOIDOSIS
Patients, n
Feature
Rheumatic disease
Rheumatoid arthritis
Ankylosing spondylitis
Other
Total
Infection
Bronchiectasis
Osteomyelitis
Other
Total
Malignancy
None
Proteinuria or renal insufficiency

Diarrhea, obstipation, or malabsorption
Goiter
Hepatomegaly
Neuropathy or carpal tunnel syndrome
Lymphadenopathy
Hematuria
Cardiac amyloidosis
31
5
6
42
6
5
5
3
19
2
1
FIGURE 3-42
Causes of secondary amyloidosis. Rheumatoid arthritis is the most
frequent cause of secondary amyloidosis. In our study of 64
patients, rheumatoid arthritis was present for a median of 18 years
before the diagnosis was made [16]. Inflammatory bowel disease,
bronchiectasis, and osteomyelitis are not uncommon causes of secondary amyloidosis. (From Gertz and Kyle [16]; with permission.)
19
Patients, n
17
14
15
10
17
17
14
14
5
0
13
38
>8
0
24-h urinary protein, g/d
n=55
91
22
9
5
3
2
2
0
FIGURE 3-43
Presenting features of secondary amyloidosis. Proteinuria is the
most frequent laboratory finding in patients with secondary amyloidosis. Involvement of the gastrointestinal tract as manifested by
diarrhea, obstipation, or malabsorption occurred in one fifth of
our patients. Treatment of secondary amyloidosis depends on the
underlying disease. Familial Mediterranean fever frequently is associated with secondary amyloidosis unless the patient is treated with
colchicine. (From Gertz and Kyle [16]; with permission.)
FIGURE 3-44
Proteinuria and renal insufficiency in patients with secondary
amyloidosis. The clinical target organ was the kidney in 91% of
patients. (From Gertz and Kyle [16]; with permission.)
25
20
Patients, %
1 1.12 2.14 >4

n=64
Amyloidosis
100
Creatinine <2.0 mg/dL, n=32
Creatinine 2.0 mg/dL, n=32
P=0.003
Survival, %
80
3.13
FIGURE 3-45
Association between serum creatinine levels and survival in patients
with secondary amyloidosis. A serum creatinine value of 2 mg/dL or
more was associated with a shorter survival than was a value of less
than 2 mg/dL. (From Gertz and Kyle [16]; with permission.)
60
40
20
0
0
24
48
72
96
120
Time, mo
Familial Amyloidosis
2
1
2
2
1 2
4
3
1 1 3
6
7 6
2
1 1
1 1
1 1
1 5
2
3
2
2 3
1
2
3
4
5
6
7
Not studied for variant transthyretin

Met-30
Ala-60
Tyr-77
His-58
Leu-33
Studiedno variant transthyretin found
Leu-64
FIGURE 3-46
Wide geographic distribution of familial amyloidosis. Familial or
hereditary amyloidosis has an autosomal dominant pattern of
inheritance. It accounts for 3.5% of our cases of amyloidosis. In
our practice, the geographic distribution is wide and not associated
with clustering. Frequently, a family history of amyloidosis was not
obtained until after amyloidosis was diagnosed [17]. More than 50
transthyretin mutations have been recognized [18]. (Adapted from
Gertz et al. [17]; with permission.)
3.14
CLASSIFICATION OF FAMILIAL AMYLOIDOSIS

Classification
Major protein component
Neuropathic: Portugal, Japan, Sweden,

and other countries
Cardiopathic: Denmark and Appalachia
in the United States
Nephropathic: familial Mediterranean
fever
Protein A
FIGURE 3-47
Classification of familial amyloidosis. Clinically, familial amyloidosis
can be classified most easily as neuropathic, cardiopathic, or nephropathic. The neuropathic form is characterized by a sensorimotor
peripheral neuropathy beginning in the lower extremities. Disturbances
of bladder and gastrointestinal function are common. Late onset may

occur with the development of symptoms in the seventh or eighth
decade of life. The nephropathic form is most often caused by familial
Mediterranean fever. This form affects persons of Mediterranean
descent and is characterized by recurrent episodes of fever and abdominal pain that begin in childhood.
Familial amyloidosis involving the kidneys has been reported by
Ostertag [19] and others [2022]. Families with apolipoprotein A1
mutation, as well as mutations in the fibrinogen -chain gene, have
been recognized. On presentation, patients with renal involvement
exhibit hypertension and mild renal insufficiency that progresses to endstage renal failure. The amyloid deposits have mutations in the fibrinogen -chain gene. This form of amyloidosis is autosomal dominant. No
peripheral neuropathy develops, and the onset of renal disease occurs in
the fifth to seventh decades of life. The mutation consists of the substitution of glutamic acid for valine at position 526 of the fibrinogen
chain. A mutation in fibrinogen has been described at position 554
[23,24]. A rare form of inherited secondary amyloidosis produces
nephropathy, deafness, and urticaria. This form has been referred to as
the Muckle-Wells syndrome [25]. (Adapted from Kyle and Gertz [26].)
Dialysis-Associated Amyloidosis
RATE OF AMYLOIDOSIS (2-MICROGLOBULIN)
WITH DIALYSIS
Years of dialysis
10
15
>20
FIGURE 3-48
Radiograph showing carpal tunnel syndrome in a patient
with dialysis-associated amyloidosis. Long-term hemodialysis
often results in carpal tunnel syndrome with pain involving
the shoulders, hands, wrists, hips, and knees. Cystic radiolucencies are common in the carpal bones. Pathologic fractures have
occurred from large amyloid deposits. The major component
of the amyloid is 2-microglobulin. (From Gertz and Kyle [3];
with permission.)
Patients with amyloidosis, %

20
3050
80100
FIGURE 3-49
Amyloidosis (2-microglobulin) with dialysis. The duration of dialysis is directly associated with the incidence of amyloidosis. Dialysisassociated amyloidosis will develop in more than 80% of patients
after 20 years of dialysis. It occurs with both hemodialysis and peritoneal dialysis. The amyloid deposition is systemic; however, involvement of visceral organs is usually modest [27,28]. Renal transplantation often leads to dramatic improvement in joint symptoms. A 2microglobulinabsorbent column may be useful in therapy [29].
Amyloidosis
3.15
References
1. Virchow R: Cited by Schwartz P: Amyloidosis: Cause and Manifestation
of Senile Deterioration. Springfield, IL: Charles C Thomas; 1970.
2. Puchtler H, Sweat F: Cited by Elghetany MT, Saleem A: Methods for
staining amyloid in tissues: a review. Stain Technol 1988, 63:201212.
3. Gertz MA, Kyle RA: Amyloidosis. In Neoplastic Diseases of the
Blood, edn 3. Edited by Wiernik PH, Canellos GP, Dutcher JP, et al.
New York: Churchill Livingstone; 1996:635677.
15. Gianni L, Bellotti V, Gianni AM, et al.: New drug therapy of amyloidoses: resorption of AL-type deposits with 4-iodo-4-deoxydoxorubicin. Blood 1995, 86:855861.
16. Gertz MA, Kyle RA: Secondary systemic amyloidosis: response and
survival in 64 patients. Medicine 1991, 70:246256.
4. Kyle RA: Amyloidosis. In Hematology: Basic Principles and Practice.

Edited by Hoffman R, Benz EJ Jr, Shattil SJ, et al. New York:
Churchill Livingstone; 1991:10381047.
17. Gertz MA, Kyle RA, Thibodeau SN: Familial amyloidosis: a study of
52 North American-born patients examined during a 30-year period.
Mayo Clin Proc 1992, 67:428440.
18. Saraiva MJM: Molecular genetics of familial amyloidotic polyneuropathy. J Peripheral Nerv Syst 1996, 1:179188.
5. Kyle RA, Gertz MA: Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995, 32:4559.
19. Ostertag B: Demonstration einer eigenartigen familiaren paraamyloidose [abstract]. Zentralbl Allg Pathol 1932, 56:253254.
6. Gertz MA, Kyle RA: Primary systemic amyloidosis: a diagnostic

primer. Mayo Clin Proc 1989, 64:15051519.
20. Weiss SW, Page DL: Amyloid nephropathy of Ostertag with special
reference to renal glomerular giant cells. Am J Pathol 1973,
72:447460.
7. Kyle RA, Greipp PR: Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clin Proc 1983, 58:665683.
8. Gertz MA, Kyle RA, Greipp PR: Hyposplenism in primary systemic
amyloidosis. Ann Intern Med 1983, 98:475477.
21. Lanham JG, Meltzer ML, De Beer FC, et al.: Familial amyloidosis of
Ostertag. Q J Med 1982, 51:2532.
13. Dhodapkar M, Jagannath S, Vesole D, et al.: Efficacy of pulse dexamethasone (DEX) plus maintenance alpha interferon (IFN) in primary
systemic amyloidosis (AL) [abstract]. Blood 1995, 86(suppl 1):442A.
22. Mornaghi R, Rubinstein P, Franklin EC: Familial renal amyloidosis:

case reports and genetic studies. Am J Med 1982, 73:609614.
23. Benson MD, Liepnieks J, Uemichi T, et al.: Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet
1993, 3:252255.
24. Uemichi T, Liepnieks JJ, Benson MD: Hereditary renal amyloidosis
with a novel variant fibrinogen. J Clin Invest 1994, 93:731736.
25. Muckle TJ: The Muckle-Wells syndrome. Br J Dermatol 1979,
100:8792.
26. Kyle RA, Gertz MA: Amyloidosis of the liver. In Schiffs Diseases of
the Liver, edn 8. Edited by Schiff ER, Sorrell MF, Maddrey WC.
Philadelphia: Lippincott-Raven; in press.
27. Gejyo F, Arakawa M: 2-microglobulin-associated amyloidoses. J Intern
Med 1992, 232:531532.
28. Kay J: 2-Microglobulin amyloidosis. Int J Exp Clin Invest 1997,
4:187211.
14. Comenzo RL, Vosburgh E, Sarnacki DL, et al.: High-dose melphalan

with blood stem-cell support for AL amyloidosis [abstract]. Blood
1995, 86 (suppl 1):206A.
29. Gejyo F, Homma N, Hasegawa S, et al.: A new therapeutic approach

to dialysis amyloidosis: intensive removal of 2-microglobulin with
adsorbent column. Artif Organs 1993, 17:240243.
9. Gertz MA, Kyle RA, OFallon WM: Dialysis support of patients with
primary systemic amyloidosis: a study of 211 patients. Arch Intern
Med 1992, 152:22452250.
10. Gastineau DA, Gertz MA, Daniels TM, et al.: Inhibitor of the thrombin time in systemic amyloidosis: a common coagulation abnormality.
Blood 1991, 77:26372640.
11. Gertz MA, Li C-Y, Shirahama T, Kyle RA: Utility of subcutaneous fat
aspiration for the diagnosis of systemic amyloidosis (immunoglobulin
light chain). Arch Intern Med 1988, 148:929933.
12. Kyle RA, Gertz MA, Greipp PR, et al.: A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 1997, 336:12021207.
Sickle Cell Disease

L.W. Statius van Eps
errick [1] was the first to discover sickle cell hemoglobin (2
S2) with sickle-shaped erythrocytes. In 1910, he described
the case of a young black student from the West Indies with
severe anemia characterized by peculiar elongated and sickle-shaped
red blood corpuscles. Herrick also noted a slightly increased volume
of urine of low specific gravity and thus observed the most frequent
feature of sickle cell nephropathy: inability of the kidney to concentrate urine normally.
CHAPTER
4.2
Sickle Cell Nephropathy

The term sickle cell nephropathy encompasses all the structural
and functional abnormalities of the kidneys seen in sickle cell
disease. These renal defects are most pronounced in homozygous sickle cell anemia (Hb SS), double heterozygous sickle cell
hemoglobin C disease (Hb SC), sickle cell hemoglobin D dis-
ease, sickle cell hemoglobin E disease (SE) disease, and sickle

cell -thalassemia. Identification of this familial autosomal
codominant disorder as an abnormality of the hemoglobin molecule was made in 1949 by Pauling and coworkers [2].
Sickle Cell Anemia

In 1959, Ingram [3] discovered the exact nature of the defect:
substitution of valine for glutamic acid at the sixth residue of the
chain, establishing sickle cell anemia as a disease of molecular
structure, a molecular disease based on one point mutation. It
is most fascinating that one substitution in the gene encoding,
with the resulting replacement of 6 glutamic acid by valine,
leads to the protean and devastating clinical manifestations of
sickle cell disease. The structural and functional abnormalities in
the kidneys of patients with sickle cell disease, all resulting from
that one point mutation, are described and discussed.
When sickle hemoglobin (Hb S) is deoxygenated the replacement of 6 glutamic acid with valine has as a consequence a
hydrophobic interaction with another hemoglobin molecule
(reproduced schematically in Fig. 4-3). One of the two subunits forms a hydrophobic contact with an acceptor site on a
subunit of a neighboring chain. An aggregation into large
polymers is triggered. The twisted ropelike structure to the right
is a polymer composed of 14 strands.
In a concentrated solution of deoxygenated Hb S, large polymers and free tetramers are demonstrated readily. However,
species of intermediate size cannot be detected. This means
polymerization of Hb S occurs easily and can be regarded as a

simple crystal solution equilibrium [4].
As a rule, renal hemodynamics are either normal or supernormal in patients with Hb SS and who are less than 30 years
of age. The filtration fraction (glomerular filtration rate/effective renal plasma flow) has been found to be decreased (mean,
14% to 18%; normal, 19% to 22%). It has been suggested that
selective damage of the juxtamedullary glomeruli might result
in a lower filtration fraction because these nephrons appear to
have the highest filtration fractions. Microradioangiographic
studies lend support to this suggestion [5].
Speculation exists as to the possible mechanisms responsible for the decline in renal hemodynamics with age, sometimes ending in renal failure with shrunken end-stage kidneys.
This decline could be the result of the loss of medullary circulation, as suggested by the microradioangiographic studies.
Another possible mechanism is the relationship between
supernormal hemodynamics, hyperfiltration, and glomerulosclerosis [6].
An inability to achieve maximally concentrated urine has
been the most consistent feature of sickle cell nephropathy.
Sickle Cell Disease
4.3
Molecular Pathogenic Mechanisms and Sickling

EF1
EF
F'
F1
A9
H23
E'
H15
E7
H'
H9
G9
FG4
C3
C4
G19
FG3
G1
G'
C3
C'
E
B11
G' C5
CD5
C6
C C3
C5
G1
B14
C6
CD5
C7
B9
E1
G3
E1
G2
G19
G9
FG5
FG4
FG3
H9
F'
D1
FG4
H'
E7
E7
F8
H15
E'
A12
A'
A'
F8
B1
FIGURE 4-1
Three-dimensional drawing of a hemoglobin molecule. Shown are the interrelationship of the two and two chains, localization of the helices, amino acids in the
chains, and iron molecules in the porphyria
structure. Of the 1 and 2 chains the helical and nonhelical segments can be identified easily. The individual amino acids are
marked as circles and connected to each
other. The dark rectangles represent the
heme group, and within their center is the
iron molecule. These heme groups are localized between the E and F helices. The helices
in a hemoglobin molecule are designated by
letters from A to H, starting from the
amino end. The whole molecule has a
spherical form with a three-dimensional
measurement of 64 by 55 by 50 .
(Adapted from Dickerson and Geis [7];
with permission.)
A1
EF
EF1
Respiratory Movement of the Hemoglobin Molecule

Shift of
chains
F
1
F'
H'
H'
F'
B'
A'
H
G
B
G'
GH
GH
C
D
H
1
H
GH
C
E
B'
G'
F'
Oxyhemoglobin
GH
A
F
D
H
F'
Deoxyhemoglobin
FIGURE 4-2
Respiratory movement of a hemoglobin
molecule. From a functional point of view
the so-called respiratory movement of the
hemoglobin molecule is of great importance. When the four oxygen atoms bind to
oxyhemoglobin, the firmly bound 1-1
and 1-2 move away from each other
slightly. After full oxygenation the heme
groups of the chains are 7 closer to
each other (R configuration). After deoxygenation the opposite occurs (T configuration). This respiratory movement (R indicates the relaxed and T the tense configuration) is of great importance in our
understanding of the pathogenesis of sickling: polymerization occurs when the T
configuration takes place. (Adapted from
Dickerson and Geis [7]; with permission.)
4.4
FIGURE 4-3
Schematic representation of the interactions
of sickle red cells. Sickle red cells (dark circles)
traverse the microcirculation, releasing oxygen from oxyhemoglobin, and change into
deoxyhemoglobin (light circles).
Deoxygenation of hemoglobin S induces a
change in conformation in which the subunits move away from each other. The
hydrophobic patch at the site of the 6
where the valine replacement has occurred
(shown as a projection) can bind to a complementary hydrophobic site of the 6 valine
replacement (shown as an indentation). This
mechanism is important for the formation of
a polymer (see Fig. 4-4). The diagram to the
right shows the assembly of deoxyhemoglobin S into a helical 14-strand fiber: a polymer is formed (see Fig. 4-5). As the deoxyhemoglobin S polymerizes and fibers align, the
erythrocyte is transformed into a sickle
shape, observed at the bottom by scanning
electron micrography. (Adapted from Bunn
[4]; with permission).
O2
Cell
Polymer
Nucleation
Alignment
Growth
FIGURE 4-4
Polymerization of sickle cell hemoglobin. This polymerization occurs in three stages: 1)
nucleation, 2) fiber growth, and 3) fiber alignment. The end stage is a complicated structure
for a helical fiber: four inner fibers surrounded by 10 outer filaments. Sickling, the process of
polymerization, occurs under three different circumstances: 1) deoxygenation, 2) acidosis,
and 3) extracellular hyperosmolality. These circumstances produce shrinking of the erythrocytes that causes elevation of the intracellular hemoglobin concentration. This mechanism
occurs in the inner medulla of the kidney and renal papillae as a result of countercurrent
multiplication. Extracellular osmolality increases with the results previously mentioned [8].
Sickle Cell Disease
4.5
Electron Microscopy and Three-Dimensional

Reconstruction of a Polymerized Fiber of Hemoglobin
FIGURE 4-5
Structures of polymerized fibers. A, Electron microscopy of a polymerized
fiber of hemoglobin S. BD, Structures of a three-dimensional reconstruction
of such a fiber. Each small sphere represents a Hb S tetramer. B, A complete
fiber, consisting of 14 grouped filaments in helical structure. C, The inner
core of four filaments. D, A combination of inner and outer filaments. (From
Edelstein [9]; with permission.)
Polymerization of Hemoglobin S
A
FIGURE 4-6
Polymerization of hemoglobin S. Polymerization of deoxygenated
hemoglobin S is the primary event in the molecular pathogenesis of
sickle cell disease, resulting in a distortion of the shape of the erythrocyte and a marked decrease in its deformability. These rigid cells are
responsible for the vaso-occlusive phenomena that are the hallmark of
the disease [4]. Interesting shapes of variable forms result depending
B
on the localization of the polymers in the cell. A collection of electron
microscopy scans of sickle cells undergoing intracellular polymerization is shown here. The slides were created in different laboratories.
A, Characteristic peripheral blood smear from a patient with sickle cell
anemia. Extreme sickled forms and target cells are seen. B, Electron
microscopy scan of normal erythrocytes.
4.6
J
C, Electron microscopy scan of a normal
erythrocyte and a sickle cell. DL, This
series of sickle cells show many possible
formations of sickled erythrocytes. The
variety of shapes results from the intracellular localization of the polymers. In bananaor sickle-shaped cells the polymers have
formed bundles of fibers oriented along the
long axis of the cell. In cells with a hollyleaf shape (panel E), the hemoglobin fibers
point in different directions.
Sickle Cell Disease
4.7
Types of Sickle Cells and Released Membrane Structures
FIGURE 4-7
Types of sickle cells and released membrane structures. Franck and
coworkers [10] reported that the normal membrane phospholipid
organization is altered in sickled erythrocytes. These authors presented evidence of enhanced trans-bilayer movement of phosphatidylcholine in deoxygenated reversibly sickled cells and put forward the
hypothesis that these abnormalities in phospholipid organization are
confined to the characteristic protrusions of these cells. Scanning
electron micrographs of various types of sickle cells and released
membrane structures are shown. A, Deoxygenated despicular red
sickle cells (RSC). B, Deoxygenated native RSC. C, Oxygenated irreversibly sickled cell. D, Spicules. E, Purified microvesicles. The free
spicules released from RSC by repeated sickling and unsickling as
well as the remnant despicular cells were studied by following the
fate of 14C-labeled phosphatidylcholine. The results are shown in
Figure 4-8. The free spicules have the same lipid composition as do
the native cell but are deficient in spectrin. These spicules markedly
enhance the rate of thrombin and prothrombin formation, explaining the prethrombotic state of the patient with sickle cell disease and
the tendency toward the occurrence of crises. The prethrombotic
state, also present in the renal circulation, stimulates sickle cell formation occurring in the inner renal medulla and papillae where
hyperosmosis also contributes to sickling and microthrombi formation
in the vasa recta. (From Franck and coworkers. [10]; with permission.)
4.8
Penetration and Deconstruction

of the Erythrocyte Membrane
Spicule formation in sickled erythrocyte
Spicule formation in
sickled erythrocyte
Band 3
Actin
Band 4.1
Spectrin
Ankyrin
FIGURE 4-8
Penetration and destruction of the erythrocyte membrane. A, The
membrane is penetrated and destroyed by the intracellular formation of polymers, resulting in spicule formation. B, Interruption
of the binding between the membrane and protein skeleton
results in a massive exchange of lipids between the inside and
outside of the cell. This process is called flip-flop. An abnormal
membrane skeleton causes an increased flip-flop. The result in the
spicule is a change of the chemical structure, increasing the tendency toward coagulation of sickle cell blood (prethrombotic
state). C, The relationship between the protein skeleton of the
erythrocyte and lipid membrane is shown. (Adapted from Franck
Sickle Cell Disease
FIGURE 4-9
Macroscopy and microradioangiographs of sickle cell kidneys. The kidneys of patients with sickle cell disease usually
are of near normal size, and most kidneys show no significant gross alterations. Abnormalities can be expected in the
renal medulla as erythrocytes form sickles more readily in the relatively hypoxic and hyperosmotic renal medulla than in
other capillary circulations. Formation of microthrombi causes further impairment of the vasa recta circulation. A and
B, Injection microradioangiographs of the kidney in a person without hemoglobinopathy are shown: the entire kidney
(panel A) and a detailed view (panel B). C and D, Injection microradioangiographs of the kidney in a patient with sickle
cell disease are shown: the entire kidney (panel C) and a detailed view (panel D). E, Injection microradioangiograph of a
kidney in a patient with sickle cell hemoglobin C disease . In the normal kidney (panel A), vasa recta are visible radiating into the renal papilla. In sickle cell anemia (panel D), vasa recta are virtually absent. Those vessels that are present
show abnormalities: they are dilated, form spirals, end bluntly, and many appear to be obliterated. In the patient with
hemoglobin SC (panel E) changes are seen intermediately between patients with hemoglobin SC and normal persons.
(From van Eps et al. [5]; with permission.)
4.9
4.10
Renal Concentrating Mechanism in a Normal Person

Juxtamedullary nephron
600
Cortex
Urine osmolality, mosmol/kg
1200
400
0
5
10
50 100
Urine arginine vasopressin, pg min1 C 1osm
500
FIGURE 4-10
AH, Models to demonstrate the principle of countercurrent multiplier in creating high urine concentration. The first panel illustrates
the relation between urine osmolality and arginine vasopressin
excretion. The long loops of Henle and their accompanying vasa
recta reaching the papillae comprise only 15% of the total nephron
population but are necessary for producing concentrated urine
[12]. As seen, the mechanisms of countercurrent multiplication and
countercurrent exchange create an increase in osmolality in the
kidney from 280 mOsm at the cortex to about 1200 mOsm/kg
H2O in the inner medulla and papillae. Reabsorption in the collecting ducts results in production of highly concentrated urine.
Medulla
Thin
segment
Vasa
recta

B
Sickle Cell Disease

Urine concentration and dilution: countercurrent multiplier
285
285
285
185
285
285
185
285
385
185
385
185
385
185
485
285
385
185
385
185
385
185
685
485
385
185
385
185
385
185
885
685
385
185
385
185
385
285
1085
885
385
185
485
285
585
385
1285
1085
385
485
Urine concentration and dilution: countercurrent multiplier

Loop of Henle
285
Descending
limb
Ascending
limb
Collecting
duct
285
100
285
100
ADH
300
300
300
100
300
300
300
Na+Cl
Urea
H 2O
100
H 2O
Urea
300
300
ADH
525
750
525
750
525
750
325
550
525
750
525
750
525
750
Na+Cl
Urea
H 2O
325
525
H 2O
Urea
525
ADH
Na+Cl
Urea
H 2O
550
H 2O
Urea
750
750
ADH
975
975
975
775
975
975
975
1200
1200
1200
1000
1200
1200
1200
Na+Cl
Urea
H 2O
Na+Cl
Urea
H 2O
775
975
975
ADH
1000
H 2O
Urea
1200
Urine
5
H 2O
Urea
1200
4.11
4.12

Urine concentration and dilution: countercurrent diffusion (exchange)
285
100
285
300
300
525
525
Na+Cl
Urea
H 2O
100
Na+Cl
Urea
H 2O
325
Na+Cl
Urea
H 2O
300
Na+Cl
Urea
H 2O
300
Na+Cl
Urea
H 2O
525
525
750
975
975
Na+Cl
Urea
H 2O
Na+
550
Urea
H 2O
Na+Cl
Urea
H 2O
Cl
Urea
H 2O
775
Na+Cl
Urea
H 2O
1200
Na+Cl
Urea
H 2O
750
1200
975
750
750
975
Loop of Henle
(countercurrent multiplier system)
975
Na+Cl
Urea
H 2O
Na+Cl
Urea
H 2O
1200
750
Na+Cl
Urea
H 2O
975
1000
525
Na+Cl
525
750
300
315
1200
1200
Vasa recta
(countercurrent exchange system)
Urine concentration and dilution: countercurrent diffusion (exchange)
285
285
300 Solute
H 2O
Solute 300
H 2O
300 Solute
H 2O
315
300
Solute 300
H 2O
300
525
525 Solute
H 2O
Solute 525
H 2O
525 Solute
H 2O
Solute 750
H 2O
750 Solute
H 2O
Solute 975
H 2O
975 Solute
H 2O
Solute 1200
H 2O
1200 Solute
H 2O
525
750 Solute
H 2O
Solute 525
H 2O
525
750
Solute 750
H 2O
750
750
975 Solute
H 2O
975
Solute 950
H 2O
975
1200 Solute
H 2O
1200
1200
Sickle Cell Disease

Urine concentration and dilution: diluting kidney
280
28
0
280
Cortex
100
280
280
Na+Cl
H 2O
Urea
f
0% of
10
280
lt r a
280
% of fil
20
e
trat
Na+ClH O Urea
2
Na+Cl
H 2O
Urea
100
280
te
3 0 % of filtrate
280
300
2 5 % of filtrate
280
100
280
280
300
Na+Cl
H 2O
Na+Cl
100
H 2O
350
325
125
H 2O
100
Na+Cl
325
H 2O
Na+Cl
H 2O
350
Na+Cl
Na+Cl 150
H 2O
350
Cl
H 2O
375
Na+Cl
H 2O
375
400
100
375
Na+Cl
375
Na+Cl
H 2O
Na+Cl
te
400
tra
2 0 % o f f il
400
350
H 2O
H 2O
Na+Cl
175
Na+Cl
375
100
H 2O
Na+Cl
Na+Cl
350
Na+
H 2O
100
10% of
filtrate
300
H 2O
Na+Cl
Na+Cl
325
Medulla
Na+Cl
H 2O
Na+Cl
H 2O
325
Na+Cl
325
300
Na+Cl
300
Na+Cl
H 2O
400
4.13
4.14

Urine concentration and dilution: concentrating kidney
285
28
5
285
Cortex
H 2O
285
285
Na+Cl
H 2O
Urea
285
lt r a
200
100
300
Cl
Urea
H 2O
325
Na+Cl
Na+Cl
Urea
H 2O
750
550
750
Na+Cl
Urea
H 2O
Na+Cl
Urea
H 2O
ADH
Na+Cl
Cl
Urea
H 2O
ADH
H 2O
Urea
Na+Cl
Urea
H 2O
775
975
Na+Cl
Urea
H 2O
+
0
120 Na Cl
0
100
25% of f iltrate
Na+Cl
0
120
525
525
750
Na+Cl
ADH
300
H 2O
Urea
975
975
ADH
H 2O
Urea 975
975
Na+Cl
H 2O
Urea
ADH
1200
1% of
filtrate
285
750
Na+Cl
Na+
Urea
H 2O
Na+Cl
750
Na+Cl
Urea
H 2O
1200
ADH
285
Na+Cl
Urea
H 2O
525
Medulla
Na+Cl
525
Na+
525
750
+
100 Na Cl
Urea
H 2O
300
Na+Cl
Urea
H 2O
375
225
Na+Cl
Urea
H 2O
2 5 % of filtrate
3 0 % of filtrate
525
H 2O
te
285
975
100
f
0% of
10
285
% of fil
20
e
trat
Na+ClH O Urea
2
Na+Cl
H 2O
Urea
1200
Sickle Cell Disease
4.15
Relationship Between Maximal Urinary Osmolality and Age

Maximum osmolality, mosm/kg H2O
Hemoglobin AA
AS
SS
SC
ACo CCo
1400
1200
1000
800
600
400
200
0
0
20 40 60
20 40 60
20 40 60
Age, y
20 40 60
20 40 60 80
FIGURE 4-11
Relationship between maximal urinary osmolality and age in normal subjects and in patients
with hemoglobinopathies. Results of an investigation into a large group of normal persons and
those with homozygotous hemoglobin disease (Hb SS; Hb SS + Hb F),
heterozygotous hemoglobin disease (Hb AS),

sickle cell hemoglobin C disease (SC), hemoglobin C trait (AC), and hemoglobin C disease
(Hb CC). Normal persons have a mean maximal urinary osmolality of 1058 SD 128
mOsm/kg H2O. The most marked impairment
in concentrating capacity occurs in Hb SS disease. Maximal urinary osmolality decreases
significantly in the first decade of life and stabilizes in patients over 10 years of age at a
mean of 434 SD 21 mOsm/kg H2O. The
measurement has been designated the fixed
maximum of sickle cell nephropathy. In
patients with Hb AS and Hb SC, a progressive
decrease in maximal urinary osmolality can be
observed with age. C hemoglobin alone (AC
or CC) does not impair the concentrating ability of the kidneys. The renal concentrating
capacity of the heterozygote (Hb AS) also is
affected, but only later in life. (Adapted from
van Eps et al. [13]; with permission.)
Relationship Between Nephron with Long

Loops and Those with Short Loops of Henle
Cortex
Subcortex
Outer medulla
Inner medulla
FIGURE 4-12
Relationship between nephron with long loops and those with short
loops of Henle. In the normal human kidney, approximately 85% of
the nephrons have short loops of Henle restricted to the outer
medullary zone. These nephrons may be largely responsible for achieving the interstitial osmolality of about 450 mOsm/kg H2O that exists at
the transition of the outer and inner medulla. The remaining 15% of
human nephrons are juxtamedullary nephrons with long loops of
Henle, extending into the inner medullary zone and renal papillae.
Together with the parallel hairpin vasa recta, these units are responsible
for further increasing interstitial osmolality during antidiuresis to about
1200 mOsm/kg H2O at the tip of the papillae. In experiments with
rats, selectively removing the papillae destroys only nephrons originating in the juxtamedullary cortex. In such animal preparations, a severe
loss of concentrating capacity during fluid deprivation has been
observed. Thus, juxtamedullary nephrons are necessary for achieving a
maximal urine osmolality. These pathophysiologic mechanisms help
clarify the abnormal findings in sickle cell nephropathy. On the basis of
these mechanisms, the concentrating defect in sickle cell disease can be
explained as a consequence of the sickling process per se and the resultant ischemic changes in the medullary microcirculation [5]. It has been
demonstrated that Hb SS erythrocytes form sickle erythrocytes within
seconds when placed in surroundings as hyperosmotic as is the renal
medulla during hydropenia [8]. Sickling of renal blood cells causes a
significant increase in blood viscosity that could interfere with the normal circulation through the vasa recta, preventing both active and passive accumulation of solute in the papillae necessary to achieve maximally concentrated urine. Increased viscosity of blood and intravascular
aggregations of Hb SS erythrocytes could also produce local hypoxia
and eventually infarction of the renal papillae.
4.16
Relationship Between Concentrating

Capacity and Patient Age
Aug. Sept.
31 10
20
30
Oct.
10
20
30
Nov.
10
20
30
Dec. Jan
10 17 20
W.J. 4 y.
Red blood cellsuspension
175 mL
Hemoglobin, Hb
%
content,
g%
20
5
CPAH ,
mL/min
CInuline , CCreatinine , Urine osmolality,

mL/min mL/min mosm/kg H2O
100
0
Filtration
fraction, %
20
Mar.
1
FIGURE 4-13
AE, Relationship between concentrating
capacity and patient age. Over a prolonged
period, we investigated the effect of multiple transfusions of hemoglobin A erythrocytes into children and adults with sickle
cell anemia (4, 7, 11, 15, and 40 years). In
the first panel, the effects of multiple transfusions of normal blood given to a 4-yearold boy with homozygotic sickle cell anemia. A significant improvement in concentrating capacity can be observed. This
diminishes in older patients.
900
700
500
200
50
200
50
1500
1000
500
30
Feb
10
15
5
4.17
Sickle Cell Disease
May June
July
31 10 20 30 10 20
30
Aug.
10 20
30
F.A. 7 y.
1000
500
20
10
B
400
CInuline ,
mL/min
200
CPAH ,
mL/min
50
1500
600
50
200
50
2000
1500
1000
Filtration
fraction, %
CInuline , CCreatinine , Urine osmolality,

mL/min mL/min mosm/kg H2O
CPAH ,
mL/min
50
200
20
30
Aug.
10 20
30
800
700
200
July
10
100
100
900
30
M.V. 11 y.
CCreatinine , Urine osmolality, Hemoglobin, Hb

mL/min
mosm/kg H2O
%
content,
g%
Hemoglobin, Hb
%
content,
g%
1100
20
15
15
Filtration
fraction, %
June
10
350 mL

350 mL
Sept. Jan. Mar.

10 6
3
15
10
5
Sept.
10 20
4.18

Dec. Feb.
'62 '65 Apr. May
June
July
29 25 22 30 10 20 30 10 20 30 10 20
M.K. 15 y.
Aug.
Sept.
Oct.
Nov.
30 10 20 30 10 20 30 10 20 30 10 20
Urine osmolality, Hemoglobin, Hb

mosm/kg H2O
%
content,
g%

350 mL
15
5
A
S
F
100
0
800
600
CCreatinine ,
mL/min
200
CPAH ,
mL/min
200
CInuline ,
mL/min
400
50
50
1500
1000
Filtration
fraction,
%
500
20
10
May
1 10
20
30
June
10
20
30
July
10
20
30
Aug.
10
20
A.P. 40 y.
CInuline , CCreatinine , Urine osmolality, Hemoglobin, Hb

mL/min
mL/min mosm/kg H2O
%
content,
g%

300 mL
15
100
800
600
400
200
50
CPAH ,
mL/min
200
50
1500
1000
Filtration
fraction,
%
500
20
10
A
S
F
Sickle Cell Disease
4.19
Relationship Between Age and Ability to Reverse the

Defect in Urinary Concentration by Blood Transfusions
8 patients; van Eps [12]
1100
Maximal urinary osmolality, mosm
FIGURE 4-14
Relationship between age and ability to reverse the defect in urinary concentration by
blood transfusions in patients with sickle cell disease. A, The maximal urinary osmolality
achieved before transfusion (lower point of each vertical line) and after multiple transfusions with normal blood (upper point of each vertical line) in 14 patients with sickle cell
disease, ranging in age from 2 to 40 years. B, The percentage of increase in maximal urinary osmolality resulting from transfusion. Maximal urinary osmolality before transfusion
is depressed at all ages; significant improvement after transfusion occurs only in children
and adolescents. (From van Eps et al. [13]; with permission.)
6 patients; Keitel [13]
800
500
200
Increase in maximal urinary osmolality, %
A
100
80
60
40
20
0
0
10
20
30
Time, y
40
50
Length of the Loops of Henle in Animals

Correlated with Kidney Concentrating Capacity
Sickle cell kidney
Beaver kidney
Long loops of Henle
not functioning
or absent
Normal kidney
14% juxtamedullary
nephrons with long loops
Medulla
Inner
zone
Outer
Cortex
Sickle cell trait:

Progressive loss in 70 y of
inner medullary
concentrating function
Sickle cell anemia:
A. Up to about 15 y: reversible
concentrating defect
B. Over 15 y: complete and irreversible
loss of inner medullary
concentrating function
FIGURE 4-15
Length of the loops of Henle in animals
correlated with kidney concentrating capacity. A, Investigations of animal species [14]
with different lengths of the loops of Henle
and correlation with the concentrating
capacity of their kidneys reveal their relationship. B, Desert animals with very long
loops of Henle can produce highly concentrated urine; in contrast, beavers living in
water-rich surroundings have only short
loops of Henle and cannot produce urine
concentrate over 450 mOsm.
4.20
Beaver
Rabbit

In sickle cell disease the long loop of Henle has been obliterated
and the concentrating capacity of the kidney is not higher than
Psammomys
400 mosm, much as in beavers. An overview has been reproduced.

(From van Eps and De Jong [15]; with permission.)
Urinary Acidification
SS Anemia
70
Ammonium chloride
T.A., -equiv/min/1.73 m2
Blood pH
75
74
73
Ammonium chloride
50
30
10
72
2
10
Ammonium chloride
10
Ammonium chloride
90
NH4+, -equiv/min/1.73 m2
Urinary pH
7.0
6.0
5.0
70
50
30

10
4.0
2
6
Time, h
10
FIGURE 4-16
A, Urinary acidification. Patients with
hemoglobin SS or SC demonstrate an
incomplete form of renal tubular acidosis.
In response to a short-duration acid load,
all of the patients studied by Goossens and
coworkers [16] with otherwise normal renal
function were unable to decrease urine pH
below 5.3, whereas normal persons achieve
a urinary pH of 5.0 or lower. Titrateable
acid (TA) and total hydrogen ion excretion
are lower in patients with Hb SS or Hb SC;
however, in most cases, ammonia excretion
is appropriate for the coexisting urine pH.
The acidification defect has been classified
as distal rather than proximal, because no
associated wasting of bicarbonate occurs,
and the acidification defect is characterized
by failure to achieve a normal minimal urinary pH during acid loading. Investigators
from several centers have found no evidence of metabolic acidosis in the absence
of a sickle cell crisis; however, they have
found changes consistent with mild chronic
respiratory alkalosis [15].
6
Time, h
10
Sickle Cell Disease

B, Relationship between renal concentrating and acidifying capacity
in Hb AS, SC, and SS and in normal persons [16].
SC
SS
Normals
AS
4.21
Maximal urinary osmolality
1200
1000
800
600
400
4.4
4.6
4.8
5.0
5.2
5.4
Minimal urinary pH
5.6
5.8
6.0
Tubular Reabsorption of Phosphate

in Sickle Cell Nephropathy
0.50
0.50
0.60
TmP/GFR 2.54.2
0.30
0.70
0.20
0.80
+
0.10
0.90
1.00
0
3
4
5
Phosphate, mg/100 mL
T.R.P.
UV/L
0.40
FIGURE 4-17
Relationship between Cp/glomerular filtration rate and serum phosphate. Closed circles represent values for patients who had fasted
from food and drink; open circles are values obtained when UpV
was 0.032 mmol/min. The continuous line shows the mean of the
values in patients with sickle cell anemia, and the hatched area
indicates the range for normal persons. Cpclearance of phosphate; TmP/GFRtubular maximum reabsorption of phosphate/
glomerular filtration rate. (Adapted from De Jong and coworkers
4.22
Blood Pressure in Sickle Cell Disease

Male
180
Female
ns
ns
ns
ns
<0.05
<0.01
<0.01
<0.01
ns
ns
<0.02
<0.05
ns
Systolic
160
140
mm Hg
FIGURE 4-18
Blood pressure and sickle cell anemia. Mean standard deviation of
systolic and diastolic blood pressure in control subjects (dotted
lines) and patients with sickle cell anemia (closed lines) who are
matched for age and gender. (From De Jong and van Eps [20].)
120
Diastolic
100
80
60
1524 2534 3544 4554
<0.05 P
1524 2534 3544 4554

Age, y
References
1. Herrick JB: Peculiar elongated and sickle shaped red blood corpuscles
in a case of severe anemia. Arch Intern Med 1910, 6:517.
2. Pauling L, et al.: Sickling cell anemia, molecular disease. Science 1949,
110:543.
3. Ingram VM: Gene mutations in human hemoglobin: the chemical
difference between normal and sickle cell hemoglobin. Nature 1959,
180:326.
4. Bunn HF: Mechanisms of disease: pathogenesis and treatment of sickle cell disease. N Engl J Med 1997, 337:762769.
5. Statius van Eps LW, Pinedo Veels C, De Vries H, De Koning J: Nature
of concentrating defect in sickle cell nephropathy, microradioangiographic studies. Lancet 1970, 1:450.
6. Hostetter TH, et al.: Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol 1981, 241:F85.
7. Dickerson RE, Geis I: The Structure and Action of Proteins. New
York: Harper and Row, 1969, 1971.
8. Perillie PE, Epstein, FH: Sickling phenomenon produced by hypertonic solutions: a possible explanation for the hyposthenuria of sicklemia.
J Clin Invest 1963, 42:570.
9. Edelstein SJ: Structure of the fibers of hemoglobin S: human hemoglobins and hemoglobinopathies: a review to 1981. Galveston: University
of Texas; 1981.
10. Franck PF, Bevers EM, Lubin BH, et al.: Uncoupling of the membrane
skeleton from the lipid bilayer: the cause of accelerated phospholipid
flip-flop leading to an enhanced procoagulant activity of sickled cells.
J Clin Invest 1985, 75:183190.
11. Frank PFH: Studies on the phospolid organization in membranes of

abnormal erythrocytes [PhD thesis]. Utrecht: State University of
Utrecht; 1984.
12. Statius van Eps LW, Schouten H, Ter Haar Romeny Wachter CCh, la
Porte-Wijsman LW: The relation between age and renal concentrating
capacity in sickle cell disease and hemoglobin C disease. Clin Chim
Acta 1970, 27:501.
13. Statius van Eps LW, Schouten H, la Porte-Wijsman LW, Struyker
Boudier AM: The influence of red blood cell transfusions on the
hyposthenuria and renal hemodynamics of sickle cell anemia. Clin
Chim Acta 1967, 17:449.
14. Schmidt-Nielsen B, ODell R: Structure and concentrating mechanism
in the mammalian kidney. Am J Physiol 1961, 200:1119.
15. Keitel HG, et al.: Hyposthenuria in sickle cell anemia: a reversible
renal defect. J Clin Invest 1956, 35:998.
16. Statius van Eps LW, De Jong PE: Sickle cell disease. In Diseases of the
Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little,
Brown; 1997:2201.
17. Goossens JP, Statius van Eps LW, Schouten H, Gieterson AL:
Incomplete renal tubular acidosis in sickle cell disease. Clin Chim
Acta 1972, 41:149.
18. De Jong PE, et al.: The tubular reabsorption of phosphate in sickle
cell nephropathy. Clin Sci 1978, 55:429.
19. De Jong PE, Landman H, Statius van Eps LW: Blood pressure in sickle
cell disease. Arch Intern Med 1982, 142:1239.
20. De Jong PE, Statius van Eps LW: Sickle cell nephropathy: new insights
into its pathophysiology. Editorial review. Kidney Int 1985, 27:711.
Renal Involvement
in Malignancy
Richard E. Rieselbach
A. Vishnu Moorthy
Marc B. Garnick
atients with malignancy are particularly vulnerable to development

of renal abnormalities [1]. Additionally, patients with renal abnormalities who have undergone kidney transplantation are at
increased risk for malignancy, which may involve the kidney [2].
Malignancy may directly involve the urinary tract. More commonly, however, the many systemic manifestations of cancer and the toxicity of its
treatment are involved in the pathogenesis of diverse clinical syndromes
involving the kidney [3].
Malignant neoplasms directly involving the renal parenchyma, renal
pelvis, or ureter may be primary or secondary in origin. Metastatic neoplasms are the cause of renal malignancy more frequently than primary
tumors. These secondary lesions are usually asymptomatic, however, and
most often are discovered incidentally only at postmortem examination
[4]. Additionally, extrarenal malignancy may involve the kidney by producing obstruction of urine flow via extrinsic compression of the urinary
tract. This occurs most often with gynecologic and other pelvic neoplasms in women and with prostatic cancer in men.
Systemic manifestations of cancer may involve the kidney via formation of immune complexes, which may produce glomerulonephritis [5].
Also, paraproteins generated by multiple myeloma and other lymphoid
neoplasms may produce renal dysfunction [6]. In addition to tumor
products, malignancy-induced metabolic abnormalities, such as hypercalcemia and hyperuricemia, may impair renal function.
Finally, a high percentage of cancer patients are candidates for aggressive chemotherapy or radiation therapy, or both. Nephrotoxicity due to
chemotherapy may manifest as acute renal failure, chronic renal failure,
or specific tubular dysfunction causing fluid and electrolyte imbalance
[7]. The nephrotoxicity of radiation therapy may be synergistic with that
of chemotherapy in some settings, or radiation therapy may by itself produce significant renal damage.
CHAPTER
5.2
CLINICAL SYNDROMES OF RENAL

INVOLVEMENT IN MALIGNANCY
Acute renal failure
Prerenal
Intrinsic
Postrenal
Hematuria and/or nephrotic syndrome
Specific tubular dysfunction and associated fluid and electrolyte disorders
Malignancy in the renal transplant patient
FIGURE 5-1
Clinical syndromes of renal involvement in malignancy. Renal
involvement in malignancy may present as one or more of four
clinical syndromes. Additionally, the incidence of a broad spectrum
of malignancies is increased in the renal transplant patient, and the
malignancy may directly involve the transplanted kidney.
Prerenal Acute Renal Failure

CAUSES OF PRERENAL ACUTE RENAL FAILURE
Clinical syndrome
Cause
ECF volume contraction (hypovolemia)
External fluid loss (skin, gastrointestinal, renal, hemorrhage)

Internal fluid loss (peritonitis, bowel obstruction, acute pancreatitis,
hemorrhage, malignant effusion)
Sepsis
Anaphylaxis
Anesthesia
Drug overdose
Myocardial infarct, failure
Arrhythmia
Pericardial tamponade
Pulmonary embolus
Arterial
Venous
Drugs that inhibit prostaglandin synthesis
Peripheral vasodilation
Impaired cardiac function
Bilateral extrarenal vascular occlusion

Functional disorders of intrarenal circulation
FIGURE 5-2
Causes of prerenal failure (ARF). Prerenal ARF is encountered frequently in the cancer patient,
particularly in association with depletion of the extracellular fluid (ECF) volume, which is
caused by excessive loss from the gastrointestinal tract due to vomiting or diarrhea
induced by cancer or its therapy. Also, hypovolemia may occur owing to internal fluid loss
due to translocation of ECF volume with
sequestration in third spaces, as seen in peritonitis, bowel obstruction, malignant effusion,
or interleukin-2 therapy [8].
A decrease in effective intravascular volume
may occur owing to peripheral vasodilation,
as frequently noted in sepsis. A decrease in
cardiac output due to cardiac tamponade secondary to malignant pericardial disease also
may produce prerenal ARF. Hepatobiliary disease may cause alterations in intrarenal hemodynamics with resultant hepatorenal syndrome, as seen in hepatic veno-occlusive disease following bone marrow transplantation
(see Fig. 5-3). The administration of nonsteroidal anti-inflammatory agents for analgesia in the cancer patient may lead to ARF by
elimination of the prostaglandin-mediated
intrarenal vasodilatation. This homeostatic
mechanism represents a critical hemodynamic
adjustment necessary for maintaining
glomerular filtration rate in a patient with
cancer in whom renal blood flow may be
decreased owing to a variety of causes.
Renal Involvement in Malignancy

60
50
Azotemia
Patients, %
40
30
20
Tumor
Stored
lysis
marrow
syndrome toxicity
HUS
CSA
ARF
10
0
10
0
Conditioning
14
21
Time, d
28
1y
FIGURE 5-3
Time distribution and frequency of renal syndromes in the setting of
bone marrow transplantation (BMT). The solid line depicts the
approximate frequency of renal insufficiency, as defined by at least a
doubling of the baseline serum creatinine concentration (azotemia);
the dotted line represents the frequency of dialysis required because of
acute renal failure (ARF). During the period of conditioning, tumor
lysis syndrome and stored marrow-infusion toxicity are most common; 10 to 28 days after transplantation, the peak incidence of ARF
is observed, most notably due to a hepatorenal-like syndrome associated with veno-occlusive disease (VOD). After 1 month, the hemolyt-
CAUSES OF INTRINSIC ACUTE RENAL FAILURE

Glomerular abnormalities
Tubular abnormalities
Interstitial abnormalities
Abnormalities of intrarenal blood

vessels
Glomerulonephritis
Ischemic acute tubular necrosis (ATN)
Exogenous nephrotoxins
Antineoplastic agents
Antimicrobials
Radiocontrast media
Anesthetic agents
Endogenous nephrotoxins
Myoglobin
Hemoglobin
Immunoglobulins and light chains
Calcium and phosphorus
Uric acid and xanthine
Drug-induced acute tubulointerstitial nephritis
Acute pyelonephritis
Tumor infiltration
Radiation nephropathy
Disseminated intravascular coagulation
Vasculitis
FIGURE 5-4
The four major causes of malignancy-associated intrinsic acute renal
failure (ARF). With glomerular abnormalities, the pathologic process
most frequently involves diffuse proliferative or crescentic glomeru-
5.3
ic-uremic syndrome (HUS) can be observed. As noted, the greatest

risk for development of ARF occurs 10 to 21 days after BMT, with
the usual cause at this time being prerenal acute renal failure due to
hepatic veno-occlusive disease. This causes a syndrome very similar to
the hepatorenal syndrome (HRS). There are five clinical similarities
between the two syndromes: 1) jaundice and portal hypertension precede the onset of ARF, 2) a very low fractional excretion of sodium
always occurs, 3) the blood urea nitrogen (BUN)/creatinine ratio is
very high, 4) mild hyponatremia and a decrease in systemic arterial
blood pressure are usually present, and 5) postmortem examination
of patients dying of this syndrome fails to reveal any structural or
morphologic basis for ARF, suggesting a hemodynamic cause [9].
In contrast to the very high incidence of hepatic VOD in patients
undergoing allogeneic BMT, autologous hematopoietic support is
associated with a much lower incidence. A recent study evaluating
renal function in 232 women treated with high-dose chemotherapy
and autologous hematopoietic support for high-risk breast cancer
revealed a frequency of hepatic VOD of 4.7 %, as compared with a
reported incidence ranging from 22% to 53% in various series of
patients undergoing allogeneic bone marrow transplantation [10]. In
this series of autologous transplants, 21% of patients developed
severe renal dysfunction, which correlated most significantly with sepsis, liver, and pulmonary disease. The major incidence of renal failure
occurred during chemotherapy, before the initiation of hematopoietic
cell support, thereby primarily incriminating the cytoreductive therapy rather than hematopoietic cell support [10]. CSAcell surface
antigen. (From Zager [9]; with permission.)
lonephritis. Although immune-complexmediated glomerular disease is
not uncommon in patients with cancer [11], glomerular disease causing ARF in the cancer patient has been reported in only a few cases
[12]. Hemolytic-uremic syndrome with vascular endothelial injury in
both the glomeruli and the intrarenal blood vessels may occur in
patients with disseminated malignancy or after chemotherapy
for malignancy.
With respect to tubular abnormalities, ARF may arise either on the
basis of ischemia or as a result of exposure to exogenous or endogenous nephrotoxins. Renal ischemia is usually the initiating factor when
ATN follows sepsis or shock or when it arises as a postsurgical complication. Cancer patients are particularly vulnerable to ARF induced
by exogenous nephrotoxins in view of their frequent exposure to a
wide variety of nephrotoxic drugs. The indicated nephrotoxins of
endogenous origin are encountered with increasing frequency in the
cancer patient.
The most frequent cause of interstitial abnormalities is acute tubulointerstitial nephritis, which may be induced in cancer patients via
hypersensitivity to various drugs. These patients frequently receive the
analgesics and antimicrobials associated with this form of ARF.
Immunosuppressed cancer patients may be particularly vulnerable to
severe acute bacterial pyelonephritis. ARF may occur in this setting,
even in the absence of urinary tract obstruction or another underlying
renal disease [13]. Tumor infiltration of the kidney may involve the
interstitium but rarely causes ARF [14]. Finally, radiation nephropathy
may occur following radiation therapy for cancer and has been associated with ARF [15], although when it occurs, it more frequently produces chronic renal failure.
The fourth major cause of intrinsic ARF is abnormalities of intrarenal
blood vessels. Disseminated intravascular coagulation may occur in
association with sepsis in the cancer patient [16]. In addition, because
the cancer patient is more often older, atheroembolic disease or malignant hypertension must be considered as a possible cause of intrarenal
vascular occlusion in the presence of ARF. Finally, vasculitis is a consideration, particularly in the presence of hepatitis B antigenemia.
5.4

Hemolytic-uremic syndrome (HUS). A 46-year-old woman with
metastatic carcinoma of the lung and congestive heart failure developed renal insufficiency over a 12-week period. A percutaneous
renal biopsy revealed that several glomeruli had the acute changes
of swelling and detachment of endothelial cells and luminal occlusion (panel A, periodic acidSchiff stain). The arterioles and arteries showed intimal cellular swelling and hyperplasia and fibrin
deposition. Immunofluorescence microscopy revealed glomerular
fibrin deposition (panel B).
Hemolytic-uremic syndrome is a thrombotic microangiopathy
presenting as an acute illness characterized by renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. Vascular
and endothelial cell injury leads to microvascular thrombosis and
ischemic organ damage. HUS can occur in diverse clinical settings,
including metastatic carcinoma, particularly of the stomach, breast,
or lung [17]. The initiating factor is presumably tumor emboli.
These patients have an extremely poor prognosis and often die
within a few weeks of diagnosis [18]. HUS also has been reported
after chemotherapy for cancer. This form of chemotherapy-related
HUS is mainly associated with mitomycin C but has also been
noted after therapy with bleomycin and platinum-containing
agents. The risk of developing mitomycin Cinduced HUS is 2% to

10%, and cumulative doses larger than 60 mg are often associated
with the disease [19]. The patients with cancer are often in remission at the time of diagnosis. The mortality rate has been as high
as 70%, usually in the first 2 months, and is related to renal failure
and sepsis.
The diagnosis of HUS should be considered in the clinical setting
of acute renal failure associated with thrombocytopenia and
microangiopathic hemolytic anemia with schistocytes (seen on a
peripheral blood smear). The renal biopsy results show a variety of
glomerular and vascular changes, such as endothelial cell swelling,
detachment of thrombi, and thrombotic occlusion of the lumen.
Fibrin is noted in the walls of blood vessels of glomeruli on
immunofluorescence microscopy. On electron microscopy, endothelial cell swelling and detachment from the basement membrane,
subendothelial granular material, and luminal thrombi may be seen
in the glomeruli. Treatment is generally supportive, including dialysis. Hemolytic-uremic syndrome with vascular endothelial injury
both in the glomeruli and in the intrarenal blood vessels may occur
in patients with disseminated malignancy or after chemotherapy
for malignancy.
FIGURE 5-6
Renal changes in humans following cisplatin administration. The
proximal convoluted tubules are dilated and show coagulation
necrosis of the epithelium and epithelial nuclear atypia. The tubular lumens contain eosinophilic material [20].
Cisplatin is the most frequently used antineoplastic agent for the
treatment of solid tumors, and the pathogenesis of its nephrotoxicity has been studied extensively. Cisplatin-induced acute renal failure
(ARF) is dose related, nonoliguric, and usually reversible. The

serum creatinine level may increase immediately after administration and often peaks in 3 to 10 days; dialysis is rarely required.
Treatment protocols involving prehydration and vigorous diuresis
with saline and mannitol have greatly decreased the incidence of
ARF. A commonly used protocol involves initiating diuresis 12 to
24 hours before cisplatin administration. Cisplatin is then infused in
isotonic saline over a 3-hour period, followed by an isotonic saline
or mannitol infusion for 24 hours thereafter. Cisplatin is usually
administered in daily divided doses for 5 days until the maximum
dose is attained, usually not to exceed 120 mg/m2 of body surface
area [7]. When this dose is exceeded, an unacceptable degree of
nephrotoxicity may occur regardless of prophylactic protocols [21].
Hypomagnesemia is frequent in patients receiving cisplatin and
may be severe (0.3 to 0.5 mEq/L). It is due to induction of a tubular
reabsorptive defect [22]. Magnesium wasting may be present for
many months but usually remits when cisplatin is discontinued.
Associated hypocalcemia and hypokalemia may persist unless hypomagnesemia has been corrected. In recent years in some settings, cisplatin has been replaced with carboplatin, which is not nephrotoxic
in usual doses (400 to 600 mg/m2). Transient ARF has been noted
in patients receiving very high doses (1600 to 2400 mg/m2),
however. (From Rieselbach and Garnick [1]; with permission.)
FIGURE 5-7
Methotrexate (MTX) nephrotoxicity. Renal biopsy specimen from a
patient treated with 3 g/m2 of MTX followed by leucovorin who
became dehydrated and developed acute renal failure. Precipitated
material in the tubules (arrow) strongly reacted with a fluorescinated
CAUSES OF RENAL FAILURE IN MULTIPLE MYELOMA

Cause
Pathogenesis
Light-chain cast nephropathy

AL amyloidosis
Intratubular precipitation of light chains

Deposition of amyloid fibers composed
of light chains (Congo red positive)
Nodular glomerulosclerosis with granular
deposits (Congo red negative) of light
chains along the basement membrane
Often incidental finding at autopsy
Rare cause of renal dysfunction
Tubular toxicity of light chains
Light-chain deposition disease
Plasma cell infiltration of the kidney

Fanconis syndrome and other tubular
dysfunction
Hypercalcemic nephropathy
Radiocontrast nephropathy
Bone resorption causing hypercalcemia

Renal tubular precipitation of uric acid
following tumor lysis
Interaction between light chains and
radiocontrast agents
FIGURE 5-8
Renal failure in multiple myeloma. The patient with multiple
myeloma is at increased risk for the development of acute renal
failure [27]. In up to 25% of patients with multiple myeloma,
5.5
rabbit anti-MTX antibody [23]. MTX nephrotoxicity may occur

with high-dose therapy (1 to 15 g/m2); at conventional doses, MTX
does not produce nephrotoxicity. Before the importance of maintaining a high urinary volume and pH was realized, renal toxicity was
noted in approximately 30% of treatment courses and was responsible for 20% of drug-related deaths during high-dose MTX-leucovorin rescue therapy [24]. MTX is excreted primarily by the kidneys
by means of glomerular filtration and tubular secretion; more than
90% of an intravenous dose appears unchanged in the urine following conventional doses [25]. During high-dose infusions, urinary
MTX levels exceed solubility and therefore drug precipitation
occurs, as illustrated previously. At physiologic systemic pH, MTX is
completely ionized; however, the un-ionized moiety predominates at
the more acidic pH usually encountered within the distal nephron,
with solubility being markedly reduced. Thus, patients receiving
high-dose MTX therapy may be more prone to development of
nephrotoxicity if they are dehydrated and excreting an acidic urine.
The 7-OH metabolite of MTX also may precipitate within the
nephrons. This metabolite may account for as much as 7% to 33%
of the MTX appearing in the urine 24 to 48 hours after intravenous
administration; its solubility is only 25% of that observed for MTX
[26]. (From Rieselbach and Garnick [1]; with permission.)
acute renal failure may be present at the time of initial diagnosis.
In others, it may occur at any time during the disease. Renal failure
can be due to diverse mechanisms. The light chains produced by
the monoclonal B lymphocytes may be nephrotoxic [28]. While the
toxicity of the light chains leads to a variety of tubular transport
disorders, including Fanconis syndrome, the intratubular precipitation of these proteins causes light-chain cast nephropathy and
acute renal failure. The light chains (usually lambda) may be transformed into Congo-redpositive amyloid fibrils and deposited diffusely throughout the body [29]. Deposition of amyloid in renal
tissue results in the nephrotic syndrome and, often, renal failure.
Biopsy of the kidney, abdominal fat pad, or rectal mucosa is useful
in the diagnosis of AL amyloidosis. Light chains may also be
deposited in a granular pattern along the basement membranes of
blood vessels in a variety of organs. In the kidney, these deposits
are noted in the glomeruli, causing an expansion of the
mesangium, and appear as nodular glomerulosclerosis. This condition is referred to as light-chain deposition disease (LCDD) [30].
Other causes of renal failure in a patient with multiple myeloma
include metabolic disturbances such as hypercalcemia and hyperuricemia. Hypercalcemia may be due to direct bone erosion by the
malignant cells or to the elaboration of cytokines, which activate
osteoclasts. The administration of radiocontrast agents to patients
with multiple myeloma may lead to interaction with light chains
and tubular precipitation, thereby causing acute renal failure. The
prognosis for recovery from acute renal failure in a patient with
multiple myeloma is generally poor unless reversible factors such as
hypercalcemia or dehydration are responsible [27].
5.6

FIGURE 5-9
Light-chain cast nephropathy. The kidney at autopsy of a 68-yearold man with multiple myeloma who died 2 years after diagnosis
owing to sepsis and renal failure. Note the dense, lamellated, and
fractured casts in the renal tubules surrounded by multinucleated
giant cells. There is also interstitial fibrosis.
FIGURE 5-10
Nephrocalcinosis in a patient with multiple myeloma. Irregular fractured hematoxylinophilic deposits of calcium are seen in this fibrotic renal tissue. Hypercalcemia may
produce serious structural changes in the kidney, resulting in acute or chronic renal failure.
Hypercalcemia is a relatively common complication of malignancy. Increased bone reabsorption is most often responsible owing to bone metastases or to the release of humoral
substances such as parathyroid hormonelike peptide or cytokines such as transforming
growth factor- [32]. Secretion of calcitriol, the active form of vitamin D, also may occur in
some lymphomas [33]. Renal dysfunction in the setting of hypercalcemia results from both
calcium-induced constriction of the afferent arteriole and the deposition of calcium in the
tubules and interstitium, leading to intratubular obstruction and secondary tubular atrophy
and interstitial fibrosis [34]. Prompt treatment generally restores renal function, but irreversible damage can occur with long-standing hypercalcemia [35]. Recovery of the glomerular filtration rate varies inversely with the extent of nephrocalcinosis, interstitial scarring,
associated obstructive uropathy, infection, and hypertension. All the foregoing reflect the
duration and severity of hypercalcemia. (From Skarin [31]; with permission.)
FIGURE 5-11
Acute uric acid nephropathy (AUAN). Intrarenal obstruction caused by uric acid precipitation in collecting ducts produces severe tubular dilatation (DeGalantha stain). This patient,
who received chemotherapy for acute lymphocytic leukemia before allopurinol was available, had a plasma urate concentration of 44 mg/dL at the time of death.
Acute uric acid nephropathy is most frequently encountered in patients with a large
tumor burden (often due to rapidly proliferating lymphoma or leukemia) in whom aggressive radiation or chemotherapy has been recently initiated. If rapid lysis of tumor cells
occurs, massive quantities of uric acid precursors (and often other tumor products) are
released. This induces a marked increase in synthesis of uric acid and thus acute hyperuricemia. The subsequent renal uricosuric response may be of sufficient magnitude to
exceed solubility limits for uric acid in the distal nephron, particularly in the presence of
dehydration or metabolic acidosis. The resultant intrarenal obstruction produces a characteristic pattern of acute renal failure [36]. In the setting of particularly extensive disease
with rapid cell lysis, profound hyperkalemia, hyperphosphatemia, and hypocalcemia (due
to precipitation of calcium phosphate) may be observed. This is termed acute tumor lysis
syndrome [37]. This syndrome usually occurs after treatment of poorly differentiated lymphoma or leukemia; if it arises spontaneously, hyperphosphatemia is not prominent
because phosphate is incorporated into rapidly proliferating tumor cells.
Rarely, xanthine nephropathy can occur during tumor lysis when allopurinol is used to
prevent the production of uric acid. The resultant xanthine oxidase inhibition can produce
a marked increase in blood and urine xanthine and hypoxanthine concentrations.
Xanthine, like uric acid, is poorly soluble in an acidic urine; xanthine crystalluria occurs
when its concentration exceeds its solubility, thereby causing obstructive nephropathy [38].
PROPHYLAXIS AND TREATMENT OF ACUTE URIC ACID

NEPHROPATHY AND ACUTE TUMOR LYSIS SYNDROME
Prophylaxis
A. Patients presenting (before chemotherapy) with evidence of large, rapidly proliferating tumor burden and
hyperuricemia
1. Correct initial electrolyte and fluid imbalance, and azotemia, if possible; dialysis as indicated for established renal
failure or unresponsive electrolyte or metabolic abnormalities
2. Maintain adequate hydration and urine output (>3 L/d). May require 4 to 5 L/24 h of intravenous hypotonic
saline or bicarbonate; diuretics as indicated
3. Give Allopurinol* (300 mg/m2) at least 3 days before therapy if possible
4. Alkalinize urine to pH >7.0 (hypotonic NaHCO3 infusion; Diamox if necessary)
5. Postpone chemotherapy (if possible) until uric acid and electrolytes are reasonably normalized
6. Continuous-flow leukapheresis might be indicated for patients with a high circulating blast count (white cell
count >100,000/mm3)
B. Patients presenting (before chemotherapy) with normouricemia, but still at risk
1. Allopurinol* 300 mg/m2; at least 2 days before therapy if possible
2. 4 to 5 L/d of intravenous fluid as described above
3. Urinary alkalinization as described above
Treatment
C. Patients presenting (usually after chemotherapy) with renal failure
1. Same as for patients with tumor and hyperuricemia if sufficient renal function remains. If dialysis is necessary,
continuous hemodialysis or hemofiltration may be preferable if severe hyperuricemia or hyperkalemia is present
2. Discontinue urine alkalinization when uric acid homeostasis is achieved (to avoid Ca3[PO412]precipitation)
3. Treat symptomatic hypocalcemia after correction of hyperphosphatemia
5.7
FIGURE 5-12
Prevention and management of acute uric
acid nephropathy (AUAN) and the acute
tumor lysis syndrome (ATLS). The metabolic consequences of rapid malignant cell lysis
are many, ranging from moderate hyperuricemia to death from hyperkalemia. The
measures employed for prevention and
management vary according to the type and
extent of the tumor and whether cytolytic
therapy has been initiated.
In recent years, with appropriate prophylaxis and dialytic therapy, AUAN and ATLS
rarely represent life-threatening problems.
When acute renal failure (ARF) does occur,
prognosis is excellent. The approach to
AUAN and ATLS is divided into two
stages. The first is to prevent or minimize
the metabolic consequences, and the second
involves treatment if prophylaxis has not
been successful. The approach to both prophylaxis and treatment includes inhibition
of xanthine oxidase, forced diuresis, and
urinary alkalinization. If treatment is not
successful and ARF develops, these patients
respond very well to hemodialysis, with
morbidity and mortality usually related to
the underlying disease process [39].
*Allopurinol dosage must be adjusted for level of renal function.
N
CH
OH
OH
OH
C
N
Xanthine
oxidase
HO
N
CH
C
N
C
N
C
N
OH
H
C
H
Allopurinol
(4-Hydroxypyrazolo pyrimidine)
Xanthine
oxidase
HO
N
COH
C
N
N
H
Uric acid
Xanthine
Hypoxanthine
HO
OH
Xanthine
oxidase
H
C
C
N
C
N
H
Oxypurinol (Alloxanthine)
(4,6-Dihydroxypyrazolo pyrimidine)
FIGURE 5-13
Allopurinol structure and metabolism. Allopurinol is a crucial component of therapy for the prevention and management of acute uric acid nephropathy and acute tumor lysis syndrome. Its
metabolism and pharmacology must be considered to avoid life-threatening toxicity [40].

Allopurinol is a structural analogue of
hypoxanthine. The product of the enzymatic
oxidation of allopurinol is the xanthine analogue oxypurinol. Both allopurinol and oxypurinol act as xanthine oxidase inhibitors.
Allopurinol is rapidly absorbed from the gastrointestinal tract and is not protein bound.
It has a half-life of just 2 to 3 hours because
it has a clearance equal to the glomerular filtration rate and is rapidly converted to oxypurinol via enzymatic oxidation. By contrast,
oxypurinol has a half-life of 18 to 30 hours
because it undergoes extensive tubular reabsorption and is dependent on renal excretion
for elimination. Thus, allopurinol dosage
must be modified according to renal function. Serious toxicity may occur in the presence of a sustained increase in oxypurinol
concentration. Oxypurinol may be removed
effectively with dialysis, since it is not protein bound. (From Rieselbach and Garnick
5.8
FIGURE 5-14
Interstitial tumor infiltration due to leukemia. Leukemic infiltrates
in this case of acute myelocytic leukemia are diffusely present
throughout the cortex of the kidney. The pelvic and parenchymal

hemorrhages are secondary to severe thrombocytopenia.
Microscopically, many myeloblasts are seen in the interstitial infiltrates. Interstitial infiltration by hematologic neoplasms is usually
bilateral, diffuse, and more prominent in the cortex [14]. Renal
failure is unusual. When it does occur, affected patients generally
present with relatively acute renal failure and a benign urinalysis.
The kidneys are grossly enlarged, as may be demonstrated by renal
ultrasound, by CT scan, or in some cases even by physical examination. The differential diagnosis in this setting includes obstruction and other tubulointerstitial disorders. The presence of large
kidneys without hydronephrosis on ultrasonography in a patient
with lymphoma or leukemia, however, is highly suggestive of
tumor infiltration. The renal prognosis is dependent on the responsiveness of the tumor to radiation or chemotherapy. A rapid reduction in renal size and return of renal function toward the baseline
level may be seen within a few days with responsive tumors. (From
Skarin [31]; with permission.)
B
A
FIGURE 5-15
Renal involvement in lymphoma. A, Renal involvement in a patient
with diffuse large cell lymphoma. There is little remaining parenchyma in this specimen, which exhibits many large, gray-white nodules
of tumor. Although primary renal lymphoma is rare, 5% to 10% of
patients with disseminated lymphoma exhibit clinically detectable
renal involvement. At autopsy, the incidence of renal involvement
by lymphoma has been estimated by several series to be more than
30% [41]. The incidence was higher in patients with lymphosarcoma or histiocytic lymphoma than in those having Hodgkins disease,
with its occurrence in mycosis fungoides being intermediate in frequency. The majority of patients had involvement of both kidneys.
Lymphoma may involve the kidney by multinodular or diffuse infil-
tration or occasionally by the presence of a large solitary tumor.

Renal failure due to parenchymal infiltration by lymphoma cells is
extremely rare. In one large series, uremia resulting from lymphomatous replacement of kidney tissue was the cause of death in
only 0.7% of patients [42]. As with leukemia, when lymphoma has
caused renal failure, chemotherapy and radiation therapy have led
to improvement in kidney function.
B, Lymphoma with renal infiltration. A 65-year-old-man presented with left flank pain and microscopic hematuria of 6 weeks
duration. He had a left renal mass demonstrable on abdominal
ultrasound. Left renal perihilar and retroperitoneal lymph node
enlargement was noted on a CT scan. He was normotensive and
had a serum creatinine level of 1.2 mg/dL. A needle biopsy of the
renal mass, under CT guidance, revealed renal parenchymal infiltration with lymphoid cells with neoplastic characteristics. (Panel A
from Skarin [31]; with permission.)
5.9
Postrenal Acute Renal Failure

CAUSES OF POSTRENAL ACUTE RENAL FAILURE
Anatomic site
Cause
Urethral obstruction
Bladder neck obstruction
Prostatic hypertrophy
Prostatic or bladder cancer
Functional: neuropathy or drugs
Extraureteral
Cancer of prostate or uterine cervix
Periureteral fibrosis
Accidental ureteral ligation during
pelvic surgery for cancer
Intraureteral
Uric acid crystals or stones
Blood clots
Pyogenic debris
Edema
Necrotizing papillitis
Bilateral ureteral obstruction

(or unilateral obstruction with
single kidney)
Nodal
obstruction
Uterus
Bladder
ulceration
Stricture
Uretovaginal
fistula
Bladder
Vesicovaginal
fistula
Vagina
FIGURE 5-16
The etiology of postrenal failure involves obstruction at various
anatomic sites by tumors of the urinary tract or surrounding tissues. Some of the more common causes of bladder neck obstruction in the cancer patient include prostatic hypertrophy [43] and
prostatic or bladder cancer [44]. Postrenal acute renal failure may
also be produced by bilateral obstruction of both ureters (or unilateral ureteral obstruction in the presence of a single kidney). This
may be caused by invasion of the ureters by bladder neoplasms or,
more commonly, by retroperitoneal spread of malignancies, particularly of colon, prostate, bronchus, or breast origin.
FIGURE 5-17
Urinary tract obstruction. Obstruction is a prominent feature of
urinary tract involvement in gynecologic cancers [45]. The ureters
may be invaded by tumor or compressed by the tumor mass or
tumor-filled lymph nodes. Ureteral stricture may be the cause of
obstruction following radiation therapy or surgery. Also, the bladder may be subject to direct extension of tumor with occlusion of
ureteral orifices. In this figure, the anterior wall of the bladder is
cut away to illustrate these as well as other forms of urinary tract
involvement by gynecologic cancers. In this setting, obstruction
may produce either acute or chronic renal failure depending on the
location of the obstruction and the rapidity of tumor growth.
(Adapted from Rieselbach and Garnick [1].)
5.10

Diagnostic approach to acute renal failure
STEP I
ACUTE
Normal recent function
Normal renal size on ultrasound
Normal HCT
CHRONIC
Prior renal dysfunction
Small kidneys on ultrasound
Anemia
STEP II
History, physical exam
Prerenal
Edema
CHF
Cirrhosis
ECFV contraction
Drugs
Postrenal
Distended bladder
Pelvic mass ( )
Enlarged kidney(s)
Flank pain
Prostatism ( )
Intrinsic renal
Hypotension
Nephrotoxins
Systemic symptoms
Trauma/surgery
STEP III
Urinalysis
RBC casts and/or

dysmorphic RBCs
Eosinophils
Acute tubulointerstitial Glomerulonephritis

nephritis
or vasculitis
Dipsticknegative
proteinuria
Epithelial cells
Granular, pigmented casts
Light-chain
cast nephropathy
Gallium
scan
Renal
biopsy
UPE
Bone marrow
biopsy
Uric acid
crystals
Benign
Acute uric
acid
nephropathy
Orthotolidine
positive on dipstick but
RBC negative in sediment
Prerenal
or
postrenal
Myoglobin
Hemoglobun
STEP IV
Blood chemistries
BUN/creatinine ratio
Calcium
Uric acid
Phoshorus
CPK, aldolase
Other blood studies

SPEM spike
C3/C4 (complement)
Haptoglobin
Eosinophilia
STEP V
Urinary diagnostic indicies
Prerenal or
glomerulonephritis
Acute uric acid

nephropathy
Light chain
nephropathy
ATN or
obstruction
UNA<20, FENA<1%
UOSM>500
Urine uric acid/

creatinine >1.0
Urine positive
for light chains
UNA>40, FENA>3%
UOSM<350
Anuria
Renal biopsy
Glomerulonephritis
Obstruction
Bilateral cortical necrosis
Exclude obstruction
Ultrasound
CT scan
Retrograde pyelogram
Bilateral renal artery or vein occlusion

Magnetic resonance angiography
Duplex ultrasonography
Digital subtraction angiography
Renal arteriography/venography
FIGURE 5-18
Diagnostic approach to acute renal failure. Acute renal failure developing in a patient with malignancy may be due
to diverse causes. It is important to employ an organized diagnostic approach to define the specific cause in a costeffective manner. The approach outlined in this figure involves five steps. Step I addresses the distinction between
acute and chronic renal failure, and step II lists the various causes of prerenal, intrinsic, and postrenal acute renal
failure (see Figs. 5-2, 5-4, and 5-16) according to data obtained from the history and physical examination.
Urinalysis is very useful in the workup of a patient with acute renal failure, particularly due to intrinsic renal
disease, as outlined in step III. The presence of red blood cell (RBC) casts or dysmorphic RBCs in the urine sedi-
ment is suggestive of
glomerulonephritis, while
eosinophiluria is indicative of acute interstitial
nephritis. Step IV
involves obtaining blood
chemistries and other
blood studies, abnormalities that may strongly
support a given diagnosis. Step V is employed in
the presence of oliguric
acute renal failure.
Urinary diagnostic
indices are used to distinguish between prerenal
acute renal failure and
glomerulonephritis, as
opposed to acute tubular
necrosis or acute obstruction. Evaluation of the
urine is also helpful in
detecting the presence of
light chains of
immunoglobulins, which
may be diagnostic of
multiple myelomainduced acute renal failure. Also, an increased
urinary uric acid/creatinine ratio may indicate
acute uric acid nephropathy. In the patient who is
anuric (<50 mL of urine
per day), it is particularly
important to rule out
obstruction. Bilateral cortical necrosis or glomerulonephritis must be considered in this setting; a
renal biopsy may be necessary for definitive diagnosis. If bilateral renal
artery or vein occlusion
is a consideration,
angiography may be indicated. ATNacute tubular necrosis; BUN
blood urea nitrogen;
CHFcongestive heart
failure; CPKcreatine
phosphokinase; ECFV
extracellular fluid volume; FENafractional
extraction of sodium;
Hcthematocrit; SPE
serum protein electrophoresis; Unaurine
sodium; Uosmurine
osmolality; UPEurine
protein electrophoresis.
5.11
Hematuria and/or the Nephrotic Syndrome

CAUSES OF HEMATURIA AND/OR
THE NEPHROTIC SYNDROME
Paraneoplastic glomerulonephritis
Minimal change nephrotic syndrome
Primary or metastatic renal cancer
Chemotherapy agents causing nephrotic syndrome
Mitomycin C
Gemcitabine
Interferon
A
FIGURE 5-20
Membranous glomerulonephritis and the nephrotic syndrome in a
patient with bronchogenic carcinoma. A 76-year-old veteran presented with ankle edema and weight gain of 8 weeks duration. He
was noted to have the nephrotic syndrome with 5 grams of proteinuria per day. A chest radiograph revealed a perihilar mass. A bronchoscopic biopsy of the mass was diagnostic of malignancy. He was
managed conservatively with diuretics and radiotherapy for the
FIGURE 5-19
Causes of hematuria and/or the nephrotic syndrome. Hematuria
and/or the nephrotic syndrome may occur in association with malignancy without causing acute or chronic renal failure. Causes may
include one of the many paraneoplastic types of glomerulonephritis,
with proteinuria and often the nephrotic syndrome resulting from
the glomerular injury; hematuria is also noted in some cases. In contrast, isolated hematuria is the predominant feature when primary
or metastatic renal cancer erodes the intrarenal vasculature.
Proteinuria, and in some cases the nephrotic syndrome, may be the
presenting nephrotoxicity of cancer chemotherapy agents.
B
chest mass. He died 10 months later. Membranous glomerulonephritis and bronchogenic carcinoma were diagnosed at autopsy.
A, Light microscopic study of the kidney of this patient. Note the
thickening of capillary walls and spikes (PAM stain). B, Immunofluorescence microscopy of renal tissue showing peripheral
glomerular capillary deposition of IgG in a granular pattern indicative of immune-complex-mediated glomerulonephritis.
5.12
C
C, Electron microscopy of the glomerulus showing subepithelial
electron-dense deposits along the capillary walls. There is effacement of the epithelial cell foot processes, which is a common finding in patients with nephrotic syndrome. D, Bronchogenic carcinoma noted at autopsy in this patient (hematoxylin and eosin stain).
Membranous glomerulonephritis is an immune-complexmediated glomerular disease, often resulting in nephrotic syndrome as a
clinical manifestation. In adults older than the age of 50, a coexisting malignancy, usually a carcinoma, may be present in up to 10%
A
FIGURE 5-21
Minimal change nephrotic syndrome in Hodgkins disease. A, Light
microscopic study of a renal biopsy specimen from a 57-year-old
man with nephrotic syndrome of 3 months duration. Urine protein
excretion was 7.1 g/d. The serum creatinine concentration was 1.3
mg/dL. The patient also had cervical lymphadenopathy, biopsy of
which revealed Hodgkins disease of the mixed cellularity type. He
was treated with irradiation to the upper mantle region with resolution of the lymphadenopathy. Proteinuria also declined to 2 g/d
in 2 weeks and was absent in 8 weeks. The glomerulus was normocellular with delicate capillary walls diagnostic of minimal change
nephrotic syndrome (PAM stain).
B, Electron microscopy of a glomerulus from the same patient
showing glomerular capillaries with extensive effacement of the
epithelial foot processes but without electron-dense deposits.
In patients with Hodgkins disease and other malignancies arising
from lymph nodes as well as different types of chronic leukemias, the
D
of cases [5]. Although a variety of malignancies have been observed
to be associated with membranous glomerulonephritis, the most
common sites are the breast, the lung, and the colon. In some
instances, the tumor antigen or antitumor antibodies have been
detected in the glomeruli. Development of the nephrotic syndrome
has been temporally related to the malignancy in several instances,
and successful cure of the malignancy has led to a remission in the
nephrotic syndrome. Relapses have been associated with reappearance of proteinuria [46].
B
occurrence of glomerular diseases has been noted [5,46]. Several histologic types of glomerular diseases have been documented in these
instances; the most common type has been minimal change nephrotic
syndrome [47]. The glomeruli of these patients are normal on light
microscopic study and are devoid of hypercellularity or capillary
wall thickening. No immunoglobulins are noted in the glomeruli on
immunofluorescence microscopy. On electron microscopy, effacement of the epithelial cell foot processes is the only abnormality present. Proteinuria has been noted to remit with cure of lymphoma
(with use of surgery, radiotherapy, or chemotherapy) in some cases;
relapses in nephrotic syndrome occur with recurrence of the tumor.
This has been documented to occur several times in some patients
[47]. The pathogenesis of minimal change nephrotic syndrome in
patients with malignancy remains unknown. It is possible that a
cytokine or tumor cell product may be responsible for the increase in
glomerular permeability with resultant proteinuria [48].
5.13
A. COMPARISON OF PARAPROTEINEMIAS
Diagnosis
Frequency*
Clinical Findings
Renal Lesions
Diagnostic Means
Multiple myeloma
Yes
Light-chain cast nephropathy

Immunoelectrophoresis or bone marrow

Light chains in urine
AL amyloidosis
Yes
Deposits of amyloid fibrils in the kidney
Light-chain deposition disease
No
Proteinuria (light chain)

Acute renal failure
Hypercalcemia
Proteinuria
Nephrotic syndrome
Proteinuria
Nephrotic syndrome
Renal or rectal biopsy

Immunoelectrophoresis
Renal biopsy
Bone marrow biopsy
Waldenstrms macroglobulinemia
Rarely
No renal symptoms or
minimal proteinuria
Monoclonal gammopathy of
unknown significance (MGUS)
Rarely
Proteinuria
Nephrotic syndrome
Nodular glomerulosclerosis with granular deposition

of light chains along the glomerular and tubular
basement and membrane; usually kappa light
chains
Intraglomerular coagula of IgM
Proliferative glomerulonephritis in some case
Bone marrow biopsy
Bone marrow biopsy
Renal biopsy
* Frequency of renal involvement.
B
A, Paraprotein abnormalities as a cause of nephrotic syndrome. This
table compares the characteristics of various paraproteinemias.
Paraproteins are abnormal immunoglobulins or abnormal
immunoglobulin fragments produced by B lymphocytes. They are monoclonal, appear in the serum or urine (or both), and cause renal damage
by several different mechanisms. Paraproteinemias comprise a group of
disorders characterized by overproduction of different paraproteins.
Multiple myeloma is a common type of paraproteinemia. The
overproduction of immunoglobulins or light chains, or both, causes
renal toxicity, directly affecting the tubular cells or forming casts

after precipitation in the tubular lumen. The light chains may be
transformed into amyloid fibrils and deposited in various tissues,
including the kidney. Amyloidosis is diagnosed by performing a
biopsy of the involved organ and staining the tissue with Congo red
stain. On occasion, the light chains do not form fibrils but are
deposited as granules along the basement membrane of blood vessels
and glomeruli. Kappa chains often behave in this manner. This entity
is called light-chain deposition disease [6] (panel B).
Paraproteins composed of IgM are noted in Waldenstrms
macroglobulinemia. Renal dysfunction is uncommon in this condition [49]. Hyperviscosity is present. On rare occasions, thrombi composed of IgM may be noted in the glomeruli of these patients.
In the most common form of paraproteinemia, monoclonal protein
is detected in the serum of an otherwise healthy person. This condition is referred to as monoclonal gammopathy of unknown significance (MGUS) and may on occasion progress to multiple myeloma
or amyloidosis [50].
B, Light-chain deposition disease (LCDD) in a patient with multiple myeloma. A light microscopic study of a renal biopsy specimen from a 65-year-old man with recently diagnosed multiple
myeloma who was found to have an elevated serum creatinine concentration (2.6 mg/dL) and proteinuria of 3 g/d. Note the nodular
mesangial lesions, capillary wall thickening, and hypercellularity
resembling diabetic nodular glomerulosclerosis.
Immunofluorescence staining was positive for kappa light chains
but negative for lambda light chains.
5.14
FIGURE 5-23
Renal cell carcinoma. With massive invasion by tumor, the renal
vein may become occluded by adherent tumor thrombus. Renal
adenocarcinoma is the most common tumor of the kidney [51]. In
the past, many of these tumors achieved large sizes before being
detected and hence were advanced in their stage and limited in
their curability by surgical resection. Today, many renal cancers
are often detected with routine abdominal computed tomography
for nonrelated indications. Once called the internists tumor
PRESENTING SIGNS AND SYMPTOMS

OF RENAL CELL CARCINOMA
Feature
Hematuria
Pain
Flank or abdominal mass
Weight loss
Symptoms from distant metastatic spread
Fever
Classic triad (pain, hematuria, mass)
Polycythemia
Acute varicocele
Frequency, %
4065
2050
2040
30
10
1520
10
<5
<5
because of the myriad paraneoplastic signs and symptoms, now

renal cancer is often termed the radiologists tumor [51,52].
Most forms of renal cancer arise from the cells of the proximal
tubular epithelium, not from adrenal rests of cells. Thus, the term
hypernephroma (ie, tumor arising from above the kidney) should
not be employed to describe this lesion.
Risk factors for the development of renal cancer include cigarette
smoking, occupational exposure to cadmium, obesity, excessive exposure to analgesics, acquired cystic disease in dialysis patients, adult
polycystic kidney disease, and other industrial exposures, such as to
asbestos, leather tanning, and certain petroleum products. Genetic
and familial forms of the disease occur, most notably with von
Hippel-Lindau disease, an autosomal dominant disorder characterized
by the development of multiple tumors of the central nervous system,
pheochromocytomas, and bilateral renal carcinomas. Several families
have been reported also to have a high incidence of renal cancer.
Genetic analyses of these patients demonstrate a balanced translocation between the short arm of chromosome 3 and either chromosome
6 or 8. Other abnormalities have been reported as well [52].
It should be noted that other primary tumors of the kidneys in
the adult include transitional cell carcinoma of the renal pelvis
and other neoplasms, such as angiomyolipoma and oncocytoma.
Metastatic lesions of the kidney include those arising from the
common epithelial cancers such as breast, lung, colon, and infiltrative lesions secondary to lymphoma and leukemias. (From
Skarin [31]; with permission.)
FIGURE 5-24
Presenting signs and symptoms of renal cell carcinoma. Patients
with renal cell cancer present with symptoms produced by the
local neoplasm, with signs and symptoms of paraneoplastic phenomena, or with other aspects of systemic disease. Alternatively,
the patient may be totally asymptomatic and may be diagnosed
from a radiologic abnormality detected on ultrasound or abdominal CT scanning. Fewer than 10% of patients present with the
classic triad of hematuria, abdominal mass, and flank pain. The
most common features include hematuria (70%), flank pain
(50%), palpable mass (20%), fever (15%), and erythrocytosis
(infrequent). Other features may include acute onset of lower
extremity edema, or, in males, the presence of a left-sided varicocele, indicating obstruction of the left gonadal vein at its point
of entry into the left renal vein by a tumor thrombus [53,54].
FREQUENCY OF SYSTEMIC EFFECTS IN PATIENTS

WITH RENAL CELL CARCINOMA
Symptom
Incidence, %
Elevated ESR
Anemia
Hypertension
Cachexia
Pyrexia
Abnormal liver function
Elevated alkaline phosphatase
Hypercalcemia
Polycythemia
Neuromyopathy
Amyloidosis
362/6.51 (55.6)
409/991 (41.3)
89/237 (37.6)
338/979 (34.5)
164/954 (17.2)
60/400 (15.0)
64/434 (14.7)
33/577 (5.7)
33/903 (3.7)
13/400 (3.3)
12/573 (2.1)
Stage I
Vena cava
Stage III
Aorta
Stage II
Stage I: Confined to kidney

Stage II: Including renal vein involvement
Stage III: Lymph node and caval involvement
Stage IV: Adjacent organ metastases
Stage IV
5.15
FIGURE 5-25
Frequency of systemic effects. The most frequent systemic manifestations of renal cell cancer are noted [55]. Other paraneoplastic
and systemic manifestations include liver function abnormalities,
high-output congestive heart failure, and manifestations of the
secretion of substances such as prostaglandins, renin, glucocorticoids, and cytokines (eg, interleukin-6). At presentation, a small
percentage of tumors are bilateral, while nearly a third of patients
have demonstrable metastatic disease, which may occur in virtually
any organ. Most common sites of metastases include lung, bone,
liver, and brain. ESRerythrocyte sedimentation rate. (From
Chisholm and Roy [55]; with permission.)
FIGURE 5-26
The staging of renal adenocarcinoma. Renal cell cancer can be
staged using one of two systems in common use. The TNM (tumor,
node, metastasis) system has the advantage of being more specific
but the disadvantage of being cumbersome; a modification of the
Robson staging system (as illustrated here) is more practical and
more widely used in the United States. In this system, stage I represents cancer that is confined to the kidney capsule; stage II indicates invasion through the renal capsule, but not beyond Gerotas
fascia; stage III reflects involvement of regional lymph nodes and
the ipsilateral renal vein or the vena cava; and stage IV indicates
the presence of distant metastases [57].
With regard to pathologic assessment, previously renal carcinomas were classified according to cell type and growth pattern. The
former included clear cell, spindle cell, and oncocytic carcinoma,
while the latter included acinar, papillary, and sarcomatoid varieties. Recently, this classification has undergone a transformation
to reflect more accurately the morphologic, histochemical, and
molecular basis of differing types of adenocarcinoma [58]. Based
on these studies, five distinct types of carcinoma have been identified: clear cell, chromophilic, chromophobic, oncocytic, and collecting duct. Each of these types has a unique growth pattern, cell
of origin, and cytogenetic characteristics [59,60]. (From Brenner
and Rector [56].)
5.16
Dialysate
Serum
Osmolality, mOsm/L
360
340
Osmotic
equilibrium
320
300
2
Dwell time, h
ADK-vol05 chap04 fig07c24p6 x 14

p
au:Khanna art:Weischedel
FIGURE 5-27
Diagnostic evaluation of and therapeutic approach to primary renal
canceran algorithm for diagnosis and management of a renal
mass. The discovery of evidence during the history or physical
examination that suggests a renal abnormality should be followed
by either an intravenous pyelogram or an abdominal ultrasound.
With increasing frequency, however, evidence of a space-occupying
lesion in the kidney is found incidentally during radiographic testing
for other unrelated conditions. Renal ultrasonography may help distinguish simple cysts from more complex abnormalities. A simple
cyst is defined sonographically by the lack of internal echoes, the
presence of smooth borders, and the transmission of the ultrasound
wave. If these three features are present, the cyst is most likely
benign. At one time, cyst puncture was used, but it seems to be
unnecessary today in the asymptomatic patient without hematuria.
Periodic repetition of the ultrasound is suggested for follow-up. If a
change in the lesion occurs, cyst puncture, needle aspiration, or CT
scanning should be considered to evaluate the lesion further.
If the sonographic criteria for a simple cyst are not met or the
intravenous pyelogram suggests a solid or complex mass, a CT scan
should be performed. If a renal neoplasm is demonstrated on CT
scanning, renal vein or vena caval involvement should be assessed
with CT scanning or magnetic resonance imaging. Although used
frequently in the past, selective renal arteriography has assumed a
more limited use, mainly in further evaluating the renal vasculature
in patients who are to undergo partial nephrectomy (nephron-sparing surgery). CT scanning is also very helpful in determining the
presence of lymphadenopathy.
The differential diagnosis of a renal mass detected on CT scanning
includes primary renal cancers, metastatic lesions of the kidney, and
benign lesions. The latter include angiomyolipomas (renal hamartomas), oncocytomas, and other rare or unusual growths. If a renal
cancer is considered based on the radiographic studies of the kidney,
the patient should undergo a preoperative staging evaluation to
assess the presence of metastases in the lung, bone, or brain.

(Continued) The operative and diagnostic approach is dictated
according to the preoperative stage of the patient. For example, the
patient who presents with stage IV disease by virtue of a positive
bone scan may need only a needle biopsy of either the kidney lesion
or the bone lesion to establish the tissue diagnosis and thus avoid
more extensive surgery on the kidney. In contrast, a patient with an
isolated pulmonary lesion may be considered for both nephrectomy
and pulmonary nodulectomy at one operative intervention.
The standard therapy for localized renal cell carcinoma is radical
nephrectomy, which includes removal of the kidney, Gerotas fascia,
the ipsilateral adrenal gland, and regional hilar lymph nodes. The
value of an extended hilar lymphadenectomy seems to be its ability
to provide prognostic information, since there is rarely a therapeutic
reason for performing this portion of the operation. In the past, the
removal of the ipsilateral adrenal gland was done routinely; today,
most data suggest that it is involved less than 5% of the time, more
frequently with large upper-pole lesions. Thus, today, ipsilateral
adrenalectomy is reserved for those patients with abnormal-appearing glands or enlarged glands on CT scan or those with large upperpole lesions, in which the probability of direct extension of the
tumor to the adrenal gland is more likely [61].
Partial nephrectomy (nephron-sparing surgery) has become more
popular, especially for patients with small tumors, for those at risk for
developing bilateral tumors, or for patients in whom the contralateral
kidney is at risk for other systemic diseases, such as diabetes or hypertension [62]. The main concern associated with partial nephrectomy
is the likelihood of tumor recurrence in the operated kidney, since
many renal cancers may be multicentric. Local recurrence rates of 4%
to 10% have been reported; lower rates have been reported when
partial nephrectomy was performed for smaller lesions (< 3 cm) with
a normal contralateral kidney. Lesions that are centrally located, however, still require radical nephrectomy. Frequent follow-up, usually
with CT scanning or ultrasonography, will be necessary in those
patients who undergo partial nephrectomy. Inferior vena caval
involvement with renal cancer occurs more frequently with rightsided tumors and is usually associated with metastases in nearly 50%
of patients. Vena caval obstruction may lead to the diagnosis; it may
present with abdominal distention from ascites, hepatic dysfunction,
nephrotic syndrome, abdominal wall venous collaterals, varicocele,
malabsorption, or pulmonary embolus. The anatomic location of the
caval thrombus is important prognostically; supradiaphragmatic
lesions, which may involve the heart, can be resected, but the prognosis is poor. Subdiaphragmatic lesions enjoy a better 5-year survival,
but the survival rate is usually less than 50% [63]. In the surgical
management of these patients, a team of specialists is required, especially if a cardiac tumor thrombectomy is contemplated.
The role of surgery in the management of metastatic disease either
at initial presentation or later remains controversial. Although most
data that support nephrectomy plus metastatectomy are anecdotal,
many patients with synchronous renal cell cancer and an isolated
pulmonary nodule may be considered for surgical resection of both
lesions. Likewise, patients who develop an isolated lesion in the liver
or lung some time following the removal of the kidney also may be
considered for surgical removal of the metastasis. Nevertheless, even
when such vigorous surgery is carried out, most patients do poorly.
Additional controversy surrounds the practice of performing
nephrectomy in patients with widespread metastatic disease as a
means of potentially improving their response to systemic therapy.
Many investigative programs require such resection, but at this writing, the practice should be considered investigational. A patient who
does experience an excellent response to systemic therapy should be
5.17
considered for nephrectomy following the response, however.

Finally, since many renal tumors can become quite large, consideration should be given to palliative nephrectomy (in the setting of
metastatic disease), especially if the patient experiences uncontrollable hematuria or pain or is catabolic secondary to the sheer mass
of the tumor.
The medical management of patients with either locally advanced
renal cancer or metastatic disease provides a great challenge to physicians and clinical investigators. Although chemotherapy and hormonal treatments have been studied extensively in patients with
metastatic renal cancer, no single treatment protocol or program has
been uniformly effective. Therefore, most physicians treating the disease usually rely on novel modalities of treatment, including biologic
response modifiers, investigational anticancer agents, differentiation
agents (such as retinoic acid), vaccines, and gene therapy. Interferon
therapy with interferon-, -, or - has led to responses in approximately 15% to 20% of treated patients [64]. Interferons demonstrate
antiproliferative activity against renal cell cancers in vitro, stimulate
immune cell function, and can modulate the expression of major histocompatibility complex molecules. Although responses have been
seen in cancers involving many different anatomic areas, patients
who have had a prior nephrectomy with isolated pulmonary metastases and who are otherwise well may enjoy a higher response rate
[65]. Duration of response is usually less than 2 years; longer lasting
remissions have been noted in a few selected patients. Interferons
have been combined with other immune modifiers as well as with
chemotherapy agents with no real improvement in patient outcome
in larger-scale trials. Several smaller trials have combined interferon
with interleukin-2 or chemotherapy agents (eg, 5-fluorouracil) with
some encouraging preliminary results.
Interleukin 2 (Il-2) has received a great deal of attention as a
potential advance in the treatment of renal cell cancer. This agent
enhances both proliferation and functioning of lymphocytes involved
in antigen recognition and tumor elimination. Initial studies used
very high doses of Il-2 in association with ex vivo populations of
lymphoid cells grown and matured under the influence of Il-2 [66].
These programs resulted in substantial toxicity, including patient
deaths, but nevertheless had early and encouraging therapeutic
results. Unfortunately, the initial encouraging results were not consistently observed in larger-scale trials. Efforts are now directed at
selectively manipulating the immune-enhancing features of the treatment, with modification of the toxic effects. In several recent studies,
the use of lower doses of Il-2 without the cellular components has
resulted in comparable results with less toxicity.
The toxicity of Il-2 is related to alterations in vascular permeability, leading to a capillary leak type of syndrome. Although the drug
is approved by the Food and Drug Administration for the management of patients with metastatic renal cell cancer, its use should be
restricted to those patients who can tolerate the side effect profile
and those patients with acceptable cardiac, renal, pulmonary, and
hepatic function.
Investigational therapies continue to be studied for renal cell cancer.
These include novel cytokines such as interleukin-12, combinations of
biologics with or without chemotherapeutic agents, circadian timing of
chemotherapy administration, vaccine therapy, various forms of cellular
therapy, and gene therapy [67]. Although all these approaches have a
solid scientific preclinical rationale, none, unfortunately, can be considered standard treatment. The sobering fact still remains that nearly
50% of all patients diagnosed with renal cell cancer die of their disease
within 5 years of diagnosis, and a substantial proportion have advanced
stages of cancer spread at initial presentation.
5.18

FIGURE 5-28
Metastatic malignant melanoma involving the kidney. The urinary
tract is a common site of melanoma metastases. If not amelanotic,
the metastatic nodules are brownish black. Metastatic infiltration
of the kidneys is often an incidental finding at autopsy but is a rare
cause of functional impairment [68]. Most renal metastases are
multiple and bilateral. Glomeruli tend to be spared, possibly
because of their lack of lymphatic channels. Pulmonary carcinoma
is the most commonly reported form of metastatic solid tumor
involving the kidneys, followed by metastatic stomach and breast
carcinoma [69].
Metastatic melanoma is an example of a tumor that may be
transplanted at the time of cadaver kidney transplantation, with
subsequent rapid proliferation in the immunosuppressed recipient;
tumor rejection may occur with cessation of immunosuppressive
therapy [70] (see Fig. 5-37). The presence of renal metastases is
often overlooked during life due to the absence of any specific
physical or laboratory findings. The laboratory finding most likely
to occur is hematuria due to tumor erosion of intrarenal vessels.
(From Skarin [31]; with permission.)
Chronic Renal Failure

CAUSES OF CHRONIC RENAL FAILURE
Glomerular abnormalities
Tubulointerstitial abnormalities
Renovascular disease
Obstruction
Glomerulonephritis
Amyloidosis
Primary renal cancer
Immunoglobulins or light chains
Radiation nephropathy
Leukemic infiltration
Lymphomatous infiltration
Metastatic infiltration
Chronic pyelonephritis
Hypertension due to malignancy
Peripheral vascular involvement by renal
or nonrenal cancer
Renal vein thrombosis
Cancer
Prostate
Cervix
Bladder
Retroperitoneal lymphoma
Primary renal
Uric acid or calcium stones
FIGURE 5-29
Causes of chronic renal failure. The glomerular abnormalities listed
may be associated with cancer but most often do not cause a significant degree of chronic renal failure; their clinical expression
most often involves hematuria or the nephrotic syndrome.
Disordered immunoglobulin production associated with multiple
myeloma is a frequent cause of interstitial abnormalities, producing
chronic renal failure in association with cancer. Renal failure has
been reported to develop in up to half of patients with myeloma at
some time during their illness and is associated with a significantly
worse prognosis [71]. The multiple causes of renal failure in myeloma have been previously reviewed (see Fig. 5-8). Radiation
nephropathy may produce chronic renal failure owing to interstitial
abnormalities and may be associated with severe hypertension.
Interstitial involvement by metastatic infiltration of the kidneys or
by hematologic neoplasms may rarely cause chronic renal failure.
The immunosuppressed status of many cancer patients serves to
increase their susceptibility to bacterial and fungal invasion of the
renal interstitium. Thus, chronic pyelonephritis may be a cause of
chronic renal failure in the cancer patient, particularly in association with chronic obstruction.
With regard to renal vascular disease, hypertension due to malignancy may produce nephrosclerosis. Hypertension may be associated with the hypercalcemia of malignancy and is observed frequently in patients with renal carcinoma. Perirenal vascular involvement
may be observed with primary renal cancer or nonrenal cancer;
renal vein thrombosis or occlusion may occur because of external
compression by tumor or direct extension of tumor. When obstruction is present at any level of the urinary tract, the continued production of urine results in an increase in volume and pressure
proximal to the obstruction. If the obstruction persists, the kidney
may be damaged progressively with resultant chronic renal failure.
The causes in obstruction causing chronic renal failure in association with cancer are similar to those noted in Figure 5-16 in the
production of postrenal acute renal failure.
5.19

Amyloidosis. A, Light microscopic study of a renal biopsy specimen from a patient with multiple myeloma and AL amyloidosis
showing eosinophilic, fluffy amyloid deposits in the glomerulus.
(Periodic acidSchiff stain.) B, When stained with Congo red and
viewed under polarized light, the amyloid deposits show applegreen birefringence. C, The amyloid fibrils viewed by means of
electron microscopy.
Amyloidosis is a generic term for a group of disorders in which
there is extracellular deposition of insoluble fibrillar proteins in a
characteristic B-pleated sheet configuration [29]. Although the proteins may be different, they all bond to Congo red stain. When the
stained tissue is viewed under polarized light, it displays apple-green
birefringence. In 10% to 15% of patients with multiple myeloma,
AL amyloidosis (composed of light chains) may occur in association
with the nephrotic syndrome and renal insufficiency. There is no
specific therapy for renal amyloidosis. Some patients have experienced remission of the nephrotic syndrome with chemotherapy for
myeloma, however. Dialysis (hemodialysis or peritoneal dialysis)
and transplantation have been of value in a small number of
patients with AL amyloidosis and end-stage renal disease [72].
5.20
POTENTIALLY NEPHROTOXIC CHEMOTHERAPEUTIC AGENTS

Risk
Drug
Alkylating agents
Cisplatin
Carboplatin
Cyclophosphamide
Ifosfamide
Streptozotocin
Semistine (methyl-CCAU)
Carmustine (BCNU)
Antimetabolites
Methotrexate
Cytosine arabinoside (Ara-A)
5-Fluorouracil (5-FU)
5-Azacitidine
6-Thiognanine
Antitumor antibiotics
Mitomycin
Mithramycin
Doxorubicin
Biologic agents
Interferons
Interleukin-2
High
Intermediate
Type of renal failure

Low
X
X
X
X
X
Acute
Chronic
Specific tubular damage
Immediate
Delayed
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Time Course
X
X
X
X
X
X
X
X
X
*Fanconis syndrome as the most severe manifestation.

Only seen with intermediate to high dose regimens.
Only seen when given in combination with mitomycin C.
Hemolytic-uremic syndrome as the most severe manifestation.
Frequent with antineoplastic doses, rare in doses used for hypercalcemia.
FIGURE 5-31
Toxic therapeutic agents. Nephrotoxicity due to antineoplastic
agents may result in chronic renal failure but also may manifest
as acute renal failure, specific tubular dysfunction, or the
nephrotic syndrome. Nephrotoxicity has been observed with use
of alkylating agents, antimetabolites, antitumor antibiotics, and
biologic agents, as outlined in the table. These neoplastic agents
may induce nephrotoxicity soon after initiation of therapy or

only after long-term administration. The risk of nephrotoxicity
varies with each agent. This table summarizes the risk of
nephrotoxicity, time of onset, and type of functional impairment
produced by each agent. (From Massry and Glassock [73];
with permission.)
FIGURE 5-32
Semustine nephropathy. A, Photomicrograph of the late stages of
semustine nephrotoxicity in a specimen obtained at autopsy.

B, Photomicrograph of a renal biopsy specimen from a patient with
advanced semustine nephrotoxicity. Semustine (methyl-CCNU) is a lipidsoluble nitrosourea that is structurally similar to carmustine (BCNU) and
lomustine (CCNU). Because of the ability of these agents to cross the
blood-brain barrier due to their high lipid solubility, and because of their
broad spectrum of antitumor activity and ease of administration, they
have been used widely. Nephrotoxicity has been a factor limiting more
widespread use, however. Semustine has proved to be the most nephrotoxic of these compounds. The degree of toxicity appears to be dose
dependent. Evidence of renal damage often is not apparent until 18 to
24 months following the completion of therapy [74]. When it occurs,
renal failure is usually progressive and irreversible. As noted in this figure, toxicity involves glomerulosclerosis, focal tubular atrophy, and varying degrees of interstitial fibrosis on light microscopic examination.
(From Harmon and coworkers [74]; with permission.)
5.21
FIGURE 5-33
Radiation nephritis is the basis for the atrophy of the superior portion of the left kidney
shown in this intravenous pyelogram. The right kidney shows straightening of its medial border due to irradiation atrophy. A, Preirradiation pyelogram; B, film showing radiation field.
Radiation nephropathy refers to damage to the kidney parenchyma and vasculature as a
result of ionizing radiation [14]. Fortunately, this disease is relatively uncommon. It was
more prevalent before meticulous detail to abdominal organ shielding was widely practiced or understood. Historically, patients receiving whole abdominal radiation therapy for
lymphoma, seminoma, or other retroperitoneal tumors were the most likely to suffer the
consequences of this disorder. Doses greater than 30 to 35 gray and single large fractions
were likely to cause damage.
Pathologically, the disease is characterized by damage to the microvasculature, proliferation of fibrous tissue, and disruption of the renal capillaries and arterioles.
Clinically, the disease manifests predominantly with renal dysfunction and hypertension.
Hematuria, oliguria, fatigue, and gradually developing renal atrophy are common manifestations. The chronic form of radiation nephropathy may occur 10 to 15 years after the
radiation treatments. (From Rieselbach and Garnick [1]; with permission.)
FIGURE 5-34
Bilateral ureteral obstruction by diffuse
large-cell lymphoma. Extensive retroperitoneal involvement is evident. Confluent
adenopathy of retroperitoneal lymph nodes
has led to bilateral encasement and compression of the ureters by pink-tan, fleshy
tumor. This may produce chronic renal failure if tumor involvement is slowly progressive or involves predominantly one ureter.
(From Skarin [31]; with permission.)
5.22
Specific Renal Tubular Dysfunction and

Associated Fluid and Electrolyte Disorders
RENAL TUBULAR DYSFUNCTION IN MALIGNANCY
Cause
Tumor-induced inappropriate hormone concentrations
PTH-like substances
Excess ADH
Deficient ADH
Adrenocortical excess
Adrenocortical insufficiency
Tumor products or metabolites
Lysozyme (AML)
Immunoglobulin light chains (MM)
Hypercalcemia (MM, osseous metastases)
Reabsorptive urate transport inhibitor (Hodgkins, solid tumors)
Intrinsic
Amyloid deposits in collecting ducts (MM)
Partial intrarenal obstruction (MM cast nephropathy)
Cyclophosphamide
Ifosfamide
Vincristine
Cisplatin
Streptozocin
Clinical presentation
Hypercalcemia
Hypophosphatemia
Hyponatremia (SIADH)
Hypernatremia (central DI)
Hypokalemia
Hyperkalemia
Hypokalemia
Fanconis syndrome
Fanconis syndrome
Urinary concentrating defect
Multiple transport defects
Hypouricemia
Nephrogenic DI
Nephrogenic DI
SIADH
Fanconis syndrome
SIADH
Hypomagnesemia
Hypophosphatemia
Fanconis syndrome
FIGURE 5-35
Renal tubular dysfunction. Specific tubular dysfunction may be encountered in association
with the four major causes listed.
Normal renal tubular function is controlled by a delicate balance of humoral mediators.
Thus, a tumor-induced inappropriate concentration of a hormone that normally contributes
to the modulation of this balance may result in a profound disturbance of tubular function,
thereby causing impairment of fluid and electrolyte balance as well as other homeostatic
defects. A tumor product appears to be the basis for renal phosphate loss in some cases, in
that the resultant hypophosphatemia regresses when the tumor is removed [75].
Hyponatremia occurs frequently in the patient with cancer; it is frequently caused by the
syndrome of inappropriate antidiuretic hormone secretion (SIADH). Bronchogenic carcinoma is the most frequent cause of this syndrome. A number of other tumors have also been
reported to cause SIADH. Disappearance of the syndrome on removal of the tumor or
improvement following successful chemotherapy has been observed frequently [76]. Cancer
is a common cause of central diabetes insipidus; metastatic lesions have been reported to
cause 5% to 20% of all cases, with breast cancer being the primary malignancy in more
than half the cases reported [77]. Adrenocortical steroid excess may be associated with
malignancies and often manifests with hypokalemia and metabolic alkalosis due to excessive mineralocorticoid effect in the distal nephron. Adrenal insufficiency may develop owing
to metastatic lesions of the adrenal glands, producing hyperkalemia and hyponatremia due
to mineralocorticoid deficiency and affecting

tubular transport at the same site.
Hypercalcemia is the most common setting
in which tumor products or metabolites can
cause specific tubular defects. In this case,
profound tubular dysfunction is observed
involving impairment of bicarbonate or sodium transport, urinary concentration, hydrogen ion secretion, or the renal handling of
potassium, phosphorus, or magnesium [35].
Massive lysozymuria may be associated with
renal damage, leading to kaliuresis and
hypokalemia [78]. Elevations of lysozyme levels are seen with acute myelogenous leukemia.
In this setting, proximal tubular defects in
urate, phosphate, and amino acid reabsorption have also been noted [79]. Isolated
hypouricemia has been reported in patients
with advanced Hodgkins disease; these
patients have increased renal clearance of
urate despite decreased serum urate levels.
Abnormal urate clearance was corrected by
successful treatment of the underlying
Hodgkins disease, suggesting a humoral basis
for this tubular defect. Hypouricemia, in association with other types of proximal tubular
dysfunction, has been associated with a variety of solid tumors. In multiple myeloma, the
proliferation of abnormal plasma cells produces large quantities of a variety of
immunoglobulins. These may produce
changes in tubular function, which result
from tubular reabsorption of the freely filtered low-molecular-weight tumor products.
These in turn interfere with normal metabolism of proximal tubular cells after their reabsorption. This toxicity produces Fanconis
syndrome, which is a complex proximal tubulopathy associated with multiple reabsorption
defects, and renal tubular acidosis, which may
be of the proximal or distal variety.
Intrinsic renal lesions produced by cancer
may cause nephrogenic diabetes insipidus, in
which the kidney is unresponsive to the action
of antidiuretic hormone (ADH), with resultant formation of inappropriately dilute urine.
This may be seen in multiple myeloma, in
which causative intrinsic lesions could include
intratubular obstruction by myeloma proteins
or amyloid deposition in collecting ducts.
Various antineoplastic agents produce a
wide array of tubular dysfunction, with
defective reabsorptive transport of magnesium constituting the defect of greatest clinical significance. AMLacute myelogenous
leukemia; DIdiabetes insipidus; MMmultiple myeloma; PTHparathyroid hormone.
5.23
Malignancy in the Renal Transplant Patient

MALIGNANCY IN THE RENAL TRANSPLANT PATIENT
Cancer of the skin and lips
Squamous cell carcinoma
Basal cell carcinoma
Malignant melanoma
Malignant lymphoma
Non-Hodgkins lymphoma
Reticulum cell sarcoma
B-cell lymphoproliferative syndromes (Epstein-Barr virus)
Kaposis sarcoma
Cutaneous form
Visceral and cutaneous form
Genitourinary cancer
Carcinoma of the native kidney (acquired cystic kidney disease)
Carcinoma of the transplanted kidney
Renal cell carcinoma
Malignant melanoma
Carcinoma of the urinary bladder (cyclophosphamide associated)
Uroepithelial tumors (associated with analgesic abuse)
Gynecologic cancer
Carcinoma of the cervix
Ovarian cancer
FIGURE 5-36
Malignancy in the renal transplant patient. In patients with end-stage
renal disease with an adequately functioning renal allograft, there is an
increased incidence of malignancy at various sites [80]. The most common form of malignancy is skin cancer. Its incidence may be as high as
24% in countries such as Australia where excessive exposure to the sun
occurs. Other forms of cancer also occur with increased incidence in the
transplant recipient. Malignant lymphoma, especially at extranodal sites
(such as the central nervous system), occurs with increased frequency.
Women with renal transplants have been observed to have an increased
incidence of cervical cancer. Kaposis sarcoma can account for 5% to
10% of posttransplant neoplasms. This tumor may be confined to the
skin or may involve the viscera.
Several factors contribute to the increased risk of cancer in the
immunosuppressed renal transplant recipient. These include loss of
immune surveillance, chronic antigenic stimulation, oncogenic potential
of the immunosuppressant agents, and viral infections leading to neoplasia. Epstein-Barr virus has been implicated in the polyclonal B-cell
lymphoproliferative disease in these patients. Lymphoproliferative disorders have been noted to occur after a median period of 56 months
when azathioprine and prednisone are used as immunosuppressive therapy. After the introduction of cyclosporine, lymphoproliferative disorders develop sooner, with a median interval of only 6 months [81].
The prognosis for patients with skin cancer remains good. Preventive
measures such as avoiding sun exposure, utilization of sun-blocking
creams, and careful periodic skin examinations are important. Patients
with Kaposis sarcoma confined to the skin may have remission rates of
up to 50% with cessation of immunosuppression or with chemotherapy. Patients with Kaposis sarcoma involving the viscera or with other
lymphoproliferative disorders do poorly, with a more rapid course than
seen in nontransplant patients with malignancy. Even those patients
responding to chemotherapy tend to have only short remissions and a
poor outcome.
FIGURE 5-37
Malignant lymphoma in the transplanted kidney. A 55-year-old
man with end-stage renal disease due to diabetic nephropathy
received a cadaveric renal transplant. He was managed with prednisone, azathioprine, and antilymphocyte globulin (ALG). The allograft functioned poorly despite therapy a week later with OKT3.
Results of a percutaneous renal biopsy were suspicious for a lymphoproliferative disorder in the renal allograft. He had a transplant
nephrectomy 5 weeks after the original surgery. Pathologic study of
the allograft showed extensive infiltration of the interstitium, renal
pelvis, and blood vessels with large round and ovoid lymphocytes
with many nucleoli and scant cytoplasm, diagnostic of a malignant
lymphoma. Special studies revealed the lymphoid cells to be polyclonal in nature, and the patients serologic testing was positive for
Epstein-Barr virus. Immunosuppression was stopped, and therapy
with ganciclovir was started.
5.24
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5.25
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Renal Involvement in
Tropical Diseases
Rashad S. Barsoum
Magdi R. Francis
Visith Sitprija
ropical nephrology is no longer a regional issue. With the enormous expansion of travel and immigration, the world has become
a global village. Today, a health problem in a particular region has
worldwide repercussions. Typical examples are the acquisition of malaria
in European airports, renal disease associated with herbal medications,
and increasing encounters of parasitic infections in immunocompromised
persons [13].
Lessons learned from the study of tropical diseases have considerably
enriched worldwide medical knowledge of the basic and clinical aspects
of nontropical diseases. Examples include better understanding of
macrophage function in vitro, the role of cytokines in acute renal failure,
and the importance of immunoglobulin A deposits in the progression of
glomerular disease [47].
The so-called typical tropical nephropathies are broadly classified as
infective or toxic. Infective nephropathies include renal diseases associated with endemic bacterial, viral, fungal, and parasitic infections. Toxic
tropical nephropathies include exposure to poisons of animal origin, such
as snake bites, scorpion stings, and intake of raw carp bile, and plant origin, such as certain mushrooms and the djenkol bean [3].
Tropical bacterial infections often are associated with renal complications that vary according to the causative organism, severity of infection,
and individual susceptibility. The principal acute infections reported to
affect the kidneys are salmonellosis, shigellosis, leptospirosis, melioidosis,
cholera, tetanus, scrub typhus, and diphtheria [816]. Renal involvement
in mycobacterial infections such as tuberculosis and leprosy usually pursues a subacute or chronic course [1719].
CHAPTER
6.2
The clinical spectrum of renal involvement extends all the way

from asymptomatic proteinuria or urinary sediment abnormalities
to fatal acute renal failure. The respective renal pathologies include
glomerular, microvascular, and tubulointerstitial lesions.
The pathogenesis of renal complications in tropical bacterial
infections is multifactorial. The principal factors are direct tissue invasion by the causative organisms and remote cellular and
humoral effects of bacterial antigens and endotoxins. The relative significance of the different pathogenetic mechanisms
varies with the causative organism.
In tropical zones many viral nephropathies are endemic, such
as those associated with human immunodeficiency virus and
hepatitis A, B, and C viruses. These are addressed in Chapter 7.
Here the focus is on an important viral disease endemic in
Southeast Asia that often causes minor epidemics in Africa and
other tropical countries, dengue hemorrhagic fever.
Mycotic infections are described in detail elsewhere.

Discussed here is a fairly common mycotic infection, mucormycosis, which occurs in underdeveloped tropical regions, particularly among immunocompromised patients. Also described is
ochratoxin, a fungal toxin often incriminated in the pathogenesis of Balkan nephropathy. Ochratoxin also contributes to progressive interstitial nephropathy in Africa [20].
Three ways exist by which parasitic infections cause renal
disease: 1) direct physical invasion of the kidneys or urinary
tract, as in schistosomiasis, echinococcosis, and filariasis; 2)
renal injury as a consequence of the acute systemic effects of
parasitic infection, eg, falciparum malaria; and 3) immunemediated renal injury resulting from the concomitant host-parasite interaction, eg, schistosomiasis, malaria, filariasis, leishmaniasis, trichinosis, echinococcosis, toxoplasmosis, and trypanosomiasis [2132].
Infective Tropical Nephropathies

Bacterial Infections
CLINICAL MANIFESTATIONS OF TROPICAL BACTERIAL NEPHROPATHIES
Disease
Salmonellosis
Shigellosis
Leptospirosis
Melioidosis
Cholera
Tetanus
Scrub typhus
Diphtheria
Tuberculosis
Leprosy
Abnormal sediment
Proteinuria
ARF
CRF
HUS
Hemolysis
DIC
Jaundice
+++
++++
++++
++++
+
+
++++
+
++*
+
+
+
+
+
+
+
+
+
++++
+++++
+
+
+
++
++
++++
++
+
+/+++
+++
++
+
+++
+
+
+
+
Commonly associated features

Gastrointestinal
Neurologic
Hemorrhagic tendency
Polyuria
Hyponatremia
Hypokalemia, acidosis
Sympathetic overflow
+
Myocarditis, polyneuritis
Retroperitoneal nodes
Lepromas
*Associated with Shigella serotype I endotoxin [33].

Visual disturbances, drowsiness, seizures, and coma in 40% of cases [34].
In 90% of cases [12].
Nephrogenic diabetes insipidus [35].
ARFacute renal failure; CRFchronic renal failure; DICdisseminated intravascular coagulation; HUShemolytic uremic syndrome; +<10%; ++10%24%;
+++25%49%; ++++50%80%; +++++>80%.
Dash indicates not reported.
FIGURE 6-1
Clinical manifestations of tropical bacterial nephropathies. Note the wide spectrum of
clinical manifestations that may ultimately reflect on the kidneys [3335].
6.3
Renal Involvement in Tropical Diseases
SPECTRUM OF RENAL PATHOLOGY IN TROPICAL BACTERIAL INFECTIONS
Disease
Salmonellosis
Shigellosis
Leptospirosis
Melioidosis
Cholera
Tetanus
Scrub typhus
Diphtheria
Tuberculosis
Leprosy
Glomerulonephritis
MPGN
EXGN
++
+
+
+
++*
MCGN
MN
NG
CGN
Vasculitis
Amyloid
G,M,A,C3,Ag
+
M,C3
ATN
++
+
+
+++
+
++
++
+
+/++
Other tubular
changes
Deposits of
immunoglobulins,
complement,
and antigen
+/+++
AIN
+
+
G,M,A,C3
+
+
++
+++
+
++
+
+
+/+++**
Cloudy swelling
Cloudy swelling
Cloudy swelling
Vacuolation
Cloudy swelling
Degeneration
Functional defects
*When associated with Schistosoma mansoni infection in Egypt [9].

Vi antigen deposits [8].
Hypokalemic nephropathy [36].
Exotoxin-induced inhibition of protein synthesis in tubule cells [37].
Usually complicates amyloidosis: 2.4%8.4% [18].
**63% in lepromatous leprosy; 2% in nonlepromatous types [38].
AINacute interstitial nephritis; ATNacute tubular necrosis; CGNcrescentic glomerulonephritis; EXGNexudative glomerulonephritis; MCGNmesangiocapillary glomerulonephritis; MNmembranous glomerulopathy; NGnecrotizing glomerulitis;
+<10%; ++10%24%; +++25%50%.
FIGURE 6-2
Spectrum of renal pathology in tropical bacterial infections [3638].
A
FIGURE 6-3
Glomerular lesions associated with tropical bacterial
infections. A, Simple proliferative glomerulonephritis in a
B
patient with shigellosis. B, Exudative glomerulonephritis in a
patient with salmonellosis.
6.4

C, Necrotizing vasculitis in a patient with leptospirosis. D, Membranous nephropathy
associated with leprosy. (Hematoxylin-eosin stain 150.)
FIGURE 6-4
Glomerular amyloid deposits in a patient with leprosy.
(Hematoxylin-eosin stain 200.)
FIGURE 6-5
Acute tubular pathology associated with
bacterial infections. A, Acute tubular
necrosis with erythrocyte aggregates in the
tubular lumina in a patient with leptospirosis. (Hematoxylin-eosin stain 250.)
B, Cortical necrosis in a child with severe
shigellosis and hemolytic uremic syndrome.
6.5
FIGURE 6-6
Extensive vacuolation of the proximal tubules (hypokalemic
nephropathy) in a patient with cholera. (Hematoxylin-eosin stain
300.) (From Sinniah and coworkers [39]; with permission.)
FIGURE 6-7
Interstitial lesions associated with bacterial infections.
A, Acute interstitial nephritis in a patient with diphtheria.
(Hematoxylin-eosin stain 100.) B, Perivenular monocytic
infiltration in a patient with scrub typhus. (Hematoxylin-eosin
stain 100.) C, Renal abscess in a patient with septicemic

melioidosis. (Hematoxylin-eosin stain 75.) D, Microabscesses in a patient with typhoid fever [40]. (Hematoxylineosin stain 75.)
6.6
FIGURE 6-8
Low-power electron micrograph. Here leptospires (arrow) in the
peritubular cortical interstitial space are seen in a patient with
leptospirosis. (Magnification 12,000.)
FIGURE 6-9
Renal tuberculosis. Seen here are multiple tuberculous granulomata
with Langhans giant cells. Diffuse interstitial tuberculosis without
definite granulomatous formation also has been described.
Bacterial infection
Direct invasion
Monocyte activation
Endothelial injury
Nonspecific
inflammatory effects
T-cell response
Monokines
Humoral
B-cell response
IL-1,6
TNF-
NO
ROM
Complement/coagulation
Antibodies
Hematologic
Platelets
Erythrocytes
DIC
Hemolysis
Hypovolemia
Cholestasis
Adhesion molecules
Immune complexes
Abscess
Glomerulonephritis
Endothelin
Renal ischemia
ATN
Jaundice
FIGURE 6-10
Common pathogenetic mechanisms of renal injury in tropical bacterial infections. Depending on the bacterial
species and strain, as well as on the hosts resistance and genetic background, bacteria may directly invade the
renal parenchyma, induce an immune reaction, injure the capillary endothelium or provoke a nonspecific
humoral or hematologic response. The subsequent evolution of these pathways may lead to different forms of
renal injury. The asterisk indicates that the role of hemolysis is augmented in patients with glucose-6-phosphate
dehydrogenase (G6PD) deficiency. ATNacute tubular necrosis; DICdisseminated intravascular coagulation;
ILinterleukin; NOnitric oxide; ROMreactive oxygen molecules; TNF-tumor necrosis factor-.
6.7
PATHOGENETIC MECHANISMS IN ACUTE TUBULAR NECROSIS

Disease
Monokines
Hypovolemia
Hemolysis
Rhabdomyolysis
Disseminated intravascular coagulation
Complement activation
+
+
++
+
+
++
+
+
+
+
++
+
+
+++
+
+
+
-
+
+
+
+
+
+
+
+
++
Salmonellosis
Shigellosis
Leptospirosis
Melioidosis
Cholera
Tetanus
Scrub typhus
Diphtheria
Leprosy
+
++*
+
+
*Elevated creatine phosphokinase in 88%, myoglobinuria in 39% of cases [14].

+<10%; ++10%24%; +++24%50%.
FIGURE 6-11
Pathogenetic mechanisms in acute tubular necrosis associated with bacterial infections.
Note the multiplicity of factors depending on the bacterial species and their host targets.
Viral Infections
FIGURE 6-12
Clinical manifestations of renal involvement in dengue hemorrhagic fever. Note that proteinuria and abnormal urinary sediment are
the most common manifestations. Also note the high incidence of
hyponatremia, like with many other tropical infections [40,41].
90
Incidence, %
80
70
60
50
40
30
20
10
0
Urinary
sediment
abnormalities
Proteinuria Hyponatremia
Lactic
acidosis
Selected important features
Acute renal
failure
6.8

FIGURE 6-13
Renal lesions in a patient with dengue hemorrhagic fever. A, Mesangial proliferative
glomerulonephritis, which usually is associated with deposits of immunoglobulins G
and M and complement 3. (Hematoxylineosin stain 200.) B, Acute tubular necrosis, which is associated with interstitial
edema and mononuclear cell infiltration.
Mycotic Infections
FIGURE 6-14
Section from a patient with mucormycosis, showing extensive tissue
necrosis, weak inflammatory cellular infiltration, and fungal hyphae
branching at right angles. (Hematoxylin-eosin stain 150.)
FIGURE 6-15
Ochratoxin-Ainduced interstitial fibrosis, showing marked intertubular scarring with patchy atrophy and collapse of tubules. This
patients serum ochratoxin-A and urinary ochratoxin-A levels were
5.18 and 3.87 ng/mL, respectively (the means for a control group
were 1.6 and 1.85 ng/mL, respectively) [20]. (Masson trichrome
stain 200.)
6.9
Parasitic Infections
Schistosoma hemalobium
Schistosoma mansoni
Echinococcosis
Plasmodium
falciparum
Quartan
malaria
FIGURE 6-16
Global distribution of important parasitic
nephropathies. Note the high prevalence of
schistosomal, malarial, filarial, and
echinococcal renal complications in Africa;
S. mansoni and hydatid in South America;
falciparum malaria and filariasis in South
East Asia and filariasis in India [3].
Schistosoma mansoni
Filariasis
FIGURE 6-17
Urinary schistosomiasis. A, A sheet of
Schistosoma haematobium ova in tissues.
(Silver stain 350.) B, S. haematobium
granuloma. Shown is a delayed hypersensitivity reaction of the host to soluble oval
antigens released from the ova through
micropores in their shells. The granuloma
is composed of mononuclear cells, a few
neutrophils, eosinophils, and fibroblasts,
surrounding a distorted egg. (Hematoxylineosin stain 300.)
6.10
FIGURE 6-18
Cystoscopic appearances of different bladder lesions associated with Schistosoma haematobium infection. A, Bilharzial (schistosomal) pseudotubercles. B, Bilharzial submucous
mass covered by pseudotubercles. C, Bilharzial ulcer surrounded by pseudotubercles.
D, Bilharzial ulcer surrounded by sandy patches. (Courtesy of N. Makar, MD.)
D
FIGURE 6-19
Postmortem specimen
showing advanced
bilharzial involvement
of the urinary tract.
Note the dirty bladder mucosa, fibrosed
muscle layer, and neoplastic growth (histologically a squamous
cell carcinoma) cut
through transversely.
The ureters are dilated, with a clear stricture at the lower end
of the right ureter.
Also seen in this
patient are bilateral
hydroureters with
submucous cystic
lesions (bilharzial
ureteritis cystica). The
kidneys show considerable scarring, with
the right kidney also
showing chronic back
pressure changes.
FIGURE 6-20
Filariasis of the
abdominal lymphatics. Lymphangiogram shows the
dilated retroperitoneal lymphatics in
a patient with filarial chyluria.
6.11
Antigens
Merozoites
Erythrocyte
Monocyte
Hemolysis
Cell membrane
changes
TH1
CIC
TNF-
Platalet
CD8+
Endothelial activation
Hemodynamic changes
Acute
tubular
necrosis
TH2
Acute inflammatory
Tubulointerstitial
nephropathy
Immunoglobulins
Immune complex disease
Acute
glomerulonephritis
Proliferative
glomerulonephritis
FIGURE 6-21
The pathogenesis of falciparum malarial renal complications. Note the infection triggers
two initially independent pathways: red cell parasitization and monocyte activation. These
subsequently interact, as the infected red cells express abnormal proteins that induce an
immune reaction by their own right, in addition to providing sticky points (knobs) for
clumping and adherence to platelets and capillary endothelium. TNF- released from the
activated monocytes shares in the endothelial activation. As both pathways proceed and
interact, a variety of renal complications develop, including acute tubular necrosis, acute
interstitial nephritis and acute glomerulonephritis. BB-lymphocyte; CD8cytotoxic T
cell; CICcirculating immune complexes; THT-helper cells (1 and 2); TNF-tumor
necrosis factor-.
FIGURE 6-22
Erythrocyte knobs in a patient with falciparum malaria [43]. These erythrocyte
knobs contain novel proteins, mainly
Plasmodium falciparum erythrocyte membrane protein (PfEMP), histidine-rich protein 1, and histidine-rich protein 2, that are
synthesized under the influence of the DNA
of the parasite [4446]. These proteins constitute the sticky points (arrows) by which
parasitized erythrocytes aggregate and
adhere to blood platelets and endothelial
cells [47,48]. ENelectron microphotograph. (Magnification 12,000.)
FIGURE 6-23
Renal lesions in a patient with falciparum malaria. A, Proliferative
and exudative glomerulonephritis, an immune-complexmediated
lesion that may lead to an acute nephritic syndrome, which usually
is reversible by antimalarial treatment. (Hematoxylin-eosin stain
175.) B, Acute tubular necrosis (ATN) associated with interstitial
mononuclear cell infiltration. ATN is seen in 1% to 4% of patients
with falciparum malaria and in up to 60% of those with malignant
malaria. (Hematoxylin-eosin stain 200.)
6.12

C, Subendothelial and mesangial malarial antigen deposits seen on
immunofluorescence. Often, complement 3, immunoglobulins M and
G, and fibrinogen also are seen. (Hematoxylin-eosin stain 200.)
CDCT
ACDC
+
ADCC
Parasite
Eosinophil
+
+
+ Neutrophil
Complement
Antigen
CIC
IL-5,13
IL-2
IgM,E,G,A
FIGURE 6-24
The broad lines of the immune response to
parasitic infections. Note the pivotal role of
the monocyte, activated by exposure to parasitic antigens, in stimulating both T-helper 1
(TH1) and T-helper 2 (TH2) cells. The different cytokine mediators and parasite elimination mechanisms are shown. BB-lymphocyte; -IFN-interferon; CICcirculating
immune complexes; GM-CSFgranulocytemacrophage colony-stimulating factor;
Igimmunoglobulin; ILinterleukin.
IL-1,6,12
GM-CSF
+
TH2
TH1
-IFN
IL-2
IL-4,5,10
Active monocytes
TH2, CD8 cells
IgG1,2,3
IL-1,6;+IFN
Initial events
Inactive monocytes
TH2 ,CD8 cells
IgM,IgG4,IgA
IL-4,5,10
Late events
FIGURE 6-25
The T-helper1T-helper 2 (TH1-TH2) cell balance that determines
the clinical expression of different parasitic nephropathies. TH1
predominance leads to either reversible acute proliferative glomerulonephritis or acute interstitial nephritis. TH2 predominance tends
to lessen the severity of the lesions and may lead to chronic
glomerulonephritis in the presence of copathogenic factors such as
concomitant infection (malaria, schistosomiasis), autoimmunity
(malaria, filariasis, schistosomiasis), or immunoglobulin A (IgA)
switching (Schistosoma mansoni) [7, 9, 4952]. CD4T-helper
cells; CD8cytotoxic cells; -INF-interferon; ILinterleukin.
6.13
FIGURE 6-26
Leishmaniasis. A, Amastigotes in peripheral
blood monocytes. Amastigotes downregulate the host cells that show no attempt at
eradicating the parasite. (Hematoxylineosin stain 450.) B, Interstitial nephritis
representing a TH1 predominant state,
which is self-limited owing to the parasiteinduced monocyte inhibition [53].
B
FIGURE 6-27
Trichinosis. A, Here Trichinella spiralis is
encysted in the muscle tissue of a patient.
(Hematoxylin-eosin stain 75.) B, Associated proliferative glomerulopathy in a
patient. This lesion usually is subclinical
but may be manifested as an acute nephritic
syndrome that can be resolved with antiparasitic treatment. This lesion represents a
TH1 predominant state. (Hematoxylineosin stain 150.)
6.14
A
FIGURE 6-28
Echinococcosis. A, Mesangiocapillary type
III glomerulonephritis. (Hematoxylin-eosin
stain 200.) B, Electron micrograph
showing subepithelial deposits. (Hematoxylin-eosin stain 25,000.) C, Peripheral part of a hydatid cyst showing the
daughter cysts in a patient. (Hematoxylineosin stain 75.)
C
FIGURE 6-29
Onchocercosis. A, The parasite Onchocerca
volvulus deposits lesions in tissues. (Hematoxylin-eosin stain 150.) B, Associated
mesangial proliferative lesion. This lesion represents a TH1 predominant state. Some
patients, however, develop an autoimmune
reaction that leads to progressive glomerulonephritis. (Hematoxylin-eosin stain 175.)
6.15
FIGURE 6-30
Quartan malarial nephropathy. A, Proliferative glomerulonephritis with capillary wall
thickening. (Hematoxylin-eosin stain
200.) B, Subendothelial deposits with splitting of the basement membrane. (Silver
stain 500.) This lesion occurs under TH2
predominance and usually is encountered in
genetically predisposed persons. This lesion
also is associated with autoimmunity or
concomitant viral infection.
FIGURE 6-31
Intestinal schistosomiasis. A, Pair of adult Schistosoma mansoni worms in colonic mucosa.
(Hematoxylin-eosin stain 75.) B, Colonic granuloma around a viable ovum. (Hematoxylin-eosin stain 150.)
FIGURE 6-32
Patient with hepatosplenic schistosomiasis,
complicating intestinal mansoniasis. Note
the shrunken liver and very large spleen,
surface marked on the abdominal wall by
black ink. Of these patients, 15% develop
clinically overt glomerular lesions. Half of
the 15% become hypertensive, most become
nephrotic at some stage, and almost all
progress to end-stage disease [54].
6.16

FIGURE 6-33
Early glomerular lesion in a patient with
schistosomiasis. A, Mesangial proliferation.
(Hematoxylin-eosin stain 200.) B, Schistosomal gut antigen deposits in the
mesangium. Other immunofluorescent
deposits at this stage include immunoglobulins M and G and complement C. This
lesion may be encountered in infection by
Schistosoma mansoni, S. haematobium, or
S. japonicum. The lesion does not necessarily progress any further. (Hematoxylin-eosin
stain 300.)
FIGURE 6-34
Histologic lesions in a patient with progressive Schistosoma
mansoni glomerulopathy. A, Mesangial proliferative glomerulonephritis. (Hematoxylin-eosin stain 150.) B, Exudative
glomerulonephritis, often encountered with concomitant
Salmonella paratyphi A infection [9]. (Hematoxylin-eosin stain
150.) C, Mesangial proliferation with areas of mesangiocapillary changes. (Hematoxylin-eosin stain 150.) D, Focal and
segmental glomerulosclerosis. (Masson trichrome stain 150.)

The two lesions in panels C and D are associated with advanced
hepatic fibrosis, impaired macrophage function, and predominant immunoglobulin A mesangial deposits [7,55]. The lesions
shown are categorized, respectively, as classes I to IV schistosomal glomerulopathy according to the classification system of the
African Association of Nephrology [54].

Pathogenesis of S. mansoni glomerulotherapy
Adult worms in
the portal vein
Egg granulomata
in the portal tracts
Autoimmunity
IgG,M,E
Periportal fibrosis
Egg granulomata
in the colonic mucosa
Antigens
Mucosal
breach
Switching
IgA
Immune complexes
Impaired macrophage function

Portosystemic collaterals
FIGURE 6-35
Pathogenesis of Schistosoma mansoni
glomerulopathy. Note the crucial role of
hepatic fibrosis, which 1) induces glomerular hemodynamic changes; 2) permits schistosomal antigens to escape into the systemic
circulation, subsequently depositing in the
glomerular mesangium; and 3) impairs
clearance of immunoglobulin A (IgA),
which apparently is responsible for progression of the glomerular lesions. IgA synthesis
seems to be augmented through B-lymphocyte switching under the influence of interleukin-10, a major factor in late schistosomal lesions [7].
Glomerular deposits

Renal amyloidosis in schistosomiasis. A, Schistosomal granuloma (top), three glomeruli with extensive amyloid
deposits (bottom), and dense interstitial infiltration and fibrosis in a patient with massive Schistosoma haematobium infection. (Hematoxylin-eosin stain 75.) B, Amyloid deposition in the mesangium associated with mild
mesangial cellular proliferation in a patient with S. mansoni glomerulopathy (African Association of Nephrology
class V). (Hematoxylin-eosin stain 175.) C, Early amyloid deposits seen as green (birefringent) deposits in a
glomerulus with considerable mesangial proliferation in a patient with hepatosplenic schistosomiasis. (Congo red
stain 200, examined under polarized light.)
6.17
6.18

Pathogenesis of schistoma-associated amyloidosis
Interleukin-1,6
Hepatocyte
Antigen
Uptake
AA protein
FIGURE 6-37
Pathogenesis of schistosoma-associated amyloidosis. The monocyte
continues to release interleukin-1 and interleukin-6 under the influence of schistosomal antigens. These antigens stimulate the hepatocytes to release AA protein, which has a distinct chemoattractant
function. The monocyte is the normal scavenger of serum AA protein, a function that is impaired in hepatosplenic schistosomiasis.
Serum AA protein accumulates and tends to deposit in tissue.
Matrix adhesion
Chemoattraction
Tissue deposition
Toxic Tropical Nephropathies

Toxins of Animal Origin
NEPHROPATHIES ASSOCIATED WITH EXPOSURE TO ANIMAL TOXINS
Acute renal failure
Snake bite
Scorpion sting
Insect stings
Jelly fish sting
Spider bite
Centipede bite
Raw carp bile
+++
+
+
+
+
+
++
Vasculitis Subnephrotic proteinuria

+
Nephrotic syndrome
+ (MPGN)
++ (MCD, MPGN, MN)
MCDminimal change disease; MNmembranous glomerulonephritis; MPGNmesangial proliferative glomerulonephritis; +<10%; ++10%24%; +++25%50%.
FIGURE 6-38
Nephropathies associated with exposure to
toxins of animal origin. Note that acute
renal failure is the most common and
important renal complication. Vascular and
glomerular lesions are occasionally encountered with specific exposures [5662].

Pathogenetic mechanisms in snake venom nephrotoxicity
Snake venom
Immunologic
reaction
Direct toxicity
Disseminated
intravascular
coagulation
Hemolysis
Rhabdomyolysis
Cytokines
Mediators
Hemodynamic
changes
Mesangiolysis
6.19
FIGURE 6-39
Pathogenetic mechanisms in snake venom
nephrotoxicity. The immediate effect of
exposure is attributed to direct hematologic
toxicity involving the coagulation system
and red cell membranes. The massive
release of cytokines and rhabdomyolysis
also contribute. Late effects may be encountered as a consequence of the immune
response to the injected antigens.
Vasculitis
Renal ischemia
Acute
glomerulonephritis
Acute tubular
necrosis
Glomerulonephritis
Toxins of Plant Origin

NEPHROPATHIES ASSOCIATED WITH EXPOSURE TO PLANT TOXINS
Acute renal failure
Hypertension
Proteinuria
Hematuria
+++
+
+++
+
++
+++
+
++++
Djenkol bean
Mushroom poisoning
Callilepis laureola
Semecarpus anacardium
FIGURE 6-40
Nephropathies associated with exposure to
toxins of plant origin. Note that with the
exception of Djenkol bean nephrotoxicity,
most plant toxins lead to acute renal failure
due to hemodynamic effects [6366].
+<10%; ++10%24%; +++25%49%; ++++50%80%.
Acknowledgment
The authors acknowledge the help of Professor Amani Amin
Soliman, Chairperson of the Parasitology Department, Cairo
University, for providing very valuable material included in

this work.
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Hyg 1979, 28:773.
Renal Disease in
Patients Infected with
Hepatitis and Human
Immunodeficiency Virus
Jacques J. Bourgoignie
T.K. Sreepada Rao
David Roth
nfection with hepatitis B virus (HBV) may be associated with a

variety of renal diseases. In the past, HBV was the major cause of
viral hepatitis in patients with end-stage renal disease (ESRD).
Introduction of rigorous infection-control strategies has led to a
remarkable decline in the spread of HBV infection in dialysis units.
Physicians also are increasingly recognizing the association between
chronic hepatitis C virus (HCV) infection and glomerular disease,
both in native kidneys and renal allografts. Liver disease caused by
HCV is a major factor in morbidity and mortality among patients
with ESRD treated with dialysis and transplantation. The first part of
this chapter focuses mainly on issues related to HCV infection. The
second part of this chapter examines the renal complications in
patients with human immunodeficiency virus (HIV) infection.
Our knowledge about HIV has increased greatly, and dramatic
advances have occurred in the treatment of patients with acquired
immunodeficiency syndrome (AIDS). For the first time since the discovery of the disease, deaths are decreasing. Nevertheless, in the
United States, as of June 30, 1997, there were over 600,000 cumulative cases of HIV infection, with over 400,000 deaths. Worldwide,
the HIV epidemic continues to spread; an estimated 20 million persons are infected with HIV. Recent advances in the clinical management of these patients result from better understanding of the replication kinetics of HIV, assays to measure viral load, availability of
CHAPTER
7.2
new effective drugs against HIV, and demonstration that

aggressive protocols combining antiviral drugs substantially
reduce HIV replication. Thus, prolonged survival of patients
with HIV infection now is common. The incidence of renal

complications in this population is expected to increase further
as patients live longer.
Hepatitis B and C Virus

RENAL DISEASE ASSOCIATED WITH
HEPATITIS B VIRUS INFECTION
Lesion
Clinical presentations
Pathogenesis
Membranous nephropathy
Nephrotic syndrome
Vasculitis, nephritic
Membranoproliferative
glomerulonephritis
Nephrotic, nephritic
Deposition of HBeAg
with anti-HBeAb
Deposition of circulating
antigen-antibody
complexes
Deposition of complexes
containing HBsAg and
HBeAg
HBeAghepatitis B antigen; HBsAghepatitis B surface antigen.
RENAL DISEASE ASSOCIATED WITH

HEPATITIS C VIRUS INFECTION
Disease
Renal manifestations
Mixed cryoglobulinemia
[611]
Hematuria, proteinuria
Positive cryoglobulins;
(often nephrotic),
rheumatoid factor
variable renal insufficiency often present
Hematuria, proteinuria
Hypocomplementemia;
(often nephrotic)
rheumatoid factor and
cryoglobulins may be
present
Proteinuria
Complement levels normal;
(often nephrotic)
rheumatoid factor
negative
Membranoproliferative
glomerulonephritis [13]
Membranous
nephropathy [14,15]
Serologic testing
FIGURE 7-2
Renal disease associated with hepatitis C. Hepatitis C virus (HCV)
infection is associated with parenchymal renal disease. Chronic
HCV infection has been associated with three different types of
renal disease. Type II or essential mixed cryoglobulinemia has been
strongly linked with HCV infection in almost all patients with this
disorder [611]. The clinical manifestations of this renal disease
include hematuria, proteinuria that is often in the nephrotic range,
and a variable degree of renal insufficiency. Essential mixed cryoglobulinemia had been considered an idiopathic disease; however,
FIGURE 7-1
Renal disease associated with hepatitis B. Infection with
hepatitis B virus (HBV) may be associated with a variety of
renal diseases [1,2]. Many patients are asymptomatic, with plasma serology positive for hepatitis B surface antigen (HBsAg),
hepatitis B core antibody (HBcAb), and hepatitis B antigen
(HBeAg). The pathogenetic role of HBV in these processes has
been documented primarily by demonstration of hepatitis B antigen-antibody complexes in the renal lesions [1,3,4]. Three major
forms of renal disease have been described in HBV infection. In
membranous nephropathy, it is proposed that deposition of
HBeAg and anti-HBe antibody forms the classic subepithelial
immune deposits [1,35]. Polyarteritis nodosa is a medium-sized
vessel vasculitis in which antibody-antigen complexes may be
deposited in vessel walls [1,2]. Finally, membranoproliferative
glomerulonephritis is characterized by deposits of circulating
antigen-antibody complexes in which both HBsAg and HBeAg
have been implicated [3].
recent studies have noted one or more of the following features in
over 95% of patients with this disorder: circulating anti-HCV antibodies; polyclonal immunoglobulin G anti-HCV antibodies within
the cryoprecipitate; and HCV RNA in the plasma and cryoprecipitate [6,7]. Furthermore, evidence exists suggesting direct involvement of HCV-containing immune complexes in the pathogenesis of
this renal disease [6]. Sansono and colleagues [12] demonstrated
HCV-related proteins in the kidneys of eight of 12 patients with
cryoglobulinemia and membranoproliferative glomerulonephritis
(MPGN) by indirect immunohistochemistry. Convincing clinical
data exist suggesting that HCV is responsible for some cases of
MPGN and possibly membranous nephropathy [1315]. In one
report of eight patients with MPGN, purpura and arthralgias were
uncommon and cryoglobulinemia was absent in three patients [13].
Circulating anti-HCV antibody and HCV RNA along with elevated
transaminases provided strong evidence of an association with
HCV infection. Establishing the diagnosis of HCV infection in
these diseases is important because of the potential therapeutic
benefit of -interferon treatment [13]. A number of reports exist
that demonstrate a beneficial response to chronic antiviral therapy
with -interferon [6,13,16,17]. Even more compelling evidence for
a beneficial effect of -interferon in HCV-induced mixed cryoglobulinemia was demonstrated in a randomized prospective trial of 53
patients given either conventional therapy alone or in combination
with -interferon [18]. Because of the likely recurrence of viremia
and cryoglobulinemia with cessation of -interferon therapy after
conventional treatment (3 106 U three times weekly for 6 mo),
extended courses of therapy (up to 18 mo) and higher dosing regimens are being studied [1921].
Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus
FIGURE 7-3
Membranoproliferative glomerulonephritis with hepatitis C.
Micrograph of a biopsy showing membranoproliferative glomerulonephritis (MPGN) in a patient with hepatitis C virus (HCV) infection. A lobulated glomerulus with mesangial proliferation and an
increase in the mesangial matrix are seen. Although still an idiopathic disease in many cases, HCV appears to be responsible for some
cases of MPGN [13,16]. It has been suggested that the decline in the
incidence of idiopathic type 1 MPGN may be partly a result of more
careful screening by blood banks, leading to a decrease in the overall
incidence of HCV infection and subsequent glomerulonephritis [16].
Envelope
Capsid glycoproteins
341 Nucleotides
Open-reading
frame
E1
E2
Protein
helicase
NS2
Replicase
C200 Epitope
C22-3
Epitope
FIGURE 7-4
Electron microscopy of membranoproliferative glomerulonephritis
from the biopsy specimen shown in Figure 7-3. Mesangial cell
interposition is noted with increased mesangial matrix. Abundant
subendothelial immunocomplex deposits are noted. Fusion of the
epithelial cell foot processes also is seen.
WORLDWIDE PREVALENCE OF ANTIHEPATITIS C

AMONG PATIENTS ON DIALYSIS
NS3 NS4a NS4b NS5a NS5b

5-1-1
SA2
ELI BA2
RI
7.3
RIBA
2
C33c C100-3
Epitope Epitope
RIBA2
Continent
2
ELISA
North America [2529]

South America [30]
Europe [3141]
Asia [4249]
New Zealand and Australia [50,51]
ELISA
RIBA1+2
2
ELISA-1 positive, %
836
39
154
1751
1.210
3000 Amino acids
5'
Genomic HCV RNA
3'
FIGURE 7-5
Diagnostic tests for HCV infection. In 1989, hepatitis C virus (HCV)
was cloned and identified as the major cause of parenterally transmitted non-A, non-B hepatitis [22]. The first serologic test for HCV
employed an enzyme-linked immunosorbent assay (ELISA-1) that
detected a nonneutralizing antibody (anti-HCV) to a single recombinant antigen. Limitations of the sensitivity and specificity of this test
led to development of second-generation tests, ELISA-2 and a recombinant immunoblot assay (RIBA-2) [23]. The standard for identifying
active HCV infection remains the detection of HCV RNA by reverse
transcriptase polymerase chain reaction. (Adapted from Roth [24].)
ELISA-1enzyme-linked immunosorbent assay-1.
FIGURE 7-6
Prevalence of anti-HCV among dialysis patients. Patients receiving
dialysis clearly are at greater risk for acquiring hepatitis C virus
(HCV) infection than are healthy subjects, based on the seroprevalence of anti-HCV antibodies among patients with end-stage renal
disease. These results of ELISA-1 testing likely underestimate true
positivity because studies have demonstrated a nearly twofold
increase in seropositivity when screening dialysis patients with the
ELISA-2 assay [52]. Additional studies have demonstrated that
most patients receiving dialysis who have anti-HCV seropositive
test results have circulating HCV RNA by polymerase chain reaction analysis, indicating active viral replication.
7.4
RISK FACTORS IN THE

POPULATION WITH END-STAGE
RENAL DISEASE AND HEPATITIS
C VIRUS INFECTION
Transfusions [24,27,30,32,5457]
Duration of end-stage renal disease
[29,30,32,35,37,5361]
Mode of dialysis [6070]
Prevalence of hepatitis C virus infection
in the dialysis unit [71,72]
TRANSMISSION OF HEPATITIS C
VIRUS IN HEMODIALYSIS UNITS
Breakdown in universal precautions [73,74]
Dialysis adjacent to an infected patient [71,75]
Dialysis equipment [46,60]
Type of dialyzer membrane [7678]
Reuse [71,72]
Pericentral
fibrosis
3%
Other
6%
Cirrhosis
9%
Hemosiderosis
15%
FIGURE 7-7
Risk of HCV in the ESRD population. Numerous studies have demonstrated a strong
association between the prevalence of hepatitis C virus (HCV) infection among patients
receiving dialysis and both the number of transfusions received and duration of dialysis
[53,61]. Although these two variables are related, the prevalence of anti-HCV in these
patients has been shown to be independently associated with both factors by regression
analysis. In contrast to patients receiving hemodialysis, patients receiving peritoneal dialysis consistently have a lower prevalence of anti-HCV antibody [6070]. Moreover, units
with a low prevalence of anti-HCV have been shown to have a lower seroconversion rate
[71]. The latter two observations coupled with the independent association of duration of
dialysis with seropositivity argue in favor of nosocomial transmission of HCV in hemodialysis units. This conclusion is further supported by data showing a decreased incidence
of HCV seroconversion in dialysis units employing isolation and dedicated equipment for
patients who test positive for HCV infection [72].
FIGURE 7-8
Transmission of HCV during dialysis. Convincing data are available that demonstrate an
increased risk of anti-HCV seroconversion associated with both a failure to strictly follow
infection control procedures and the performance of dialysis at a station immediately adjacent to that of a patient testing positive for anti-HCV [7175]. Units using dedicated
machines have shown a decreased incidence of seroconversion [51]. The literature provides
conflicting data on the likelihood of passage of HCV RNA into dialysis ultrafiltrate and
the risk of contamination by reprocessing filters [71,72,7678]. At this time the Centers
for Disease Control does not recommend that patients who are HCV positive be isolated
or dialyzed on dedicated machines and has no official policy concerning reuse of machines
in these patients [79].
Chronic active
hepatitis
42%
Reactive
hepatitis
18%
Chronic
persistent
hepatitis
6%
FIGURE 7-9
Liver disease among anti-HCVpositive dialysis patients. Serum
alanine aminotransferase levels are elevated in only 24% to 67%
of dialysis patients who test positive for the anti-hepatitis C virus
(HCV) [80]. Caramelo and colleagues [81] evaluated liver biopsies
from 33 patients on hemodialysis who tested positive using ELISA-2
and found a variety of histologic patterns; however, over 50% of
these patients had chronic hepatitis or cirrhosis. No correlation has
been found between mean levels of serum aminotransferase and
severity of liver disease [81]. At this time, liver biopsy is the only
reliable method to determine the extent of hepatic injury in patients
with end-stage renal disease infected with HCV. Liver function tests
and HCV serology testing may help identify patients who are at risk
for liver disease. However, a liver biopsy should be obtained before
initiating therapy or as part of the evaluation before transplantation. Liver biopsy can identify patients with advanced histologic
liver injury who may not be good candidates for transplantation or
can be used as a baseline before starting -interferon therapy. (From
Caramelo and colleagues [81]; with permission.)
FIGURE 7-10
Liver disease after kidney transplant. Biochemical abnormalities
reflecting liver injury have been reported in 7% to 34% of kidney
recipients in the early period after transplantation [23,8286].
Morbidity and mortality associated with liver disease, however, are
rarely seen until the second decade after transplantation [87]. Liver
dysfunction can be secondary to viral infections, such as hepatitis B
and C, herpes simplex virus, Epstein-Barr virus, and cytomegalovirus, in addition to the hepatotoxicity associated with several
immunosuppressive agents (azathioprine, tacrolimus, and cyclosporine) [88]. However, hepatitis C virus infection has been demonstrated convincingly to be the primary cause of posttransplantation
liver disease in renal allograft recipients [89,90].
PREVALENCE OF LIVER DISEASE AFTER

KIDNEY TRANSPLANTATION
First decade, %
Second decade, %
Acute liver disease: 565

Chronic liver disease: 515
Chronic liver disease: 540

Death from liver failure: 1030
TRANSMISSION OF HEPATITIS C VIRUS INFECTION

BY CADAVERIC DONOR ORGANS
Posttransplantation HCV infection status
Reference
Anti-HCV, n/n (%)
HCV RNA, n/n (%)
Pereira et al. [91,92]

Roth et al. [93]
Tesi et al. [94]
Vincente et al. [95]
Wreghtt et al. [96]
16/24(67)
10/31(32)
15/43(35)
1/7(14)
6/15(40)
23/24(96)
Not available
21/37(57)
1/7(14)
12/14(86)
Recipient 3a (Donor 1a)
5
Recipient 1b (Donor 1a)
Recipient strain
Donor strain
Both strains
Patient, n
4
3
2
1
Pretransplant 0
6
9
12
15 18
Months after transplant
21
24
7.5
27
FIGURE 7-11
Organ donor hepatitis C virus (HCV) transmission. Most recipients
of a kidney from a donor positive for hepatitis C virus RNA will
become infected with HCV if the organ is preserved in ice. ELISA1 testing of serum samples from 711 cadaveric organ donors identified 13 donors positive for anti-HCV infection; 29 recipients of
organs from these donors were followed [91,92]. The prevalence of
HCV RNA in these allograft recipients increased from 27% before
transplantation to 96% after transplantation. In contrast, studies
from centers using pulsatile perfusion of the kidney during preservation have confirmed transmission of HCV in only about 56% of
cases [93,94]. Several factors might explain the discrepancy in
transmission rates. One possibility may involve differences in organ
preservation. Zucker and colleagues [97] demonstrated that pulsatile perfusion removed 99% of the estimated viral burden in the
kidney, and centers using pulsatile perfusion have consistently
reported lower transmission rates than do centers preserving
organs on ice. Additional factors could include geographic variation in HCV quasi-species and the magnitude of the circulating
viral titer in the donor at the time of harvesting.
FIGURE 7-12
Patterns of hepatitis C virus (HCV) infection after transplantation of
a kidney from a positive donor into a positive recipient. In a simple
but important study, Widell and colleagues [98] demonstrated three
differing virologic patterns of HCV infection emerging after kidney
transplantation from a donor infected with HCV into a recipient
infected with HCV. Superinfection with the donor strain, persistence of the recipient strain, or long-term co-infection with both
the donor and recipient strain may result. The clinical significance
of infection with more than one HCV strain has not been determined in the transplantation recipient with immunosuppression,
although no data exist to suggest that co-infection confers a worse
outcome. For this reason, many centers will transplant a kidney
from a donor who was infected with HCV into a recipient infected
with HCV rather than discard the organ. (Data from Widell and
colleagues [98]; with permission.)
7.6
IMPACT ON OUTCOME OF HEPATITIS C VIRUS INFECTION

CONTRACTED BEFORE TRANSPLANTATION
After transplantation*
Reference
Fritche et al. [99]
Pereira et al. [100]
Roth et al. [90]
Ynares et al. [101]
Antihepatitis C
virus infection
Actuarial graft survival, % Actuarial patient survival, %
ELISA-2 positive
ELISA-2 negative
ELISA-2 positive
ELISA-2 negative
RIBA-2 positive
RIBA-2 negative
ELISA-1 positive
ELISA-1 negative
32(10)
53(10)
50
59
81(5)
80(5)
33(10)
25(10)
58(8)
82(8)
59
85
63(5)
63(5)
53(10)
54(10)
FIGURE 7-13
Pretransplant HCV infection effect on outcome. Reports have varied from different
centers concerning the impact of pretransplantation hepatitis C virus (HCV) infection
on outcome after transplantation. Patient
survival and graft survival were significantly worse among patients with anti-HCV
infection in some studies [99,100]; in other
studies a measurable impact could not be
detected [90,101]. Some of these differences
could be attributed to geographic variation
in the prevalence of various HCV genotypes,
differing immunosuppressive protocols, and
length of follow-up after transplantation.
ELISAenzyme-linked immunosorbent assay; RIBArecombinant immunoblot assay.

*Numbers in parentheses indicate years after transplatation.
GLOMERULAR DISEASE IN KIDNEY RECIPIENTS

INFECTED WITH HEPATITIS C VIRUS
Reference
Cockfield and
Prieksaitis [102]
Huraib et al. [103]
Morales et al. [104]
Roth et al. [105]
Morales et al. [106]
Number of antiHCVpositive patients
Histologic diagnosis
MGN MPGN DPGN
CGN
Total cases of GN
51
11*
30
166
98
409
0
7
0
15
5
0
5
0
1
0
0
0
1
0
0
0
7
7
5
15
CGNcrescentic glomerulonephritis; DPGNdiffuse proliferative GN; MGNmembranous GN;

MPGNmembranoproliferative GN.
*No specific diagnosis.
FIGURE 7-14
Glomerular disease in HCV positive recipients. Chronic hepatitis C virus (HCV) infection
has been associated with several different immune-complexmediated diseases in the renal
allograft, including membranous and membranoproliferative glomerulonephritis (MPGN)
[102106]. From a cohort of 98 renal allograft recipients with HCV, Roth and colleagues [105] detected de novo membranoproliferative glomerulonephritis in the
biopsies of five of eight patients with proteinuria of over 1 g/24 h [105]. Compared
with a control group of nonproteinuric kidney recipients infected with HCV, patients
with MPGN had viral particles present in
greater amounts in the high-density fractions of sucrose density gradients associated
with significant amounts of IgG and IgM.
Thus, deposition of immune complexes containing HCV genomic material may be
involved in the pathogenesis of this form of
MPGN. The differential diagnosis for significant proteinuria in a patient infected with
HCV after transplantation should include
immune-complex glomerulonephritis.
Similarly, if the renal allograft biopsy shows
immune-complex glomerulonephritis, the
patient should be tested for HCV infection
without regard to serum alanine aminotransferase levels.
INTERFERON THERAPY FOR PATIENTS IN END-STAGE

RENAL DISEASE WITH HEPATITIS C VIRUS INFECTION
Reference
Study population Patients, n Clearing of HCV RNA, % Comments
Pol et al. [107]
HD
19
53
Casanovas et al.
[108]
HD
10
10
Koenig et al. [109]
HD
37
65
Duarte et al. [110]
HD
NA
Raptopoulou-Gigi
et al. [111]
HD
19
77
Magnone et al. [112]
TX
NA
6/7 (86%) rejection
Rostaing et al. [113]
TX
16
33
6/16 (37%) acute renal failure
Harihara et al. [114]
TX
3/3(100%) renal failure
Thervet et al. [115]
TX
13
Izopet et al. [116]
TX
15
Ozgur et al. [117]
TX
NA
All with improved liver histology
HDhemodialysis; NAnot available; TXtransplantation.
7.7
FIGURE 7-15
Interferon in HCV-positive end-stage renal
disease (ESRD) and transplant patients. Interferon therapy in patients infected with
hepatitis C virus (HCV) who have ESRD
has been studied in both patients receiving
dialysis and transplantation recipients.
Some studies have reported encouraging
early responses [107111]. Relapses are
common after cessation of treatment, however, and many transplantation recipients
have experienced deterioration in allograft
function [112116]. Based on the poor outcomes reported in transplantation recipients, additional studies are needed. These
studies would evaluate the long-term benefits of a strategy in which infected patients
who have ESRD are treated with -interferon while on dialysis in an effort to clear
viremia before the planned transplantation.
Further study of protocols using extended
treatment periods coupled with differing
dosing regimens are necessary to determine
the optimal therapy for the patient infected
with HCV who has ESRD.
Human Immunodeficiency Virus

RENAL COMPLICATIONS OF HUMAN
IMMUNODEFICIENCY VIRUS INFECTION
Acid-base and electrolyte disturbances
Acute renal failure
Human immunodeficiency virusassociated nephropathies
Renal infections and tumors
PATHOGENESIS OF HYPONATREMIA IN PATIENTS

WITH ACQUIRED IMMUNODEFICIENCY SYNDROME
Hypovolemia
Tubular dysfunction
Mineralocorticoid deficiency
Syndrome of inappropriate antidiuretic hormone
Hemodilution
FIGURE 7-16
Renal complications of HIV. Renal complications are frequent, and
these rates are expected to increase as patients with HIV live
longer. Many renal diseases are incidental and are the consequences
of opportunistic infections, neoplasms, or the treatment of these
infections and tumors. The renal diseases include a variety of acidbase and electrolyte disturbances, acute renal failure having various
causes, specific HIV-associated nephropathies, and renal infections
and tumors.
FIGURE 7-17
Hyponatremia pathogenesis in AIDS. Single and mixed acid-base
disturbances, as well as all types of electrolyte disorders, can be
observed in patients with AIDS. These disturbances and disorders
develop spontaneously in patients with complications of AIDS or
follow pharmacologic interventions and usually are not associated
with structural lesions in the kidneys unless renal failure also is
present. Hyponatremia is the most prevalent electrolyte abnormality,
occurring in 36% to 56% of patients hospitalized with AIDS
[118122]. In the absence of an evident source of fluid loss, volume
depletion may be related to renal sodium wasting as a result of
Addisons disease or hyporeninemic hypoaldosteronism [123125].
In euvolemic patients, hyponatremia is compatible with nonosmolar
inappropriate secretion of antidiuretic hormone [120,121,126].
Hyponatremia in patients with hypervolemia is dilutional in
origin as a result of excessive free water intake in a context of
renal insufficiency [122].
7.8
ELECTROLYTE COMPLICATIONS OF DRUGS USED TO

TREAT ACQUIRED IMMUNODEFICIENCY SYNDROME
Hypernatremia: foscarnet, rifampin, amphotericin B
Hyperkalemia: pentamidine, ketoconazole, trimethoprim
Hypokalemia: rifampin, didanosine, amphotericin B, foscarnet
Hypomagnesemia: pentamidine, amphotericin B
Hypocalcemia: foscarnet, pentamidine, didanosine
Hypercalcemia: foscarnet
Hypouricemia: rifampin
Hyperuricemia: didanosine, pyranzinamide, ethambutol
Tubular acidosis: amphotericin B, trimethoprim, cidofovir, rifampin, foscarnet
FIGURE 7-18
Drugs causing electrolyte complications. A number of drugs used
in the treatment of patients with AIDS can induce acid-base or
electrolyte abnormalities from direct renal toxicity (didanosine,
CAUSES OF ACUTE RENAL FAILURE

Prerenal azotemia, acute tubular necrosis
Allergic interstitial nephritis
Obstructive nephropathy
Rhabdomyolysis, myoglobinuric acute renal failure
Thrombotic thrombocytopenic purpura, hemolytic
uremic syndrome
Rapidly progressive glomerulonephritis
30%, most often in patients with AIDS and prerenal azotemia from hypovolemia, hypotension,
severe hypoalbuminemia, superimposed sepsis, or drug nephrotoxicity (radiocontrast dyes, foscarnet, acyclovir, pentamidine, cidofovir, amphotericin B, nonsteroidal anti-inflammatory drugs,
and antibiotics) [129138]. The clinical presentation, laboratory findings, and course of acute
tubular necrosis do not differ in patients with AIDS and those in other clinical settings.
Prevention includes correction of fluid and electrolyte abnormalities and dosage adjustments of
potentially nephrotic drugs. Identification and withdrawal of the offending agents usually result
in recovery of renal function. Dialysis may be needed before renal function improves. Less
frequent causes of acute renal failure include allergic acute interstitial nephritis; complicating
treatments with trimethoprim and sulfamethoxazole, rifampin, or acyclovir; and acute
obstructive nephropathy, resulting from the intrarenal precipitation of crystals of sulfadiazine,
acyclovir, urate, or protease inhibitors [134,139146]. Obstructive uropathy without
hydronephrosis also may develop in patients with lymphoma as a result of lymphomatous
ureteropelvic infiltration or retroperitoneal fibrosis [147149]. Rhabdomyolysis with myoglobinuric acute renal failure usually occurs in the setting of cocaine use [150]. Instances of acute
renal failure associated with intravascular coagulation related to thrombotic thrombocytopenic
purpura (TTP) or hemolytic uremic syndrome (HUS) have been reported (vide infra). Rare
causes of acute renal failure include disseminated microsporidian infection or histoplasmosis
[151,152]. A clinical presentation of acute renal failure also can be seen in patients with acute
immunocomplex postinfectious glomerulonephritis, crescentic glomerulonephritis, or fulminant
HIV-associated glomerulosclerosis.
2.4
1.4
0.4
7
6
5
4
3
2
1
0
7
6
5
4
3
2
1
0
1
5
Day
Urine volume, L/d
-0.6
Serum creatinine,
mg/dL
Acyclovir, g/d IV
FIGURE 7-19
Causes of acute renal failure. Acute renal
failure is related to complications of AIDS, its
treatment, or the use of diagnostic agents in
about 20% of patients [129,130]. Acute tubular necrosis occurs with a prevalence of 8% to
foscarnet, pentamidine, cidofovir, rifampin, and amphotericin B),

other organ toxicity (didanosine, foscarnet, and rifampin), or
interference with uric acid metabolism. Hypernatremia may be
the result of drug-induced diabetes insipidus. Hyperkalemia can
occur in 16% to 24% of patients with AIDS, even in the absence
of renal insufficiency. Hypokalemia is associated with tubular
nephrotoxicity. Hypocalcemia may result from urinary losses of
magnesium and hypomagnesemia (pentamidine and amphotericin B)
or from drug-induced pancreatitis (pentamidine, didanosine, and
foscarnet). Hypercalcemia occurs in association with granulomatous
disorders, disseminated cytomegalovirus infection, lymphoma,
human T-cell leukemia (HTLV) related to HTLV-I infection or
foscarnet administration. Hypouricemia was described in 22% of
patients as a result of an intrinsic tubular defect in urate transport
unrelated to drug therapy. In contrast, hyperuricemia usually is
the result of drug interference with purine metabolism (didanosine)
or tubular urate secretion (pyrazinamide and ethambutol). In the
absence of clinical manifestations that readily explain acid-base
or electrolyte disturbances, a careful review of the pharmacopeia
used to treat patients with HIV infection is mandated. Extensive
reviews of the complications associated with drugs are available
[127,128].
FIGURE 7-20
Acyclovir nephrotoxicity. Drugs may induce acute renal failure by
more than one mechanism. For instance, acute renal failure may
complicate the use of acyclovir as a result of intrarenal precipitation
of acyclovir crystals, acute interstitial nephritis, or acute tubular
necrosis [139,144,153]. An example of nonoliguric acute tubular
necrosis associated with administration of large doses of intravenous
acyclovir is illustrated, which was readily reversible on decreasing
the dose of acyclovir from 2.4 to 0.4 g/24 h. Patients infected with
HIV can exhibit a broad spectrum of conditions that may affect the
kidneys. Renal biopsy is useful for diagnostic and prognostic purposes when the cause of acute renal failure is not clinically evident. In a
recent study of 60 patients with acute renal failure, a percutaneous
renal biopsy yielded a pathologic diagnosis in 13% that was not
expected clinically [154].
MANAGEMENT OF SEVERE
ACUTE RENAL FAILURE
Conservative
Recovered
Needing dialysis
Not initiated
Initiated
Recovered
HIV
Non-HIV
20 (14%)
85%
126
42%
73
56%
42 (14%)
83%
264
22%
207
47%
NS
0.003
NS
7.9
FIGURE 7-21
Acute renal failure management. Rao and Friedman [155] compared the course of 146
patients with severe acute renal failure (serum creatinine >6 mg/dL) infected with HIV
with a group of 306 contemporaneous persons not infected with HIV but with equally
severe acute renal failure. The patients infected with HIV were younger than those in the
group not infected (mean age 38.4 and 55.2 years, respectively; P<0.001) and were more
often septic (52% and 24%, respectively; P<0.001). Over 80% of patients in each group
recovered renal function when conservative therapy alone was sufficient. When dialysis
intervention was needed, it was not initiated more often in the group with HIV than in the
control group (42% and 24%, respectively; P<0.003). In those patients in whom dialysis
was initiated, recovery occurred in about half in each group. Overall, the mortality in
patients with severe acute renal failure was not significantly different in those with HIV
infection from those in the group not infected with HIV (immediate mortality, 60% and
56%, respectively; mortality at 3 months, 71% and 60%, respectively).
NS not significant.
NEPHROPATHIES
ASSOCIATED WITH
HUMAN IMMUNODEFICIENCY
VIRUS INFECTION
Focal segmental or global glomerulosclerosis
Diffuse and global mesangial hyperplasia
Others:
Immune-complex glomerulopathies
Hemolytic uremic syndrome, thrombotic
thrombocytopenic purpura
100
Percent
75
FIGURE 7-22
Nephropathies associated with HIV. The literature refers to the glomerulosclerosis associated
with human immunodeficiency virus (HIV) as HIV-associated nephropathy. However, HIVassociated nephropathies may include a spectrum of renal diseases, including HIV-associated
glomerulosclerosis, HIV-associated immune-complex glomerulonephritis (focal or diffuse
proliferative glomerulonephritis, immunoglobulin A nephropathy) and HIV-associated
hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Diffuse
mesangial hyperplasia and minimal change disease also may be associated with HIV, particularly in children. Therefore, the nomenclature of HIV-associated nephropathies should be
amended to list the associated qualifying histologic feature [156]. All types of glomerulopathies have been observed in patients with HIV-infection. Their prevalence and severity
vary with the population studied. Focal segmental or global glomerulosclerosis is most prevalent in black adults. In whites, proliferative and other types of glomerulonephritis predominate. In children with perinatal acquired immunodeficiency syndrome, glomerulosclerosis,
diffuse mesangial hyperplasia, and proliferative glomerulonephritis are equally prevalent.
Glomerulosclerosis
Diff. mesangial hyperplasia
Other
50
25
0
Caribbean blacks
(n=22)
American blacks
(n=11)
Whites
(n=12)
FIGURE 7-23
Glomerulosclerosis associated with HIV. In the United States, HIVassociated focal segmental or global glomerulosclerosis was
described originally in 1984 in large East Coast cities, particularly
New York and Miami [157159]. This entity initially was considered with skepticism because it was not seen in San Francisco,
where most patients testing seropositive were white homosexuals
[160,161]. In New York, patients with glomerulosclerosis were
largely black intravenous (IV) drug abusers, a group of patients in

whom heroin nephropathy was prevalent. Thus, concern existed
that this entity merely represented the older heroin nephropathy
now seen in HIV-infected IV drug abusers. However, in a Miamibased population of adult non-IV drug users with glomerular disease
and HIV infection, 55% of Caribbean and American blacks had
severe glomerulosclerosis, 9% had mild focal glomerulosclerosis,
and 27% had diffuse mesangial hyperplasia. In contrast, two of 12
(17%) whites had a mild form of focal glomerulosclerosis, 75%
had diffuse mesangial hyperplasia, and none had severe glomerulosclerosis. These morphologic differences were reflected in more
severe clinical presentations, with blacks more likely to manifest
proteinuria in the nephrotic range (>3.5 g/24 h) and renal insufficiency (serum creatinine concentration (>3 mg/dL). Whites often had
proteinuria under 2 g/24 h and serum creatinine values less than 2
mg/dL [162]. In blacks, glomerulosclerosis has been described in
all groups at risk for HIV infection, including IV drug users, homosexuals, patients exposed to heterosexual transmission or to contaminated blood products, and children infected perinatally [163,164].
Subsequent reports confirmed the unique clinical and histopathologic manifestations of HIV-associated glomerulosclerosis and its
striking predominance in blacks independent of IV drug abuse
[165]. Racial factors explain the absence of HIV-associated
glomerulosclerosis in whites and Asians. The cause of this strong
racial predilection is unknown.
7.10
TWO CASE HISTORIES OF PATIENTS WITH HUMAN IMMUNODEFICIENCY

VIRUS INFECTION ASSOCIATED WITH GLOMERULOSCLEROSIS
41-year-old black Jamaican woman
28-year-old black Haitian man
October 1985:
Viral syndrome. 135 lbs; proteinuria, 1+; serum creatinine, 0.5 mg/dL; blood pressure, 130/70 mm Hg
December 1986:
Fever, fatigue, cough. 120 lbs; proteinuria, 1+; interstitial
pneumonia; serum creatinine, 1.5 mg/dL; ex-husband
used intravenous drugs; 11-cm, echogenic kidneys
February 1987:
3+ edema. 116 lbs; proteinura, 12.7 g/24 h; serum creatinine, 11.4 mg/dL; albumin, 2.5 g/dL; blood pressure,
150/86; renal biopsy showed focal segmental
glomerulosclerosis
May 1987:
100 lbs; patient died after 3 months of hemodialysis
from sepsis and cryptococcal meningitis
A dockworker until 3 months before admission, when

fevers began to occur. No identifiable risk factor. He
presented with a blood pressure of 110/80 mm Hg,
periorbital and trace ankle edema, interstitial pneumonia, and diffuse adenopathies. Serum creatinine
increased from 5.3 to 9 mg/dL in 6 days; albumin, 1.6
g/dL; proteinuria, 6.9 g/24 h; 15-cm, echogenic kidneys. Renal biopsy showed focal segmental glomerulosclerosis. Lymph node biopsy showed
Mycobacterium gordonae. This patient returned to
Haiti after six hemodialyses.
FIGURE 7-24
These two patients illustrate typical presenting
features of HIV-associated glomerulosclerosis,
ie, proteinuria, usually in the nephrotic range;
normal-sized or large echogenic kidney; and
renal insufficiency rapidly progressing to endstage renal disease (ESRD). The onset of the
nephropathy is often abrupt, with uremia and
massive nonselective proteinuria (sometimes
in excess of 20 g/24 h). These fulminant
lesions may present as acute renal failure in
patients who were well only a few weeks or
months before hospitalization. In other
patients, minimal proteinuria and azotemia at
presentation increase insidiously over a period
of several months until a nephrotic syndrome
becomes evident, with rapid evolution thereafter to uremia and ESRD. Hypertension and
peripheral edema may be absent even in the
context of advanced renal insufficiency or
severe nephrotic syndrome. The status of the
patients HIV infection rather than the presence of renal disease per se has the greatest
impact on survival.
PATHOLOGIC FEATURES OF GLOMERULOSCLEROSIS

ASSOCIATED WITH HUMAN IMMUNODEFICIENCY
VIRUS INFECTION
Collapsed glomerular capillaries
Visceral glomerular epitheliosis
Microcystic tubules with variegated casts
Focal tubular simplification
Interstitial lymphocytic infiltration
Endothelial reticular inclusions
FIGURE 7-25
Ultrasonography of a hyperechogenic 15-cm kidney in a patient
with HIV-associated glomerulosclerosis, nephrotic syndrome, and
renal failure.
FIGURE 7-26
Pathologic features of glomerulosclerosis. None of the features listed is pathognomonic. The concomitant presence of glomerular and
tubular lesions with tubuloreticular inclusions in the glomerular
and peritubular capillary endothelial cells, however, is highly suggestive of glomerulosclerosis associated with human immunodeficiency virus infection [134,166171].
FIGURE 7-27
Glomerulosclerosis. Micrograph of segmental glomerulosclerosis
with hyperplastic visceral epithelial cells (arrows).
FIGURE 7-29
Collapsing glomerulosclerosis. Micrograph of global collapsing
glomerulosclerosis. No patent capillary lumina are present. In the
same patient, normal glomeruli, glomeruli with segmental sclerosis,
and glomeruli with global sclerosis may be found [172].
7.11
FIGURE 7-28
More advanced glomerulosclerosis. Micrograph of a more
advanced stage of glomerulosclerosis with large hyperplastic visceral epithelial cells loaded with hyaline protein droplets, interstitial
infiltrate, and tubules filled with proteinaceous material.
FIGURE 7-30
Dilated microcystic tubules. Micrograph of massively dilated microcystic tubules filled with variegated protein casts adjacent to normal-sized glomeruli. These casts contain all plasma proteins. The
tubular epithelium is flattened. The tubulointerstitial changes likely
play an important role in the pathogenesis of the renal insufficiency
and offer one explanation for the rapid decrease in renal function.
7.12

FIGURE 7-31
Diffuse mesangial hyperplasia and nephrotic syndrome. Micrograph
of diffuse mesangial hyperplasia in a child with perinatal AIDS and
nephrotic syndrome. Both diffuse and global mesangial hyperplasia
are identified in 25% of children with perinatal AIDS and proteinuria. The characteristic microcystic tubular dilations and the kidney
enlargement of glomerulosclerosis associated with human immunodeficiency virus infection are absent in patients with diffuse mesangial hyperplasia.
FIGURE 7-32
Tubuloreticular cytoplasmic inclusions. Micrograph of tubuloreticular cytoplasmic inclusions in
glomerular endothelial cell. The latter are virtually diagnostic of nephropathy associated with
HIV infection, provided systemic lupus erythematosus has been excluded. On immunofluorescent examination, findings in the glomeruli are nonspecific and similar in HIV-associated
glomerulosclerosis and idiopathic focal segmental glomerulosclerosis. These findings consist
largely of immunoglobulin M and complement C3 deposited in a segmental granular pattern
in the mesangium and capillaries. The same deposits also occur in 30% of patients with
AIDS without renal disease [134,163,167].
HIV infection
HIV in glomerular, tubular

epithelial cells
Cytopathic
effects
HIV gene
products
HIV in lymphocytes,
monocytes
Cytokines,
growth factors
Glomerular epithelial cell proliferation

Tubular epithelial cell apoptosis and proliferation
Glomerulosclerosis
Tubular microcysts
FIGURE 7-33
Possible pathogenic mechanisms of glomerulosclerosis associated
with HIV infection. HIV-associated glomerulosclerosis is not the
result of opportunistic infections. Indeed, the nephropathy may be
the first manifestation of HIV infection and often occurs in patients
before opportunistic infections develop. HIV-associated glomerulosclerosis also is not an immune-complex-mediated glomerulopathy
because immune deposits are generally absent. Three mechanisms
have been proposed: direct injury of renal epithelial cells by infective
HIV, although direct renal cell infection has not been demonstrated
conclusively and systematically; injury by HIV gene products; or injury
by cytokines and growth factors released by infected lymphocytes and
monocytes systemically or intrarenally or released by renal cells
after uptake of viral gene products. The variable susceptibility to
glomerulosclerosis also suggests that unique viral-host interactions
may be necessary for expression of the nephropathy
[132,156,166,173175].
Transplantation of kidneys between normal mice

and mice transgenic of noninfectious HIV
Transgenic kidney
in
normal mouse
Normal kidney
in
transgenic mouse
Kidney develops
glomerulosclerosis
Kidney remains
disease-free
FIGURE 7-34
HIV proteins in glomerulosclerosis. HIV-associated glomerulosclerosis has been viewed as a complication that occurs either as a direct
cellular effect of HIV infection or HIV gene products in the kidney,
as an indirect effect of the dysregulated cytokine milieu existing in
patients with acquired immunodeficiency syndrome, or both. Studies
involving reciprocal transplantation of kidneys between normal and
mice transgenic of noninfectious HIV clearly show that the pathogenesis of HIV-glomerulosclerosis is intrinsic to the kidney [176]. In
these studies, HIV-glomerulosclerosis developed in kidneys of transgenic mice transplanted into nontransgenic littermates, whereas kidneys from normal mice remained disease-free when transplanted into
HIV-transgenic mice [176]. These findings suggest that HIV gene
proteins, rather than infective HIV, may induce the nephropathy
either through direct effects on target cells or indirectly through the
release of cytokines and growth factors.
7.13
TREATMENT OPTIONS OF GLOMERULOSCLEROSIS

ASSOCIATED WITH HUMAN IMMUNODEFICIENCY
VIRUS INFECTION
Antiretroviral therapy
Corticosteroids
Cyclosporine
Dialysis
FIGURE 7-35
Treatment of glomerulosclerosis. There have been no prospective
controlled randomized trials of any therapy in patients with nephropathy associated with HIV infection. Thus, the optimal treatment is
unknown. Individual case reports and studies, often retrospective,
on a small number of patients suggest a beneficial effect of
monotherapy with azidothymidine (AZT) on progression of renal
disease [177179]. No reports exist on the effects of double or
triple antiretroviral therapy on the incidence or progression of
renal disease in patients with HIV who have modest proteinuria or
nephrotic syndrome. The incidence of HIV-associated glomerulosclerosis may be declining as a result of prophylaxis with AZT,
trimethoprim and sulfamethoxazole, or other drugs. Using logistic
regression analysis, Kimmel and colleagues [180] demonstrated an
improved outcome related specifically to antiretroviral therapy.
Steroids usually have been ineffective on proteinuria or progression
of renal disease in adults and children. Recently, 20 adult patients
with HIV-associated glomerulosclerosis or mesangial hyperplasia
with proteinuria over 2 g/24 h and serum creatinine over 2 mg/dL
were studied. These patients showed impressive decreases in proteinuria and serum creatinine when given 60 mgd of prednisone for
2 to 6 weeks [181]. Complications of steroid therapy, however,
were common. These include development of new opportunistic
infections, steroid psychosis, and gastrointestinal bleeding. The
short-term improvement in renal function may correlate with an
improvement in tubulointerstitial mononuclear cell infiltration
[182]. In a single report of three children with perinatal AIDS,
HIV-associated glomerulosclerosis, and normal creatinine clearance,
cyclosporine induced a remission of the nephrotic syndrome [183].
This report has not been confirmed, and the use of cyclosporine in
adults with HIV-associated glomerulosclerosis has not been studied.
7.14
4.0
3.5
4.0
3.5
P=0.006
Fosinopril
Control
3.0
2.5
2.0
1.5
1.0
0.5
0
0
9
Urinary protein, g/24 h
8
7
12
Week
16
20
24
12
Week
16
20
24
P=0.006
Fosinopril
Control
6
5
4
FIGURE 7-36
Effect of angiotensin-converting enzyme (ACE) inhibitors on progression of glomerulosclerosis associated with HIV infection. Serum
ACE levels are increased in patients with HIV infection [184]. Kimmel
and colleagues [180], using captopril, and Burns and colleagues [185],
using fosinopril, demonstrated a renoprotective effect of ACE
inhibitors in patients with biopsy-proven HIV-associated glomerulosclerosis. In the former study, the median time to end-stage renal
disease was increased from 30 to 74 days in nine patients given
6.25 to 25 mg captopril three times a day. In the latter study, 10
mg of fosinopril was given once a day to 11 patients with early
renal insufficiency (serum creatinine <2 mg/dL). Serum creatinine
and proteinuria remained stable during 6 months of treatment with
fosinopril. In contrast, patients not treated with fosinopril exhibited
progressive and rapid increases in serum creatinine and proteinuria.
Similar outcomes prevailed in patients with proteinuria in the
nephrotic range and serum creatinine levels less than 2 mg/dL.
Captopril also is beneficial to the progression of the nephropathy
in HIV-transgenic mice [186]. The mechanism(s) of the renoprotective
effects of ACE inhibitors are unclear and may include hemodynamic
effects, decreased expression of growth factors, or an effect on HIV
protease activity. Renal biopsy early in the course of the disease is
important to define the renal lesion and guide therapeutic intervention.
3
2
1
0
0
SURVIVAL OF PATIENTS WITH HUMAN

IMMUNODEFICIENCY VIRUS INFECTION
RECEIVING CHRONIC HEMODIALYSIS
Reference
Year
Patients
Rao et al. [187]

Ortiz et al. [188]
1987
1988
Feinfeld et al. [189]
1989
Ribot et al. [190]
1990
Schrivastava et al. [191]

Kimmel et al. [192]
Ifudu et al. [193]
1992
1993
1997
79 AIDS
17 AIDS
12 carriers
5 AIDS
10 carriers
8 AIDS
28 carriers
44 AIDS
23 AIDS
34 AIDS
Mean survival, mo
<3
3
16
13
16
88% <12
96% >12
41% >15
14.7
57
FIGURE 7-37
Survival rates in dialysis patients. Once end-stage renal disease
(ESRD) develops and supportive maintenance dialysis is needed, the
complications of HIV are the dominant factor in patient survival, as
they are in patients with HIV infection without renal involvement.
Asymptomatic patients on chronic hemodialysis survive longer than
do patients with AIDS on chronic hemodialysis. Patients with AIDS
also may develop malnutrition, wasting, and failure to thrive that are
unresponsive to intensive nutritional support [131]. Recent studies,
however, show that the survival of patients with AIDS maintained on
chronic hemodialysis is improving. Enhanced survival has been
attributed to antiviral drugs, better prophylaxis, and aggressive treatment of opportunistic infections. We have seen four patients with
HIV infection survive for more than 10 years on hemodialysis.
Chronic hemodialysis and chronic ambulatory peritoneal dialysis are
equally appropriate treatments for patients with HIV infection and
ESRD. Universal precautions should be used for peritoneal dialysis
and hemodialysis alike, because infectious HIV is present in peritoneal effluent and blood.
PREDICTORS OF SURVIVAL OF PATIENTS WITH

HUMAN IMMUNODEFICIENCY VIRUS INFECTION
RECEIVING CHRONIC HEMODIALYSIS
CD4
Blood pressure, systolic
Infection rate
Proteinuria
Edema +/
Antiretroviral therapy +/-
0.668
0.496
0.519
0.537
14.5 vs 6.1 mo
15.2 vs 62. mo
<0.001
<0.02
<0.01
<0.02
<0.01
<0.01
RECOMMENDED ANTIRETROVIRAL THERAPY

Combination of two reverse transcriptase inhibitors
Aggressive triple therapy, including a protease
inhibitor for patients who are
Symptomatic of acquired immunodeficiency
syndrome
Asymptomatic with CD4 <500 cells/L
Asymptomatic with CD4 >500 cells/L but viral
load > 20,000
OTHER NEPHROPATHIES
ASSOCIATED WITH HUMAN
IMMUNODEFICIENCY VIRUS
INFECTION
Immune-complex glomerulopathies
Proliferative glomerulonephritis
Lupus-like nephropathy
Hemolytic uremic syndrome, thrombotic
thrombocytopenic purpura
FIGURE 7-40
Other nephropathies associated with HIV.
A variety of immune-complex-mediated
glomerulopathies have been documented in
patients with HIV infection. Some represent
glomerular diseases associated with HIV
infection, whereas others may be incidental
or manifestations of associated diseases.
7.15
FIGURE 7-38
Predictors of survival. Perinbasekar and colleagues [194] analyzed
those factors associated with better survival in patients infected
with HIV receiving chronic hemodialysis. A low CD4 lymphocyte
count, low systolic blood pressure, increased infection rate, nephrotic
range proteinuria, lack of edema, and lack of antiretroviral therapy
are associated with decreased survival.
FIGURE 7-39
Antiretroviral therapy. Recommended antiretroviral therapy for patients with HIV infection
without renal disease includes therapies with two drugs for all patients, combining two
reverse transcriptase inhibitors. Aggressive early intervention with triple antiviral drugs, one
of which is a protease inhibitor, should be offered to patients symptomatic of AIDS,
asymptomatic patients with CD4 counts under 500/L, and asymptomatic patients with
CD4 counts over 500/L and plasma HIV RNA levels over 20,000 copies/mL [195].
Reduced dosages are required for reverse transcriptase inhibitors in renal insufficiency.
Although the clearance information on these drugs is limited, additional dosing is not
necessary in patients receiving maintenance dialysis. No dosage reduction is needed for
protease inhibitors.
Proliferative glomerulonephritides represent instances of postinfectious glomerulonephritis

or manifestations of hepatitis C co-infection [196199]. Alternatively, proliferative
glomerulonephritides may result from renal depository of preformed circulating immune
complexes with specificity for HIV proteins and are HIV-associated [199]. In patients
infected with HIV, membranous glomerulonephritis has been associated with hepatitis B,
hepatitis C, syphilis, and systemic lupus erythematosus [198,200203]. Lupus-like nephritis
has been reported in children and adults with HIV infection in association with membranous, mesangial, and intracapillary proliferative glomerular lesions [204]. IgA nephropathy
has been reported in association with HIV infection. The occurrence of IgA nephropathy
may not be coincidental and is HIV-associated. Indeed, circulating immune complexes composed of idiotypic IgA antibody reactive with anti-HIV IgG or IgM were identified in two
patients, and the identical immune complex was eluted from the renal biopsy tissue of one
patient studied [199,205]. Unlike HIV-associated glomerulosclerosis, HIV-associated IgA
nephropathy has been reported exclusively in white patients with early HIV infection
exhibiting microscopic or macroscopic hematuria, absent or modest azotemia, and slowly
progressive disease [206]. Instances of intravascular coagulation related to TTP or HUS are
recognized with increased frequency and may be the first manifestation of HIV infection,
although most develop at a late stage of the disease. The cause of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) in patients infected with HIV is
unknown. Plasma tissue plasminogen activator is increased in patients infected with HIV
who have thrombotic microangiopathy [207]. There is no association with Escherichia coli
0154:H7 infection, and intercurrent infections have been demonstrated in only one third of
patients. Renal involvement in TTP usually is minimal, whereas vascular and glomerular
involvement are more frequent and extensive in HUS and can lead to renal cortical necrosis.
Therapy with plasmapheresis, using fresh frozen plasma replacement, should be instituted
as soon as the diagnosis of HIV-related HUS/TTP is made [208].
7.16
RENAL INFECTIONS AND TUMORS ASSOCIATED WITH

HUMAN IMMUNODEFICIENCY VIRUS INFECTION
Pathogens
Neoplasms
Cytomegalovirus
Candida
Nocardia
Cryptococcus
Pneumocystis
Mycobacterium
Toxoplasma
Histoplasma
Aspergillus
Herpes
Kaposis sarcoma
Carcinoma
Lymphoma
Myeloma
FIGURE 7-41
Other renal findings in patients with AIDS include infections and
tumors. Almost all opportunistic infections seen in patients with AIDS
may localize in the kidneys as manifestations of systemic disease.
However, rarely are these infections expressed clinically, and often
they are found at autopsy. Cytomegalovirus infection is the most
common [209]. Referrals to a urologist are reported for renal and
perirenal abscesses with uncommon organisms (Candida, Mucor
mycosis, Aspergillus, and Nocardia). Nephrocalcinosis can occur in
association with pulmonary granulomatosis, Mycobacterium
aviumintracellulare infection, or as a manifestation of extrapulmonary pneumocystis infection. Renal tuberculosis is a manifestation
of miliary disease. Non-Hodgkins lymphoma and Kaposis sarcoma
are the most frequently found renal neoplasms in patients with
AIDS, usually as a manifestation of disseminated involvement.
References
1. Johnson RJ, Couser WG: Hepatitis B infection and renal disease:
clinical, immunopathogenetic and therapeutic considerations. Kidney
Int 1990, 37:663.
2. Lai KN, Lai FM: Clinical features and natural history of hepatitis B
virusrelated glomerulopathy in adults. Kidney Int 1991, 35(suppl):S40.
3. Takekoshi Y, Tochimaru H, Nagatta Y, Itami N:
Immunopathogenetic mechanisms of hepatitis B virusrelated
glomerulopathy. Kidney Int 1991, 35(suppl):S34.
4. Lai KN, Li PK, Lui SF, et al.: Membranous nephropathy related to
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176. Bruggeman LA, Dikman S. Meng C, et al.: Nephropathy in human
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177. Babut-Gay ML, Echard M, Kleinknecht D, et al.: Zidovudine and
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184. Ouelette DR, Kelly JW, Anders JT: Serum angiotensin converting
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188. Ortiz C, Meneses R, Jaffe D, et al.: Outcome of patients with human
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197. Korbet SM, Schwartz MM: Human immunodeficiency virus infection
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5:277282.
Renal Involvement
in Sarcoidosis
Garabed Eknoyan
arcoidosis is a clinicopathologic syndrome resulting from dispersed organ involvement by a noncaseating granulomatous
process of unknown cause. The clinical manifestations of sarcoidosis are protean, depending on the affected organs; however, the
principal targets of sarcoidosis are the lungs and thoracic lymph
nodes, which almost always are involved. As a rule, it is a disease of
insidious onset that pursues a chronic course, with episodic remissions and exacerbations. The severity and diversity of its clinical
manifestations depend on the extent of infiltrating granulomatous
lesions of the involved organs and that of the number of affected
organs. When diffuse and widespread the disease may pursue an
acute fulminant course. Diagnosis depends on demonstration of the
characteristic pathologic lesion of noncaseating granulomas within
the affected organ.
Sarcoidosis is a common (1 to 40 cases per 100,000 population)
disease of the relatively young (mean age 40 years), with a proclivity
for racial (3.5 times more in blacks), ethnic (Scandinavian), and seasonal occurrence (summer rather than winter). Reports of community
outbreaks, work-related risks, familial clustering, occurrence after
organ transplantation, and experimental induction in animals by
injection of affected tissue homogenates from humans strongly suggests an infective cause that remains to be identified.
Two associated metabolic abnormalities of diagnostic and clinical
import are elevated levels of calcitriol (1,25-dihydroxy-vitamin D3)
and angiotensin-converting enzyme (ACE). Neither is unique to sarcoidosis. Elevated levels of calcitriol are consequent to the capacity of
the infiltrating macrophages of the granulomas to synthesize calcitriol.
Elevated levels of ACE are consequent to that of the multinucleated
giant and epithelioid cells that ultimately develop in the granulomas,
along with that of the infiltrating macrophages, to produce ACE. Of
these, the elevated levels of calcitriol are the more important because
they account for the abnormal calcium metabolism that occurs in most
patients. Elevated levels of ACE are of no known clinical consequence
CHAPTER
8.2
and are of limited value in diagnosis; however, they can be useful in follow-up of the course of the disease and patient response
to treatment.
In symptomatic cases, steroids are highly effective in suppressing the cellular inflammatory reaction of sarcoidosis and
in reversing most forms of organ dysfunction caused by granulomatous infiltration. Therapy with prednisone (30 to 40 mg/d)
for 8 to 12 weeks, with gradual tapering of the dose (10 to
20 mg/d) over 6 to 12 months, is usually sufficient. Persistent
dysfunction can result from residual fibrosis after reversal of
the active granulomatous lesions. Close monitoring of patients

is essential during tapering and after discontinuation of steroid
therapy, because 25% of treated patients experience relapse.
Other drugs that have been used in cases unresponsive to
steroids are methotrexate, chloroquine, azathioprine, and
cyclophosphamide. Of these, methotrexate seems to be more
effective.
The prognosis is worse in blacks, the elderly, and those
patients who fail to respond to steroids or have extensive multiorgan involvement.
Pathophysiology and Diagnosis

Pathology of granulomatous lesions in lungs affected by sarcoidosis.
The diagnosis of sarcoidosis depends on demonstration of the characteristic lesion of noncaseating granulomas within the affected organs.
As with other epithelioid granulomas, the more commonly involved
organs are the lungs and liver. A, A section of a normal lung is shown.
(Pentachrome stain 10.) B, Multiple noncaseating granulomas and
areas of mononuclear cell infiltration of the lung interstitium charac-
teristic of sarcoidosis are shown. (Hematoxylin-eosin stain 10.)

C and D, Lesions in the lung are illustrated, showing their course from
a cellular inflammatory response, which may be asymptomatic (panel
C), to that of the fibrotic resolution (panel D). The fibrotic response
usually accounts for the permanent loss of normal parenchyma and
organ function. (Hematoxylin-eosin stain 10 and pentachrome
10, respectively.) (From Newman et al. [1]; with permission.)
Renal Involvement in Sarcoidosis

Pathogenesis of granulomatous
lesions
Mononuclear cell infiltration
Macrophage aggregation
Synthesis of 1,25-dihydroxy-vitamin D3
Epithelioid and multinucleated

giant cells
Synthesis of angiotensin-converting
enzyme
Encapsulating rim
CD4>CD8 (except in rare cases)
B cells, few
Fibroblasts
Mast cells
CYTOKINES IMPLICATED IN
PERPETUATING GRANULOMAS
FIGURE 8-2
Pathogenesis of granulomatous lesions. Mononuclear cell infiltration is the initial step in the sequence of events that leads to granuloma formation. Recruited macrophages then differentiate into
epithelioid and multinucleated giant cells. Activated lymphocytes
are interspersed in the evolving lesion and come to form a rim
around the granulomas. In time, fibroblasts, mast cells, and collagen fibers begin to encapsulate the mature sarcoid granuloma.
Cultured granulomatous homogenates exhibit 1-hydroxylase
activity and are capable of converting 25-hydroxy-vitamin D3 to its
active 1,25-dihydroxylated form, calcitriol. This capacity resides in
the infiltrating macrophages and is not unique to sarcoidosis but a
feature of most other granulomatous disorders. Although lacking
in specificity to be of diagnostic merit, radioactive gallium scans
can be used as noninvasive methods of assessing the activity of sarcoid granulomas. The uptake of radioactive gallium by the
macrophages and lymphocytes reflects the activity of the infiltrating cells in affected organs.
SARCOIDOSIS FREQUENCY OF ORGAN INVOLVEMENT

Patients, %
Interferon-
Interleukin-2, 6, and 1
Chemoattractants
Adhesion molecules
Tumor necrosis factor-
FIGURE 8-3
Cytokines implicated in perpetuating granulomas. Cytokines released by the infiltrating
mononuclear cells and T-cell lymphocytes
initiate the cascade of inflammatory reaction
that results in subsequent formation of the
noncaseating granulomas that characterize
sarcoidosis. It is the loss of the otherwise
balanced ability of cytokines to modulate
the inflammatory response that accounts for
the progression of the initial inflammatory
reaction to granulomatous formation, and
ultimately to the more detrimental process
of fibrosis. Macrophages are critical in
inducing fibroblasts to proliferate and
deposit fibronectin and collagen in the
extracellular matrix.
8.3
Thoracic
Stage I: hilar adenopathy
Stage II: hilar adenopathy plus
pulmonary infiltration
Stage III: pulmonary infiltration
Dermatologic
Erythema nodosum, lupus pernio, papules, macules, plaques
Ophthalmic
Uveitis, iritis, conjunctivitis
Nervous system
Peripheral neuropathy, Bells palsy
Gastrointestinal
Liver
Spleen
Cardiac
Renal
Musculoskeletal
Polyarthritis, lower > upper
90100
25
25
10
4070
510
120
1015
FIGURE 8-4
Frequency of organ
involvement.
Sarcoidosis is a
multisystem disease.
Parenchymal
involvement by
granulomatous
lesions is most
common in the
lungs, whereas that
of renal involvement
is relatively rare.
8.4
DIFFERENTIAL DIAGNOSIS OF
PULMONARY SARCOIDOSIS
Sarcoidosis
Beryllium exposure
Hypersensitivity pneumonitis
Idiopathic pulmonary fibrosis
Mycobacterial infection
Fungal infections
Methotrexate-induced pneumonitis
LABORATORY FINDINGS
IN SARCOIDOSIS
Hyperglobulinemia
Abnormal liver function tests
Anergy
Leukopenia
Hyperuricemia
Hypercalciuria
Hypercalcemia
Elevated calcitriol (1,25-dihydroxy-vitamin D3)
Elevated angiotensin-converting enzyme
Cryoglobulinemia
FIGURE 8-5
Differential diagnosis of pulmonary sarcoidosis. The lungs are the principal organs involved
in sarcoidosis. Pulmonary involvement may or may not be associated with hilar lymphadenopathy. In contrast to the pulmonary diseases listed, pulmonary symptoms may be
absent in sarcoidosis even in the presence of extensive pulmonary lesions seen on chest radiographs. Pulmonary symptoms develop when the disease is in its late fibrotic phase and are
associated with airway obstruction.
FIGURE 8-6
Laboratory findings in sarcoidosis. The diagnosis of sarcoidosis depends on the demonstration of the characteristic pathologic lesion of noncaseating granulomas within the
affected organs. Several laboratory abnormalities characterize sarcoidosis and are useful in
supporting but not establishing the diagnosis. Hyperglobulinemia is a principal feature,
being present in two thirds of cases. About half of patients have liver involvement, with
some abnormality of liver function tests; anergy is present in about half of patients;
leukopenia is present in 25% to 30%. Hypercalciuria is common because of increased levels of calcitriol. In 50% to 60% of patients levels of angiotensin-converting enzymes are
elevated. Fever is present in about one third of patients.
RENAL INVOLVEMENT IN SARCOIDOSIS

Patients, %
Calcium metabolism
Hypercalciuria
Hypercalcemia
Nephrolithiasis
Nephrocalcinosis
Tubulointerstitial nephritis
Granulomatous
Fibrotic
Glomerulopathy
Membranous
Proliferative
Focal segmental glomerulosclerosis
Arteritis
Granulomatous angiitis
Obstructive nephropathy
Retroperitoneal lymphadenopathy
5060
1020
10
510
1540
1020
Rare
Rare
Rare
FIGURE 8-7
Renal involvement in sarcoidosis. The principal manifestations of
renal involvement in sarcoidosis are the functional abnormalities
resulting from the altered metabolism of calcium as a result of the
increased synthesis of 1,25-dihydroxy-vitamin D3 by the
macrophages of the granulomatous lesions. The consequent
increased calcium absorption from the gastrointestinal tract results
in the hypercalciuria that can be detected in more than half of
patients. The frequency of hypercalciuria depends on the extent of
granulomatous lesions and on the time of the year, being more
common in spring and summer when exposure to the sun is greatest. Hypercalcemia is less common and usually depends on coexistent deterioration of renal function when the capacity of the kidney
to excrete calcium is compromised. In most patients, hypercalciuria
is asymptomatic. Its principal manifestations are inability to concentrate the urine and polyuria. Nephrolithiasis occurs in about
10% of patients; another 10% develop nephrocalcinosis.

Abnormal calcium metabolism and
pathophysiology of renal involvement in sarcoidosis
Sarcoid
granulomas
Parathyroid hormone
secretion
Levels of calcitriol
Intestinal calcium absorption

and bone resorption
Tubular calcium
absorption
Hypercalciuria
Calcium load for

renal excretion
Renal calcium
deposition
Renal
Function
Outflow tract parenchymal
Total calcium
excretion
Nephrolithiasis
Nephrocalcinosis
Hypercalcemia
FIGURE 8-8
Abnormal calcium metabolism and pathophysiology of renal involvement in sarcoidosis.
Increased synthesis of calcitriol (1,25-dihydroxy-vitamin D3) by the macrophages of the
granulomatous lesions of sarcoidosis are at the core of the abnormal calcium metabolism
that accounts for the principal manifestations of renal involvement of sarcoidosis (gray
boxes). Patients with hypercalciuria, which by far is the most common, may remain asymp-
8.5
tomatic, and the disease may go undetected.

Polyuria and a reduced capacity to concentrate the urine are its main manifestations.
Either of these two features may be the result
of tubulointerstitial nephritis caused by sarcoidosis, and can be present in the absence of
any altered calcium metabolism.
Nephrocalcinosis also may be asymptomatic.
In contrast, nephrolithiasis presents as renal
colic or hematuria. Hypercalcemia develops
only when the load of calcium to be excreted
exceeds the ability of the kidneys to excrete
the calcium load, either because of reduced
renal function or, less commonly, when the
amount of calcium absorbed is excessive. The
magnitude of hypercalcemia determines its
symptomatology. The circulating level of
parathyroid hormone should be determined
in patients with hypercalcemia. An increase
in the prevalence of parathyroid adenomas
seems to occur in sarcoidosis. In hypercalcemia caused by elevated levels of calcitriol
and by reduced renal excretion of calcium,
parathyroid hormone levels should be negligible. Detection of elevated levels of parathyroid hormone should lead to the search for
an adenoma. Patient management is directed
at reducing calcitriol synthesis by treating the
granulomatous lesions with steroids. Equally
important measures in the management of
such patients are restriction of calcium
intake, avoidance of dietary supplements that
contain vitamin D, shunning exposure to
sunlight, and increased fluid intake.

Micrograph of granulomatous lesions of the renal interstitium that
are observed in 15% to 40% of patients with sarcoidosis. The
highest rate reported in the literature is 40%. This figure is based
on autopsy findings, which often reveal occasional granulomas of
the kidney without any evidence of functional or clinical abnormality. The lower figure of 15%, or less, more clearly reflects diffuse
infiltration of the kidneys with granulomas associated with clinical
evidence of abnormal renal function, as shown here. Generally,
enlarged kidneys are noted on renal ultrasonography.
8.6
GRANULOMATOUS LESIONS
IN RENAL SARCOIDOSIS
Lesion
Drug-induced
Sarcoid
Other (less common):
Tuberculosis
Brucellosis
Vasculitis
Systemic lupus
erythematosus
Idiopathic
Patients, %
FIGURE 8-10
Differential diagnosis of granulomatous lesions in renal sarcoidosis. Once considered rare,
granulomatous interstitial nephritis is now observed in 10% of kidney biopsy results. Most
of these are seen in cases of drug hypersensitivity. The commonly implicated drugs are antibiotics and nonsteroidal anti-inflammatory drugs. Sarcoidosis and Wegeners granulomatosis
each account for 5% to 10% of cases observed on kidney biopsy. Other less common and
rather rare causes include tuberculosis, angiitis, and lupus erythematosus. In some 15% to
20% of cases, the cause of the granulomatous lesions is never established.
5570
510
510
1520
Clinical Course
FIGURE 8-11
Micrograph of fibrosis. As a rule, abnormal renal function in
patients with sarcoidosis is due to tubulointerstitial nephritis rather
than granulomatous infiltration, which certainly is true in patients
with progressive loss of renal function. Fibrosis may occur in the
absence of granulomas but generally reflects the residual fibrosis of
granulomatous lesions that have subsided or responded to steroid
therapy. It is important to monitor renal function closely in such
patients and initiate proper measures to retard the course of progressive renal failure.
As with all other forms of tubulointerstitial nephritis, tubular
dysfunction is a common finding in such cases. The reduction in
the glomerular filtration rate usually is modest but can progress to
end-stage renal disease. Progression to end-stage disease tends to
occur in older men who have minimal pulmonary involvement.
Pre-R
Serum creatinine, mg/100mL
7
6
5
4
8.7
FIGURE 8-12
Clinical course of granulomatous nephritis. Extensive granulomatous
infiltration of the kidneys can result in acute renal failure as a presenting clinical feature of sarcoidosis in the absence of any evidence
of other organ involvement. As a rule, improvement in renal function occurs after steroid therapy (R), as shown here, in the clinical
course of one such patient. (From Bolton et al. [2]; with permission.)
3
2
1
60
50
40
30
20
10
Hematocrit, %
40
30
20
10
Prednisone
qod, mg
60
30
September
October
Nov. Dec. Jan. Feb. Mar. April May June July
Time, mo
CASE REPORT OF A PATIENT WITH SARCOIDOSIS

HAVING RETROPERITONEAL FIBROSIS
Patient profile
A man aged 40 years with established diagnosis of pulmonary sarcoidosis that had
responded to steroids
Presentation: hypertension (200/140 mm Hg) and proteinuria (4 g/d)
Intravenous pyelogram: asymmetric kidneys with delayed appearance of contrast on right
Surgery: sclerotic matrix affecting aorta and proximal renal artery
Kidney biopsy: focal and global glomerulosclerosis, interstitial fibrosis
Postoperative course: persistent hypertension
FIGURE 8-13
Obstructive nephropathy due to sarcoidosis. Acute deterioration of
renal function in sarcoidosis very rarely results from obstructive
nephropathy caused by intrarenal granulomatous infiltrates or
from extensive retroperitoneal lymphadenopathy or fibrosis causing obstruction of the renal vasculature or ureteral outflow [3,4].
(From Grodin et al. [3]; with permission.)
8.8
CASE REPORT OF A PATIENT WITH SARCOIDOSIS

HAVING GLOMERULOPATHY
CASE REPORT OF A PATIENT WITH RECURRENT

GRANULOMATOUS SARCOID NEPHRITIS IN A
TRANSPLANTED KIDNEY
Patient profile
Aged 13 y
A man aged 57 years with 3 months history of progressive edema

Past history: pulmonary sarcoidosis, treated with steroids for 10 years, on 5 mg 4 times
a day on admission
Physical examination: blood pressure, 180/95 mm Hg; peripheral edema
Laboratory test results: blood urea nitrogen, 32 mg/dL; creatinine, 4.3 mg/dL; albumin,
2.9 g/dL; cholesterol, 543 mg/dL; urinalysis, 68 erythrocyte/high-power field, 3 +
protein; 24-h urine protein, 1.5 g
Kidney biopsy: membranous glomerulopathy; no granulomas
FIGURE 8-14
Sarcoid-associated glomerulopathy. Whereas renal involvement in
sarcoidosis primarily is due to abnormalities of calcium metabolism
and tubulointerstitial nephritis, rare cases of glomerulopathy have
been associated with sarcoidosis. The detection of an abnormal urine
sediment and proteinuria in a patient with sarcoidosis should always
lead to consideration of glomerular disease. A variety of glomerular
lesions have been reported in patients with sarcoidosis, including
membranous glomerulopathy, minimal change disease, membranoproliferative glomerulonephritis, focal glomerulosclerosis, immunoglobulin A nephropathy, and crescentic glomerulonephritis. Of these,
membranous glomerulopathy is more common. These rare cases may
represent a chance coexistence of two separate diseases; however,
their occurrence in a disease of altered immunity may reflect a
causative association. Mesangial deposits of C3 have been observed
in cases of sarcoid granulomatous nephritis in the absence of any clinical evidence of glomerular disease. Circulating immune complexes
are detected in about half of cases of sarcoidosis in the absence of
any evidence of renal involvement by granulomatous nephritis or
glomerular lesions. As such, the presence of immune-mediated
glomerulopathy may well be more than coincidental in occasional
cases in which the patient may be predisposed by genetic or other
as yet unidentified factors. (From Taylor et al. [5]; with permission.)
Aged 19 y
Aged 26 y
Sarcoidosis with pulmonary, hepatic, and ophthalmic symptoms

Responded to steroids
Steroids discontinued due to cataract and hypertension
Renal involvement progressive to end-stage renal disease
Cadaveric transplantation after 3 months of dialysis
Medications: azathioprine, 75 mg per day; prednisone tapered to
15 mg 4 times a day
Creatinine, 3.1 mg/dL; creatinine clearance, 20 mL/min;
blood pressure, 150/84 mm Hg
Transplanted kidney biopsy: diffuse granulomatous infiltration
Treatment: prednisone increased to 60 mg/d for 6 wk
Response: creatine, 2.5 mg/dL; creatinine clearance, 35 mL/min
FIGURE 8-15
Recurrent granulomatous sarcoid nephritis in a transplanted kidney. In patients with sarcoidosis having renal involvement whose
renal failure has progressed to end-stage renal disease, kidney
transplantation can be successful. However, due consideration
should be given to the fact that recurrence of sarcoidosis in renal
allografts have been reported. Conversely, documented cases exist
in which sarcoidosis was transmitted by cardiac or bone marrow
transplantation. This observation has been taken as evidence of an
infectious or transmissible cause of sarcoidosis that highlights the
problem of transplantation in patients with sarcoidosis. (From
Shen et al. [6]; with permission.)
References
1.
2.
3.
Newman LS, Rose CS, Maier LA: Sarcoidosis. N Engl J Med 1997,
336:12241234.
Bolton WK, Atuk NO, Rametta C, et al.: Reversible renal failure from
isolated granulomatous renal sarcoidosis. Clin Nephrol 1976,
5:8892.
Grodin M, Filastre JP, Ducastelle T, et al.: Sarcoidosis retroperitoneal
fibrosis, renal arterial involvement and unilateral focal glomerulosclerosis. Arch Intern Med 1980, 140:12401242.
4.
5.
Cuppage FE, Emmott DF, Duncan KA: Renal failure secondary to sarcoidosis. Am J Kidney Dis 1990, 11:519521.
Taylor RG, Fisher C, Hoffbrand BI: Sarcoidosis and membranous
glomerulonephritis: a significant association. Br Med J 1982,
284:12971298.
Shen SY, Hall-Craggs M, Posner JN, Shalozz B: Recurrent sarcoid
granulomatous nephritis and reactive tuberculin test in a renal transplant recipient. Am J Med 1986, 80:699702.
Casella FJ, Allon M: The kidney in sarcoidosis. J Am Soc Nephrol
1993, 3:15551562.
Romer FK: Renal manifestations and abnormal calcium metabolism in
sarcoidosis. Quart J Med 1980, 49:233247.
Fuss M, Pepersack T, Gillet C, et al.: Calcium and vitamin D metabolism in granulomatous diseases. Clin Rheumatol 1992, 11:2836.
Hanedouche T, Grateau G, Noel LH, et al.: Renal granulomatous sarcoidosis: Report of 6 cases. Nephrol Dial Transplant 1990, 5: 1824.
Essential Mixed
Cryoglobulinemia
Giuseppe DAmico
Franco Ferrario
p to the end of the 1980s, the cause of about 30% of both type
II and III mixed cryoglobulinemias (MC) in patients was not
known, and this subgroup of patients were referred to as having essential mixed cryoglobulinemia. Essential mixed cryoglobulinemia was characterized clinically by systemic signs, mainly purpura,
arthralgias, and fever, together with hepatic, neurologic, and renal
symptoms. During this decade, antibodies against hepatitis C virus
(HCV) antigens and HCV RNA (which is a marker of active viremia)
have been detected in the serum of up to 90% of these patients.
Only when a monoclonal rheumatoid factor, usually an
immunoglobulin Mk (IgMk), is the anti-IgG component of the mixed
cryoglobulinemia (type II MC) does this distinctive glomerular and vascular involvement of the kidney occur. The most frequent histologic picture, especially in the acute stages, is a membranoproliferative glomerulonephritis (MPGN) with subendothelial deposits, with some characterizing features both by light and electron microscopy. However, a less
distinctive picture of lobular MPGN is found at biopsy in 20% of
patients, and of a mesangioproliferative glomerulonephritis in another
20%. In all cases, the two components of MC, IgG, and IgM, together
with complement, are found by immunofluoroscopy.
The clinical picture varies during the long-term course of the disease, being characterized by periods of temporary reactivation
(nephritic or nephrotic syndrome, sometimes with rapidly occurring
renal insufficiency) and long-lasting periods of partial remission. Only
infrequently does end-stage renal failure develop; however, mortality
as a result of the other complications of the systemic disease (mainly
cardiovascular) is rather frequent.
CHAPTER
9.2
During acute flare-ups, antiviral treatment (interferon-) is insufficient to control the renal disease, even when it reduces viremia.
Steroids, usually associated with immunosuppressive drugs
(cyclophosphamide), are then necessary to control renal disease.
Hepatitis C virus can infect B lymphocytes and stimulate
them to synthesize the cryoprecipitating polyclonal rheumatoid
factors responsible for type III MC. In some patients with this
polyclonal B-cell activation, additional but as yet uncharacter-
ized events might induce the shift to abnormal proliferation of

a clone of B cells, producing a monoclonal IgM rheumatoid factor. Thus, a type II MC is induced that can be considered a lymphoproliferative disorder. It has been suggested that the IgMk
produced by this permanent clone of B cells has affinity for the
glomerular matrix and can deposit, in the glomerulus together
with the IgG to which it binds in the blood, IgG that probably
acts as an anti-HCV antigen antibody.
CLASSIFICATION OF CRYOGLOBULINEMIAS AND ASSOCIATED DISEASES

Type I: single monoclonal IgA,
IgG, or IgM
Type II: polyclonal IgG bound to

monoclonal anti-IgG rheumatoid factor*
Multiple myeloma
B-lymphocytic neoplasm
Waldenstrms macroglobulinemia
Diffuse lymphoma
Chronic lymphocytic leukemia
Chronic lymphocytic leukemia
Idiopathic monoclonal gammopathy
Sjgrens syndrome
Essential
Type III: polyclonal IgG bound to polyclonal anti-IgG rheumatoid factor*

Autoimmune diseases: SLE, polyarteritis nodosa, rheumatoid arthritis, scleroderma,
Sjgrens syndrome, and Hench-Schonlein purpura
Infections diseases: mononucleosis, cytomegalovirus, hepatitis B, subacute bacterial
endocarditis, leprosy, malaria, schistosomiasis, toxoplasmosis, AIDS
Miscellaneous diseases: primary proliferative glomerulonephritis, lymphoma, chronic
hepatitis, biliary cirrhosis
Essential
*Usually IgM.
From Brouet and coworkers [1]; with permission.
FIGURE 9-1
Classification of cryoglobulinemias and associated diseases as proposed
by Brouet and coworkers in 1974 [1]. Up to the end of the 1980s, the
cause of about 30% of both types II and III mixed cryoglobulins was
DETECTION OF CIRCULATING CRYOGLOBULINS AND

DETERMINATION OF CRYOPRECIPITATE
Prewarm syringe, needle, and tubes at 37C
Take 20 mL of whole blood and put it immediately at 37C
Incubate for 2 h at 37C to allow clotting
Centrifuge twice at 1700 g X 10 at 37C to discard platelets and erythrocytes
Cryoglobulins precipitate reversibly from cooled serum
Keep serum at 4C in a conical graduate tube
Look at the serum after 7 d
Centrifuge serum at 400 g X 10 at 4C and calculate the cryocrit as the percentage of
packed cryoglobulins and serum ratio
not clear, and this group of mixed cryoglobulinemias was called essential
[2,3]. As indicated in Figure 9-4, it now is evident that most essential
mixed cryoglobulinemias are associated with hepatitis C virus infection.
FIGURE 9-2
Correct methodology for detecting circulating cryoglobulins.
Cryoglobulins are immunoglobulins that precipitate reversibly from
cooled serum.
9.3
Renal Involvement in Essential Mixed Cryoglobulinemia

Immunoglobulin composition and clonality of mixed cryoglobulins characterized by
immunofixation. The cryoglobulins (isolated, as indicated in Fig. 9-2) are resuspended in
three volumes of cold phosphate-buffered saline at 4C and then washed by centrifuging
at 1700 g for 10 minutes at 4C; the supernatant is discarded. This procedure is repeat-
ed at least four times. Next, the cryoprecipitate is solubilized in three volumes of

phospate-buffered saline at 37C before
gel electrophoresis is performed.
A, Example of type II mixed cryoglobulin; the immunoglobulin M rheumatoid factor contains but not light chains and
therefore is monoclonal. B, Example of
type III mixed cryoglobulin; the immunoglobulin M rheumatoid factor contains
both and light chains and therefore is
polyclonal. (Beckman Paragon IFE gel.)
PREVALENCE OF HEPATITIS C VIRUS AND HEPATITIS C VIRUS RNA

IN ESSENTIAL AND SECONDARY MIXED CRYOGLOBULINEMIAS*
Study
Types of mixed cryoglobulinema
Ferri et al. [5]

Galli et al. [6]
II and III EMC

II and III EMC
Pechre-Bertschi et al. [7]

Agnello et al. [8]
Misiani et al. [9]
Pasquariello et al. [10]
Cacoub et al. [11]
II and III EMC

II EMC
II EMC
II EMC with GN
II and III EMC
SMC
II and III EMC
II EMC
II EMC wtih GN
III EMC
Bichard et al. [12]

DAmico, Unpublished data
Serum HCV antibodies

Patients tested, n
Positive patients, %
52
129
63
15
19
75
26
63
52
41
28
13
54
80
70
87
42
96
100
52
27
95
93
77
Serum HCV RNA

Patients tested, n
Positive patients, %
7
19
28
7
16
71
84
93
100
63
15
41
28
13
93
95
93
77
*According to published data [4].

EMCessential mixed cryoglobulinemia; GNglomerulonephritis; HCVhepatitis C virus; SMCsecondary mixed cryoglobulinemia.
FIGURE 9-4
Second-generation enzyme-linked immunosorbent assay has
been used by all the authors listed here (with the exception
of Agnello and coworkers [9], who used a recombinant
immunoblot assay) to measure antihepatitic C virus (HCV)
antibodies. The prevalence of positivity of HCV RNA

in the 15 patients studied by Bichard and coworkers [12]
increased from 60% to 93% when cryoprecipitate from
serum was tested.
9.4
FREQUENT EXTRARENAL SIGNS IN PATIENTS WITH

TYPES II AND III MIXED CRYOGLOBULINEMIA
Signs and symptoms
Cutaneous purpura
Arthralgias
Fever
Hepatosplenomegaly
Neuropathy
Abdominal pain
Prevalence during course of disease, %

95
85
60
95
40
30
FIGURE 9-5
Extrarenal signs frequently present in patients with types II and III
mixed cryoglobulinemia, either essential or due to hepatitis C virus
infection, with or without cryoglobulinemic nephropathy. In
patients with cryoglobulinemic nephropathy, the systemic signs
usually appear months or years before renal complications develop.
The onset of these signs, however, may be concomitant with or
even subsequent to the onset of renal signs. Abdominal pain is due
to mesenteric vsasculitis [13].
FIGURE 9-6
A purpuric rash of the legs in a patient with mixed cryoglobulinemia associated with hepatitis C virus infection.
DISTINCTIVE FEATURES OF MEMBRANOPROLIFERATIVE

GLOMERULONEPHRITIS, OR CRYOGLOBULINEMIC GLOMERULONEPHRITIS
Exudative component
The major constituent of intracapillary proliferation is an infiltration of leukocytes, mainly monocytes, that
sometimes is massive.
Intraluminal thrombi
Huge deposits of cryoglobulins called intraluminal thrombi sometimes fill the capillary lumen.
Interposition of monocytes in the double contour of the capillary wall
Monocytes, in close contact with the subendothelial deposits of cryoglobulins, are interposed between the glomerular
basement membrane and the newly formed membranelike material, to give the double-contoured appearance of the
capillary wall, whereas peripheral interposition of mesangial matrix and cells is moderate.
Structured crystalloid deposits on electron microscopy
Intraluminal and subendothelial deposits of cryoglobulins sometimes show a specific fibrillar structure on
Vasculitis of small and medium-sized arteries
Necrotizing arteritis, without concomitant features of segmental necrotizing glomerulonephritis, is found in one
third of patients.
FIGURE 9-7
The distinctive features of the membranoproliferative glomerulonephritis. This disorder, called cryoglobulinemic glomerulonephritis, occurs only in patients with
type II mixed cryoglobulinemia, especially
in the acute stage of the disease [4,14]. In
about 20% of patients with type II mixed
cryoglobulinemia, a less distinctive picture
of lobular membranoproliferation is found,
whereas an additional 20% exhibit mild
mesangial proliferation. These various types
of histologic lesions can be found by repeat
biopsies in the same patient during different
stages of the disease.
FIGURE 9-8
Membranoproliferative exudative glomerulonephritis in patients
with type II mixed cryoglobulinemia. The marked endocapillary
hypercellularity also is due to massive intraglomerular infiltration of
mononuclear leukocytes, mainly monocytes (Fig. 9-9). Mesangial
cell proliferation and mesangial matrix expansion are mild. Many
loops show a thickened glomerular capillary wall, with frequent
double-contoured basement membrane. (Trichrome stain 250.)
9.5
FIGURE 9-9
Immunohistochemical staining with antimonocyte-macrophage
antibody (CD68). This reaction confirms that the intracapillary
hypercellularity is due mainly to accumulation of these mononuclear leukocytes. Their average number in acute stages of cryoglobulinemic glomerulonephritis is four times greater than in severe
proliferative lupus nephritis [15]. (Immunoperoxidase 250.)

Monocyte in close contact with a massive endocapillary deposit showing phagocytic activity.
(Uranyl acetatelead citrate 8000.) (Courtesy of Department of Pathology, San Carlo
Borromeo Hospital, Milan, Italy.)

Presence of huge intracapillary deposits typical of cryoglobulinemic
glomerulonephritis. These huge intracapillary deposits are called
intraluminal thrombi. The only possible differential diagnosis is
with glomerulonephritis secondary to Waldenstrm macroglobulinemia. The glomerulus shows morphologic lesions similar to
those seen in Figure 9-8, characterized by marked endocapillary
hypercellularity mainly a result of mononuclear leukocyte accumulation. Two large intraluminal deposits, stained in green and red,
are evident in the part of the glomerular tuft opposite the vascular
pole. It is now well known that these deposits are expressions of
acute and massive intracapillary precipitation of circulating cryoglobulins. (Trichrome stain 250.)
9.6

FIGURE 9-12
Electron microscopy of subendothelial and endocapillary deposits showing an amorphous
structure. In a minority of cases, as illustrated here, a specific annular and cylindrical
structure is shown. This structure is identical to that seen in the in vitro precipitate of the
same patients and consists of cylinders 100- to 1000-m long, with a hollow axis, appearing in cross-sections as annular bodies [16]. (Uranyl acetatelead citrate 22,000.)
(Courtesy of Department of Pathology, San Carlo Borromeo Hospital, Milan, Italy.)
FIGURE 9-13
Silver stain showing the double-contoured appearance of the basement membrane. This morphologic aspect is diffuse and more
clearly visible than in idiopathic membranoproliferative glomerulonephritis or lupus nephritis. (Silver stain 250.)
FIGURE 9-14
Interposition of monocytes in cryoglobulinemic glomerulnephritis.
Two monocytes containing lysosomes are interposed, together with
electron-dense subendothelial deposits, between the glomerular basement membrane and the newly formed basement-membranelike
material of the double-contoured capillary wall. The interposition of
monocytes is a distinctive feature of cryoglobulinemic glomerulnephritis [17,18]. Mesangial matrix and mesangial cell interposition, however, usually are less evident than in idiopathic membranoproliferative
glomerulonephritis, as is glomerular sclerosis. (Uranyl acetate-lead citrate 8000.) (Courtesy of Department of Pathology, San Carlo
Borromeo Hospital, Milan, Italy.)
FIGURE 9-15
Morphologic pattern of lobular glomerulonephritis. This pattern is
present in 20% of cases, characterized by intense mesangial proliferation and peripheral mesangial matrix expansion associated with
centrolobular sclerosis. This histologic picture is indistinguishable
from that of idiopathic membranoproliferative glomerulonephritis
type I, except for the presence of some degree of monocyte infiltration. (Trichrome 250.)
9.7
FIGURE 9-16
The glomerulus showing only mild mesangial proliferation and
mesangial matrix expansion. Thickening of the glomerular basement membrane is not evident. This picture frequently is present in
cases clinically characterized only by mild urinary abnormalities
(inactive phase). Moreover, in many cases in which a biopsy is taken
during the acute phase of the disease with typical membranoproliferative patterns with or without thrombi, a second renal biopsy will
show clear regression of the morphologically acute lesions with only
mild mesangioproliferative alteration. (Trichrome 250.)
B
The pattern of immunohistologic glomerular staining varies
according to the different glomerular patterns seen on light
microscopy. A, Diffuse granular subendothelial deposits along the
capillary walls, with or without very rare intraluminal thrombi.
(Immunoglobulin M 250). B, Intense massive staining of the
deposits totally filling the capillary lumina. Faint and irregular
parietal deposits also are present. (Immunoglobulin 250.)
C, Parietal deposits with more evident peripheral lobular distribution. (Immunoglobulin 250.) The components of mixed cryoglobulinemia immunoglobulin M and G, usually associated with
C3, are the most frequently found immunoreactants.
9.8
FIGURE 9-18
Interstitial infiltrates having different degrees of intensity and diffusion. When present, these infiltrates are composed not only of T lymphocytes and monocyte macrophages, as in most glomerular diseases,
but also of B lymphocytes. (Periodic acidSchiff reaction 100.)

Arteritis of small and medium-sized arteries. In about one third of
cases an arteritis of small and medium-size arteries also is present.
The artery shows diffuse fibrinoid necrosis of the vessel wall (in
red) and intraparietal and perivascular leukocyte infiltration. It is
worth emphasizing that even in the presence of renal arteritis we
have never found in patients with cryoglobulinemia a picture of
necrotizing crescentic glomerulonephritis, now considered a specific
aspect of capillaritis in primary vasculitis (antineutrophil cytoplasm
antibodyassociated). This finding suggets that the vasculitic damage is limited to arterial vessels of larger size. (Trichrome 100.)
RENAL SYNDROME AT PRESENTATION IN PATIENTS

WITH CRYOGLOBULINEMIC GLOMERULONEPHRITIS
AND ASSOCIATED HISTOLOGIC LESION
Renal syndrome
Patients, %
Isolated proteinuria with microscopic hematuria, sometimes associated with moderate

chronic renal insufficiency
55
Acute nephritic syndrome, sometimes complicated by acute oliguric renal failure
25
Nephrotic syndrome
20
Frequent histologic features

(MPGN), with moderate infiltration of monocytes
Lobular MPGN
Mesangioproliferative glomerulonephritis
MPGN with leukocytic infiltration, or intraluminal
thrombi owing to abrupt massive precipitation
of cryoglobulins, usually associated with renal
and systemic vasculitis, or both
MPGN, frequently of lobular type, with some
infiltration of monocytes
FIGURE 9-20
Renal syndrome at presentation in patients
with cryoglobulinemic glomerulonephritis
and associated histologic lesion. During the
course of this disease, both the systemic and
renal signs may vary remarkably, with periods of exacerbation alternating with periods of quiescence. Very often, exacerbation
of the extrarenal signs is associated with
exacerbation of renal disease (recurrent
episodes of nephritic or nephrotic syndrome); however, a flare-up of renal disease
may occur even in the absence of exacerbation of the extrarenal signs. Partial or total
prolonged remission occurs spontaneously
or after treatment in 10% to 15% of
patients. Arterial hypertension frequently is
severe and is present in most patients with
cryoglobulinemic nephropathy.
LABORATORY ABNORMALITIES IN
ESSENTIAL MIXED CRYOGLOBULINEMIA
CLINICAL OUTCOMES OF 105 PATIENTS STUDIED

IN THREE MILAN HOSPITALS FROM 1966 TO 1990
Circulating cryoglobulins
Cryocrits ranging from 2% to 70%, with large variations during the course of the disease
Hypocomplementemia
Very low levels of early C components (C1q and C4) and CH50; slightly low levels of
C3; and high levels of late C components, C5 and C9
FIGURE 9-21
Relevant laboratory abnormalities in essential mixed cryoglobulinemia. During the course of this disease, cryoglobulins may temporarily become undetectable. Low levels of serum C4 cannot be
corrected by treatment. Low levels of C3 frequently are found during clinical flare-ups and can be corrected by treatment.
TREATMENT OF ACUTE RENAL EXACERBATIONS

OF CRYOGLOBULINEMIC GLOMERULONEPHRITIS
AND VASCULITIS
Steriods are used to control inflammatory renal and systemic involvement
Cytotoxic drugs are used to block production of new cryoglobulins by the specific
lymphocytic clone that produces the monoclonal immunoglobulin Mk RF, and
therefore, the precipitating cryoglobulins
Plasma exchange is used to remove circulating cryoglobulins from the blood before
they deposit in the glomerulus and arterial walls
PROPOSED TREATMENT FOR MIXED

CRYOGLOBULINEMIA ASSOCIATED WITH HEPATITIS
C VIRUS INFECTION
Drug
Dosage
Duration
Interferon-
Steriods
3.06.0 MU, 3 times weekly

Methylprednisolone, 0.751.0 g/d, intravenously
Prednisone, 0.5 mg/kg of body weight tapered
over a few weeks until maintenance dose of
1015 mg/d is achieved
2 mg/kg of body weight
Exchanges of 3 L of plasma, 3 times weekly
612 mo
3d
6 mo
Cyclophosphamide
Plasmapheresis
9.9
34 mo
23 wk
49% cumulative 10-year probability of survival, without renal failure

40% of patients died, mostly from cardiovascular diseases, liver failure, or infections
14% of patients progressed to chronic renal failure and required dialysis
14% of patients achieved complete and prolonged remission of renal symptoms
FIGURE 9-22
The clinical outcomes in 105 patients studied in three hospitals in
Milan, Italy, between 1966 and 1990. The medial total follow-up
time from clinical onset was approximately 11 years [19].
FIGURE 9-23
This approach to treatment of the acute renal exacerbations of
cryoglobulinemia and vasculitis used previously when the viral
cause of the disease was unknown is still valid now that the viral
cause is evident. It is a common experience that the antiviral agent
interferon-, when given alone, does not control renal complications in the acute stage of the disease [20].
FIGURE 9-24
The proposed treatment for mixed cryoglobulinemia associated with
hepatitis C virus infection in the presence of severe acute signs of
renal involvement, ie, glomerulonephritis and vascultits. Plasma
exchange is used only when acute renal insufficiency caused by massive precipitation of cryoglobulins is present. Interferon- is given
for more than 6 months only when negation of hepatitis C virus
RNA is achieved in the first months, suggesting a beneficial effect
on the viremia. Only the antiviral treatment with interferon- eventually associated with low doses of steriods to conrol the systemic
signs of mixed cryoglobulinemias should be given if renal involvement is mild. The association of interferon- with another antiviral
agent ribavirin, 0.6 to 1.0 g/d orally, now is being tested in patients
with hepatitis C virus infection, with promising results [20].
9.10
Infection by HCV
Emergence of a
permanent clone
producing IgMk RF
B lymphocyte
IgMk RF
HCV
IgG Ab
Serum
HCV-IgG
HCV-IgG-IgMk
Deposition of anti-HCV Precipitation of In situ binding of

immune complexes
the circulating HCV-IgG Ab to
predeposited IgMk Glomerulus
type II cryo
MPGN without
cryoglobulinemia
Cryoglobulinemic GN
FIGURE 9-25
The mechanisms of renal complications induced by hepatitis C virus
(HCV) infection, with or without associated mixed cryoglobulinemia,
according to our hypothesis. As illustrated, the prevalent pathogenetic
mechanism is the deposition in the glomerulus of a monoclonal IgM
rheumatoid factor (RF) with particular affinity for the glomerular
matrix, which is produced by permanent clones of B lymphocytes
infected by HCV. It is unknown whether the IgM RF deposits in the
glomerulus alone, with subsequent in situ binding of IgG (perhaps
bound already to viral antigens, or as a complex composed of HCV
antigens, IgG anti-HCV antibodies, and IgMk RF). Only recently
have specific HCV-related proteins been detected in glomerular structures using indirect immunochemistry. As depicted on the left, it is
possible that in a minority of cases immune complexes composed of
HCV antigens and anti-HCV IgG antibodies can deposit directly in
the glomerular structures, in the absence of a concomitant type II MC
with a monoclonal IgM RF. This deposition induces an immune-complex glomerulonephritis similar to that described in patients infected
with the hepatitis B virus. (Adapted from DAmico [21].)
Acknowledgments
We thank Dr. M.P. Rastaldi of the Division of Nephrology and Drs. E. Schiaffino and R. Boeri of the
Department of Pathology of the Hospital of San Carlo Borromeo for their help.
References
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of cryoglobulins: a report of 86 cases. Am J Med 1974, 57:775778.
2. Meltzer M, Franklin EC, Elias K, et al.: Cryoglobulinemia: a clinical
and laboratory study. II. Cryoglobulins with rheumatoid factor
activity. Am J Med 1966, 40:837856.
3. Gorevic PD, Kassab HJ, Levo Y, et al.: Mixed cryoglobulinemia:
clinical aspects and long-term follow-up of 40 patients. Am J Med
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4. DAmico G: Cryoglobulinemic glomerulonephritis: a membranoproliferative glomerulo-nephritis induced by hepatitis C virus. Am J Kidney
Dis 1995, 25:361369.
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with mixed cryoglobulinemia. Arthritis Rheum 1991, 34:16061610.
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8. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection
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membranoproliferative glomerulonephritis associated with hepatis C
virus [letter]. Am J Nephrol 1993, 13:300304.
11. Cacoub P, Lunel Fabiani F, Musset L, et al.: Mixed cryoglobulinemia
and hepatitis C virus. Am J Med 1994, 96:124132.
12. Bichard P, Ounanian A, Girard M, et al.: High prevalence of hepatitis C virus
RNA in the supernatant and the cryoprecipitate of patients with essential and
secondary type II mixed cryoglobulinemia. J Hepatol 1994, 21:5863.
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essential mixed cryoglobulinemia (EMC). In Proceedings of the XXI
Congress of the European Dialysis and Transplant Association. Edited
by Davison PJ, Guillou PJ. London: Pitman; 1985:527547.
14. DAmico G, Colasanti G, Ferrario F, Sinico RA: Renal involvement in
essential mixed cryoglobulinemia. Kidney Int 1989, 35:10041014.
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renal leukocytes to disease activity in lupus and cryoglobulinemic
glomerulonephritis. Nephron 1988, 50:1423.
16. Cordonnier D, Martin H, Groslambert P, et al.: Mixed IgG-IgM cryoglobulinemia with glomerulonephritis. Immunochemical fluorescent
and ultrastructural study of kidney and in vitro cryoprecipitate. Am J
Med 1975, 59:867872.
17. Mazzucco G, Monga G, Casanova S, Cagnoli L: Cell interposition in
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Kidney Disease and

Hypertension in Pregnancy
Phyllis August
idney disease and hypertensive disorders in pregnancy are discussed. Pregnancy in women with kidney disease is associated
with significant complications when renal function is impaired
and hypertension predates pregnancy. When renal function is well
preserved and hypertension absent, the outlook for both mother and
fetus is excellent. The basis for the close interrelationship between
reproductive function and renal function is intriguing and suggests
that intact renal function is necessary for the physiologic adjustments
to pregnancy, such as vasodilation, lower blood pressure, increased
plasma volume, and increased cardiac output.
The renal physiologic adjustments to pregnancy are reviewed,
including hemodynamic and metabolic alterations. The common
primary and secondary renal diseases that may occur in pregnant
women also are discussed. Some considerations for the management of
end-stage renal disease in pregnancy are given.
Hypertensive disorders in pregnancy are far more common than is
renal disease. Almost 10% of all pregnancies are complicated by
either preeclampsia, chronic hypertension, or transient hypertension.
Preeclampsia is of particular interest because it is associated with
life-threatening manifestations, including seizures (eclampsia), renal
failure, coagulopathy, and rarely, stroke. Significant progress has been
made in our understanding of some of the pathophysiologic manifestations of preeclampsia; however, the cause of this disease remains
unknown. The diagnostic categories of hypertension in pregnancy,
pathophysiology of preeclampsia, and important principles of prevention and treatment also are reviewed.
CHAPTER
10
10.2
Anatomic Changes in the Kidney During Pregnancy
Increased kidney size
Increased renal blood flow

Increased glomerular filtration rate
FIGURE 10-1
Anatomic changes in the kidney during pregnancy. During pregnancy,
kidney size increases by about 1 cm. More striking are the changes in
the urinary tract. The calyces, renal pelvis, and ureters dilate. The
dilation is more marked on the right side than the left and is apparent
as early as the first trimester. Hormonal mechanisms and mechanical
obstruction are responsible. Intravenous pyelography may demonstrate the iliac sign in which ureteral dilation terminates at the level of
the pelvic brim where the ureter crosses the iliac artery. Ureteral dilation and urinary stasis contribute to the increased incidence of asymptomatic bacteriuria and pyelonephritis in pregnancy.
Dilation of urinary tract
Changes in Renal Function During Pregnancy

Uric acid reabsorption
Renin
Renal vasodilation
Renal blood flow
Serum creatinine
Urinary protein
Aldosterone
Sodium reabsorption
Water reabsorption
Urinary calcium
Glucosuria
Aminoaciduria
FIGURE 10-2
Changes in renal function during pregnancy. Marked renal hemodynamic changes are apparent by the end of the first trimester.
Both the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) increase by 50%. ERPF probably increases to a
greater extent, and thus, the filtration fraction is decreased during
early and mid pregnancy. Micropuncture studies performed in animals suggest the basis for the increase in GFR is primarily the
increase in glomerular plasma flow [1]. The average creatinine level
and urea nitrogen concentration are slightly lower than in pregnant
women than in those who are not pregnant (0.5 mg/d and 9
mg/dL, respectively). The increased filtered load also results in
increased urinary protein excretion, glucosuria, and aminoaciduria.
The uric acid clearance rates increase to a greater extent than does
the GFR. Hypercalciuria is a result of increased GFR and of
increases in circulating 1,25-dihydroxy-vitamin D3 in pregnancy
(absorptive hypercalciuria). The renin-angiotensin system is stimulated during gestation, and cumulative retention of approximately
950 mEq of sodium occurs. This sodium retention results from a
complex interplay between natriuretic and antinatriuretic stimuli
present during gestation [2].
10.3
Kidney Disease and Hypertension in Pregnancy
Serum Electrolytes in Pregnancy

A Altered osmoregulation:
B Serum chloride levels are
Serum sodium and Posm

with Osmotic Threshold
for the argenine vasopressin
release and thirst
unchanged compared with

women who are not pregnant
Na+
136 mEq/L
Cl104 mEq/L
3.7 mEq/L
K+
20 mEq/L
HCO3
C Mild hypokalemia may be
D Mild respiratory alkalosis is
observed due to glomerular

filtration rate, urine flow,
and aldosterone
FIGURE 10-3
Serum electrolytes in pregnancy. A, During normal gestation, serum
osmolality decreases by 10 mosm/L and serum sodium (Na+) decreases
by 5 mEq/L. A resetting of the osmoreceptor system occurs, with
decreased osmotic thresholds for both thirst and vasopressin release
[3]. B, Serum chloride (Cl-) levels essentially are unchanged during
pregnancy. C, Despite significant increases in aldosterone levels
during pregnancy, in most women serum potassium (K+) levels are
either normal or, on average, 0.3 mEq/L lower than are values in
women who are not pregnant [4]. The ability to conserve potassium may be a result of the elevated progesterone in pregnancy [5].
D, Arterial pH is slightly increased in pregnancy owing to mild
respiratory alkalosis. The hyperventilation is believed to be an
effect of progesterone. Plasma bicarbonate (HCO-3) concentrations
decrease by about 4 mEq/L [6].
associated with small decreases

in plasma bicarbonate
Blood Pressure and the Renin-Aldosterone

System in Pregnancy
120
14
12
PRA, ng/mL/h
Blood pressure, mmHg
110
100
90
Sitting
Standing
80
10
8
6
70
**
60
(N)
50
4
PRA
Postpartum angiotensinogen values
12
16
20
24
28
32
36
40
PP
Gestation, wk
FIGURE 10-4
Blood pressure and the renin-aldosterone system in pregnancy.
Normal pregnancy is associated with profound alterations in
cardiovascular and renal physiology. These alterations are
accompanied by striking adjustments of the renin-angiotensinaldosterone system. A, Blood pressure and peripheral vascular
resistance decrease during normal gestation. The decrease in
blood pressure is apparent by the end of the first trimester of
*
*
**
*
(7)
(16)
(18) (18) (18) (19) (18) (18)(15)
(19)
12
16
PP
20
24
28
32
36 38
Gestation, wk
pregnancy and often approaches prepregnancy levels at term.

B, Despite the decrease in blood pressure, plasma renin activity
(PRA) increases during the first few weeks of pregnancy; on
average, close to a fourfold increase in PRA occurs by the end of
the first trimester, with additional increases until at least 20
weeks. The source of the increased renin is thought to be the
maternal renal release of renin.
10.4
Urine aldosterone
Plasma aldosterone
Urine sodium
Urine potassium
200
120
100
80
80
60
60
40
40
20
20

C, Changes in renin are associated with commensurate changes in
the secretory rate of aldosterone. Although a correlation exists
between the increase in renin and that of aldosterone, the latter
increases to a greater degree in late pregnancy. This observation
suggests that other factors may regulate secretion to a greater degree
than does angiotensin II in late gestation. Urinary aldosterone
24-hr Na+ and K+, mEq
100
Plasma aldosterone, ng/100mL
Urine aldosterone, g/d
150
100
50
0
8
12
16
20
24
28
32
36
38
PP
Gestation, wk
increases in late gestation to a greater degree than does plasma

aldosterone, which may reflect an increased production of the
3-oxo conjugate measured in urine. D, Despite the marked increases in aldosterone during pregnancy, 24-hour urinary sodium and
potassium excretion remain in the normal range. PP postpartum.
(From Wilson and coworkers [7]; with permission.)
Functional Significance of the Stimulated

Renin-Angiotensin System in Pregnancy
85
25
80
20
75
70
P < 0.005
*
65
PRA, mg/mL/h
MAP, mm Hg
Pregnant (n = 9)
Nonpregnant (n = 8)
10
5
60
*
P < .05
15
0
T=0
T = 60
T=0
T = 60
FIGURE 10-5
Functional significance of the stimulated renin-angiotensin system
(RAS) in pregnancy. We determine whether changes in the RAS in
pregnancy are primary, and the cause of the increase in plasma volume, or whether these changes are secondary to the vasodilation
and changes in blood pressure. To do so, we administered a single
dose of captopril to normotensive pregnant women in their first
and second trimesters and age-matched normotensive women who
were not pregnant. We then measured mean arterial pressure (MAP)
and plasma renin activity (PRA) before and 60 minutes after the dose.
A, Despite similar baseline blood pressures, blood pressure decreased
more in pregnant women compared with those who were not pregnant in response to captopril. This observation suggests that the
RAS plays a greater role in supporting blood pressure in pregnancy. B, Baseline PRA was higher in pregnant women compared with
those who were not pregnant, and pregnant women had a greater
increase in renin after captopril compared with those who were not
pregnant. Ttime. (From August and coworkers [8]; with permission.)
10.5
Pregnancy and the Course of Renal Disease

INTERRELATIONSHIPS BETWEEN
PREGNANCY AND RENAL DISEASE
Impact of pregnancy on renal disease
Impact of renal disease on pregnancy
Hemodynamic changes hyperfiltration

Increased proteinuria
Intercurrent pregnancy-related illness,
eg, preeclampsia
Possibility of permanent loss
of renal function
Increased risk of preeclampsia

Increased incidence of prematurity,
intrauterine growth retardation
FIGURE 10-6
Pregnancy may influence the course of renal disease. Some women
with intrinsic renal disease, particularly those with baseline azotemia
and hypertension, suffer more rapid deterioration in renal function
after gestation. In general, as kidney disease progresses and function
deteriorates, the ability to sustain a healthy pregnancy decreases. The
presence of hypertension greatly increases the likelihood of renal
deterioration [2]. Although hyperfiltration (increased glomerular
filtration rate) is a feature of normal pregnancy, increased intraglomerular pressure is not a major concern because the filtration
fraction decreases. Possible factors related to the pregnancy-related
deterioration in renal function include the gestational increase in
proteinuria and intercurrent pregnancy-related illnesses, such as
preeclampsia, that might cause irreversible loss of renal function.
Women with renal disease are at greater risk for complications
related to pregnancy such as preeclampsia, premature delivery,
and intrauterine growth retardation.
Diabetes Mellitus and Pregnancy

RENAL DISEASE CAUSED
BY SYSTEMIC ILLNESS
Gestation in pregnant women with diabetic
nephropathy is complicated by the following:
Increased proteinuria, 70%
Decreased creatinine clearance, 40%
Increased blood pressure, 70%
Preeclampsia, 35%
Fetal developmental problems, 20%
Fetal demise, 6%
FIGURE 10-7
Diabetes mellitus is a common disorder in pregnant women. Patients with overt nephropathy
are likely to develop increased proteinuria and mild but usually reversible deteriorations in
renal function during pregnancy. Hypertension is common, and preeclampsia occurs in
35% of women. (From Reece and coworkers [9]; with permission.)
10.6
Pregnancy and Systemic Lupus Erythematosus

RENAL DISEASE ASSOCIATED WITH SYSTEMIC ILLNESS
Pregnancy and SLE*
Antiphospholipid antibody syndrome in pregnancy
Poor outcome is associated with the following:

Active disease at conception
Disease first appearing during pregnancy
Hypertension, azotemia in the first trimester
High titers of antiphospholipid antibodies or
lupus anticoagulant
Increased fetal loss

Arterial and venous thromboses
Renal vasculitis, thrombotic microangiopathy
Preeclampsia
Treatment: heparin and aspirin?
*Systemic lupus erythematosus (SLE) is unpredictable during pregnancy.
FIGURE 10-8
Patients with systemic lupus erythematosus
(SLE) often are women in their childbearing
years. Pregnancies in women with evidence
of nephritis are potentially hazardous, particularly if active disease is present at the time
of conception or if the disease first develops
during pregnancy. When hypertension and
azotemia are present at the time of conception the risk of complications increases, as it
does with other nephropathies [1014]. The
presence of high titers of antiphospholipid
antibodies also is associated with poor pregnancy outcome [15]. The presence of antiphospholipid antibodies or the lupus anticoagulant is associated with increased fetal
loss, particularly in the second trimester;
increased risk of arterial and venous thrombosis; manifestations of vasculitis such as
thrombotic microangiopathy; and an
increased risk of preeclampsia. Treatment
consists of anticoagulation with heparin
and aspirin.
Lupus Versus Preeclampsia

LUPUS FLARE-UP VERSUS PREECLAMPSIA
Proteinuria
Hypertension
Erythrocyte casts
Azotemia
Low C3, C4
Abnormal liver function test results
Low platelet count
Low leukocyte count
SLE
PE
+
+
+
+
+
+
+
+
+
+
+/+/-
Ccomplement; minus signabsent; plus signpresent; PEpreeclampsia;

SLEsystemic lupus erythematosus.
FIGURE 10-9
In the second or third trimester of pregnancy a clinical flare-up of
lupus may be difficult to distinguish from preeclampsia. Treatment
of a lupus flare-up might involve increased immunosuppression,
whereas the appropriate treatment of preeclampsia is delivery. Thus,
it is important to accurately distinguish these entities. Preeclampsia
is rare before 24 weeks gestation. Erythrocyte casts and hypocomplementemia are more likely to be a manifestation of lupus, whereas
abnormal liver function test results are seen in preeclampsia and not
usually in lupus.
10.7
Chronic Primary Renal Disease in Pregnancy

CAUSES OF CHRONIC PRIMARY
RENAL DISEASE IN PREGNANCY
FIGURE 10-10
Primary renal disease in pregnancy that is chronic (ie, preceded pregnancy) may result
from any of the causes of renal disease in premenopausal women. Overall, the outcome in
pregnancy is favorable when the serum creatinine level is less than 1.5 mg/dL and blood
pressure levels are normal in early pregnancy.
Anatomic, congenital
Glomerulonephritis
Polycystic kidney disease
Advanced Renal Disease Caused by

Polycystic Kidney Disease
POLYCYSTIC KIDNEY DISEASE
AND PREGNANCY
Increased incidence of urinary tract infection
Maternal hypertension associated with poor outcome
Extrarenal complications: subarachnoid hemorrhage,
liver cysts
FIGURE 10-11
Although advanced renal disease caused by polycystic kidney disease (PKD) usually develops after childbearing, women with this condition may have hypertension or mild
azotemia. Certain considerations are relevant to pregnancy. Pregnancy is associated with
an increased incidence of asymptomatic bacteriuria and urinary infection that may be
more severe in women with PKD. The presence of maternal hypertension has been shown
to be associated with adverse pregnancy outcomes [16]. Pregnancy has been reported to be
associated with increased size and number of liver cysts owing to estrogen stimulation.
Women with intracranial aneurysms may be at increased risk of subarachnoid hemorrhage
during labor.
Management of Chronic Renal Disease During Pregnancy

MANAGEMENT OF CHRONIC RENAL
DISEASE DURING PREGNANCY
Preconception counseling
Multidisciplinary approach
Frequent monitoring of blood pressure (every 12 wk) and renal function (every mo)
Balanced diet (moderate sodium, protein)
Maintain blood pressure at 120140/8090 mm Hg
Monitor for signs of preeclampsia
FIGURE 10-12
Management of chronic renal disease during pregnancy is best
accomplished with a multidisciplinary team of specialists.
Preconception counseling permits the explanation of risks involved
with pregnancy. Patients should understand the need for frequent
monitoring of blood pressure and renal function. Protein restriction
is not advisable during gestation. Salt intake should not be severely
restricted. When renal function is impaired, modest salt restriction
may help control blood pressure. Blood pressure should be maintained at a level at which the risk of maternal complications owing
to elevated blood pressure is low. Patients should be monitored
closely for signs of preeclampsia, particularly in the third trimester.
10.8
Renal Disease During Pregnancy

MOST COMMON CAUSES OF DE NOVO
RENAL DISEASE IN PREGNANCY
Glomerulonephritis
Lupus nephritis
Acute renal failure
FIGURE 10-13
Renal disease may develop de novo during pregnancy. The usual
causes are new-onset glomerulonephritis or interstitial nephritis,
lupus nephritis, or acute renal failure. Rarely, obstructive uropathy
develops as a result of stone disease or large myomas that have
increased in size during pregnancy.
Investigation of the Cause of Renal Disease During Pregnancy

RENAL EVALUATION
DURING PREGNANCY
Serology
Function
Ultrasonography
Biopsy: <32 wk
Deteriorating function
Morbid nephrotic syndrome
FIGURE 10-14
Investigation of the cause of renal disease during pregnancy can be conducted with serologic, functional, and ultrasonographic testing. Renal biopsy is rarely performed during gestation. Renal biopsy usually is reserved for situations in which renal function suddenly deteriorates without apparent cause or when symptomatic nephrotic syndrome occurs, particularly when azotemia is present. Almost no role exists for renal biopsy after gestational week
32 because at this stage the fetus will likely be delivered, independent of biopsy results [17].
New-Onset Azotemia, Proteinuria, and Hypertension

Occurring in the Second Half of Pregnancy
INTRINSIC RENAL DISEASE VERSUS PREECLAMPSIA
Serum creatinine
Urinary protein
Uric acid
Blood pressure
Liver function test results
Platelet count
Urine analysis
Renal disease
Preeclampsia
>1.0 mg/dL
Variable
Variable
Variable
Normal
Normal
Variable
0.81.2 mg/dL
>300 mg/d
>5.5 mg/dL
>140/90 mm Hg
May be increased
May be decreased
Protein, with or without
erythrocytes, leukocytes
FIGURE 10-15
New-onset azotemia, proteinuria, and hypertension occurring in
the second half of pregnancy should be distinguished from preeclampsia. Most cases of preeclampsia are associated with only
mild azotemia; significant azotemia is more suggestive of renal disease. Azotemia in the absence of proteinuria or hypertension would
be unusual in preeclampsia, and thus, would be more suggestive of
intrinsic renal disease. Thrombocytopenia, elevated liver function
test results, and significant anemia are not typical features of renal
disease (except for thrombotic microangiopathic syndromes) and
are features of the variant of preeclampsia known as the hemolysis,
elevated liver enzymes, and low platelet count (HELLP) syndrome.
10.9
Acute Tubular Necrosis and Pregnancy

ACUTE RENAL FAILURE
IN PREGNANCY
Acute tubular necrosis; hemodynamic factors, toxins,
serious infection, and so on
Acute interstitial nephritis
Acute fatty liver of pregnancy
Preeclampsia-HELLP syndrome
Microangiopathic syndromes
Acute cortical necrosis: obstetric hemorrhage
FIGURE 10-16
Most pregnant women with acute renal failure have acute tubular necrosis secondary to
either hemodynamic factors, toxins, or serious infection. Occasionally, glomerulonephritis
or obstructive nephropathy may be seen. Acute cortical necrosis may complicate severe
obstetric hemorrhage. Acute renal failure may be a complication of the rare syndrome of
acute fatty liver of pregnancy, a disorder that occurs late in gestation characterized by
jaundice and severe hepatic dysfunction. This syndrome has features that overlap with the
hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome variant of
preeclampsia as well as microangiopathic syndromes (eg, hemolytic uremic syndrome and
thrombotic thrombocytopenic purpura).
HELLPhemolysis, elevated liver enzymes, and low

platelet count.
HELLP Syndrome, AFLP, TTP, and HUS

DIFFERENTIAL DIAGNOSIS OF MICROANGIOPATHIC
SYNDROMES DURING PREGNANCY
Hypertension
Renal insufficiency
Fever, neurologic
symptoms
Onset
Platelet count
Liver function test
results
Partial thromboplastin
time
Antithrombin III
HELLP
AFLP
TTP
HUS
80%
Mild to moderate
0
2550%
Moderate
0
Occasional
Mild to moderate
++
Present
Severe
0
3rd trimester
Low to very low
High to very high
Any time
Low to very low
Usually normal
Postpartum
Low to very low
Usually normal
Normal to high
3rd trimester
Low to very low
High to extremely
high
High
Normal
Normal
Low
Low
Normal
Normal
AFLPacute fatty liver of pregnancy; HELLPhemolysis, elevated liver enzymes, and low platelet count;
HUShemolytic uremic syndrome; TTPthrombotic thrombocytopenic purpura.
Adapted from Saltiel et al. [18].
FIGURE 10-17
Hemolysis, elevated liver enzymes, and low
platelet count (HELLP) syndrome; acute
fatty liver of pregnancy (AFLP); thrombotic
thrombocytopenic purpura (TTP); and
hemolytic uremic syndrome (HUS) have similar clinical and laboratory features [18,19].
The subtle differences are summarized.
(Adapted from Saltiel and coworkers [18].)
10.10
Fertility in Women in End-Stage Renal Disease

DIALYSIS AND PREGNANCY
Successful outcome, 2030%
High incidence of prematurity
Outcome related to residual maternal renal function
Management:
Increased hours on dialysis
Erythropoietin therapy
Blood pressure control
Therapy with low doses of heparin
Continuous ambulatory peritoneal dialysis versus
hemodialysis ?
FIGURE 10-18
Because fertility is decreased in end-stage renal disease, pregnancy is uncommon in women
on chronic dialysis. When pregnancies occur, however, only about 20% to 30% are successful, with the chances of success increasing when residual renal function exists [20]. The
overall strategy should be to maintain blood chemistry levels as close as possible to normal
by increasing the number of hours of dialysis to 20 or more. Erythropoietin may be used
in pregnancy. Blood pressure control is important, and low doses of heparin should be
used to prevent bleeding. There are no apparent advantages of chronic ambulatory peritoneal dialysis compared with hemodialysis. The incidence of worsening maternal hypertension and subsequent premature delivery is high.
Fertility and Renal Transplantation

FIGURE 10-19
Fertility is restored after successful renal transplantation.
Pregnancy outcome is improved if renal function is normal and
hypertension is absent. It is advisable to wait 2 years after transplantation before pregnancy so that renal function is stable and
doses of immunosuppressants are lowest [21]. Cyclosporine, prednisone, and azathioprine are safe during pregnancy and are not
associated with fetal abnormalities. Limited experience exists with
mycophenolate mofetil during pregnancy.
RENAL TRANSPLANTATION AND PREGNANCY

Prognosis depends on blood pressure and baseline renal function
(<1.52 mg/dL; normal blood pressure)
Controversy over whether pregnancy accelerates graft loss
Patients are advised to wait 2 y after transplantation before pregnancy
Hypertensive Disorders in Pregnancy

Developing nations
Developed nations
Sepsis
8%
Hemorrhage
20%
Sepsis
40%
HTN
15%
Other
25%
100800/100,000
(deaths, births)
Embolism
20%
Abortion
17%
Other
25%
HTN
17%
Hemorrhage
13%
12/100,000
(deaths, births)
FIGURE 10-20
Mortality and hypertension. Worldwide, hypertensive disorders are a
major cause of maternal mortality, accounting for almost 20% of maternal deaths. Most deaths occur in women with eclampsia and severe
hypertension (HTN) and are due to intracerebral hemorrhage [22].
FETAL CONSEQUENCES OF
MATERNAL HYPERTENSION
DURING PREGNANCY
CLASSIFICATION OF
HYPERTENSIVE DISORDERS
IN PREGNANCY
3- to 6-fold increase in stillbirths

5- to 15-fold increase in intrauterine growth restriction
Premature delivery
Long-term developmental and neurologic problems
Preeclampsia, eclampsia
Chronic hypertension
Chronic hypertension with superimposed preeclampsia
Transient hypertension
FIGURE 10-21
Hypertensive disorders in pregnancy are
associated with increased incidences of stillbirth, fetal growth restriction, premature
delivery, and long-term developmental problems secondary to prematurity. These complications are more frequent when hypertension is due to preeclampsia.
FIGURE 10-22
Several classification systems exist for hypertensive disorders of pregnancy. The one used
most commonly in the United States is that
proposed in 1972 by the American College
of Obstetricians and Gynecologists and
endorsed by the National High Blood
Pressure Education Program. The distinction
is made between the pregnancy-specific
hypertensive disorder (preeclampsia, and the
convulsive form, eclampsia) and chronic
hypertension that precedes pregnancy, which
usually is due to essential hypertension.
Women with chronic hypertension are at
greater risk for preeclampsia (2025%).
Transient hypertension refers to late pregnancy elevations in blood pressure, without
any of the laboratory or clinical features of
preeclampsia. This disorder may recur with
each pregnancy (in contrast to preeclampsia,
which usually is a disease of first pregnancy)
and usually indicates a genetic predisposition
to essential hypertension.
CLINICAL FEATURES OF CHRONIC

HYPERTENSION IN PREGNANCY
Women are older, more likely to be multiparous
Hypertension: present before 20 wk, or documented previous pregnancy
Blood pressure may be significantly lower or normal in mid pregnancy
Risk of superimposed preeclampsia of 1530%
10.11
CLINICAL FEATURES
OF PREECLAMPSIA
Historical:
Nulliparity
Multiple gestations
Family history
Preexisting renal or vascular decrease
Hypertension:
140/90 mm Hg after 20 wk or
30 mm Hg increase in systolic pressure or
15 mm Hg increase in diastolic pressure
Sudden appearance of edema,
especially in hands and face
Rapid weight gain
Headache, visual disturbances,
abdominal or chest pain
FIGURE 10-23
The diagnosis of preeclampsia is strengthened when one or more of the risk factors
are present. Hypertension develops after 20
weeks, with normal blood pressures in the
first half of pregnancy. Although edema is a
feature of many normal pregnancies, its
sudden appearance in the face and hands in
association with a rapid weight gain, is suggestive of preeclampsia. Headache, visual
disturbances, and abdominal or chest pain
are signs of impending eclampsia.
FIGURE 10-24
Women with chronic hypertension are usually older and may be
multiparous. Although hypertension often is detectable before
20 weeks, in some women the pregnancy-mediated vasodilation
is sufficient to normalize blood pressure so that women with
stage 1 or 2 hypertension may have normal blood pressures by
the time of their first antepartum visit. The risk of preeclampsia
is substantially increased in women with chronic hypertension.
10.12
LABORATORY ABNORMALITIES IN PREECLAMPSIA

AND CHRONIC HYPERTENSION
Renal:
Creatinine
Uric acid
Urinary protein
Urinary calcium
Heme:
Hematocrit
Platelets
Liver function tests:
Alanine aminotransferase
Albumin
Chronic hypertension
Preeclampsia
Normal
Normal
<300 mg/d
>200 mg/d
Increased; increased
blood urea nitrogen,
creatinine
Increased (>5.5 mg/dL)
>300 mg/d
<150 mg/d
Normal
Normal
Increased (>38%)
Decreased
Normal
Normal
Normal
Increased
Increased
Decreased
Pathophysiology of preeclampsia
Fetal
syndrome
(IUGR, IUD, prematurity)
Maternal
syndrome
(HTN, renal, CNS)
Maternal disease
Vasoplasm
Intravascular coagulation
Endothelial dysfunction
Placental disease
Abdominal implantation
Placental vascular lesions
Genetic susceptibility
(maternal x fetal)
FIGURE 10-25
Laboratory tests are helpful in making the diagnosis of preeclampsia.
In addition to proteinuria, which may occur late in the course of the
disease, hyperuricemia, mild azotemia, hemoconcentration, and hypocalciuria are observed commonly. Some women with preeclampsia
may develop a microangiopathic syndrome with hemolysis, elevated
liver enzymes, and low platelet counts (HELLP). The presence of the
HELLP syndrome usually reflects severe disease and is considered an
indication for delivery. Women with uncomplicated chronic hypertension have normal laboratory test results unless superimposed
preeclampsia or underlying renal disease exists.
FIGURE 10-26
Preeclampsia is a syndrome with both maternal and fetal manifestations. Current evidence suggests that an underlying genetic predisposition leads to abnormalities in placental adaptation to the
maternal spiral arteries that supply blood to the developing fetoplacental unit. These abnormalities in the maternal spiral arteries
lead to inadequate perfusion of the placenta and may be the earliest changes responsible for the maternal disease. The maternal disease is characterized by widespread vascular endothelial cell dysfunction, resulting in vasospasm and intravascular coagulation and,
ultimately, in hypertension (HTN), renal, hepatic, and central nervous system (CNS) abnormalities. The fetal syndrome is a consequence of inadequate placental circulation and is characterized by
growth restriction and, rarely, demise. Premature delivery may
occur in an attempt to ameliorate the maternal condition. IUD
intrauterine death; IUGRintrauterine growth retardation.
10.13
FIGURE 10-27
A positive family history is a risk factor for preeclampsia, and the incidence is approximately 4 times greater in first-degree relatives of index cases [23]. Cooper and coworkers
[24] also noted an increased incidence in relatives by marriage (eg, daughter-in-laws), and
10 instances in which the disease occurred in one but not the other monozygotic twin.
These data raise the possibility of paternal or fetal genetic influence [24]. The mode of
inheritance of preeclampsia is not known. Several possibilities have been suggested, including a recessive gene with the possibility of a maternal-fetal genotype-by-genotype interaction or a dominant maternal gene with incomplete penetrance.
GENETICS OF PREECLAMPSIA
Increased incidence observed in mothers, daughters,
granddaughters of probands
Mode of inheritance unknown:
Single recessive gene ?
Shared maternal-fetal recessive gene ?
Dominant gene with incomplete penetrance ?
Normal pregnancy
Preeclampsia
Fetus
(placenta)
B
Myometrium
Spiral arteries
Cytotrophoblast
stem cells
Decidua
Mother
(uterus)
Cell column of
anchoring villus
AV Fetal
Uterine
blood
vessels
stroma
Basement
membrane
Syncytiotrophoblast
FV
Maternal
blood
space
Invasion
Zone I
Zone II and III
Zone IV
Zone V
A
Umbilical artery
Villus
(containing fetal
arteriole and venule)
Intervillus space
(maternal blood)
Umbilical vein
FIGURE 10-28
Uteroplacental circulation in normal pregnancy and preeclampsia.
A, Normal placentation involves the transformation of the branches
of the maternal uterine arteriesthe spiral arteriesfrom thickwalled muscular arteries into saclike flaccid vessels that permit
delivery of greater volumes of blood to the uteroplacental unit.
B, Evidence exits that in women with preeclampsia this process is
incomplete, resulting in relatively narrowed spiral arteries and
decreased perfusion of the placenta [25].
FIGURE 10-29
Transformation of the spiral arteries. A, The process by which the
maternal spiral arteries are transformed into dilated vessels in pregnancy is believed to involve invasion of the spiral arterial walls by
endovascular trophoblastic cells. These cells migrate in retrograde
fashion, involving first the decidual and then the myometrial segments of the arteries and then causing considerable disruption at
all layers of the vessel wall. The mechanisms involved in this complex process are only beginning to be elucidated. These mechanisms involve alterations in the adhesion molecules of the invading
trophoblast cells, such that they acquire an invasive phenotype and
mimic vascular endothelial cells [26].
10.14
(b)
CTBs
(a)
Endothelium
Tunica
media
Fully modified
region
Partially modified
region
Decidua
(c)
Unmodified
region
Myometrium
Placental
ischemia
Lipid peroxides
Cytokines
Endothelial cell damage
Platelet aggregation
Thromboxane A2
Serotonin, PDGF
PGI2
NO
Endothelin
Mitogenic factors
(eg, PDGF)
Systemic
vasoplasm
Organ flow
Intravascular
coagulation
Thrombin

B, In women destined to develop preeclampsia, trophoblastic invasion of the spiral arteries is incomplete; it may occur in the decidual but not the myometrial segments of the artery, and in some vessels the process does not occur at all. The arteries, therefore,
remain thick-walled and muscular, the diameters in the myometrial
segments being half those measured during normal pregnancy.
Recently, it has been reported that in preeclampsia the invading
cytotrophoblasts fail to properly express adhesion receptors necessary for normal remodeling of the maternal spiral arteries [27].
This failure of cytotrophoblast invasion of the spiral arteries is considered to be the morphologic basis for decreased placental perfusion in preeclampsia. (a)fully modified regions. (b)partially
modified vessel segments. (c)unmodified vessel segments in the
myometrium. AVanchoring villus; CTBscytotrophoblast cells;
FVfloating villi. (From Zhou and coworkers [27]; with permission.)
FIGURE 10-30
Pathophysiology of preeclampsia. A major unresolved issue in the
pathophysiology of preeclampsia is the mechanism whereby abnormalities in placental modulation of the maternal circulation lead to
maternal systemic disease. The current schema, which is a hypothesis, depicts a scenario whereby placental ischemia leads to the
release of substances that might be toxic to maternal endothelial
cells. The resulting endothelial cell dysfunction also results in
increased platelet aggregation. These events lead to the widespread
systemic vasospasm, intravascular coagulation and decreased organ
flow that are characteristic of preeclampsia. NOnitric oxide;
PDGFplatelet-derived growth factor; PGI2prostacyclin 2.
10.15
Central nervous sytem
Visual disturbances
Seizures
Hyperemia, focal anemia
Thrombosis, hemorrhage
Cardiac
Cardiac output
Plasma volume
Atrial natriuretic factor
Pulmonary edema
Hepatic
Periportal hemorrhagic necrosis
Subcapsular hematoma
Alanine aminotransferase
Vasospasm
Reduced flow
Intravascular coagulation
Vascular
Blood pressure
Angiotensin II sensitivity
Renal
Endotheliosis
Proteinuria
Renal blood flow
Urinary sodium, uric acid,
and calcium excretion
Plasma renin activity
FIGURE 10-31
Maternal manifestations of preeclampsia. Preeclampsia is a multisystem maternal disorder, with dramatic alterations in
heart, kidney, circulation, liver, and brain. Interestingly, all of these abnormalities resolve within a few weeks of delivery.
10.16
Placental hormones
(eg, estrogen, progesterone)
The endothelium
and platelet-vessel
wall interaction
Endothelial
cells
Thr
Platelets
PThr
cGMP
TXA2
5-HT
Circulating endothelial toxins
S
NO/PGl2 1
Relaxation
Antiproliferation
Sympathetic nervous system

Vascular smooth
muscle cells
cGMP/cAMP
AII
5-HT
Compensatory
responses:
Plasma renin
Aldosterone
Endothelin
Contraction
Proliferation
S2
TX ET
FIGURE 10-32
Hypertension in preeclampsia. Although the mechanism of the increased blood pressure in preeclampsia is
not established, evidence suggests it may involve multiple processes. A possible scenario involves the following:
decreased placental production of estrogen and progesterone, both of which have hemodynamic effects;
increased circulating endothelial toxins, possibly released from a poorly perfused placenta; and increased
activity of the sympathetic nervous system. These processes may then result in alterations in platelet vascular
endothelial cell function, with decrease in vasodilators such as nitric oxide and prostacyclin and increased production
of vasoconstrictors
such as endothelin (ET).
Compensatory suppression of the reninangiotensin system
occurs, suggesting that
excess angiotensin II
(AII) does not play a
major role in preeclamptic
hypertension (HT).
Finally, sodium retention
owing to renal vasoconstriction may further
increase blood pressure.
cAMPcyclic adenosine
monophosphate; cGMP
cyclic guanosine
monophosphate; 5-HT
serotonin; PThr
parathyroid hormone;
S2serotonergic receptors;
Thrthombin TX
thromboxane; TXA2
thromboxane A2.
(Adapted from Lscher
and Dubey [28];
with permission.)
Renin
Proteinuria
Renal vasodilation
Renal blood flow
FIGURE 10-33
Light microscopy of the renal lesion of preeclampsia: glomerular
endotheliosis. On light microscopy, the glomeruli from preeclamptic women are characterized by swelling of the endothelial and
mesangial cells. This swelling results in obliteration of the capillary
lumina, giving the appearance of a bloodless glomerulus. On occasion, the mesangium, severely affected, may expand. Thrombosis
and fibrinlike material and foam cells may be present, and epithelial crescents have been described in rare instances [2].
Urinary calcium
Hypocalciuria
Urate excretion
FIGURE 10-34
Functional renal alterations in preeclampsia. The functional consequences of glomerular endotheliosis and of the hormonal alterations in preeclampsia are summarized in this schematic diagram
of the nephron in preeclampsia. Suppression of the reninangiotensin system occurs, probably in response to vasoconstriction and elevated blood pressure. The glomerular lesion leads to
proteinuria, which may be heavy. Renal hemodynamic changes
include modest decreases in the glomerular filtration rate (GFR)
and renal blood flow (RBF). Decreased sodium and uric acid excretion may be caused by increased proximal tubular reabsorption.
The mechanism for the marked hypocalciuria is not known.
Control Odds ratio and 95% Cl (horizontal line)

therapy
(antiplatelet: placebo)
Trial
Number of trials
Antiplatelet
therapy
Smaller studies
(<200 women)
11
10/319
(3.1%)
50/284
(17.6%)
5/156
5/303
12/565
69/1570
9/103)
313/4659
8/74
17/303
9/477
94/1565
11/105)
352/4650
Larger studies:
EPHREDA (1990)
Hauth (1993)
Italian (1993)
Sibai (1993)
Viinikka (1993)
CLASP (1994)
All larger trials
413/7356
491/7174
All trials
17
423/7675
(5.5%)
541/7458
(7.3%)
Odds ratio
Overall results
25% SD 6
odds reduction
(2p = 0.00002)
0 0.5 1.0 1.5

Antiplatelet
therapy
better
Favors calcium
Study
Marya et al.,1987
Villar et al.,1987
Lopez-Jaramillo et al.,1989
Lopez-Jaramillo et al.,1990
Montanaro et al.,1990
Villar and Repke,1990
Belizan et al.,1991
Cong et al.,1993
Sanchez-Ramos et al.,1994
Pooled estimate
0.001
Antiplatelet
therapy
worse
Favors control
0.65 (0.311.38)
0.43 (0.063.14)
0.03 (0.0020.49)
0.07 (0.0041.27)
0.25 (0.061.03)
0.13 (0.0072.65)
0.66 (0.341.27)
0.19 (0.0094.10)
0.22 (0.070.74)
0.38 (0.220.65)
0.01
0.1
OR
1.0
10.0
10.17
FIGURE 10-35
Prevention of preeclampsia with low-dose
aspirin. Investigators have sought methods
to prevent preeclampsia (eg, salt restriction,
prophylactic diuretics, and high-protein
diets). One approach that has been extensively investigated in the last 10 years is
therapy with low-dose aspirin. It was
hypothesized that such therapy reversed the
imbalance between prostacyclin and thromboxane that may be responsible for some of
the manifestations of the disease. Several
large trials now have been completed, and
most have had negative results. Shown here
is an overview of the effects of aspirin on
proteinuric preeclampsia reported from all
trials of antiplatelet therapy (through 1994)
as analyzed by the Collaborative Low-dose
Aspirin in Pregnancy (CLASP) Collaborative
Group [28]. Odds ratios (area proportional
to amount of information contributed) and
99% confidence interval (CI) are plotted for
various trials. A black square to the left of
the solid vertical line suggests a benefit (however, this indication is significant at 2p >0.01
only if the entire CI is to the left of solid vertical line). (From CLASP Collaborative
Group [29]; with permission.)
FIGURE 10-36
Prevention of preeclampsia using calcium
supplementation. Another preventive strategy
that has been extensively investigated, with
conflicting outcomes, is calcium supplementation. The rationale for this approach is
based on the observations that low dietary
calcium intake may increase the risk for
preeclampsia, and that preeclampsia is characterized by abnormalities in calcium metabolism
that suggest a calcium deficit, eg, decreased
vitamin D and hypocalciuria [31]. A recent
meta-analysis of 14 trials of calcium supplementation in pregnancy concluded that calcium supplementation during pregnancy leads
to reductions in blood pressure and a lower
incidence of preeclampsia. In contrast, a
large randomized trial of calcium supplementation in 4589 low-risk women failed to
demonstrate a benefit of calcium therapy
[31]. CIconfidence interval; ORodds
ratio. (From Bucher and coworkers [30];
with permission.)
10.18
TREATMENT OF PREECLAMPSIA
Close monitoring of maternal and fetal conditions
Hospitalization in most cases
Lower blood pressure for maternal safety
Seizure prophylaxis with magnesium sulfate
Timely delivery
ANTIHYPERTENSIVE THERAPY
IN PREECLAMPSIA
Decreased uteroplacental blood flow and placental
ischemia are central to the pathogenesis of
preeclampsia.
Lowering blood pressure does not prevent or cure
preeclampsia and does not benefit the fetus unless
delivery can be safely postponed.
Lowering blood pressure is appropriate for maternal safety:
maintain blood pressure at 130150/85100 mm Hg.
FIGURE 10-37
Treatment of preeclampsia requires close monitoring of both the maternal and fetal condition to maximize chances of avoiding catastrophes such as seizures, renal failure, and fetal
demise. Close surveillance is best accomplished in the hospital in all but the mildest cases.
Maternal hypertension should be treated to avoid cerebrovascular and cardiovascular
complications. Magnesium sulfate is the treatment of choice for seizure prophylaxis and
usually is instituted immediately after delivery. When the fetus is mature, delivery is indicated in all cases. When the fetus is immature, the decision to deliver is made after carefully assessing both the maternal and fetal condition. When maternal health is in jeopardy,
delivery is necessary, even with a premature fetus.
FIGURE 10-38
Some controversy exists regarding when to institute antihypertensive therapy in women
with preeclampsia. The basis for this controversy is that decreased uteroplacental perfusion
is believed to be important in the pathophysiology of this disorder, and concern exists that
lowering maternal blood pressure may compromise uteroplacental blood flow and lead to
fetal distress. Furthermore, lowering maternal blood pressure does not cure preeclampsia.
Thus, antihypertensive therapy is instituted when the blood pressure reaches a level at
which the physician considers the maternal condition to be in danger from hypertension.
For most physicians, this treatment threshold is at approximately 150/100 mm Hg.
Aggressive lowering of blood pressure is not advisable.
ANTIHYPERTENSIVE THERAPY IN PREECLAMPSIA

Imminent delivery
Delivery postponed
Hydralazine (intravenous, intramuscular)

Labetalol (intravenous)
Calcium channel blockers
Diazoxide (intravenous)
Methyldopa
Labetalol, other blockers
Hydralazine
blockers
Clonidine
FIGURE 10-39
When blood pressure increases acutely and delivery is likely within
the next 24 hours, use of a parenteral antihypertensive agent is
preferable. Intravenous hydralazine or labetalol are acceptable
agents for pregnant women, and both have been used successfully
in preeclampsia. Calcium channel blockers should be used with
caution because they may act synergistically with magnesium sulfate, resulting in precipitous decreases in blood pressure. Rarely,
agents such as diazoxide may be needed; however, when hypertension is severe, maternal safety takes priority over pregnancy status.
When delivery can be postponed safely for several days, an oral
agent is indicated. Methyldopa is one of the safest drugs in pregnancy and has been used extensively with excellent maternal and
fetal outcome. Labetalol and other blockers have been used successfully in preeclampsia. Calcium channel blockers also may be
used as either second- or third-line agents. Oral hydralazine is safe
in pregnancy. Limited experience exists with blockers or clonidine, although anecdotal reports suggest these agents are safe.
10.19

Treatment alogrithm for chronic hypertension
Systolic
Preconception
140
Screen for secondary hypertension (pheo, renovascular hypertension)

Counseling: Increased risk of preeclampsia (25%)
Lifestyle adjustments: increase rest, decrease exercise
Adjust medications: discontinue ACE inhibitors
130
120
110
Diastolic
150
100
First trimester
90
Diastolic BP, mm Hg
90100
<90
80
Consider careful
decrease in
BP medication
70
60
Prepregnancy
10
20
28
32
38
100
Adjust medications:
Increase medication
Stop ACE and
angiotensin II blockers
Decrease diuretic dose
Baseline evaluation for secondary hypertension if clinically suspected
Gestation, wk
FIGURE 10-40
Blood pressure changes during pregnancy in women with chronic
hypertension. Women with preexisting or chronic hypertension
during pregnancy have a favorable prognosis, unless preeclampsia
develops. The risk of superimposed preeclampsia is about 25%.
Women with this complication are at greater risk for fetal complications during pregnancy, including premature delivery, growth
restriction, and perinatal mortality.
Women with chronic hypertension experience a decrease in blood
pressure during pregnancy that may permit withdrawal of some or
all antihypertensive medication. In those women with uncomplicated chronic hypertension (solid line), blood pressure decreases in the
first trimester, then may decrease even further in the second trimester.
An increase in both systolic and diastolic blood pressure may occur
during the third trimester to levels at prepregnancy or early first
trimester. In those women who develop superimposed preeclampsia
(broken lines), blood pressure often decreases in the first trimester.
There is often a failure to decrease further in the second trimester,
however, and blood pressures may actually begin to increase slightly.
Blood pressure then increases significantly when preeclampsia
develops [33].
ANTIHYPERTENSIVE THERAPY
FOR CHRONIC HYPERTENSION
DURING PREGNANCY
Methyldopa
blockers (labetalol)
Hydralazine
Diuretics
Second trimester
Nonpharmacologic treatment
Home BP monitoring
Adequate rest
Diastolic BP, mm Hg
90100
<90
Consider careful
decrease in
BP medication
Continue treatment
100
Indicates significant
hypertension:
consider stopping work;
close surveillance
for preeclampsia
Third trimester
Increased surveillance for preeclampsia
Check BP every 2 weeks
FIGURE 10-41
Treatment algorithm for chronic hypertension. Ideally, patients
with chronic hypertension should be evaluated before pregnancy so
that secondary hypertension can be diagnosed and treated appropriately. Women can be counseled regarding the need for possible
life-style adjustments, and medications can be adjusted. Blood pressure (BP) medications may require adjustment, depending on the
magnitude of the pregnancy-related changes in blood pressure. In
the latter half of pregnancy, close surveillance for early signs of
preeclampsia increases the likelihood the condition will be diagnosed before it progresses to a severe stage.
FIGURE 10-42
The overall treatment goals of chronic hypertension in pregnancy are to ensure a successful full-term delivery of a healthy infant without jeopardizing maternal well-being. The
level of blood pressure control that is tolerated in pregnancy may be higher, because the
risk of exposure of the fetus to additional antihypertensive agents might outweigh the benefits to the mother (for the duration of pregnancy) of having a normal blood pressure.
Most antihypertensive agents have been evaluated only sporadically during gestation, and
careful follow-up of children exposed in utero to many of the agents is lacking. The only
antihypertensive agent for which such follow-up exists is methyldopa. Because no adverse
effects have been documented in offspring of exposed mothers, methyldopa is considered
to be one of the safest drugs during pregnancy. blockers and calcium channel blockers
are acceptable second- and third-line agents. Diuretics can be used at low doses, particularly in salt-sensitive hypertensive patients on chronic diuretic therapy. Angiotensin-converting enzyme inhibitors are contraindicated in pregnancy because they adversely affect
fetal renal function. Angiotensin II receptor antagonists are presumed to have similar
effects but have not been evaluated in human pregnancy.
10.20
References
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models. Clin Obstet Gynaecol 1987, 1:789.
2. Lindheimer MD, Katz AI: The kidney and hypertension in pregnancy.
In The Kidney, edn 4. Edited by Brenner BM, Rector FC. Philadelphia:
WB Saunders Co; 1991:15511595.
3. Davison JM, Shiells EA, Philips PR, Lindheimer MD: Serial evaluation
of vasopressin release and thirst in human pregnancy: role of chorionic
gonadotropin in the osmoregulatory changes of gestation. J Clin
Invest 1988, 81:798.
4. Lindheimer MD, Richardson DA, Ehrlich EN, Katz AI: Potassium
homeostasis in pregnancy. J Reprod Med 1987, 32:517.
5. Brown MA, Sinosich MJ, Saunders DM, Gallery EDM: Potassium
regulation and progesterone-aldosterone interrelationships in human
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6. Lim VS, Katz AI, Lindheimer MD: Acid-base regulation in pregnancy.
Am J Physiol 1976, 231:1764.
7. Wilson M, Morganti AA, Zervoudakis I, et al.: Blood pressure, the reninaldosterone system and sex steroids throughout normal pregnancy. Am J
Med 1980, 68:97.
8. August P, Mueller FB, Sealey JE, Edersheim TG: Role of reninangiotensin system in blood pressure regulation in pregnancy.
Lancet 1995, 345:896897.
9. Diabetic nephropathy. Pregnancy performance and fetal-maternal
outcome. Am J Obstet Gynecol 1988, 159:56.
10. Hayslett JP, Lynn RI: Effect of pregnancy in patients with lupus
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11. Houser MT, Fish AJ, Tagatz GE, et al.: Pregnancy and systemic lupus
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12. Fine LG, Barnett EV, Danovitch GM, et al.: Systemic lupus erythematosus
in pregnancy. Ann Intern Med 1981, 94:667.
13. Imbasciati E, Surian M, Bottino S, et al: Lupus nephropathy and
pregnancy. A study of 26 pregnancies in patients with systemic
lupus erythematosus and nephritis. Nephron 1984, 36:46.
14. Jungers P, Dougodos M, Pelissier C, et al.: Lupus nephropathy and
pregnancy. Report of 104 cases in 36 patients. Arch Intern Med 1982,
142:771.
15. Lockshin MD, Druzin MC, Goel S, et al.: Antibody to cardiolipin as a
predictor of fetal distress on death in pregnant patients with systemic
lupus erythematosus. N Engl J Med 1985, 313:152.
16. Chapman AB, Johnson AM, Gabow PA: Pregnancy outcome and its
relationship to progression of renal failure in autosomal dominant
polycystic kidney disease. J Am Soc Nephrol 1994, 5:11781185.
17: Lindheimer MD, Davison JM. Renal biopsy during pregnancy:
To b... or not to b... Br J Obstet Gynecol 1987, 94:932.
18. Saltiel C, Legendre, Grunfeld JP, et al.: Hemolytic uremic syndrome in
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Thrombotic Thrombocytopenic Purpura. Edited by Kaplan BS,
Trompeter RS, Moake JL. New York: Marcel Dekker; 1992:241254.
19. Sibai BM, Kustermann L, Velasco J: Current understanding of severe

preeclampsia, pregnancy-associated hemolytic uremic syndrome,
thrombotic thrombocytopenic purpura, hemolysis, elevated liver
enzymes, and low platelet syndrome, and postpartum acute renal
failure: different clinical syndromes or just different names? Curr
Opinion Nephrol Hypertens 1994, 3:436445.
20. Hou S: Peritoneal dialysis and hemodialysis in pregnancy. Clin Obstet
Gynaecol (Balliere) 1994, 8:491510.
21. Davison JM: Pregnancy in renal allograft recipients: problems, prognosis,
and practicalities. Clinc Obstet Gynaecol (Balliere) 1994, 8:511535.
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vascular response to placentation in pregnancies complicated by
preeclampsia and small for gestational age infants. Br J Obstet
Gynaecol 1986, 93:10491059.
26. Zhou Y, Fisher SJ, Janatpour M: Human cytotrophoblasts adopt a
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27. Zhou Y, Damsky CH, Fisher SJ: Preeclampsia is associated with failure
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development of superimposed preeclampsia. Am J Obstet Gynecol
1990, 163:16121621.
Collagen Vascular Diseases
and Dysproteinemias
Jo H.M. Berden
Karel J.M. Assmann
enal involvement in systemic lupus erythematosus (SLE), dysproteinemias, and certain rheumatic diseases, namely rheumatoid arthritis, Sjgrens syndrome, and scleroderma (systemic
sclerosis), is discussed. SLE is a systemic autoimmune disease that can
lead to disease manifestations in almost every organ. SLE is characterized by the formation of a wide array of autoantibodies mainly
directed against nuclear autoantigens, of which antibodies against
double-stranded DNA (dsDNA) are the most prominent. Although
the cause is still obscure, considerable progress has been made recently by identification of the nucleosome as the major driving autoantigen in SLE and the possible role of disturbances in apoptosis in disease development. The section on SLE reviews the major clinical and
serologic features of the disease, the serologic analysis, new insights
into the pathophysiology of lupus nephritis, and the histologic assessment of kidney biopsies. The therapeutic options for treatment of
lupus nephritis are discussed as are the results of treatment of endstage renal disease in patients with SLE.
The second part of this chapter deals with the renal involvement in
dysproteinemias. The renal lesions of these diseases, characterized by
an overproduction of abnormal immunoglobulins or their subunits,
are quite heterogeneous. Because the kidney often is affected in these
disorders, it is not unusual for examination of a kidney biopsy specimen to reveal clues for the diagnosis. On immunofluorescence, the
distribution of the light or heavy chain isotype, or both, can be detected in the tissue deposits, whereas electron microscopy can define the
ultrastructural organization. Incidence and types of renal involvement, the pathogenesis and risk factors for the various types of renal
lesions, the histology of the different renal manifestations, and an
CHAPTER
11
11.2
overview of the therapy are given. The renal manifestations of

cryoglobulinemias and fibrillary and immunotactoid glomerulonephritis also are discussed.
The third part of this chapter presents a concise review of

renal involvement in rheumatoid arthritis, Sjgrens syndrome,
and scleroderma.
Systemic Lupus Erythematosus

CUMULATIVE INCIDENCE OF CLINICAL SYMPTOMS
AND AUTOANTIBODY FORMATION IN SYSTEMIC
LUPUS ERYTHEMATOSUS
Percent
Frequency of major clinical symptoms
Musculoarticular symptoms
Cutaneous manifestations
Renal involvement
Neuropsychiatric disease
Pulmonary and cardiac disease
Hematologic abnormalities
Occurrence of major autoantibody specificities
Antinuclear autoantibody
Antidouble-stranded DNA
Antihistone
Antinucleosome
Anti-Sm
Anti-ribonucleoprotein (RNP)
AntiSjgrens syndrome (SS-A) (Ro)
Anti-SS-B (La)
Anticardiolipin
Antierythrocyte
Antilymphocyte
Antithrombocyte
6095
5580
4055
3060
2040
6085
95
6075
5070
Up to 80
1030
1030
2060
1540
1030
5060
5070
1030
FIGURE 11-1
This overview of the major clinical symptoms illustrates the systemic
character of lupus erythematosus. Depending on patient selection,
renal involvement occurs in up to half of patients. In almost all
patients, antibodies are formed against nuclear antigens, as detected
by antinuclear antibody (ANA) testing. These ANAs are either directed
against nucleic acids (DNA), nuclear proteins (histones, Sm, ribonucleoprotein, Sjgrens syndrome-A [SS-A], and SS-B) or nucleosomes
that consist of DNA and the DNA binding proteins histones. In
addition, antibodies can be formed against the anionic phospholipid
cardiolipin. This latter antibody specificity is characteristic for the
antiphospholipid syndrome either primary or secondary to systemic
lupus erythematosus. All these antigens recognized by lupus autoantibodies share the property that they are present in apoptotic blebs at
the surface of cells undergoing apoptosis. In addition to these ANAs,
autoantibodies against blood cells frequently develop in lupus, giving
rise to hemolytic anemia positive on Coombs testing, lymphopenia,
or thrombopenia.
EPIDEMIOLOGIC AND GENETIC CHARACTERISTICS

OF SYSTEMIC LUPUS ERYTHEMATOSUS
Epidemiology
Genetics
Prevalence: between 25 and 250 per 100,000

persons, depending on racial and geographic
background
Race: more prevalent in Asians and blacks
Gender: female preponderance; gender ratio
between 20 and 40 years; male:female, 1:9
Age: onset mainly between 2040 y
Concordancy in twins
Monozygotic: 5060%
Dizygotic: 510%
Familial aggregation in 10%
Association with the following:
HLA: B7, B8, DR2, DR3, DQW1
Complement:
C4A Q0
C1q or C4 deficiency
Fc receptor IIA low-affinity
phenotype
X chromosome ?
FIGURE 11-2
The major epidemiologic characteristics of systemic lupus erythematosus are listed. The prevalence of the disease depends on ethnic
background. The highest prevalence is seen in Asians and Blacks.
As in other systemic autoimmune diseases, there is a striking preponderance in women, especially during childbearing age. This preponderance is related to hormonal status. Animal studies have shown
that estrogens have a facilitating effect on disease expression, whereas androgens have a suppressive effect. The importance of estrogens
is further substantiated by the fact that changes in the hormonal
homeostasis (eg, at onset of puberty, during use of oral anticontraceptives, and during pregnancy and puerperium) are associated with
an increased frequency of lupus onset and disease flare-up. The
genetic susceptibility is illustrated by the concordance of the disease
in twins, occurrence of familial aggregation, and association with
certain genes, mainly human leukocyte antigens (HLA).
11.3
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias
ANA test
THE 1982 REVISED AMERICAN RHEUMATISM

ASSOCIATION CRITERIA FOR CLASSIFICATION
OF SYSTEMIC LUPUS ERYTHEMATOSUS
Criterion
1. Malar rash
2. Discoid rash
3. Photosensitivity
4. Oral ulcers
5. Arthritis (two or more joints)
6. Serositis:
Pleuritis or pericarditis
7. Renal disorder:
Proteinuria > 0.5 g/24 h or cellular casts (red,
hemoglobin, granular, tubular, or mixed)
8. Neurologic disorder:
Seizures or psychosis
9. Hematologic disorder:
Hemolytic anemia or leukopenia (<4
109/L) or lymphopenia (<1.5 109/L)
or thrombopenia (<100 109/L)
10. Immunologic disorder:
Positive LE cell test result or positive
antidouble-stranded DNA or positive
anti-Sm or false-positive TPI/VDRL test
11. Antinuclear antibody
Sensitivity, %*
Specificity, %*
57
18
43
27
86
56
96
99
96
96
37
86
51
94
20
98
59
89
85
93
99
49
*The sensitivity was calculated as the percentage of patients with SLE who were positive
for this criterion over those in whom this criterion was analyzed. The specificity was
calculated as the percentage of the number of patients in the control group who were
negative or normal for that criterion over those in whom this criterion was analyzed.
TPItreponemal immobilization; VDRLVenereal Disease Research Laboratory.
Data from Tan et al. [1].
FIGURE 11-3
These criteria were selected for their sensitivity and specificity in
classifying patients with systemic lupus erythematosus (SLE). In the
selection process, these criteria were analyzed in 177 patients with
SLE and 162 patients in the control group matched for age, gender,
and race. Patients in the control group had a nontraumatic nondegenerative connective tissue disease, mainly rheumatoid arthritis (n = 95).
The presence of four of these criteria for the diagnosis of SLE has a
sensitivity of 96% and specificity of 96% in patients with SLE. For
the purpose of identifying patients in clinical studies, it is determined
that a patient has SLE when at least four of these criteria are present,
serially or simultaneously, during any interval of observation.
Negative
No further evaluation
unless strong clinical
suspicion
Positive
?
Western blot test
on nuclear extracts
Negative
Crithidia lucillae
?
anti-ENA
Positive
Ouchterlony
immunodiffusion
using ENAs
Farr assay
FIGURE 11-4
Algorithm for analysis of antinuclear antibodies (ANA) in systemic
lupus erythematosus. To demonstrate the presence of antinuclear
antibodies the ANA test is used as a screening procedure. Details
of this ANA test and the different ANA patterns are given in Figure
11-5. A positive ANA test result indicates the presence of antinuclear
antibodies. Although the pattern of ANA can give an indication
about the specificity of the antinuclear antibody, additional tests
are needed to define this specificity. Antibody specificity to doublestranded DNA (dsDNA) can be identified by the Crithidia assay
(Fig. 11-6), in which a single-celled organism is used that has purely dsDNA in the kinetoplast. When this test result is positive, the
titer of anti-dsDNA antibodies can be determined using the Farr
assay (Fig. 11-7). When these anti-dsDNA test results are negative,
ANA positivity is most likely caused by antibodies directed against
nuclear proteins. Autoantibodies can be analyzed by the Western
blot test on nuclear extracts (Fig. 11-8). The advantage of this
technique over the Ouchterlony technique using extractable nuclear
antigens (ENA), is that the Western blot test allows identification
of a large number of autoantibody specificities in one test, although
both tests do not completely overlap.
FIGURE 11-5
Patterns of antinuclear antibody (ANA)
staining. The ANA test is carried out by incubation of the serum with either preparations
of cultured cells (eg, human cervical carcinoma cells [HeLa cells]) or sections of normal
tissue (mostly liver). Antibodies bound to the
nucleus are detected by a fluorescinated anti
human immunoglobulin antibody that can
reveal four distinctive staining patterns:
A, homogeneous; B, rim or peripheral;
11.4
Nucleus
Mitochondrion
Kinetoplast
+ dsDNA
Anti-dsDNA
Crithidia luciliae
Fluorescent
labeled
antihuman
immunoglobulin

C, speckled; and D, nucleolar. Although not
conclusive, these patterns can give an indication about the autoantibody specificity causing the nuclear staining. The homogeneous
and peripheral patterns mainly are caused
by autoantibodies directed against the nucleosome (histoneDNA complex) or doublestranded DNA. The speckled pattern can
be observed in antibodies against the nuclear
proteins Sm, ribonucleoprotein, Sjgrens syndrome-A [SS-A] (Ro), SS-B (La), Jo-1, topoisomerase I, and anticentromere antibodies.
The nucleolar staining is associated with antibodies against nucleolus-specific RNA, as
seen in certain limited forms of scleroderma.
(From Maddison [2]; with permission.)
FIGURE 11-6
Screening for antidoubled-stranded DNA (dsDNA) antibodies
using the Crithidia assay. The hemoflagellate Crithidia luciliae contains in its kinetoplast pure dsDNA, not complexed to proteins [3].
Serially diluted serum samples are added to the slide carrying
Crithidia cells. Binding of antibodies is visualized by fluorescinated
antiimmunoglobulin G antibodies. Antibodies to dsDNA are
almost pathognomonic for systemic lupus erythematosus and therefore can be regarded as marker antibodies [4]. (From Klippel and
Croft [5]; with permission.)
Fluorescence of kinetoplast
Test serum containing anti-dsDNA
Radiolabeled dsDNA added
DNAanti-DNA complexes precipitated

by ammonium sulphate
Radioactivity in precipitate measured
FIGURE 11-7
Farr assay for quantitative measurement of anti-double-e-stranded DNA (dsDNA) antibodies. The serum to be tested is added to a tube containing radiolabeled dsDNA. When
antibodies to dsDNA are present, they bind to the dsDNA. Eventually, formed complexes
are precipitated in 50% ammonium sulfate. By testing several dilutions of the serum and
comparing them with a standard curve the results can be expressed in units per milliliter.
Because high salt conditions are used, this assay detects only high avidity anti-dsDNA
antibodies [4]. Positivity and titer in this Farr assay are correlated with renal disease in
patients with systemic lupus erythematosus. This titer can be used to monitor lupus disease activity together with complement levels and clinical parameters. In 80% to 90%
of cases, disease onset or flare-up is associated with increases in anti-dsDNA titers in the
Farr assay [6]. (From Maddison [2]; with permission.)
Topo I
Scl-55
RNP
70,000
SS-B
SS-50
A
Sm
B
B
C
Centromere
CR-17
D
Dysregulation of apoptosis
Persistence of autoreactive T cells
Decreased
phagocytosis
Quantitative and qualitative
changes in nucleosomes
Antinucleosome Ab, anti-DNA Ab
In situ binding of
nucleosomes to GBM (HS?)
Deposition of circulating
nucleosome-Ab complex
Nucleosome-mediated Ab-binding to GBM
Activation of complement, glomerulonephritis
FIGURE 11-9
Hypothesis for the pathophysiology of lupus nephritis. In recent
years, evidence has emerged that the process of apoptosis is disturbed
in systemic lupus erythematosus (SLE). The first indication was found
in the MRL/l lupus mouse model, in which a deficiency of the Fas
receptor was identified [9]. Activation of this Fas receptor induces
apoptosis. Transgenic correction of the Fas-receptor defect prevents
development of lupus [10]. In human SLE, Fas receptor expression is
normal; however, a number of other observations indicate abnormalities in apoptosis [11,12] (Fig. 11-10). Alterations in apoptosis can
lead to the persistence of autoreactive T and B cells, because apoptosis is the major mechanism for the elimination of autoreactive cells. In
addition, these alterations can lead to quantitative and qualitative differences in the release of nucleosomes (Fig. 11-10).
Nucleosomes are the basic structures of chromatin. They consist of
pairs of the core histones H2A, H2B, H3, and H4 around which double-stranded DNA (dsDNA) is wrapped twice. DNA in the circulation
11.5
FIGURE 11-8
Western blot test of autoantibodies on nuclear extracts. Nuclear proteins extracted from human cervical carcinoma cells (HeLa cells) are
separated on polyacrylamide gel and transferred to nitrocellulose.
Subsequently, identical strips of the blot are incubated with various
patient sera. Binding of autoantibodies can be visualized with peroxidase or alkaline phosphataselabeled antihuman immunoglobulin.
Lane 1: anti-ribonucleoprotein (RNP)
and centromere (CR-17) activity
Lane 2: anti-Sm (B/B-D)
Lane 3: anti-RNP and anti-Sm
Lane 4: antiSjgrens syndrome (SS-B) (La)
Lane 5: anticentromere
Lane 6: antitopoisomerase I (Topo I)
Antibodies against Sm are rather specific for systemic lupus erythematosus (SLE) and can be used as marker antibody, anti-ribonucleoprotein for mixed connective tissue disease (MCTD), centromere (CR17) for the limited variant of scleroderma, SS-B for
Sjgrens syndrome and SLE, and topoisomerase I for systemic scleroderma. The Western blot test is a simplified version of the currently available technique, which allows identification of autoantibodies to much more autoantigens. Reference 7 provides a full
description of the diagnostic possibilities. (From Van Venrooij et al.
of patients with SLE is present in the form of oligonucleosomes [13];
the only way to generate these oligonucleosomes is by the process of
apoptosis. Presently, ample evidence exists that the autoimmune
response in SLE is T-celldependent and autoantigen-driven [14].
However, dsDNA is very poorly immunogenic, which is in line with
the fact that antigen-presenting cells cannot present DNA-derived
oligonucleotides to T cells by way of their major histocompatibility
complex class II molecules. However, recently it has become evident
that the nucleosome is the driving autoantigen in SLE.
In murine lupus, T cells specific for nucleosomes have been identified. These T cells not only drive the formation of nucleosome-specific autoantibodies (ie, antibodies that react with the intact nucleosome but not with its constituent DNA and histones) but also the
formation of anti-DNA and antihistone antibodies [15]. The histone-derived epitopes that drive these responses recently have been
identified [16]. These nucleosome-specific autoantibodies precede
the emergence of anti-dsDNA and antihistone antibodies, suggesting
that the loss of tolerance for nucleosomes is an initial key event in
SLE [17,18]. Both in human and murine lupus, nucleosome-specific
antibodies are detected in up to 80% of cases [1820].
Figure 11-11 illustrates the central role of the nucleosome in the generation of the antinuclear autoantibody repertoire. These antinucleosome and anti-DNA antibodies, after complex formation with the
nucleosome, can localize in the glomerular basement membrane
(GBM) by way of binding to heparan sulfate (HS). This binding occurs
through binding of the cationic histone part of the nucleosome to the
anionic HS, as demonstrated by in vivo perfusion studies [21]. The relevance of this binding mechanism for lupus nephritis was shown by
the elution of nucleosome-specific autoantibodies from glomeruli,
identification of nucleosome deposits in glomeruli of patients with
lupus nephritis, and presence of nucleosomeantinucleosome antibody
complexes in the glomerular capillary wall in patients with lupus
nephritis [18,2225]. The pathophysiologic significance of this nucleosome-mediated binding to the GBM was illustrated by the observation
that heparin could prevent this binding and inhibit the glomerular
inflammation and proteinuria in lupus mice [26]. References 11 and
14 provide a more detailed description of these mechanisms.
11.6
INDICATIONS FOR A DISTURBED APOPTOSIS IN

HUMAN SYSTEMIC LUPUS ERYTHEMATOSUS
Finding
Study
Increased expression of Fas receptor

Circulating levels of soluble Fas
Increased
Normal
Increased in vitro apoptosis of lymphocytes
Abnormal anti-CD3induced apoptosis
Apoptosis-induced alterations of autoantigens
Proteolysis
Mysler et al. [28], Lorenz et al. [29]
Phosphorylation
Reactive oxygen speciesmediated damage
Apoptosis-induced surface expression
of autoantigens
Decreased phagocytosis of apoptotic cell
Cheng et al. [30]

Goel et al. [31], Knipping et al. [32]
Lorenz et al. [29], Emlen et al. [33]
Kovacs et al. [34]
Casciola-Rosen et al. [35],
Casiano et al. [36],
Rosen and Casciola-Rosen [37],
Casiano [38]
Utz et al. [39]
Cooke et al. [40]
Casciola-Rosen et al. [41],
Jordan and Kuebler [42]
Herrmann et al. [43]
Chromatin
Anti-HMG
B cell
Anti-DNA
B cell
MHC II-Peptide
CD40L
Anti-Histone
B cell
CD40
CD4
Histonepeptide
Th cell
FIGURE 11-10
On the one hand, indications exist that apoptosis is increased in
human systemic lupus erythematosus (SLE) (eg, increased Fas expression and increased in vitro apoptosis). On the other hand, some findings suggest that apoptosis is decreased (eg, increased levels of soluble Fas, increased bcl-2 expression, and decreased anti-CD3induced
apoptosis). Bcl-2 is a physiologic inhibitor of apoptosis, and transgenic induction of bcl-2 overexpression leads to lupuslike autoimmunity [27]. Although presently it is difficult to reconcile these findings,
it is clear that changes in the delicate balances governing apoptosis
can lead to apoptosis at the wrong moment (too late) or at the
wrong place (systemically instead of locally).
TCR
Anti-nucleosome
B cell
FIGURE 11-11
Central role of T cells specific for nucleosomal histone peptides in
the generation of the antinuclear autoantibody repertoire in systemic lupus erythematosus. The cascade begins with the uptake of
nucleosomes by B cells by way of their antigen receptor. After
endosomal antigen processing, these B cells present histone peptides to T cells. After activation of the T cell, it provides help to the
presenting B cell, leading to the formation of nucleosome-specific
autoantibodies. Binding of B cells to other determinants on the
nucleosome (B cells specific for DNA, histones, or the nonhistone
chromosomal peptides high-mobility group proteins [HMG]) and
antigen-processing by these B cells, can generate additional antinuclear autoantibody responses (antidoubled-stranded DNA, antihistone, and anti-HMG). This intramolecular antigen-spreading owing
to different endosomal antigen-processing revealing cryptic neoepitopes, is now known for a number of autoimmune responses [44].
MHCmajor histocompatibility complex; TCRT-cell receptor.
(From Datta and Kaliyaperumal [45]; with permission.)
WORLD HEALTH ORGANIZATION MORPHOLOGIC

CLASSIFICATION OF LUPUS NEPHRITIS
(1995 REVISED VERSION)
Class
I. Normal glomeruli
A. Nil (by all techniques)
B. Normal on light microscopy but deposits seen on electron or immunofluorescence microscopy
II. Pure mesangial alterations (mesangiopathy)
A. Mesangial widening, mild hypercellularity, or both
B. Moderate hypercellularity
III. Focal segmental glomerulonephritis (associated with mild or moderate
mesangial alterations)
A. Active necrotizing lesions
B. Active and sclerosing lesions
C. Sclerosing lesions
IV. Diffuse glomerulonephritis (Severe mesangial, endocapillary, or mesangiocapillary
proliferation, and/or extensive subendothelial deposits. Mesangial deposits are present invariably and subepithelial deposits often, and may be numerous.)
A. Without segmental lesions
B. With active necrotizing lesions
C. With active and sclerosing lesions
D. With sclerosing lesions
V. Diffuse membranous glomerulonephritis
A. Pure membranous glomerulonephritis
B. Associated with lesions of category II (A or B)
VI. Advanced sclerosing glomerulonephritis
FIGURE 11-12
The various morphologic manifestations of lupus nephritis are
classified in several categories based on criteria formulated in
1974, modified in 1982 and 1995, and designated as the World
Health Organization (WHO) classification of lupus nephritis
[46,47]. The different forms of glomerulonephritis, as morphologically defined by the WHO classification, also are characterized by
typical patterns of deposits of several classes of immunoglobulins
and complement factors [48]. Class I lupus nephritis has been
defined by normal glomeruli by all techniques, or by normal
glomeruli on light microscopy, with minor deposits as seen on
immunofluorescence (IF) or electron microscopy (EM). Class I
lupus nephritis is believed to be a rare manifestation, and its existence is challenged by many pathologists.
The mildest form of lupus nephritis, class II, is characterized by a
mild or moderate increase of mesangial cells accompanied by mesangial deposits of immunoglobulins and complement. These mesangial
deposits are regarded as the most characteristic immunopathologic
feature of lupus nephritis. The more severe forms of lupus nephritis
not only show an increase of mesangial deposits but also deposits
11.7
along the capillary loops. Dependent on the severity of the morphologic damage, the extent of immune deposits, and whether less or
more than half of glomeruli are affected, this form of proliferative
lupus nephritis was divided into focal segmental glomerulonephritis
(class III) and diffuse glomerulonephritis (class IV). The distinction
between class III and class IV, however, is arbitrary; it also is unreliable in clinical practice. Therefore, the recent modification of the
WHO classification (1995) proposes a new definition of classes III
and IV lupus nephritis.
All more severe forms of proliferative lupus nephritis are included
in class IV and specified as mild, moderate, or severe, depending
on the severity on the glomerular damage. In active lesions there
occurs a large increase in mesangial cells; an influx of monocytes
or granulocytes; so-called hyaline thrombi in the capillary lumina;
and necrosis of the capillary loops, defined as severe mesangial
proliferative or endocapillary proliferative glomerulonephritis, and
sometimes with varying degrees of extracapillary proliferation. In
chronic disease, mesangiocapillary lesions are present with extensive subendothelial deposits (wire loops), duplication of the
glomerular basement membrane (GBM), cellular interposition,
and varying increases of mesangial cells and matrix. On electron
microscopy, the deposits have a homogeneous or fine granular
structure with sometimes organized fingerprint patterns.
Frequently, tubuloreticular structures are present in the cytoplasm
of endothelial cells, inclusions also found in viral infections, such
as human immunodeficiency virus, and related to -interferon.
Class III is now restricted to patients with active or sclerosing focal
segmental necrotizing lesions accompanied by mild increase of
mesangial cells.
Membranous lupus nephritis (class V) is hardly distinguishable
from the idiopathic form of lupus nephritis. However, membranous
lupus nephritis often is accompanied by a mild or moderate increase
of mesangial cells or matrix, and the subepithelial deposits contain
more classes of immunoglobulins (so-called full-house) than does
the idiopathic form. In addition, it is not unusual to find small
subendothelial and mesangial deposits. The subepithelial deposits
are either globally distributed along the glomerular basement membrane (GBM) or more segmentally localized. The subepithelial
deposits also are a frequent occurrence in class IV lupus nephritis.
According to the most recent version of the WHO classification
[47], class V is now restricted to cases that are predominantly characterized by subepithelial immune complexes. More advanced or
end-stage cases of focal and diffuse proliferative lupus nephritis
characterized by a pronounced sclerosis and hyalinosis are classified
as class VI lupus nephritis.
Interstitial fibrosis, accompanied by tubular atrophy and influx of
mononuclear cells, is a frequent finding, especially in the chronic forms
of classes III, IV, and V. Lesions resembling chronic tubulointerstitial
nephritis without glomerular alterations also have been described in
some patients with SLE. In these cases, on immunofluorescence, it is
not unusual to find granular immune complexes in the tubular basement membranes. Reference 47 provides additional information on the
1995 revised WHO classification. Examples of the different forms of
SLE nephritis are presented in Figs. 11-14 to 11-20. (From Churg and
11.8

FIGURE 11-13
The value of the analysis of lupus glomerulonephritis according to
the World Health Organization (WHO) classification for prognosis
and treatment can be enhanced by including indices of activity and
chronicity. These indices were proposed in the National Institutes
of Health (NIH) index [49]. The extent of the active and chronic
lesions is assessed according to the scoring system here. A chronicity index of 3 or higher and an activity index of 12 or higher are
associated with a significantly greater risk for the development of
end-stage renal disease [14].
NATIONAL INSTITUTES OF HEALTH HISTOLOGIC

SCORING SYSTEM FOR ACTIVITY AND CHRONICITY
IN LUPUS NEPHRITIS
Activity index
Chronicity index
Glomerular sclerosis
Fibrous crescents
Tubulointerstitial
Endocapillary hypercellularity
Leukocyte infiltration
Fibrinoid necrosis, karyorrhexis*
Cellular crescents*
Hyalin deposits, wire loops
Mononuclear cell infiltration
Maximal score
24
Glomerular
Fibrosis
Tubular atrophy
12
Scoring per item from 0 to 3; for parameters with asterisks, the score is doubled.
Histology of Lupus Nephritis

U
C
FIGURE 11-14
Lupus nephritis class II. A, A moderate increase of mesangial cells is seen on light microscopy. B, Immunofluorescence. Mesangial deposits of immunoglobulin G. C, Electron
microscopy shows electron-dense deposits restricted to the mesangial area. Lcapillary
lumen; Uurinary space. (Panel A, methenamine silver. Original magnification 400,
520, 10,000, respectively.)
FIGURE 11-15
Lupus nephritis class III. A, Segmental necrotizing lesion surrounded by
an increased number of epithelial cells. B, Immunofluorescence. Next
to mesangial deposits of immuno-globulin G there also are deposits in
the periphery of some loops (arrows). C, Immunofluorescence. Fibrin
11.9
C
deposits in a necrotizing lesion. According to the 1995 modified World
Health Organization classification, this is a characteristic immunopathologic lesion of class III lupus nephritis. (Panel A, methenamine
silver. Original magnification 400, 400, 520, respectively.)
FIGURE 11-16
Lupus nephritis class IV on light microscopy and immunofluorescence. A and B,
Diffuse endocapillary proliferative pattern
of injury with an increase of mesangial
cells and an influx of mononuclear cells
and some granulocytes. Panel B shows a
necrotizing lesion (arrow). C, A mesangiocapillary pattern of injury with duplication
of the glomerular basement membrane
(GBM), an increase of mesangial cells and
matrix, and massive subendothelial deposits
(wire loops). In addition, spikes (membranous component) can be found on the
epithelial side of the GBM (arrow). D,
Immunofluorescence. The characteristic
pattern of the immune deposits
(immunoglobulin G) of class IV lupus
nephritis, predominantly localized along
the capillary wall. (Panels A, B, C,
methenamine silver. Original magnification
360, 360, 740, 300, respectively.)
11.10

FIGURE 11-17
Lupus nephritis class IV. A representative electron micrograph
shows diffuse lupus nephritis with subendothelial and mesangial
electron-dense deposits with additional massive subepithelial
deposits (asterisk). GBMglomerular basement membrane;
Uurinary space. (Original magnification 12,000.)
GBM
*
U
C
FIGURE 11-18
Lupus nephritis class V. A, Discrete spikes on the epithelial side of the glomerular basement
membrane (GBM) (arrows), and a moderate increase of mesangial cells. B, Immunofluorescence. Fine granular deposits of immunoglobulin G along the capillary wall in a characteristic
membranous pattern. C, Electron micrograph reveals electron-dense deposits on the epithelial
side of the GBM between spikes. Between an increased number of mesangial cells small
deposits also are present (arrows). Lcapillary lumen; Sspikes; Uurinary space. (Panel A,
methenamine silver, original magnification 700, 400, 3100, respectively.)
11.11
FIGURE 11-19
Lupus nephritis class VI. Sclerosing glomerulonephritis with extensive sclerosis of most of the capillary tuft. (Methenamine silver,
original magnification 700.)
FIGURE 11-20
Chronic tubulointerstitial nephritis.
A, Extensive interstitial fibrosis accompanied by tubular atrophy and a mononuclear
cell infiltration B, Immunofluorescence.
Granular deposits of immunoglobulin G
in tubular basement membranes. (Panel A,
methenamine silver, original magnification
100, 400, respectively.)
Incidence of the different forms

of lupus nephritis, %
Class IV 57
Class III 15
Class II 10
Class I 1
Class VI 2
Class V 15
FIGURE 11-21
Incidence of the different forms of lupus nephritis classified according to the World Health
Organization (WHO) classification. The incidence of the different forms categorized according to the WHO classification depends on patient selection and ethnic background. The
percentages represent an average of the data reported in the literature. Most patients have
a diffuse proliferative form of lupus nephritis (WHO class IV).
11.12
100
Class II
Class III
Class IV
Class V
80
Percentage
60
40
20
FIGURE 11-22
Incidence of renal manifestations and serologic
abnormalities in the different forms of lupus nephritis. The clinical manifestations of lupus nephritis are
not different from other forms of glomerulonephritis
and include a nephritic sediment (dysmorphic erythrocytes and erythrocyte casts), proteinuria or
nephrotic syndrome, impaired renal function, and
hypertension. Although certain clinical manifestations are more prevalent in certain forms (nephrotic
syndrome for World Health Organization (WHO)
wC
n
sio
/lo
ten
An
ti-d
sDN
A+
per
Hy
ctio
un
al f
ren
red
pai
Im
Ne
ph
rot
ic s
Pro
ynd
tein
rom
a
uri
ent
im
sed
tive
Ac
class V, nephritic sediment for WHO class IV), it is

clear that on the basis of clinical symptoms it is not
possible to classify the form of nephritis correctly.
This inability underlines the necessity for obtaining a
renal biopsy specimen. In addition, listed are the
occurrence of both a positive result on performing a
Farr assay and a low complement 3 level for the different forms of lupus nephritis. Anti-dsDNA
antidouble-stranded DNA. (Adapted from Appel
et al. [50]).
TREATMENT OF THE DIFFERENT

FORMS OF LUPUS NEPHRITIS
World Health Organization
classification
I
II
III, IV
Treatment options
Treatment guided by extrarenal lesions
Corticosteroids:
Cyclophosphamide pulses, oral prednisone
Methylprednisolone pulses, azathioprine,
low doses oral prednisone
Corticosteroids
(and azathioprine or cyclophosphamide)
No further immunosuppression ?
Supportive treatment
V
VI
FIGURE 11-23
Treatment options for the different forms of lupus nephritis are
summarized. Only for World Health Organization (WHO) classes
III, IV, and V are a limited number of prospective studies available.
For the other forms, a balanced compilation is made from the literature and personal experience. Reference 14 supplies a more detailed
analysis of the therapeutic options. For class I lupus nephritis, no
specific renal therapy is necessary; treatment is dictated by the presence of extrarenal symptoms.
In general, patients with class II lupus nephritis respond satisfactorily to monotherapy with oral corticosteroids. The patient, however,
4
Chronicity index
must be monitored for transition to a more severe form, which is

generally heralded by worsening of clinical renal symptoms.
For patients with classes III and IV lupus nephritis, corticosteroid
monotherapy is not sufficient (Fig. 11-24). Cytotoxic immunosuppressive therapy, either cyclophosphamide or azathioprine, should
be added to the treatment. The choice of one of these drugs over
the other is discussed in Figures 11-24, 11-25, and 11-26.
According to a recent analysis [51], patients with a pure membranous lupus nephritis without a proliferative component (class V,
according to the 1995 revised WHO classification) respond satisfactorily to corticosteroid monotherapy. Patients who have a membranous
nephropathy with a proliferative component (formerly classified as
WHO class VC or VD) have a much worse prognosis and should be
treated as are patients with a class IV lupus nephritis. When a patient
with class V (A or B) lupus nephritis does not respond to corticosteroids, addition of azathioprine or cyclophosphamide should be
considered (as in idiopathic membranous glomerulonephritis, in
which oral treatment seems to be superior over monthly intravenous
pulses [5254]). When cyclophosphamide treatment is initiated the
therapeutic response should be evaluated after 6 months, and the
drug should be discontinued if no improvement has occurred [55].
Treatment of WHO class VI nephritis should be balanced on
weighing the risks of intensification of immunosuppressive treatment and the expected benefits. When renal function already is
strongly impaired and the renal biopsy specimen shows predominantly chronic irreversible lesions, further deterioration of renal
function may be unavoidable. Therefore, an increase in immunosuppressive therapy is questionable. This approach is strengthened
by the fact that lupus disease activity mostly subsides during renal
replacement therapy. Results of renal transplantation are good,
and the disease rarely recurs after transplantation [14].
FIGURE 11-24
Change in chronicity index in repeat biopsies after treatment
with prednisone (PRED) alone or prednisone and cytotoxic drugs
(CTD). The addition of cytotoxic drugs to the treatment regimen
of patients with World Health Organization (WHO) class III or IV
nephritis clearly improves renal and patient survival [56,57]. The
pathophysiologic basis for this beneficial effect is illustrated, displaying the change in chronicity index between the first and second kidney biopsies over time. As can be seen during prednisone
monotherapy, there is a clear increase of the chronicity index (A);
0
PRED
-2
-4
0
11.13
33
66
Time interval, m
99
132
11.14
Azathioprine
Oral cyclophosphamide
Intravenous cyclophosphamide
Combined use of azathioprine and
cyclophosphamide

whereas in patients treated with prednisone and cytotoxic drugs
(B) the chronic lesions, on average, do not progress. Various studies have shown that this chronicity index is the strongest predictor
of development of end-stage renal disease [14]. (From Balow et al.
Chronicity index
-2
CTD
-4
0
33
66
132
100
IVCY
AZCY
20
POCY
AZ
40
60
PRED
80
100
0
99
Time interval, m
Cumulative survival, %
Probability of end-stage renal disease
20
40
60
FIGURE 11-25
A, The probability of end-stage renal disease in patients with proliferative lupus nephritis treated with different drug regimens. This update
of the prospective trial by the National Institutes of Health (NIH) on
the treatment of these patients clearly demonstrates that prednisone
monotherapy, in a significantly greater proportion of patients, leads
to the development of end-stage renal disease compared with patients
on regimens containing cytotoxic drugs. The results between azathioprine and drug regimens containing cyclophosphamide are not significantly different. Note that in up to 7 years the results do not differ
between the different treatment groups. From these studies it is clear
that although the therapeutic efficacy is equal for the three treatment
regimens containing cyclophosphamide, less side effects occurred in
patients treated with intravenous pulses of cyclophosphamide.
B, Renal survival in patients with World Health Organization
(WHO) class IV lupus nephritis treated with either cyclophosphamide (CPM) or azathioprine (AZ). The NIH trial [56,59] did
not reveal a significant difference between the therapeutic efficacy
of cyclophosphamide and azathioprine (A). However, the side
60
CPM
40
20
AZA
80 100 120 140 160 180 200 220

Months
80
24
48
72
96
120
Months
effects of both drugs are not identical. Cyclophosphamide has

a greater bone marrow toxicity, leads to amenorrhea in many
patients, is teratogenic, and displays an unique urothelial toxicity
(hemorrhagic cystitis and bladder carcinoma). Therefore, prospective studies comparing cyclophosphamide with azathioprine are
warranted but not available. The results of the NIH trial are compared with those reported for azathioprine [57,6062]. This analysis, carried out by Cameron [57], does not reveal a significant difference between cyclophosphamide and azathioprine. A recent
meta-analysis [63] again showed that monotherapy with prednisone
was inferior to treatment with cytotoxic drugs in combination with
steroids. However, as in the NIH trial and the analysis by Cameron,
no differences were found between cyclophosphamide and azathioprine in preserving renal function. AZazathioprine; AZCY
combined therapy with azathioprine and cyclophosphamide;
IVCYintravenous pulses of cyclophosphamide; POCYoral
cyclophosphamide. (Panel A from Steinberg and Steinberg [59];
with permission. Panel B from Cameron [57]; with permission.)
11.15
RISK FACTORS FOR DEVELOPMENT OF END-STAGE RENAL DISEASE IN SYSTEMIC LUPUS ERYTHEMATOSUS
Clinical characteristics
Treatment characteristics
Histologic characteristics
Demographic characteristics
Elevated initial serum creatinine

Nephrotic range proteinuria
Low C3
Hematocrit 26%
Hypertension
Persistent disease activity
No normalization of elevated creatinine

Treatment with prednisone only
World Health Organization class IV

Activity index 12
Chronicity index 3
Male gender
Black race
Age 24 y
Low socioeconomic status
FIGURE 11-26
These risk factors were identified in different analyzes in
different patient groups. Not all these parameters were confirmed in all studies, probably because of differences in definitions used, composition of the cohort studied, duration of
follow-up, and so on. The most powerful predictors seem to be

an elevated serum creatinine level at entry into the trial, a
chronicity index of 3 or higher, and persistent or remitting renal
disease activity [14,64].
100
100
Patients, %
Survival, %
Hemodialysis
CAPD
80
80
60
40
All patients
Hemodialysis
CAPD
20
60
40
20
0
0
12
24
36
48
60
Months on dialysis
FIGURE 11-27
Survival of patients with systemic lupus erythematosus (SLE) on
dialysis. Although initially dialysis treatment was not offered to
patients with SLE because of the systemic nature of their illness, it
later became clear that patients with SLE tolerate dialysis treatment
as well as do patients with non-SLE renal diseases. The overall
patient survival is good (90% at 5 years), and no differences exist
in patient survival between those treated with continuous ambulatory peritoneal dialysis (CAPD) as compared with hemodialysis.
(Data from Nossent et al. [65].)
110
>10
Maximal Nonrenal SLEDAI
FIGURE 11-28
Severity of systemic lupus erythematosus (SLE) disease activity during
hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).
Lupus disease activity generally decreases during dialysis treatment.
As assessed by the SLE Disease Activity Index (SLEDAI) [66], the
maximal nonrenal SLEDAI decreased during dialysis in 49% of
patients, remained stable in 42%, and showed progression in 9%.
Despite the fact that immunosuppression was minimized, in 90%
of patients cytotoxic drug therapy was discontinued and in 55%
the dose of steroids was considerably reduced [65]. In addition, in
this analysis no differences were found in disease activity in patients
treated with either hemodialysis or CAPD. The maximal nonrenal
SLEDAI scores were divided in three groups: 0, no extrarenal disease activity; 1 to 10, moderate extrarenal disease activity; over 10,
high extrarenal disease activity.
11.16

25
100
20
Number of patients
80
Actuarial Survival, %
Before dialysis
During dialysis
After transplantation
60
40
Patient/SLE
Patient/non-SLE
Graft/SLE
Graft/non-SLE
20
15
10
0
0
12
24
Months after transplantation
36
110
>10
Maximal nonrenal SLEDAI score
FIGURE 11-29
Graft and patient survival after renal transplantation in patients
with systemic lupus erythematosus (SLE). For this analysis only
patients with first transplantations using a cadaveric donor kidney
were included. Both graft and patient survival were calculated for
165 patients with SLE who received transplantation between 1984
and 1992. These data are compared with the results in 21,726
patients with non-SLE glomerular diseases who received transplantation in the same time period. Both graft and patient survival were
not significantly different between the two groups. (From Berden
[14]; with permission. Data from G. Persijn, Eurotransplant,
Leiden, the Netherlands.)
FIGURE 11-30
Lupus disease activity after renal transplantation. Disease activity
was assessed in 28 patients with systemic lupus erythematosus
(SLE) by calculating the maximal nonrenal SLE Disease Activity
Index (SLEDAI) in the time periods before dialysis, during dialysis,
and after renal transplantation. The maximal nonrenal SLEDAI
scores were divided in three groups: 0, no extrarenal disease activity; 1 to 10, moderate extrarenal disease activity; over 10, high
extrarenal disease activity. Note that before dialysis all patients had
extrarenal lupus disease activity but that after renal transplantation
no patient had high disease activity. These data illustrate that the
decrease in disease activity that begins during dialysis treatment
continues after renal transplantation. In addition, recurrence of
lupus nephritis after renal transplantation is rare [67]. (From
Berden [14]; with permission. Data from Nossent et al. [68].)
Renal Involvement in Dysproteinemias

Heavy chains
Light chains
Only light chains

17%
IgD/IgE
1%
IgG
59%
IgA
23%
None
10%
60%
30%
FIGURE 11-31
Frequency of isotypes of heavy and light chains produced by
nonimmunoglobulin (Ig) M myelomas. Most paraproteins produced belong to the IgG class. Note that in approximately 20%
of myelomas only light chains are produced, of which two thirds
belong to the isotype and one third to the isotype [69,70].
These frequency distributions mirror those of Ig classes and light
chain isotypes in the serum.
11.17
FIGURE 11-32
Incidence of renal involvement in dysproteinemias. This incidence
is not identical for all paraproteinemias. The reason is directly
related to the frequency and degree of light chain proteinuria [71].
Igimmunoglobulin. (From Pruzanski [72]; with permission.)
100
90
80
Cumulative incidence, %
70
60
50
40
30
20
10
0
IgG
IgA
IgD
Paraproteinemia
Types of renal involvement in dysproteinemias

Uncontrolled proliferation of single B cell
Overproduction, secretion of monoclonal Ig or Ig fragment
Monoclonal Ig deposition diseases
Renal localization in different forms
Fibrils
Crystals
Casts
Granular precipitates
AL (or AH)
amyloidosis
Fanconi's
syndrome
Myeloma cast
nephropathy
LCDD
LHCDD
HCDD
Organized structures
Tubules, fibrils
Paraproteins
Cryoglobulins
Type I
TypeII
Immunotactoid GN
Fibrillary GN
Nonamyloidotic
FIGURE 11-33
Types of renal involvement in dysproteinemias. The uncontrolled proliferation of a
B-cell clone leads to overproduction of a monoclonal immunoglobulin (Ig), either an
intact molecule or fragments thereof (light or heavy chains). These molecules can
deposit in the kidney and other vital

organs, depending on the immunoglobulin
class, light or heavy chain isotype, and
other only partly understood physiochemical properties. The terminology used in
these disorders is sometimes confusing and
inconsistent. We use the definitions proposed by Gallo and Kumar [73]. All diseases characterized by deposits of monoclonal immunoglobulinrelated material
are named monoclonal immunoglobulin
deposition diseases (MIDD). These deposits
can occur in several forms, as outlined in
the figure, and are identified by specific
stains (such as congo red) and on immunofluorescence and electron microscopy. The
histologic and clinical manifestations are
dependent on the type of deposition.
Included in this overview are fibrillary and
immunotactoid glomerulonephritis, which
in certain cases also show deposits containing monoclonal immunoglobulins. AH
heavy chain amyloidosis; ALlight chain
amyloidosis; GNglomerulonephritis;
HCDDheavy chain deposition disease;
LCDDlight chain DD; LHCDDlight
and heavy chain DD.
11.18
Pathogenesis of renal lesions in dysproteinemias

Deposition either as light chain,
amyloid, or cryglobulins
Reabsorption of light chains

Toxic
injury
Glomerulus
Decreased sodium and light chain

reabsorption and increased distal delivery
Tubular atrophy
PCT
DT
Cortex
Light chains
filtered
Outer
medulla
Plasma cell
invasion
CCT
PR
Cast
injury
Giant cell infiltration

interstitial infiltration
TAL
LC + THP = cast
Inner
medulla
FIGURE 11-34
Pathogenesis of the different types of renal lesions in dysproteinemias. Paraproteins can
deposit in the glomerular basement membrane (GBM) (and tubular basement membrane
[TBM]) either as light or heavy chains, unmodified immunoglobulins, amyloids, or cryoglobulins. Because of their size of 22 kD, light chains are freely filtered through the GBM. These light
chains are then reabsorbed by proximal tubular cells. This process can induce a cascade of
events. Because some of these light chains are

relatively resistant to proteolysis, they can
induce lysosomal damage. This damage can
give rise to functional impairment of the
proximal tubular cell, leading to a decreased
resorptive capacity (eg, for sodium and light
chains) and thereby increasing the distal delivery. When this lysosomal overload leads to
intracellular crystal formation, Fanconis syndrome may ensue. Increased distal delivery of
light chains can then induce precipitation of
light chains together with Tamm-Horsfall protein (THP) that is secreted in the loop of
Henle. This precipitation is enhanced by an
increased tubular fluid sodium chloride concentration. Other factors that enhance cast
formation are listed in Figure 11-43. This
intratubular cast formation leads to obstruction, tubular damage, and an interstitial
inflammatory response with leakage of THP
in the interstitium, inducing macrophage
influx and giant cell formation. This entity is
known as myeloma cast nephropathy. Finally,
interstitial plasma cell invasion may occur in
patients with myeloma, although this rarely
leads to clinical symptoms and most often is
only diagnosed by kidney biopsy specimen or
is seen at autopsy. CCTcortical collecting
tubule; DTdistal tubule; LClight chains;
PCTproximal convoluted tubule; PRpars
recta; TALthin ascending limb. (Adapted
from Winearls [69].)
Histology of Renal Lesions in Dysproteinemias

Light chain amyloidosis. Amyloid deposits associated with dysproteinemias are predominantly
composed of fragments of the light chain variable region (AL amyloidosis) and very rarely of
fragments of heavy chain variable regions (AH amyloidosis) [74]. On light microscopy, this
type of amyloid is indistinguishable from amyloid of other origin. The homogeneous and
amorphous material, faintly pink-stained with eosin or sometimes brownish-stained with
methenamine silver, is deposited in the mesangium and along the capillary loops of the
glomeruli, in the vessels, and occasionally in the interstitium. Amyloid frequently is localized
in the glomerular basement membrane (GBM) as sheaths of fibrils or spicules that are larger
and more irregularly arranged than are the spikes in membranous glomerulopathy. Congo
redstained sections viewed under polarized light reveal the specific apple-green birefringence,
the gold standard for the diagnosis. Amyloid deposits are sometimes stained with commercially available antisera against light chains. In addition, these deposits also are positive for amyloid P, heparan sulfate proteoglycan, and apolipoprotein E. On electron microscopy, amyloid
is composed of long, randomly distributed, nonbranching fibrils with diameters of 8 to 12 nm.
A, Amyloid deposits in mesangium and the capillary wall (arrows: spicules).
11.19

B, Amyloid deposits in the renal arteries
in a congo redstained slide and viewed
under polarized light. Amyloid has an
apple-green color. C, Immunofluorescence.
Amyloid deposits in the mesangium stained
with anti- antibodies. (Panel A, methenamine silver. Original magnification 550,
350, 400, respectively.)
C
U
Pod
GBM
FIGURE 11-36
Light chain amyloidosis on electron microscopy. A, Characteristic fibrillar pattern of
amyloid deposits. Long, randomly distributed, nonbranching fibrils with diameters
of 8 to 12 nm. B, Amyloid fibrils in the
capillary lumen and capillary wall with
extension through the glomerular basement
membrane (GBM) into the subepithelial
space (arrow) fibrils arranged in parallel
forming spicules). (Original magnification
48,000, 20,000, respectively.)

Light chain deposition disease. In about 60% of patients with this renal lesion, nodular
expansion of the mesangium is seen that resembles nodular diabetic nephropathy [75,76]. The
nodules stained purple with periodic acidSchiff (PAS) stain have a homogeneous appearance,
and those stained with methenamine silver are pink-brownish in color. In a few cases, a more
mesangiocapillary pattern of injury is present. The tubular basement membranes (TBMs) are
thickened, as seen in the PAS-stained sections.

In the remaining cases, no renal lesions can
be seen on light microscopy. On immunofluorescence, linear staining of basement membranes of glomeruli, tubuli, and vessels can
be observed for one of the light chains ( >
). In most cases, the TBMs are more heavily stained than are the glomerular basement
membranes (GBMs). Congo red staining is
negative for amyloid. On electron microscopy, fine granular electron-dense material
can be found in most cases along the
endothelial side of the GBM, in the mesangium, and along the interstitial side of the
TBM. A few cases of heavy chain and of light
and heavy chain deposition disease have been
described, in most cases with identical morphologic characteristics as described in light
chain deposition disease [77,78].
A, Nodular glomerulosclerosis with nodular increase of mesangial matrix. B, Linear
staining of the GBM, mesangium, Bowmans
capsule, and TBM for the light chain.
11.20

C and D, Electron-dense granular
deposits in the GBM (C) and around
the TBM (D). Lcapillary lumen; Pod
podocyte. (Panel A, methenamine silver.
Original magnification 400, 400,
15,000, 6500, respectively.)
Pod
GBM
L
TBM
FIGURE 11-38
Cast nephropathy. The casts have a homogeneous, fractured, or crystalline appearance with
sharp angular or irregular edges and are present in the distal and collecting tubules [73].
These casts are composed of aggregated or light chains mixed with Tamm-Horsfall protein (THP). Sometimes the tubular cells shows necrosis accompanied by disruptions of the
tubular basement membrane (TBM). Proximal tubular cells show hyaline droplets or vacuoles with needlelike, tubular, or complex crystalline material. Casts are surrounded by
macrophages and multinucleated giant cells. On electron microscopy, the casts have a granular, homogeneous, or fibrillary appearance with occasional needlelike crystals. The fibrils
that surround the casts are probably THP. In most cases, a varying degree of interstitial
fibrosis exists, accompanied by mononuclear cell infiltration and tubular atrophy. Congo
red staining for amyloid is usually negative. The glomeruli are normal.
A, Low magnification with casts in the distal tubules, and interstitial fibrosis with
atrophic tubules (chronic tubulointerstitial nephritis). B, Brown-colored cast surrounded
by macrophages. C, Eosinophilic homogeneous cast. D, Immunofluorescence. Casts are
stained for light chains. (Panels A, B, C, methenamine silver. Original magnification
160, 400, 600, 200, respectively.)
11.21
FIGURE 11-39
Fanconis syndrome in a patient with
light chain proteinuria. A, Vacuolization
of proximal tubular epithelial cells. Vacuoles
contain light-brown-colored material.
B, Immunofluorescence. The granular material in tubular cells is stained for light chains.
C, Low-power view of a proximal tubular
epithelial cell with vacuoles containing organized or crystalline material. D, High-power
view of the vacuoles containing tubular or
ladderlike crystalline structures. BBbrush
border. (Panel A, methenamine silver.
Original magnification 600, 400, 7000,
19,000, respectively.)
B
BB
11.22
C
A
FIGURE 11-40
Glomerular deposition of immunoglobulin A- paraproteins. No paraproteins or cryoglobulins
could be found in the serum of this patient. In addition, the urinary excretion of light chains
was not detectable. A, A mesangiocapillary pattern of injury with deposition of eosinophilic
material in the capillary wall and mesangium. B, Immunofluorescence. The deposits were
positive for light chains (and immunoglobulin A). C, Ultrastructurally, below the glomerular
basement membrane, organized deposits composed of parallel arranged fibrils or gridlike
structures can be seen. (Panel A, methenamine silver, original magnification 400, 400,
25,000, respectively.)
A
Glomerular deposition of immunoglobulin G in a patient
with multiple myeloma. A, Glomerulus with many intracapillary protein thrombi. B, The material was composed of
B
closely packed tubules arranged in parallel. (Panel A,
toluidine blue. Original magnification 600, 130,000,
respectively.)
11.23
FIGURE 11-42
Mixed cryoglobulinemia. Of the three types of cryoglobulins, types I and II contain monoclonal immunoglobulins (Ig). Type I cryoglobulins occur in monoclonal gammopathies and
lymphomas and consist of a single monoclonal immunoglobulin. Type II cryoglobulins (also
called mixed cryoglobulinemia) occur in systemic infections, autoimmune diseases, and malignancies. Type II cryoglobulins consist of two components, a monoclonal immunoglobulin,
most frequently IgM, with rheumatoid factor activity directed to the polyclonal IgG component. Various patterns of glomerular injury can be found, such as a diffuse endocapillary proliferative glomerulonephritis with a prominent influx of monocytes, or a mesangiocapillary
glomerulonephritis. Less frequently, a diffuse mesangial proliferative, sclerosing glomerulonephritis, or both can be seen. Eosinophilic aggregates along the glomerular basement membrane (GBM) or in the lumina designated as thrombi frequently are present. Type II cryoglobulinemia is sometimes accompanied by a vasculitis. The aggregates in the glomeruli of type I,
as seen on immunofluorescence, have a composition identical to that of the cryoglobulins in
the serum. The deposits in type II contain IgG, IgM, and complement. Ultrastructurally, the
deposits usually demonstrate an organized or crystalline appearance. In type I, the deposits
frequently are organized in closely packed fibrils, long tubules, or crystals. In type II, short
tubulo-annular structures can be found. Sometimes aggregates in the glomeruli composed of
a single monoclonal immunoglobulin component can be demonstrated in patients without
evidence of a monoclonal immunoglobulin or cryoglobulins in the serum.
A, Diffuse endocapillary proliferative glomerulonephritis with prominent influx of
mononuclear cells. B, Mixed pattern of injury in a patient with Sjgrens syndrome.
Intracapillary thrombi, increase of mesangial cells and matrix, and occasionally duplication
of the GBM. C, Immunofluorescence with staining for IgM. D, Electron microscopy of tubular and annular structures in the glomerular deposits. (Parts A, B, methenamine silver.
Original magnification 400, 400, 200, 120,000, respectively.)
FIGURE 11-43
Biopsy specimen of immunotactoid glomerulonephritis with immunoglobulin A
deposits. The patient had no signs of a monoclonal gammopathy or lymphoma. A, Mild
increase of mesangial matrix with segmental
irregularity of the capillary wall. B,
Immunofluorescence. The deposits are positive for (and immunoglobulin A) C, Below
the glomerular basement membrane, seen is
an accumulation of short microtubules with a
diameter of about 30 nm. (Part A,
methenamine silver. Original magnification
400, 400, 25,000, respectively.)
11.24

Immunotactoid and fibrillary glomerulonephritis are comprised of
lesions characterized by the deposition of immunoglobulins (and complement) arranged in randomly distributed fibrils or microtubules in
the capillary wall and mesangium [89,90]. These lesions are thicker
than are amyloid fibrils and are negative on congo-red staining.
Although presently it is not clear whether these forms of glomerulonephritis are different disease entities or are different morphologic
expressions of one disease, some morphologic and clinical features
exist that suggest fibrillary glomerulonephritis must be distinguished
from immunotactoid glomerulonephritis [91]. Immunotactoid
glomerulonephritis shows deposition of microtubules with diameters
of 35 to 50 nm and commonly is associated with a lymphoproliferative disease. The deposited immunoglobulins frequently are of monoclonal composition. In contrast, fibrillary glomerulonephritis is characterized by fibrils with diameters of about 18 to 20 nm. The deposited immunoglobulins usually are polyclonal and very rarely
monoclonal. An association with a lymphoproliferative disease is
uncommon in contrast to immunotactoid glomerulonephritis.
C
FIGURE 11-44
Fibrillary glomerulonephritis. A, Moderate widening of mesangial areas by increase of
matrix. B, Immunofluorescence. Heavy staining for IgG (and complement, and light
chains). C, Ultrastructurally, randomly distributed long fibrils with diameters of 18 to
22 nm are localized in the capillary wall. (Panel A, methenamine silver. Original magnification 400, 300, 27,000, respectively.)
CLINICAL PRESENTATION, FREQUENCY, AND CAUSES

OF RENAL INVOLVEMENT IN DYSPROTEINEMIAS
Acute deterioration of renal function (510%)
Dehydration
Hypercalcemia
Cast nephropathy
Chronic renal insufficiency (4575%)
Myeloma cast nephropathy
Light chain (AL) amyloidosis
Interstitial plasma cell infiltration (rare)
Proteinuria-nephrotic syndrome (5080%)
Light chain (AL) amyloidosis
Light chain deposition disease
Heavy chain deposition disease
Cryoglobulinemic glomerular lesions
Fanconis syndrome (1%)
Secondary lesions (2030%)
Pyelonephritis
Nephrocalcinosis
Hyperuricemic nephropathy
FIGURE 11-45
Renal involvement in dysproteinemias can lead to different clinical
manifestations: acute renal failure; progressive deterioration of renal
function; proteinuria, which very often is in the nephrotic range; or,
seldom, Fanconis syndrome. Furthermore, a number of secondary
conditions may occur that can induce additional renal damage.
Certain features are associated with particular clinical symptoms.
The type of clinical lesion that develops is predominantly determined
by the so-called nephrotoxic characteristics of the excreted light
chains, as demonstrated by infusion of light chains into mice. These
infusions led to the same type of renal lesion as in humans [79,80].
Some of these nephrotoxic factors are listed in Figure 11-43.
11.25
RISK FACTORS FOR RENAL INVOLVEMENT

IN DYSPROTEINEMIAS
Factors enhancing amyloid formation
Unfolding of paraprotein
Light chain
Factors enhancing cast nephropathy
High urinary excretion of light chains
Binding of light chain to Tamm-Horsfall protein (THP)
Iso-electric point of light chain 5.1 ? (enhances binding to anionic THP (pI:3.2)
Tendency to self-aggregation of light chains
Light chain
High levels of acute-phase proteins
Resistance of light chain to urinary or macrophage-derived proteases
Factors enhancing monoclonal immunoglobulin deposition
Light chain
Presence of hydrophobic aminoacids in CDR1 or CDR2 of VL-chain
Deletion of CH1 domain Fc part immunoglobulin
Factors enhancing acute renal failure
Hypercalcemia (1944%)*
Dehydration (1065%)
Urinary tract infection (844%)
Nephrotoxic drugs (aminoglycosides; nonsteroidal anti-inflammatory drugs) (026%)
Intravenous radio contrast media (011%)
Loop diuretics
*Percentage of patients in which this factor contributed to the development
of acute renal failure.
From Winearls [69]; with permission.
FIGURE 11-46
Factors reported in the literature to be associated with development
of the different renal lesions in patients with myeloma are summarized.
The amyloidogenic potential is enhanced by certain amino acids that
promote unfolding of the light chain and by the isotype of the light
chain. In amyloidosis, the variable regions of the light chains are
deposited predominantly after metabolization by macrophages. A
number of factors have been characterized that enhance the binding
of light chains to Tamm-Horsfall protein (THP), which is a critical
event in the development of cast nephropathy. In monoclonal immunoglobulin deposition diseases, the granular deposits are composed
mainly of the constant regions of light (and seldom heavy) chains.
Hypercalcemia, which frequently occurs in patients with myeloma
and results from increased interleukin-6mediated bone resorption,
can contribute to renal impairment by way of different mechanisms:
dehydration (hyperemesis and nephrogenic diabetes insipidus),
induction of nephrocalcinosis, and enhancement of light chain
aggregation with THP. All other factors either diminish tubular
flow or increase distal tubular sodium concentration, thereby again
enhancing cast formation.
11.26
TREATMENT OF RENAL LESIONS IN DYSPROTEINEMIAS

Renal therapy
Antitumor therapy
Preventive measures:
Rehydration, forced diuresis (>3 L/24 h)
Correction hypercalcemia
Alkalinization of urine (pH 7)
Cessation of nephrotoxic drugs
Treatment of infections
Colchicine ?
Plasmapheresis in acute renal failure
Recovery of renal function increases from 018% in the control group to
4384% with plasmapheresis
Dialysis
54% survival after 1 y, and 25% after 2 y
Theoretically, PD could result in a better removal of light chains
Light chain amyloidosis: 29 patients; high nonrenal mortality rate, 30% recurrence rate
Light chain deposition disease: 12 patients; 50% recurrence rate
Cryoglobulinemia: 50% recurrence rate
Multiple myeloma: 18 patients with low-grade disease; 8 alive, 5 succumbed to infection,
and 5 to recurrence
Melphalan-prednisone
First-line therapy: 45% remission rate
Vincristine-adriamycine-dexamethazone (VAD)*
Second-line therapy: relapses, 40% remission; refractory cases, 25% remission
High-dose chemotherapy and bone marrow transplantation
Relatively good results in patients without renal involvement. No data for patients
with renal involvement
*VAD protocol has the advantage that drug metabolism is independent of kidney function, whereas the melphalan dose must be adjusted to renal function.
FIGURE 11-47
Treatment should be directed at ameliorating the renal lesion and
reduction of the production of paraproteins. In patients with myeloma it is very important to prevent situations that could precipitate
acute renal failure. In this respect, dehydration and hypercalcemia
are very harmful. Measures should be taken to maintain a high fluid
intake. When radiocontrast agents are necessary, hydration before
the study decreases the chance of intratubular cast formation
between light chains and the contrast agent. Alkalization of the
urine can reduce the interaction between light chains and TammHorsfall protein (THP). Nephrotoxic drugs (such as nonsteroidal
anti-inflammatory drugs and gentamycin) should not be used
because they further enhance tubular dysfunction. Experimental
studies suggest that colchicine may be helpful in reducing cast formation either by decreasing THP secretion or modifying the interaction between THP and light chains. Presently, no data exist that
document the clinical efficacy of this treatment.
Plasmapheresis has the potential to remove the toxic light chains
from the circulation, although in certain patients the serum concentration can be rather low. Plasmapheresis alone does not reduce the
rate of production of the paraprotein; therefore, this treatment
should be combined with chemotherapy. Patients with extensive
cast formation and interstitial changes seem to respond less well to
plasmapheresis that do those without cast formation and interstitial changes [81]. Of two controlled studies, only one showed a
beneficial effect of addition of plasmapheresis to chemotherapy
[82,83]. The major determinant for success seems to be a good
response to chemotherapy [83]. Furthermore, patients with extensive cast formation and interstitial changes seem to respond less
well to chemotherapy than do those without cast formation and
interstitial changes [81,83]. The patient with end-stage renal disease can be treated with dialysis, although survival is poor and
dependent on the success of chemotherapy.
The experience of renal transplantation in patients with dysproteinemias is, for obvious reasons, rather limited. The results are rather
disappointing with a high mortality rate, especially in patients with
multiple myeloma and amyloidosis. Patients surviving for more than
1 year show a high recurrence rate [8487]. Discussion of antitumor
therapy is beyond the scope of this review. Briefly, treatment with
melphalan and prednisone is considered to be the first choice, whereas more aggressive treatment with vincristine-adriamycin-dexamethasone is given to patients who do not respond to or who relapse after
melphalan and prednisone therapy. Recently, more encouraging
results have been obtained with ablative chemotherapy and stem-cell
reinfusion [88]. PDperitoneal dialysis.
11.27
Renal Involvement in Rheumatic Diseases

Causes of renal involvement in
rheumatoid arthritis
MGN
14%
MesPGN
23%
AA amyloidosis
18%
No lesions
15%
TIN
9%
Vasculitis, CGN, other
21%
FIGURE 11-48
Causes of renal involvement in rheumatoid arthritis. In rheumatoid
arthritis, a variety of renal disorders may occur secondary to either
the underlying disease or to drugs used to treat it. The most frequent abnormality is a mesangial proliferative glomerulonephritis
(MesPGN) with, in most cases, only mesangial immunoglobulin M
(IgM) and sometimes IgA and complement 3 (C3) deposits. IgG and
C1q deposits are very rare. A correlation exists with the levels of
rheumatoid factor; however, the underlying mechanism is unclear.
Clinically, MPGN is characterized by hematuria and proteinuria.
Membranous glomerulopathy (MGN) in rheumatoid arthritis is
mostly associated with gold or D-penicillamine treatment. MGN
is seen more frequently in patients after therapy with D-penicillamine (714%) than after gold therapy (39%). When a patient
RENAL MANIFESTATIONS IN SJGRENS SYNDROME

Manifestation
Interstitial nephritis with or without tubular dysfunction
Tubular dysfunction (distal > proximal) associated with
interstitial infiltrates and granuloma formation
Clinical symptoms:
Type 1 renal tubular acidosis
Fanconis syndrome
Hypokalemia
Glomerulonephritis
Mesangiocapillary glomerulonephritis
Vasculitis
Mostly extrarenal (skin, muscle, nerve);
occasionally in the kidney
%
3060
2025
35
<5
is positive for HLA-DR3 the risk for gold-induced MGN increases

10- to 30-fold and that for D-penicillamine increases 3- to 10-fold.
Discontinuation of therapy leads to remission of the proteinurianephrotic syndrome in almost all cases, although it may be a year
before complete recovery is achieved. MGN may occur in patients
with rheumatoid arthritis not treated with gold or D-penicillamine.
The mechanism for this is not clear.
Amyloidosis is associated with active joint disease. This type of
amyloidosis is secondary to the deposition of the acute-phase reactant serum amyloid A (SAA) protein. This SAA is partly digested
by macrophages and deposited in the tissues as AA amyloid. When
a patient with active rheumatoid arthritis develops a nephrotic syndrome, AA amyloidosis is the most likely cause. No good treatment options exist for AA amyloidosis, other than treating the
underlying disease. Renal transplantation in these patients is associated with a 3-year patient survival rate of 50% [92]. Especially in
the early period after transplantation, there were high cardiovascular- and infection-related mortality rates. The rate of recurrence
was approximately 20%.
The development of tubulointerstitial nephritis (TIN) in patients
with rheumatoid arthritis is related to the prolonged use of analgesics, especially multicomponent analgesics and nonsteroidal antiinflammatory drugs. A number of other renal conditions may develop in patients with rheumatoid arthritis. Vasculitis is associated
with long-standing and nodular rheumatoid arthritis with high
levels of rheumatoid factor. This condition may be associated with
a crescentic glomerulonephritis (CGN) that, on immunofluorescence, is negative for immunoglobulin and complement deposits,
as in Wegeners granulomatosis. The best treatment consists of
cyclophosphamide and prednisone. References 93 and 94 provide
more details on renal involvement in rheumatoid arthritis. Because
the histologic abnormalities are not specific for rheumatoid arthritis,
no histologic examples are given. They can be found elsewhere in
this book. (Data from Emery and Adu [94].)
FIGURE 11-49
The clinical manifestations of the tubulointerstitial nephritis in
Sjgrens syndrome can vary and depend on localization of the
functional impairment. Occasionally, symptoms of tubular dysfunction precede development of symptoms of Sjgrens syndrome. It is
unclear what causes these tubular dysfunctions. When the degree
of tubulointerstitial damage is not chronic, corticosteroids are beneficial. Glomerular involvement is rare in Sjgrens syndrome. When
a glomerulonephritis is present, the patient should be evaluated for
the presence of cryoglobulins and existence of systemic lupus erythematosus. Reference 95 provides a more detailed description of
this subject.
11.28
RENAL INVOLVEMENT IN SCLERODERMA

Incidence of renal involvement
Risk factors for renal crisis
Clinical characteristics of renal crisis
Therapy for renal crisis
Based on autopsy studies, 6070%

Based on clinical symptoms, 3050%
Scleroderma renal crisis, 1015%
Diffuse form of scleroderma

Rapid progression of skin lesions
HLA BW35, DR3, DR5
Race (Blacks > whites)
Use of corticosteroids or cyclosporine A?
Cold exposure ?
Acute onset
Marked to severe (malignant) hypertension
(10% of patients remain normotensive)
Features of malignant hypertension
Micro-angiopathic hemolytic anemia and
thrombopenia
Mostly normal urinary sediment
(in cases with malignant hypertension
hematuria possible)
Progressive decline of renal function
Prevention of reduction of renal perfusion

(eg, dehydration, diuretics, cyclosporin A,
nonsteroidal anti-inflammatory drugs)
(even in patients with normotension)
Renal replacement therapy
FIGURE 11-50
The main features of renal involvement in scleroderma are summarized. The major manifestation is the so-called renal crisis. Besides
this often life-threatening manifestation, other patients may display
milder forms of renal involvement, clinically characterized by mild
proteinuria or slight deterioration of kidney function. Renal involvement is more common in patients with the diffuse form of scleroderma that is serologically characterized by antibodies against topoisomerase I or RNA polymerase III. Patients with progressive skin disease should be monitored carefully for hypertension and signs of
renal involvement. Early institution of angiotensin-converting enzyme
(ACE) inhibition in patients with micro-albuminuria can prevent further deterioration of kidney function [96,97]. ACE inhibition is also
the mainstay of treatment for patients with scleroderma renal crisis,

because it will significantly reduce progression to renal failure,
increase the chance of recovery if renal failure has already developed,
and improve the 1-year patient survival rate. Renal replacement therapy (hemodialysis or continuous ambulatory peritoneal dialysis)
should be offered to patients whose renal function does not recover.
The patient survival rate, however, is lower than in patients with
other collagen-vascular diseases such as lupus nephritis. Limited
experience with renal transplantation indicates that successful transplantation is possible, especially in patients with quiescent disease.
Recurrence in the transplanted kidney has been reported [84].
References 96 to 98 provide more extensive reviews on the subject.
FIGURE 11-51
Scleroderma. In the acute phase, small- and
medium-sized renal arteries show mucoid
thickening of the intima with severe narrowing of the lumen. Sometimes these lesions are
accompanied by thrombosis and fibrinoid
necrosis of the arterioles and glomeruli.
Morphologically, the vascular alterations
resemble malignant nephrosclerosis (malignant hypertension) or hemolytic-uremic syndrome. In the chronic phase, the mucoid
intimal material is replaced by fibrous tissue.
A, Severe narrowing of a small-sized
renal artery owing to extensive endothelial
widening with ischemia of glomeruli.
B, Accumulation of mucopolysaccharide
material in the widened endothelial layer.
11.29

C, Severe intimal fibrosis of a medium-sized artery of a more
chronic phase of scleroderma. (Panel A, methenamine silver, original magnification 100. Panel B, alcian blue stain, original magnification 100. Panel C, cellulose acetate butyrate stain, original
magnification 150.)
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Principles of Dialysis:
Diffusion, Convection,
and Dialysis Machines
Robert W. Hamilton
hronic renal failure is the final common pathway of a number

of kidney diseases. The choices for a patient who reaches the
point where renal function is insufficient to sustain life are
1) chronic dialysis treatments (either hemodialysis or peritoneal dialysis),
2) renal transplantation, or 3) death. With renal failure of any cause,
there are many physiologic derangements. Homeostasis of water and
minerals (sodium, potassium, chloride, calcium, phosphorus, magnesium, sulfate), and excretion of the daily metabolic load of fixed
hydrogen ions is no longer possible. Toxic end-products of nitrogen
metabolism (urea, creatinine, uric acid, among others) accumulate in
blood and tissue. Finally, the kidneys are no longer able to function as
endocrine organs in the production of erythropoietin and 1,25-dihydroxycholecalciferol (calcitriol).
Dialysis procedures remove nitrogenous end-products of catabolism and begin the correction of the salt, water, and acid-base derangements associated with renal failure. Dialysis is an imperfect treatment
for the myriad abnormalities that occur in renal failure, as it does not
correct the endocrine functions of the kidney.
Indications for starting dialysis for chronic renal failure are empiric
and vary among physicians. Some begin dialysis when residual glomerular
filtration rate (GFR) falls below 10 mL/min /1.73 m2 body surface
area (15 mL/min/1.73 m2 in diabetics.) Others institute treatment
when the patient loses the stamina to sustain normal daily work and
activity. Most agree that, in the face of symptoms (nausea, vomiting,
anorexia, fatigability, diminished sensorium) and signs (pericardial
friction rub, refractory pulmonary edema, metabolic acidosis, foot or
wrist drop, asterixis) of uremia, dialysis treatments are urgently indicated.
CHAPTER
1.2
Dialysis as Treatment of End-Stage Renal Disease
FUNCTIONS OF THE KIDNEY AND PATHOPHYSIOLOGY OF RENAL FAILURE

Function
Dysfunction
Salt, water, and acid-base balance

Water balance
Sodium balance
Potassium balance
Bicarbonate balance
Magnesium balance
Phosphate balance
Excretion of nitrogenous end products
Urea
Creatinine
Uric acid
Amines
Guanidine derivatives
Endocrine-metabolic
Conversion of vitamin D to active metabolite
Production of erythropoietin
Renin
Salt, water, and acid-base balance

Fluid retention and hyponatremia
Edema, congestive heart failure, hypertension
Hyperkalemia
Metabolic acidosis, osteodystrophy
Hypermagnesemia
Hyperphosphatemia, osteodystrophy
Excretion of nitrogenous end products
?Anorexia, nausea, pruritus, pericarditis, polyneuropathy, encephalopathy, thrombocytopathy
Endocrine-metabolic
Osteomalacia, osteodystrophy
Anemia
Hypertension
FIGURE 1-1
Functions of the kidney and pathophysiology of renal failure.
Blood
Membrane
Dialysate
Na+
Na+
K+
K+
Ca2+
HCO3
Ca2+
HCO3
Creatinine
Urea
Creatinine
Urea
FIGURE 1-2
Statue of Thomas Graham in George
Square, Glasgow, Scotland. The physicochemical basis for dialysis was first
described by the Scottish chemist Thomas
Graham. In his 1854 paper On Osmotic
Force he described the movements of
various solutes of differing concentrations
through a membrane he had fashioned
from an ox bladder. (From Graham [1].)
FIGURE 1-3
Membrane fluxes in dialysis. Dialysis is the process of separating elements in a solution by
diffusion across a semipermeable membrane (diffusive solute transport) down a concentration gradient. This is the principal process for removing the end-products of nitrogen
metabolism (urea, creatinine, uric acid), and for repletion of the bicarbonate deficit of the
metabolic acidosis associated with renal failure in humans. The preponderance of diffusion
as the result of gradient is shown by the displacement of the arrow.
1.3
Principles of Dialysis: Difusion, Convection, and Dialysis Machines
Bicarbonate
concentrate
Acidified
concentrate
Air
embolus
detector
Water
Pump
Heater
Membrane unit
Pump
Patient
Mix 1
Conductivity
monitor
Mix 2
Volume
balance
system
Deaerator
Spent
dialysate
pump
Spent
dialysate
Drain
Ultrafiltrate
pump
Heat
exchanger
FIGURE 1-4
Simplified schematic of typical hemodialysis system. In hemodialysis,
blood from the patient is circulated through a synthetic extracorporeal
membrane and returned to the patient. The opposite side of that
membrane is washed with an electrolyte solution (dialysate) containing the normal constituents of plasma water. The apparatus contains
a blood pump to circulate the blood through the system, proportioning
Dialysate
Blood
Blood
Dialysate
Blood
Dialysate
Blood
leak
detector
Blood
pump
Heparin
pump
pumps that mix a concentrated salt solution with water purified by

reverse osmosis and/or deionization to produce the dialysate, a means
of removing excess fluid from the blood (mismatching dialysate
inflow and outflow to the dialysate compartment), and a series of
pressure, conductivity, and air embolus monitors to protect the
patient. Dialysate is warmed to body temperature by a heater.
FIGURE 1-5
The hemodialysis membrane. Most membranes are derived from
cellulose. (The earliest clinically useful hemodialyzers were made
from cellophane sausage casing.) Other names of these materials
include cupraphane, hemophan, cellulose acetate. They are usually
sterilized by ethylene oxide or gamma irradiation by the manufacturer. They are relatively porous to fluid and solute but do not
allow large molecules (albumin, vitamin B12) to pass freely. There
is some suggestion that cupraphane membranes sterilized by ethylene
oxide have a high incidence of biosensitization, meaning that the
patient may have a form of allergic reaction to the membrane.
Polysulfone, polyacrylonitrile, and polymethylmethacrylate membranes
are more biocompatible and more porous (high flux membranes).
They are most often formed into hollow fibers. Blood travels down
the center of these fibers, and dialysate circulates around the outside
of the fibers but inside a plastic casing. Water for dialysis must meet
critical chemical and bacteriologic standards. These are listed in
Figures 1-6 and 1-7.
1.4
ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL

INSTRUMENTATION CHEMICAL STANDARD FOR
WATER FOR HEMODIALYSIS
Substance
Concentration (mg/L)
Aluminum
Arsenic
Barium
Cadmium
Calcium
Chloramine
Chlorine
Chromium
Copper
Fluoride
Lead
Magnesium
Mercury
Nitrate
Potassium
Selenium
Silver
Sodium
Sulfate
Zinc
FIGURE 1-6
Association for the Advancement of Medical Instrumentation
(AAMI) chemical standards for water for hemodialysis. Before
hemodialysis can be performed, water analysis is performed.
Water for hemodialysis generally requires reverse osmosis treatment and a deionizer for polishing the water. Organic materials,
chlorine, and chloramine are removed by charcoal filtration.
(From Vlchek [2]; with permission.)
0.01
0.005
0.1
0.001
2.0
0.1
0.5
0.014
0.1
0.2
0.005
4.0
0.0002
2.0
8.0
0.009
0.005
70
100
0.1
ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL

INSTRUMENTATION BACTERIOLOGIC STANDARDS
FOR DIALYSIS WATER AND PREPARED DIALYSATE
Colony-forming units/mL
Dialysis water
Prepared dialysate
<200
<2000
dn
dc
= DA
dt
dx
FIGURE 1-8
Factors that govern diffusion, where dn/dt
= the rate of movement of molecules per
unit time; D = Ficks diffusion coefficient;
FIGURE 1-7
Association for the Advancement of Medical Instrumentation
(AAMI) bacteriologic standards for dialysis water and prepared
dialysate. Excess bacteria in water can lead to pyrogen reactions.
Treated water supply systems are designed so that there are no
dead-end connections. Because the antiseptic agents (chlorine and
chloramine) have been removed in water treatment, the water is
prone to develop such problems if stagnation is allowed. (From
Bland and Favero [3]; with permission.)
A = area of the boundary through which molecules move; dc = concentration

gradient; and dx = distance through which molecules move. Hemodialysis depends
on the process of diffusion for removal of solutes. The amount of material removed
depends on the magnitude of the concentration gradient, the distance the molecule
travels, and the area through which diffusion takes place. For this reason those
dialyzers that have a large surface area, thin membranes, and are designed to maximize
the effect of concentration gradient (countercurrent design) are most efficient at
removing solutes.
Principles of Dialysis: Difusion, Convection, and Dialysis Machines
D=
250
FIGURE 1-9
Ficks diffusion constant, where D = Ficks diffusion coefficient, k = Boltzmans constant;
T = absolute temperature; = viscosity; N = Avogadros number; M = molecular weight;
and = partial molal volume. The diffusion constant is proportional to the temperature of
the solution and inversely proportional to the viscosity and the size of the molecule removed.
4N
3
FIGURE 1-10
Effect of blood flow on clearance of various solutes, Fresenius F-5 membrane. The amount
of solute cleared by a dialyzer depends on the amount delivered to the membrane. The
usual blood flow is 300400 mL/min, which is adequate to deliver the dialysis prescription. On institution of dialysis to a very uremic patient the blood flow is decreased to 160
to 180 mL/min to avoid disequilibrium syndrome. As time goes on, blood flow can be
increased to standard flows as the patient adjusts to dialysis. Most patients require
hemodialysis at least thrice weekly. From this graph it is also evident that small molecules
such as urea (molecular weight 60 D) are cleared more easily than large molecules such as
vitamin B12 (molecular weight 1355 D).
Urea
Creatinine
Phosphate
200
Clearance, mL/min
k
6
Vitamin B12
150
1.5
100
50
0
0
100
200
300
Blood flow, mL/min
400
FIGURE 1-11
Hydrostatic ultrafiltration also takes place during hemodialysis.
Because the spent dialysate effluent pump (see Fig. 1-4) creates negative pressure on the dialysate compartment of the membrane unit
and the blood pump creates positive pressure in the blood compartment, there is a net hydrostatic pressure gradient between the compartments. This causes a flow of water and dissolved substances
from blood to the dialysate compartment. The process of solute
transfer associated with this flow of water is called convective
transport. In hemodialysis, the amount of lowmolecular weight
solute (eg, urea) removed by convection is negligible. In the continuous renal replacement therapies, this is a major mechanism for
solute transport.
200
100
Pressure, mmHg
100
200
300
400
Blood
compartment
Dialysate
Net transmembrane
compartment
pressure
1.6

FIGURE 1-12
Dialysis membranes differ in their ability to remove fluid. Differences in ultrafiltration
coefficient (UFR) are shown for two different membranes, F-5 and F-50. The F-50 is
considered a high-flux membrane.
35
UFR, mL/h/mmHg
30
25
20
15
10
5
0
F5
F50
References
1.
Graham T: The Bakerian lectureon osmotic force. Philos Trans R

Soc Lond 1854, 144:177228.
2.
Vlchek DL: Monitoring a hemodialysis water treatment system. In AAMI

Standards and Recommended Practices, vol. 3. Arlington, VA: Association
for the Advancement of Medical Instrumentation; 1993:267277.
3.
4.
Bland LA, Favero MS: Microbiologic aspects of hemodialysis systems. In

AAMI Standards and Recommended Practices, vol. 3. Arlington, VA:
Association for the Advancement of Medical Instrumentation; 1993:257265.
Daniels F, Alberty RA: Physical Chemistry. New York : John Wiley &
Sons; 1955.
Dialysate Composition
in Hemodialysis and
Peritoneal Dialysis
Biff F. Palmer
he goal of dialysis for patients with chronic renal failure is to

restore the composition of the bodys fluid environment toward
normal. This is accomplished principally by formulating a
dialysate whose constituent concentrations are set to approximate
normal values in the body. Over time, by diffusional transfer along
favorable concentration gradients, the concentrations of solutes that
were initially increased or decreased tend to be corrected. When an
abnormal electrolyte concentration poses immediate danger, the
dialysate concentration of that electrolyte can be set at a nonphysiologic level to achieve a more rapid correction. On a more chronic basis
the composition of the dialysate can be individually adjusted in order
to meet the specific needs of each patient.
Dialysate Composition for Hemodialysis

In the early days of hemodialysis, the dialysate sodium concentration
was deliberately set low to avoid problems of chronic volume overload such as hypertension and heart failure. As volume removal
became more rapid because of shorter dialysis times, symptomatic
hypotension emerged as a common and often disabling problem during dialysis. It soon became apparent that changes in the serum sodium
concentrationand more specifically changes in serum osmolality
were contributing to the development of this hemodynamic instability.
A decline in plasma osmolality during regular hemodialysis favors a
CHAPTER
2.2
um from
erbate hemodynamic instability during the dialysis procedure

[21]. In this regard, the intradialysis drop in blood pressure
noted in patients dialyzed against a low-calcium bath, while
statistically significant, is minor in degree [22,23]. Nevertheless,
for patients who are prone to intradialysis hypotension avoiding low calcium dialysate concentration may be of benefit. On
the other hand, the use of a lower calcium concentration in the
dialysate allows the use of increased doses of calcium-containing
phosphate binders and lessens dependence on binders containing
aluminum. In addition, use of 1,25-dihydroxyvitamin D can be
liberalized to reduce circulating levels of parathyroid hormone
and, thus, the risk of inducing hypercalcemia. With dialysate
calcium concentrations below 1.5 mmol/L, however, patients
need close monitoring to ensure that negative calcium balance
does not develop and that parathyroid hormone levels remain
in an acceptable range [24].
plasma to dialysate. The use of a higher sodium concentration
Dialysate Composition for Peritoneal Dialysis
fluid shift from the extracellular space to the intracellular

space, thus exacerbating the volume-depleting effects of dialysis. With the advent of high-clearance dialyzers and more efficient dialysis techniques, this decline in plasma osmolality
becomes more apparent, as solute is removed more rapidly.
Use of dialysate of low sodium concentration would tend further to enhance the intracellular shift of fluid, as plasma tends
to become
even more hyposmolar consequent to the movement of sodi-
dialysate (>140 mEq/L) has been among the most efficacious

and best tolerated therapies for episodic hypotension [13].
The high sodium concentration prevents a marked decline in
the plasma osmolality during dialysis, thus protecting the extracellular volume by minimizing osmotic fluid loss into the cells.
In the early 1960s acetate became the standard dialysate
buffer for correcting uremic acidosis and offsetting the diffusive
losses of bicarbonate during hemodialysis. Over the next several
years reports began to accumulate that linked routine use of
acetate with cardiovascular instability and hypotension during
dialysis. As a result, dialysate containing bicarbonate began to
re-emerge as the principal dialysate buffer, especially as advances
in biotechnology made bicarbonate dialysate less expensive and
less cumbersome to use. For the most part, the bicarbonate concentration used consistently in most dialysis centers is 35
mmol/L. Emphasis is now being placed on individually adjusting
the dialysate bicarbonate concentration so as to maintain the
predialysis tCO2 concentration above 23 mmol/L [1216].
Increasing evidence suggests that correction of chronic acidosis
is of clinical benefit in terms of bone metabolism and nutrition.
Dialysis assumes a major role in the maintenance of a normal
serum potassium concentration in patients with end-stage renal
disease. Excess potassium is removed by using a dialysate with a
lower potassium concentration, so that a gradient is achieved
that favors movement of potassium. In general, one can expect
only up to 70 to 90 mEq of potassium to be removed during a
typical dialysis session. As a result, one should not overestimate
the effectiveness of dialysis in the treatment of severe hyperkalemia. The total amount removed varies considerably and is
affected by changes in acid-base status, in tonicity, in glucose and
insulin concentration, and in catecholamine activity [1720].
The concentration of calcium in the dialysate has implications
for metabolic bone disease and hemodynamic stability. Like the
other constituents of the dialysate, the calcium concentration
should be tailored to the individual patient [21]. Some data suggest
that lowering the dialysate calcium concentration would exac-
To meet the ultrafiltration requirements of patients on peritoneal

dialysis, the peritoneal dialysate is deliberately rendered hyperosmolar relative to plasma, to create an osmotic gradient that
favors net movement of water into the peritoneal cavity. In
commercially available peritoneal dialysates, glucose serves as
the osmotic agent that enhances ultrafiltration. Available concentrations range from 1.5% to 4.25% dextrose. Over time, the
osmolality of the dialysate declines as a result of water moving
into the peritoneal cavity and of absorption of dialysate glucose.
The absorption of glucose contributes substantially to the calorie
intake of patients on continuous peritoneal dialysis. Over time,
this carbohydrate load is thought to contribute to progressive
obesity, hypertriglyceridemia, and decreased nutrition as a
result of loss of appetite and decreased protein intake. In addition,
the high glucose concentrations and high osmolality of currently
available solutions may have inhibitory effects on the function
of leukocytes, peritoneal macrophages, and mesothelial cells
[25]. In an attempt to develop a more physiologic solution, various
new osmotic agents are now under investigation. Some of these
may prove useful as alternatives to the standard glucose solutions.
Those that contain amino acids have received the most attention.
The sodium concentration in the ultrafiltrate during peritoneal dialysis is usually less than that of extracellular fluid, so
there is a tendency toward water loss and development of hypernatremia. Commercially available peritoneal dialysates have a
sodium concentration of 132 mEq/L to compensate for this tendency toward dehydration. The effect is more pronounced with
increasing frequency of exchanges and with increasing dialysate
glucose concentrations. Use of the more hypertonic solutions
and frequent cycling can result in significant dehydration and
hypernatremia. As a result of stimulated thirst, water intake and
weight may increase, resulting in a vicious cycle.
Potassium is cleared by peritoneal dialysis at a rate similar to
that of urea. With chronic ambulatory peritoneal dialysis and
10 L of drainage per day, approximately 35 to 46 mEq of potassium is removed per day. Daily potassium intake is usually
greater than this, yet significant hyperkalemia is uncommon in
these patients. Presumably potassium balance is maintained by
increased colonic secretion of potassium and by some residual
2.3
Dialysate Composition in Hemodialysis and Peritoneal Dialysis

renal excretion. Given these considerations, potassium is not
routinely added to the dialysate.
The buffer present in most commercially available peritoneal
dialysate solutions is lactate. In patients with normal hepatic
function, lactate is rapidly converted to bicarbonate, so that
each mM of lactate absorbed generates one mM of bicarbonate.
Even with the most aggressive peritoneal dialysis there is no
appreciable accumulation of circulating lactate. The rapid
metabolism of lactate to bicarbonate maintains the high
dialysate-plasma lactate gradient necessary for continued
absorption. The pH of commercially available peritoneal dialysis

solutions is purposely made acidic by adding hydrochloric acid
to prevent dextrose from caramelizing during the sterilization
procedure. Once instilled, the pH of the solution rises to values
greater than 7.0. There is some evidence that the acidic pH of
the dialysate, in addition to the high osmolality, may impair the
hosts peritoneal defenses [25,26].
To avoid negative calcium balanceand possibly to suppress
circulating parathyroid hormonecommercially available peritoneal dialysis solutions evolved to have a calcium concentration
150
Interstitial
space
Cell
Cell
Low-sodium dialysate
BUN
Intravascular
space
H2O
Decreased
osmolality
BUN
Step
Linear
Exponential
High-sodium dialysate
BUN
H2O
Stable osmolality
H2O
BUN
Na
H2O
Less vascular refilling

Peripheral vasoconstriction
Exacerbated autonomic
insufficiency
-inhibits afferent sensing
- CNS efferent outflow
Venous pooling secondary
to PGE2
Na concentration, mEq/L
Baseline
145
140
Hypotension
1
of 3.5 mEq/L (1.75 mmol/L). This concentration is equal to or

slightly greater than the ionized concentration in the serum of
most patients. As a result, there is net calcium absorption in
most patients treated with a conventional chronic ambulatory
peritoneal dialysis regimen. As the use of calcium-containing
phosphate binders has increased, hypercalcemia has become a
common problem when utilizing the 3.5 mEq/L calcium
dialysate. This complication has been particularly common in
patients treated with peritoneal dialysis, since they have a much
greater incidence of adynamic bone disease than do hemodialysis
patients [27]. In fact, the continual positive calcium balance
associated with the 3.5-mEq/L solution has been suggested to
be a contributing factor in the development of this lesion. The
low bone turnover state typical of this disorder impairs accrual
2
Time, h
of administered calcium, contributing to the development of

hypercalcemia. As a result, there has been increased interest in
using a strategy similar to that employed in hemodialysis,
namely, lowering the calcium content of the dialysate. This
strategy can allow increased use of calcium-containing phosphate
binders and more liberal use of 1,25-dihydroxyvitamin D to
effect decreases in the circulating level of parathyroid hormone.
In this way, development of hypercalcemia can be minimized.
Dialysate Na in Hemodialysis
2.4
INDICATIONS AND CONTRAINDICATIONS FOR USE

OF SODIUM MODELING (HIGH/LOW PROGRAMS)
Indications
Intradialysis hypotension
Cramping
Initiation of hemodialysis in setting of severe azotemia
Hemodynamic instability (eg, intensive care setting)
Contraindications
Intradialysis development of hypertension
Large interdialysis weight gain induced by high-sodium dialysate
Hypernatremia
FIGURE 2-1
Use of a low-sodium dialysate is more often associated with intradialysis hypotension as a result of several mechanisms [4]. The
drop in serum osmolality as urea is removed leads to a shift of
water into the intracellular compartment that prevents adequate
refilling of the intravascular space. This intracellular movement of
Dialysate Buffer in Hemodialysis

Acid concentrate
NaCl
CaCl
KCL
MgCl
Acetic acid
Dextrose
NaHCO3
concentrate
NaHCO3
Pure H2O
Final dialysate
Na
Cl
Ca
Acetate
K
HCO3
Mg
Dextrose
137 mEq/L
105 mEq/L
3.0 mEq/L
4.0 mEq/L
2.0 mEq/L
33 mEq/L
0.75 mEq/L
200 mg/dl
water, combined with removal of water by ultrafiltration, leads to contraction of the

intravascular space and contributes to the development of hypotension. High-sodium
dialysate helps to minimize the development of hypo-osmolality. As a result, fluid can be
mobilized from the intracellular and interstitial compartments to refill the intravascular
space during volume removal. Other potential mechanisms whereby low-sodium dialysate
contributes to hypotension are indicated. Nasodium; BUNblood urea nitrogen;
PGE2prostaglandin E2.
FIGURE 2-2
There has been interest in varying the concentration of sodium (Na) in the dialysate during
the dialysis procedure so as to minimize the potential complications of a high-sodium solution
and yet retain the beneficial hemodynamic effects. A high sodium concentration dialysate is
used initially and progressively the concentration is reduced toward isotonic or even hypo-
H 2O
MECHANISMS BY WHICH ACETATE BUFFER

CONTRIBUTES TO HEMODYNAMIC INSTABILITY
Directly decreases peripheral vascular resistance in approximately 10% of patients
Stimulates release of the vasodilator compound interleukin 1
Induces metabolic acidosis via bicarbonate loss through the dialyzer
Produces arterial hypoxemia and increased oxygen consumption
?Decreased myocardial contractility
tonic levels by the end of the procedure. The concentration of sodium can be reduced in a linear, exponential, or step pattern. This
method of sodium control allows for a diffusive sodium influx early
in the session to prevent a rapid decline in plasma osmolality secondary to efflux of urea and other small-molecular weight solutes.
During the remainder of the procedure, when the reduction in
osmolality accompanying urea removal is less abrupt, the dialysate
is sodium level is set lower, thus minimizing the development of
2.5
hypertonicity and any resultant excessive thirst, fluid gain, and hypertension in the interdialysis period. In some but not all studies, sodium modeling has been shown to be effective in treating intradialysis hypotension
5.0
and cramps [5-11].

FIGURE 2-3
Indications and contraindications for use of sodium modeling
(high/low programs). Use of a sodium modeling program is not indicated in all patients. In fact most patients do well with the dialysate
sodium set at 140 mEq/L. As a result the physician needs to be
aware of the benefits as well as the dangers of sodium remodeling.
Start hemodialysis
Plasma potassium, mM
4.5
4.0
3.5
3.0
End hemodialysis
2.5
0
2
Time, h
Dialysis
membrane
FACTORS RELATED TO DIALYSIS THAT AFFECT

DISTRIBUTION OF POTASSIUM BETWEEN CELLS
AND THE EXTRACELLULAR FLUID
K+
Factors that enhance cell potassium uptake
Insulin
2-adrenergic receptor agonists
Alkalemia
Factors that reduce cell potassium uptake or increase potassium efflux
2-adrenergic receptor blockers
Acidemia (mineral acidosis)
Hypertonicity
-adrenergic receptor agonists
FIGURE 2-4
The current utilization of a bicarbonate dialysate requires a specially designed system that mixes a bicarbonate and an acid concentrate with purified water. The acid concentrate contains a small
amount of lactic or acetic acid and all the calcium and magnesium.
The exclusion of these cations from the bicarbonate concentrate
prevents the precipitation of magnesium and calcium carbonate
that would otherwise occur in the setting of a high bicarbonate
concentration. During the mixing procedure the acid in the acid
Dialysis
membrane
K+
K+
B
K+
Less K
removal
Glucose-containing dialysate
Correction of metabolic acidosis
during hemodialysis
Pre-dialysis treatment with -stimulants
concentrate reacts with an equimolar amount of bicarbonate to

generate carbonic acid and carbon dioxide. The generation of carbon dioxide causes the pH of the final solution to fall to approximately 7.07.4. The acidic pH and the lower concentrations in the
final mixture allow the calcium and magnesium to remain in solution. The final concentration of bicarbonate in the dialysate is
approximately 3338 mmol/L.
2.6
FIGURE 2-5
Step 1: Control serum

phosphate
Low-phosphate diet
(8001000 mg/d)
Phophate binders
Step 2: Normalize
serum calcium
If calcium is still low
after control of
phosphate, treat with
1,25-(OH)2 vitamin D
Use calcium-containing
phosphate binders
1.01.5 g dietary calcium
Step 3: Control
secondary
hyperparathyroidism
Treat with 1,25(OH)2
vitamin D
Individualize
dialysate calcium
Low-calcium dialysate
Low-calcium dialysate
High-calcium
dialysate
Helps prevent hypercalcemia

secondary to high-dose
calcium containing phosphate
binders and vitamin D
Monitor for negative
calcium balance
Promotes positive
calcium balance
Suppresses parathyroid
hormone levels
Better hemodynamic stability
Risk of hypercalcemia
? Risk of adynamic bone disease
Mechanisms by which acetate buffer contributes to hemodynamic

instability. Although bicarbonate is the standard buffer in use
today, hemodynamically stable patients can be dialyzed safely using
as acetate-containing dialysis solution. Since muscle is the primary
site of metabolism of acetate, patients with reduced muscle mass
tend to be acetate intolerant. Such patients include malnourished
and elderly patients and women.
Dialysate Potassium in
Hemodialysis
2.7
FIGURE 2-6
ADVANTAGES AND DISADVANTAGES OF INDIVIDUALIZING VARIOUS COMPONENTS OF HEMODIALYSATE

Dialysate component
and adjustment
Advantages
Disadvantages
Sodium:
Increased
More hemodynamic stability, less cramping
Dipsogenic effect, increased interdialytic weight gain,

? chronic hypertension
Intradialytic hypotension and cramping more common
Decreased (rarely used)

Calcium:
Increased
Decreased
Potassium:
Increased
Decreased
Bicarbonate:
Increased
Decreased
Magnesium:
Increased
Decreased
Less interdialytic weight gain

Suppression of PTH, promotes hemodynamic stability in HD
Permits greater use of vitamin D and calcium containing
phosphate binders
Hypercalcemia with vitamin D and high-dose calcium-containing

phosphate binders, ? contribution to adynamic bone disease in PD
Potential for negative calcium balance, stimulation of PTH,
slight decrease in hemodynamic stability
Less arrhythmias in setting of digoxin or coronary heart disease

? improved hemodynamic stability
Permits greater dietary intake of potassium with less hyperkalemia
? improvement in myocardial contractility
Limited by hyperkalemia
Corrects chronic acidosis thereby benefits nutrition and bone metabolism

Less metabolic alkalosis
Post-dialysis metabolic alkalosis

Potential for chronic acidosis
? Less arrhythmias, ? hemodynamic benefit

Permits greater use of magnesium containing phosphate binders which in tum
permits reduced dose of calcium binders and results in less hypercalcemia
Potential for hypermagnesemia

Symptomatic hypomagnesemia
Increased arrhythmias, may exacerbate autonomic insufficiency
Plasma potassium concentration can be expected to fall rapidly in the early stages of dialysis, but as it drops, potassium removal becomes less efficient [17,18]. Since potassium is
freely permeable across the dialysis membrane, movement of potassium from the intracellular space to the extracellular space appears to be
the limiting factor that accounts for the smaller fractional decline in potassium concentration at lower plasma potassium concentrations.
COMPOSITION OF A
COMMERCIALLY AVAILABLE
PERITONEAL DIALYSATE
Solute
Sodium, mEq/L
Potassium, mEq/L
Chloride , mEq/L
Calcium , mEq/L
Magnesium, mEq/L
D, L-Lactate, mEq/L
Glucose, g/dL
Osmolality
pH
Dianeal PD-2
132
0
96
3.5
0.5
40
1.5, 2.5, 4.25
346, 396, 485
5.2
Presumably, the movement of potassium out of cells and into the extracellular space is
slower than the removal of potassium from the extracellular space into the dialysate, so a
disequilibrium is created. The rate of potassium removal is largely a function of its predialysis
concentration. The higher the initial plasma concentration, the greater is the plasma-dialysate
gradient and, thus, the more potassium is removed. After the completion of a standard
dialysis treatment there is an increase in the plasma concentration of potassium secondary
to continued exit of potassium from the intracellular space to the extracellular space in an
attempt to re-establish the intracellular-extracellular potassium gradient.
FIGURE 2-7
2.8
The total extracellular potassium content is only about 50 to

60 mEq/L. Without mechanisms to shift potassium into the cell, small potassium loads would lead to severe hyperkalemia. These mechanisms are of particular importance in patients with end-stage
renal disease since the major route of potassium excretion
is eliminated from the body by residual renal clearance and
enhanced gastrointestinal excretion.
FIGURE 2-8
During a typical dialysis session approximately 80 to 100 mEq/L
of potassium is removed from the body. A, Potassium (K) flux from
the extracellular space across the dialysis membrane exceeds the
flux of potassium out of the intracellular space. B, The movement
of potassium between the intra- and extracellular spaces is controlled by a number of factors that can be modified during the dialysis procedure [17,18]. As compared with a glucose-free dialysate,
a bath that contains glucose is associated with less potassium
removal [19]. The presence of glucose in the dialysate stimulates
insulin release, which in turn has the effect of shifting potassium
into the intracellular space, where it becomes less available for
removal by dialysis. Dialysis in patients who are acidotic is also
associated with less potassium removal since potassium is shifted
into cells as the serum bicarbonate concentration rises. Finally,
patients treated with inhaled stimulants, as for treatment of
hyperkalemia, will have less potassium removed during dialysis
since stimulation causes a shift of potassium into the cell [20].
High-Efficiency and
High-Flux Hemodialysis
Sivasankaran Ambalavanan
Gary Rabetoy
Alfred K. Cheung
emodialysis remains the major modality of renal replacement

therapy in the United States. Since the 1970s the drive for
shorter dialysis time with high urea clearance rates has led to
the development of high-efficiency hemodialysis. In the 1990s, certain
biocompatible features and the desire to remove amyloidogenic 2microglobulin has led to the popularity of high-flux dialysis. During
the 1990s, the use of high-efficiency and high-flux membranes has
steadily increased and use of conventional membrane has declined [1].
In 1994, a survey by the Centers for Disease Control showed that
high-flux dialysis was used in 45% and high-efficiency dialysis in 51%
of dialysis centers (Fig. 3-1) [1].
Despite the increasing use of these new hemodialysis modalities the
clinical risks and benefits of high-performance therapies are not welldefined. In the literature published over the past 10 years the definitions
of high-efficiency and high-flux dialysis have been confusing.
Currently, treatment quantity is not only defined by time but also by
dialyzer characteristics, ie, blood and dialysate flow rates. In the past,
when the efficiency of dialysis and blood flow rates tended to be low,
treatment quantity was satisfactorily defined by time. Today, however,
treatment time is not a useful expression of treatment quantity because
efficiency per unit time is highly variable.
CHAPTER
3.2
Dialyzers
50
HIGH-PERFORMANCE EXTRACORPOREAL THERAPIES FOR

END-STAGE RENAL DISEASE
Centers, %
40
FIGURE 3-2
The four highperformance extracorporeal therapies
for end-stage renal
disease are listed [2].
High-efficiency hemodialysis
High-flux hemodialysis
Hemofiltration, intermittent
Hemodiafiltration, intermittent
30
20
10
0
1986
1988
1990
1992
1994
1996
Year
FIGURE 3-1
Centers using high-flux dialyzers have increased threefold from
1986 to 1996 because of their ability to remove middle molecules.
(From Tokars and coworkers [1]; with permission.)
DEFINITIONS OF FLUX, PERMEABILITY, AND EFFICIENCY

Flux
Measure of ultrafiltration capacity
Low and high flux are based on the ultrafiltration coefficient (Kuf)
Low flux: Kuf <10 mL/h/mm Hg
High flux: Kuf >20 mL/h/mm Hg
Permeability
Measure of the clearance of the middle molecular weight molecule (eg, 2-microglobulin)
General correlation between flux and permeability
Low permeability: 2-microglobulin clearance <10 mL/min
High permeability: 2-microglobulin clearance >20 mL/min
Efficiency
Measure of urea clearance
Low and high efficiency are based on the urea KoA value
Low efficiency: KoA <500 mL/min
High efficiency: KoA >600 mL/min
Komass transfer coefficient; Asurface area.
FIGURE 3-3
Definitions of flux, permeability, and efficiency. The urea value KoA,
as conventionally defined in hemodialysis, is an estimate of the clearance of urea (a surrogate marker of low molecular weight uremic
toxins) under conditions of infinite blood and dialysate flow rates.
The following equation is used to calculate this value:
1-Kd/Qb
QbQd
KoA=
ln
Qb-Qd
1-Kd/Qd
where Ko = mass transfer coefficient
A = surface area
Qb = blood flow rate
Qd = dialysate flow rate
ln = natural log
Kd = mean of blood and dialysate side urea clearance
As conventionally defined in hemodialysis, flux is the rate of water
transfer across the hemodialysis membrane. Dissolved solutes are
removed by convection (solvent drag effect).
Permeability is a measure of the clearance rate of molecules of
middle molecular weight, sometimes defined using 2-microglobulin
(molecular weight, 11,800 D) as the surrogate [3,4]. Dialyzers that
permit 2-microglobulin clearance of over 20 mL/min under usual
clinical flow and ultrafiltration conditions have been defined as highpermeability membrane dialyzers. Because of the general correlation
between water flux and the clearance rate of molecules of middle
molecular weight, the term high-flux membrane has been used
commonly to denote high-permeability membrane.
High-Efficiency and High-Flux Hemodialysis
FIGURE 3-4
Theoretic KoA profile of high- and low-flux dialyzers and highand low-efficiency dialyzers. Note that here the definition of KoA
applies to the product of the mass transfer coefficient and surface
area for solutes having a wide range of molecular weights, and is
not limited to urea. Note also the logarithmic scales on both axes
[3]. Komass transfer coefficient; Asurface area. (From Cheung
and Leypoldt [3]; with permission.)
1000
High flux
100
KOA, mL/min
3.3
10
Low flux
1
High efficiency
Low efficiency
0.1
0.01
10
100
1000
100,000
10,000
Solute molecular weight, D
FIGURE 3-5
Classification of high-performance dialysis. Some authors have defined high-efficiency
hemodialysis as treatment in which the urea clearance rate exceeds 210 mL/min. High-flux
dialysis, arbitrarily defined as a 2-microglobulin clearance of over 20 mL/min, is achieved
using high-flux membranes [3,4].
CLASSIFICATION OF HIGHPERFORMANCE DIALYSIS

High-efficiency low-flux hemodialysis
High-efficiency high-flux hemodialysis
Low-efficiency high-flux hemodialysis
400
CHARACTERISTICS OF HIGH-EFFICIENCY DIALYSIS
Urea clearance rate, mL/min
350
KOA=1000
300
250
KOA=500
200
150
Urea clearance rate is usually >210 mL/min

Urea KoA of the dialyzer is usually >600 mL/min
Ultrafiltration coefficient of the dialyzer (Kuf) may be high or low
Clearance of middle molecular weight molecules may be high or low
Dialysis can be performed using either cellulosic or synthetic membrane dialyzers
100
50
0
0
50
150
250
350
450
500
Blood flow rate, mL/min
FIGURE 3-6
Comparison of urea clearance rates between low- and high-efficiency
hemodialyzers (urea KoA = 500 and 1000 mL/min, respectively).
The urea clearance rate increases with the blood flow rate and
gradually reaches a plateau for both types of dialyzers. The plateau
value of KoA is higher for the high-efficiency dialyzer. At low blood
flow rates (<200 mL/min), however, the capacity of the high-efficiency dialyzer cannot be exploited and the clearance rate is similar to
that of the low-flux dialyzer [3,6]. Komass transfer coefficient;
Asurface area. (From Collins [6]; with permission.)
FIGURE 3-7
Characteristics of high-efficiency dialysis. High-efficiency dialysis is
arbitrarily defined by a high clearance rate of urea (>210 mL/min).
High-efficiency membranes can be made from either cellulosic or
synthetic materials. Depending on the membrane material and surface
area, the removal of water (as measured by the ultrafiltration coefficient or Kuf) and molecules of middle molecular weight (as measured
by 2-microglobulin clearance) may be high or low [3,4,6,7].
3.4

FIGURE 3-8
Differences between high- and low-efficiency hemodialysis.
Conventional hemodialysis refers to low-efficiency low-flux
hemodialysis that was the popular modality before the 1980s [3,6].
DIFFERENCES BETWEEN HIGH- AND

LOW-EFFICIENCY HEMODIALYSIS
Dialyzer KoA
Blood flow
Dialysate flow
Bicarbonate dialysate
High efficiency, mL/min
Low efficiency, mL/min
600
350
500
Necessary
<500
<350
<500
Optimal
TECHNICAL REQUIREMENTS
FOR HIGH-EFFICIENCY DIALYSIS
High-efficiency dialyzer
Large surface area (A)
High mass transfer coefficient (Ko)
Both (high KoA)
High blood flow (350 mL/min)
High dialysate flow (500 mL/min)
Bicarbonate dialysate
FIGURE 3-9
Technical requirements for high-efficiency
dialysis. The KoA is the theoretic value of
the urea clearance rate under conditions of
infinite blood and dialysate flow. High blood
and dialysate flow rates are necessary to
achieve optimal performance of high-efficiency dialyzers. Bicarbonate-containing
dialysate is necessary to prevent symptoms
associated with acetate intolerance (ie, nausea,
vomiting, headache, and hypotension),
worsening of metabolic acidosis, and cardiac arrhythmia [6,8,9]. Komass transfer
coefficient; Asurface area.
CONCENTRATION OF DIALYSATE
IN HIGH-EFFICIENCY DIALYSIS
Dialysate
Concentration
Sodium
Potassium
Acetate
Bicarbonate
Magnesium
Calcium
Glucose
139145 mEq/L
04 mEq/L
2.54.5 mEq/L
3540 mEq/L
1 mEq/L
2.53.5 mEq/L
0200 mg/dL
FIGURE 3-10
Concentration of dialysate in high-efficiency
dialysis. Although the concentration of
other ions is variable, high bicarbonate
concentration, relative to that of acetate,
is essential for high-efficiency dialysis in
order to minimize the transfer of acetate
into the patient.
FACTORS INFLUENCING BLOOD

FLOW IN HIGH-EFFICIENCY
HEMODIALYSIS
Type of access
Native arteriovenous fistulae, polytetrafluoroethylene grafts, twin catheter systems:
high blood flow rate, >350 mL/min
Permanent catheters, temporary intravenous
catheters: low blood flow rate, <350 mL/min
Needle design: size, thickness, and length
Blood tubing
Pump design
FIGURE 3-11
Factors influencing blood flow in high-efficiency hemodialysis. Arteriovenous fistulae
often have blood flow rates of over 1000
mL/min, as measured by current noninvasive
devices. Polytetrafluoroethylene grafts and
the newly introduced twin catheter systems
also are capable of providing the blood
flow rates necessary for high-efficiency
hemodialysis. In contrast, most other temporary or semipermanent catheters cannot
provide sufficient blood flow reliably
enough for adequate dialysis delivery in a
short time period. Needles, blood tubing
diameter, and blood pumps may also contribute to this problem [8,9].
CAUSES OF HIGH-EFFICIENCY
DIALYSIS FAILURE
Access-related
Low blood flow rate
High recirculation rate
Time-related
Patient not adherent to prescribed time
Staff not adherent to prescribed time
Failure to adjust time for conditions such as alarm,
dialysate bypass, and hypotension
FIGURE 3-12
Causes of high-efficiency dialysis failure.
The maintenance of a high blood flow rate
(>350 mL/min) is essential for high-efficiency
hemodialysis. Fistula recirculation, regardless
of the blood flow rate, compromises
achievement of the urea Kt/V goal.
Interruptions during the prescribed short
treatment time further compromise the
overall delivery of the prescribed Kt/V [6,7].
Kurea clearance; ttime of therapy;
Vvolume of distribution.
BENEFITS OF HIGHEFFICIENCY DIALYSIS

Higher clearance of small solutes, such as urea,
compared with conventional dialysis without
increase in treatment time
Better control of chemistry
Potentially reduced morbidity
Potentially higher patient survival rates
FIGURE 3-13
Benefits of high-efficiency dialysis. With
improved control of biochemical parameters
(such as potassium, hydrogen ions, phosphate,
urea, and other nitrogenous compounds)
the potential exists for reduced morbidity
and mortality without increasing dialysis
treatment time [5,7].
CHARACTERISTICS OF HIGH-FLUX DIALYSIS

Dialyzer membranes are characterized by a high ultrafiltration coefficient
(Kuf > 20 mL/h/mm Hg)
High clearance of middle molecular weight molecules occurs (eg, 2-microglobulin)
Urea clearance can be high or low, depending on the urea KoA of the dialyzer
Dialyzers are made of either synthetic or cellulosic membranes
High-flux dialysis requires an automated ultrafiltration control system
3.5
LIMITATIONS OF HIGHEFFICIENCY DIALYSIS

Low margin of safety if short treatment
time is prescribed
Potential vascular access damage
Dialysis disequilibrium syndrome
FIGURE 3-14
Limitations of high-efficiency dialysis.
Removal of a large volume of fluid over a
short time period (22.5 h) increases the likelihood of hypotension, especially in patients
with poor cardiac function or autonomic
neuropathy. The loss of a fixed amount of
treatment time has a proportionally greater
impact during a short treatment time than
during a long treatment time. Thus, the
margin of safety is narrower if a short
treatment time is used in conjunction with
high-efficiency dialysis compared with
conventional hemodialysis with a longer
treatment time. Although unproved, high
blood flow rates may predispose patients to
vascular access damage. Rapid solute shifts
potentially precipitate the dialysis disequilibrium syndrome in those patients with a very
high blood urea nitrogen concentration,
especially during the first treatment [3,7,9].
FIGURE 3-15
Characteristics of high-flux dialysis. Because of the high ultrafiltration coefficients of high-flux membranes, high-flux dialysis requires
an automated ultrafiltration control system to avoid accidental
profound intravascular volume depletion. Because high-flux membranes tend to have larger pores, clearance of middle molecular
weight molecules is usually high. Urea clearance rates for high-flux
dialyzers are still dependent on urea KoA values, which can be
either high (ie, high-flux high-efficiency) or low (ie, high-flux lowefficiency) [3,4,10]. Komass transfer coefficient; Asurface area.
3.6
TECHNICAL REQUIREMENTS
FOR HIGH-FLUX DIALYSIS
POTENTIAL BENEFITS OF
HIGH-FLUX DIALYSIS
High-flux dialyzer
Automated ultrafiltration control system
FIGURE 3-16
Technical requirements for high-flux dialysis.
Because of the potential for reverse filtration
(movement of fluid from dialysate to the
blood compartment) to occur, use of a
pyrogen-free dialysate is preferred but not
mandatory. Bicarbonate concentrate used
to prepare dialysate is particularly prone to
bacterial overgrowth when stored for more
than 2 days [5,8].
Delayed onset and risk of dialysis-related amyloidosis

because of enhanced 2-microglobulin clearance
[11,12]
Increased patient survival resulting from higher
clearance of middle molecular weight molecules
[12,13,15,16]
Reduced morbidity and hospital admissions [14,16]
Improved lipid profile [16,17]
Higher clearance of aluminum [18]
Improved nutritional status [19,20]
Reduced risk of infection [16,21]
Preserved residual renal function [22]
Low-flux low-efficiency
CA90
CF12
Low-flux high-efficiency
CA150
T150
High-flux low-efficiency
F50
PAN 150P
High-flux high-efficiency
CT190
F80
Enhanced drug clearance, requiring supplemental

dose after dialysis
High cost of dialyzers
FIGURE 3-18
Limitations of high-flux dialysis. The
enhanced clearance of drugs depends on
the physicochemical characteristics of
the specific drug and dialysis membrane.
Because of their relative high costs, highflux dialyzers are usually reused.
FIGURE 3-17
Potential benefits of high-flux dialysis.
Data are accumulating that support many
potential benefits of high-flux dialysis.
Large-scale randomized prospective trials,
however, are unavailable.
EXAMPLES OF COMMONLY USED DIALYZERS

Dialyzer type
LIMITATIONS OF
HIGH-FLUX DIALYSIS
Material
Surface area, m2
KoA (in vitro), mL/min
Cellulose acetate
Cuprammonium
0.9
0.7
410
418
Cellulose acetate
Cuprammonium
1.5
1.5
660
730
Polysulfone
Polyacrylonitrile
0.9
1.0
520
420
Cellulose triacetate
Polysulfone
1.9
1.8
920
945

Adapted from Leypoldt and coworkers [4] and Van Stone [22].
FIGURE 3-19
Examples of commonly used dialyzers.
Efficiency refers to the capacity to remove
urea; flux refers to the capacity to remove
water, and indirectly, the capacity to remove
molecules of middle molecular weight.
Cellulosic membranes can be either low flux
or high flux. Similarly, synthetic membranes
can be either low flux or high flux. Highefficiency membranes usually have large
surface areas.
3.7
Solutes
Cb
Cb
Cb
Postdilution
Ultrafiltrate
Solute flux
Fluid flux
Cd
Solute flux
Predilution
Blood
Membrane
Ultrafiltrate
FIGURE 3-20
Solute transport in hemodialysis. The primary
mechanism of solute transport in hemodialysis
is diffusion, although convective transport
is also contributory. Solutes small enough
to pass through the dialysis membrane diffuse
down a concentration gradient from a higher
plasma concentration (Cb) to a lower dialysate
concentration (Cd). The arrow represents
the direction of solute transport.
Postdilution
Ultrafiltrate
Dialysate
Predilution
Blood
Blood
Membrane
Ultrafiltrate
FIGURE 3-21
Solute clearance in hemofiltration.
Hemofiltration achieves solute clearance
by convection (or the solvent drag effect)
through the membrane. In contrast to
diffusive hemodialysis, fluid flux is a prerequisite for the removal of solutes during
hemofiltration, whereas the concentration
gradient is not. For small solutes (eg, urea)
that traverse the membrane unimpeded,
concentrations in the blood compartment
(Cb) and ultrafiltrate compartment (Cuf)
are equivalent. For some molecules of middle molecular weight whose movement
across the membrane is partially restricted,
Cuf is lower than is Cb (ie, the sieving coefficient, defined as Cuf/Cb, is less than 1.0).
Blood
FIGURE 3-22
Fluid replacement in hemofiltration.
Because hemofiltration achieves substantial solute clearance by removing large
volumes of plasma water (which contains
the dissolved solutes), the removed fluid
must be replaced. The replacement fluid
can be infused into the extracorporeal
circuit before the blood enters the filter
(predilution, or replacement before expenditure) or after the blood leaves the filter
(postdilution). More replacement fluid is
required when it is given before filtration
rather than after to provide equivalent
solute clearance because the plasma in
the filter (and therefore the ultrafiltrate)
is diluted in the predilution mode.
FIGURE 3-23
Addition of diffusive transport in hemodiafiltration. In hemodiafiltration, diffusive transport
is added to hemofiltration to augment the clearance of solutes (usually small solutes such
as urea and potassium). Solute clearance is accomplished by circulating dialysate in the
dialysate-ultrafiltrate compartment. Hemodiafiltration is particularly useful in patients
who have hypercatabolism with large urea generation.
3.8
Membranes
Bacteria
Macrophage
ET
FIGURE 3-24
Backfiltration, or reverse filtration, of endotoxins (ET) from dialysate to blood. Reverse
filtration of ET is particularly prone to occur when high-flux membranes are used and the
dialysate is heavily contaminated with bacteria (>2000 CFU/mL) and may result in pyrogenic
reactions. The dialysis membranes are impermeable to intact ET; however, their fragments
(some of which still are pyrogenic) may be small enough to traverse the membrane. Although
the membrane is impermeable to bacteria and blood cells, a mechanical break in the membrane
could result in bacteremia.
ET fragments
Dialysate
Membrane
Blood
H 2O
H 2O
H 2O
H 2O
H 2O
FIGURE 3-25
Dialysis membranes with small and large pores. Although a general correlation exists
between the (water) flux and the (middle molecular weight molecule) permeability of dialysis
membranes, they are not synonymous. A, Membrane with numerous small pores that allow
high water flux but no 2-microglobulin transport. B, Membrane with a smaller surface
area and fewer pores, with the pore size sufficiently large to allow 2-microglobulin transport.
The ultrafiltration coefficient and hence the water flux of the two membranes are equivalent.
A
H 2O
H 2O
H 2O
H 2O
A
FIGURE 3-26
Scanning electron microscopy of a conventional low-flux-membrane
hollow fiber (panel A) and a synthetic high-flux-membrane hollow fiber
(panel B). The low-flux membrane consists of a single layer of relatively
homogenous material. The high-flux membrane has a three-layer structure, ie, finger, sponge, and skin. The skin is a thin semipermeable layer
that functions as the selective barrier; it is mechanically supported by
the sponge and finger layers. (Magnification: finger, 14,000; sponge
17,000; skin 85,000.) (Courtesy of Goehl H, Gambrogroup).
3.9
Dialysate flow rate

FIGURE 3-27
Effect of the dialysate flow rate (Qd) on the urea clearance rate by
a high-efficiency dialyzer with a urea KoA value of 800 mL/min.
At low blood flow rates (<200 mL/min), no difference exists in
urea clearance rates between the two different Qd conditions,
because equilibrium in urea concentrations between blood and
dialysate is readily achieved. When the blood flow rate is high
(>300 mL/min), the higher Qd maintains a higher concentration
gradient for diffusion of urea, and therefore, the urea clearance
rate is higher. Recent studies have shown that the KoA value of dialyzers also increases with higher dialysate flow rates [4], presumably
because of more uniform distribution of dialysate flow. Therefore, the
actual urea clearance rate may increase further (red line). Komass
transfer coefficient; Asurface area.
300
Urea clearance rate, mL/min
280
260
240
220
200
180
160
Qd=800
Qd=500
140
120
100
200
250
300
350
400
450
500
Backfiltration
Blood flow
Pressure, mm Hg
150
Dialysate flow
Blood /Dialysate
inlet
outlet
Pbi
Blood /Dialysate
outlet
inlet
140
Pdi
130
Ultrafiltrate
x
Back filtrate
120
Pdo
110
100
Pbo
FIGURE 3-28
Pressure inside the blood compartment (dark colored arrow) and
the dialysate compartment (light colored arrow) with a fixed net
zero ultrafiltration rate. The pressure gradually decreases in the
blood compartment as blood travels from the inlet toward the outlet.
Beyond a certain point along the dialyzer length (x, where the two
pressure lines intersect), the pressure in the dialysate compartment
exceeds that in the blood compartment, forcing fluid to move from
the dialysate to the blood compartment. This movement of fluid
in the direction opposite to that of the designed ultrafiltration is
called backfiltration. Backfiltration may carry with it contaminants
(eg, endotoxins) from the dialysate. Increasing the net ultrafiltration rate shifts the pressure intersection point to the right and
diminishes backfiltration.
3.10
References
1. Tokars JI, Alter MJ, Miller E, et al.: National surveillance of dialysis
associated disease in the United States: 1994. ASAIO J 1997,
43:108119.
13. Chandran PKG, Liggett R, Kirkpatrick B: Patient survival on

PAN/AN 69 membrane hemodialysis: a ten year analysis. J Am Soc
Nephrol 1993, 4:11991204.
2. United States Renal Data System, 97: Treatment modalities for ESRD
patients. Am J Kidney Dis 1997, 30:S54S66.
14. Hornberger JC, Chernew M, Petersen J, Garber AM: A multivariate

analysis of mortality and hospital admissions with high-flux dialysis.
J Am Soc Nephrol 1992, 3:12271236.
3. Cheung AK, Leypoldt JK: The hemodialysis membranes: a historical

perspective, current state and future prospect. Sem Nephrol 1997,
17:196213.
4. Leypoldt JK, Cheung AK, Agodoa LY, et al.: Hemodialyzer mass
transferarea coefficients for urea increase at high dialysate flow rates.
Kidney Int 1997, 51:20132017.
5. Collins AJ, Keshaviah P: High-efficiency, high flux therapies in
clinical dialysis. In Clinical Dialysis, edn 3. Edited by Nissenson AR.
1995:848863.
6. Collins AJ: High-flux, high-efficiency procedures. In Principles and
Practice of Hemodialysis. Edited by Henrich W. Norwalk, CT:
Appleton & Large; 1996:7688.
7. von Albertini B, Bosch JP: Short hemodialysis. Am J Nephrol 1991,
11:169173.
8. Keshaviah P, Luehmann D, Ilstrup K, Collins A: Technical requirements
for rapid high-efficiency therapies. Artificial Organs 1986, 10:189194.
9. Shinaberger JH, Miller JH, Gardner PW: Short treatment. In
Replacement of Renal Function by Dialysis, edn 3. Edited by Maher
JF. Norwell, MA: Kluwer Academic Publishers; 1989:360381.
10. Barth RH: High flux hemodialysis: overcoming the tyranny of time.
Contrib Nephrol 1993, 102:7397.
11. Van Ypersele, De Strihou C, Jadoul M, et al.: The working party on
dialysis amyloidosis: effect of dialysis membrane and patients age on
signs of dialysis-related amyloidosis. Kidney Int 1991, 39:10121019.
12. Koda Y, Nishi S, Miyazaki S, et al.: Switch from conventional to highflux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients. Kidney Int 1997, 52:10961101.
15. Hakim RM, Held PJ, Stannard DC, et al.: Effect of the dialysis membrane
on mortality of chronic hemodialysis patients. Kidney Int 1996,
50:566570.
16. Churchill DN: Clinical impact of biocompatible dialysis membranes
on patient morbidity and mortality: an appraisal of evidence. Nephrol
Dial Trans 1995, 10(suppl):5256.
17. Seres DS, Srain GW, Hashim SA, et al.: Improvement of plasma
lipoprotein profiles during high flux dialysis. J Am Soc Nephrol 1993,
3:14091415.
18. Mailloux LU: Dialysis modality and patient outcome. UpToDate Med
1995.
19. Parker TF III, Wingard RL, Husni L, et al.: Effect of the membrane
biocompatibility on nutritional parameters in chronic hemodialysis
patients. Kidney Int 1996, 49:551556.
20. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney
Int 1996, 50:343357.
21. Hakim RM, Wingard RL, Parker RA, et al.: Effects of biocompatibility
on hospitalizations and infectious morbidity in chronic hemodialysis
patients. J Am Soc Nephrol 1994, 5:450.
22. Van Stone JC: Hemodialysis apparatus. In Handbook of Dialysis, edn 2.
Edited by Daugirdas JT, Ing TS. Boston/New York: Little, Brown &
Co.; 1994:3152.
Principles of
Peritoneal Dialysis
Ramesh Khanna
Karl D. Nolph
eritoneal dialysis is a technique whereby infusion of dialysis solution into the peritoneal cavity is followed by a variable dwell
time and subsequent drainage. Continuous ambulatory peritoneal dialysis (CAPD) is a continuous treatment consisting of four to
five 2-L dialysis exchanges per day (Fig. 4-1A). Diurnal exchanges last
4 to 6 hours, and the nocturnal exchange remains in the peritoneal
cavity for 6 to 8 hours. Continuous cyclic peritoneal dialysis, in reality, is a continuous treatment carried out with an automated cycler
machine (Fig. 4-1B). Multiple short-dwell exchanges are performed at
night with the aid of an automated cycler machine. Other peritoneal
dialysis treatments consist of intermittent regimens (Fig. 4-2A-C).
During peritoneal dialysis, solutes and fluids are exchanged between
the capillary blood and the intraperitoneal fluid through a biologic
membrane, the peritoneum. The three-layered peritoneal membrane
consists of 1) the mesothelium, a continuous monolayer of flat cells,
and their basement membranes; 2) a very compliant interstitium; and
3) the capillary wall, consisting of a continuous layer of mainly nonfenestrated endothelial cells, supported by a basement membrane. The
mesothelial layer is considered to be less of a transport barrier to fluid
and solutes, including macromolecules, than is the endothelial layer
[1]. The capillary endothelial cell membrane is permeable to water
through aquaporins (radius of approximately 0.2 to 0.4 nm) [2]. In
addition, small solutes and water are transported through ubiquitous
small pores (radius of approximately 0.4 to 0.55 nm). Sparsely populated large pores (radius of approximately 0.25 nm, perhaps mainly
venular) transport macromolecules passively. Diffusion and convection
move small molecules through the interstitium with its gel and sol
phases, which are restrictive owing to the phenomenon of exclusion
[3,4]. The splanchnic blood flow in the normal adult ranges from 1.0
to 2.4 L/min, arising from celiac and mesenteric arteries [5]. The lymphatic vessels located primarily in the subdiaphragmatic region drain
fluid and solutes from the peritoneal cavity through bulk transport.
CHAPTER
4.2
The extent of lymph drainage from the peritoneal cavity is a subject of controversy owing to the lack of a direct method to measure lymph flow.
Dialysis solution contains electrolytes in physiologic concentrations to facilitate correction of acid-base and electrolyte
abnormalities. High concentrations of glucose in the dialysis
solution generate ultrafiltration in proportion to the overall
osmotic gradient, the reflection coefficients of small solutes
relative to the peritoneum, and the peritoneal membrane
hydraulic permeability. Removal of solutes such as urea, creatinine, phosphate, and other metabolic end products from the body
depends on the development of concentration gradients between
blood and intraperitoneal fluid, and the transport is driven by the
process of diffusion. The amount of solute removal is a function
of the degree of its concentration gradient, the molecular size,
membrane permeability and surface area, duration of dialysis, and
charge. Ultrafiltration adds a convective component proportionately more important as the molecular size of the solute increases.
The peritoneal equilibration test is a clinical tool used to characterize the peritoneal membrane transport properties [6]. Solute
transport rates are assessed by the rates of their equilibration
between the peritoneal capillary blood and dialysate (see Fig. 4-8).
The ratio of solute concentrations in dialysate and plasma at specific times during the dwell signifies the extent of solute transport. The
fraction of glucose absorbed from the dialysate at specific times can

be determined by the ratio of dialysate glucose concentrations
at specific times to the initial level in the dialysis solution. Tests
are standardized for the following: duration of the preceding
exchange before the test; inflow volume; positions during
inflow, drain, and dwell; durations of inflow and drain; sampling methods and processing; and laboratory assays [7].
Creatinine and urea clearance rates are the most commonly used
indices of dialysis adequacy in clinical settings. Contributions
of residual renal clearances are significant in determining the
adequacy of dialysis. The mass-transfer area coefficient (MTAC)
represents the clearance rate by diffusion in the absence of ultrafiltration and when the rate of solute accumulation in the dialysis
solution is zero. Peritoneal clearance is influenced by both blood
and dialysate flow rates and by the MTAC [8]. Therefore, the
maximum clearance rate can never be higher than any of these
parameters. At infinite blood and dialysate flow rates, the clearance
rate is equal to the MTAC and is mass-transferlimited. Large molecular weight solutes are mass-transferlimited; therefore, their
clearance rates do not increase significantly with high dialysate flow
rates [9]. In CAPD, blood flow and MTAC rates are higher than is
the maximum achievable urea clearance rate. However, the urea
clearance rate approximately matches the dialysate flow rate, suggesting that the dialysate flow rate limits CAPD clearances.
Peritoneal Dialysis Regimens

Day
Night
Day
Night
Day
Night
Day
Night
Left
2.0
1.0
0.0
Right
2.0
1.0
0.0
Exchanges, n
FIGURE 4-1
Continuous peritoneal dialysis regimens.
A, Continuous ambulatory peritoneal dialysis (CAPD); B, continuous cyclic peritoneal
dialysis (CCPD) is shown. Multiple sequential exchanges are performed during the day
and night so that dialysis occurs 24 hours a
day, 7 days a week.
4.3
Principles of Peritoneal Dialysis
Day
Night
Day
Day
Night
Day
FIGURE 4-2
Intermittent peritoneal dialysis regimens.
Peritoneal dialysis is performed every day
but only during certain hours. A, In daytime
ambulatory peritoneal dialysis (DAPD),
multiple manual exchanges are performed
during the waking hours. B, Nightly peritoneal dialysis (NPD) is also performed
while patients are asleep using an automated
cycler machine. One or two additional daytime manual exchanges are added to
enhance solute clearances.
Night
Left
2.0
1.0
0.0
Left
Night
2.0
1.0
0.0
Solute Removal
Blood urea nitrogen, mg/dL
24
100
60
40
20
0
Dialysate
Blood
20
0
80
160
240
320
400
480
Creatinine, mg/dL
20
80
FIGURE 4-3
Solute removal. Solute concentration gradients are at maximum at
the beginning of dialysis and diminish gradually as dialysis progresses. As the gradients diminish, the solute removal rates decrease.
Solute removal can be enhanced by increasing the dialysate flow
12
8
4
Dialysate
Blood
560
Time, min
16
40
80
120
160 200
Time, min
240
280
320
360
rate by either increasing the intraperitoneal dialysate volume per

exchange or increasing the frequency of exchange. By convection
or enhanced diffusion, solutes are able to accompany the bulk flow
of water. (From Nolph and coworkers [10]; with permission.)

1.0
1.0
0.9
0.9
Dialysate to plasma ratio
0.8
0.7
0.6
0.5
0.4
Urea
Creatinine
Uric acid
Phosphorus
Inulin
Calcium
0.3
0.2
0.1
0
100
200
Dwell time, h
0.5
0.4
Urea
Creatinine
Uric acid
Phosphorus
Inulin
Calcium
0.3
100
200
Total dialysate volume (V)
Creatnine dialysate to
plasma ratio (D/P)
Low transport
0.5
0.6
0.1
FIGURE 4-4
Solute removal. The rates of change of solute concentrations are
similar for 1.5% dextrose dialysis solutions (panel A) and 4.25%
dextrose dialysis solutions (panel B). Hypertonic exchanges enhance
solute removal owing to larger drain volumes. Net solute diffusion
ceases at equilibration when the dialysate to plasma solute ratio (D/P)
High transport
0.7
0.2
300
500
400
Dwell time, min
1.0
0.8
2600
2300
2000
1700
0
NIPD
DAPD
NTPD CCPD
(NE)
FIGURE 4-5
Solute removal. In a highly permeable membrane, smaller molecules
(ie, urea and creatinine) are transported at a faster rate from the
blood to dialysate than are larger molecules, enhancing solute removal.
Similarly, glucose (a small solute used in the peritoneal dialysis solution
to generate osmotic force for ultrafiltration across the peritoneal membrane) is also transported faster, but in the opposite direction. This
high transporter dissipates the osmotic force more rapidly than does
the low transporter. Both osmotic and glucose equilibriums are
attained eventually in both groups, but sooner in the high transporter group. Intraperitoneal volume peaks and begins to diminish
earlier in the high transporter group. When the membrane is less
permeable, solute removal is lower, ultrafiltration volume is larger
at 2 hours or more, and glucose equilibriums are attained later.
300
500
400
Dwell time, min
is near 1.0. Smaller size solutes (ie, urea and creatinine) diffuse
across the membrane faster, equilibrate sooner, and are influenced
more by exchange frequency as compared with larger size solutes
(ie, uric acid, phosphates, inulin, and proteins). (From Nolph and
CAPD
3 4
5
Dwell time, h
CCPD
(DE)
Creatinine clearance
per exchange (Ccr)
4.4
D/P=1
Ccr=V
2
1
Ccr=V D/P
3 4
5
Dwell time, h
Consequently, intraperitoneal volume peaks later. Ultrafiltration in

a low transporter peaks late during dwell time. Therefore, a low
transporter continues to generate ultrafiltration even after 8 to 10
hours of dwell. The solute creatinine dialysate to plasma ratio
(D/P) increases linearly during the dwell time. Patients with average
solute transfer rates have ultrafiltration and mass transfer patterns
between those of high and low transporters. NIPDnightly intermittent peritoneal dialysis; NTPDnighttime tidal peritoneal dialysis; DAPDdaytime ambulatory peritoneal dialysis; CAPDcontinuous ambulatory peritoneal dialysis; CCPD (NE)continuous
cyclic peritoneal dialysis (night exchange); CCPD (DE)continuous cyclic peritoneal dialysis (day exchange). (From Twardowski
150
140
130
120
110
100
90
Inflow
Sodium, mLq/L
1.5% dextrose
dialysis solutions
100 200 300 400 500

Dwell time, min
150
140
130
120
110
100
90
Inflow
Sodium, mLq/L
Serum and
dialysate
4.25% dextrose
dialysis solutions
FIGURE 4-6
Solute sieving. A, Dialysate sodium concentration is initially reduced and tends to return
to baseline later during a long dwell exchange of 6 to 8 hours. B, Dialysate sodium concentration decreases, particularly when using 4.25% dextrose dialysis solution, because of
the sieving phenomenon. Removal of water during ultrafiltration unaccompanied by sodium,
in proportion to its extracellular concentration, is called sodium sieving [7,12]. The peritoneum offers greater resistance to the movement of solutes than does water. This probably
relates to approximately half the ultrafiltrate being generated by solute-free water movement
through aquaporins channels. Therefore, ultrafiltrate is hypotonic compared with plasma.
Dialysate chloride is also reduced below simple Gibbs-Donnan equilibrium, particularly
during hypertonic exchanges. Patients with a low peritoneal membrane transport type tend
to reduce dialysate sodium concentration more than do other patients. Therefore, during a
short dwell exchange of 2 to 4 hours, net electrolyte removal per liter of ultrafiltrate is
well below the extracelluar fluid concentration. As a result, severe hypernatremia, excessive
thirst, and hypertension may develop. This hindrance can be overcome by lowering the
dialysate sodium concentration to 132 mEq/L. In patients who use cyclers with short dwell
exchanges and who generate large ultrafiltration volumes, lower sodium concentrations
may need to be used (such as 118 mEq/L for 2.5% glucose solutions or 109 mEq/L for
4.25% solutions). In continuous ambulatory peritoneal dialysis with long dwell exchanges
of 6 to 8 hours, significant sieving usually does not occur, whereas in automated peritoneal
dialysis with short dwell exchanges, sieving may occur. Sieving predisposes patients to
thirst and less than optimum blood pressure control, especially in those who have low-normal serum sodium levels, those with low peritoneal membrane transporter rates, or both.
(From Nolph and coworkers [10]; with permission.)
Serum and dialysate
100 200 300 400

Dwell time, min
500
FIGURE 4-7
Fluid removal by ultrafiltration. During peritoneal dialysis, hyperosmolar glucose solution
generates ultrafiltration by the process of osmosis. Water movement across the peritoneal
membrane is proportional to the transmembrane pressure, membrane area, and membrane
hydraulic permeability. The transmembrane pressure is the sum of hydrostatic and osmotic
pressure differences between the blood in the peritoneal capillary and dialysis solution in
the peritoneal cavity. Net transcapillary ultrafiltration defines net fluid movement from the
peritoneal microcirculation into the peritoneal cavity primarily in response to osmotic
pressure. Net ultrafiltration would equal the resulting increment in intraperitoneal fluid
volume if it were not for peritoneal reabsorption, mostly through the peritoneal lymphatics.
Peritoneal reabsorption is continuous and reduces the intraperitoneal volume throughout
the dwell. A, The net transcapillary ultrafiltration rate decreases exponentially during the
dwell time, owing to dissipation of the glucose osmotic gradient secondary to peritoneal
glucose absorption and dilution of the solution glucose by the ultrafiltration. Later in the
exchange net, ultrafiltration ceases when the transcapillary ultrafiltration is reduced to a
rate equal to the peritoneal reabsorption. B, When the transcapillary ultrafiltration rate
decreases below that of the peritoneal reabsorption rate, the net ultrafiltration rate becomes
negative. Consequently, the intraperitoneal volume begins to diminish. Thus, peak ultrafiltration and intraperitoneal volumes are observed before osmotic equilibrium during an exchange.
Transcapillary ultrafiltration
Lymphatic absorption
600
500
mL/h
400
300
Peak ultrafiltration
volume
200
4.5
100

0
Peak intraperitoneal volume
2800
Intraperitoneal
2
Dwell time, h
Dialysate
2600
2400
0
2
Dwell time, h
4.6
Dialysate
Serum
Osmolality, mOsm/L
360
340
300
Glucose, mOsm/L
Osmotic
equilibrium
320
2
3
Dwell time, h
Dialysate
Serum
2000
Hypothetical
glucose
equilibrium
1000

C, Osmotic equilibrium most likely precedes glucose equilibrium
because of both solute sieving and the higher peritoneal reflection
coefficient of glucose compared with other dialysate solutes, allowing net transcapillary ultrafiltration to continue at a low rate even
after osmotic equilibrium. D, Ultrafiltration can be maximized by
measures that delay osmotic equilibrium, which can be accomplished by using hypertonic glucose solutions, larger volumes, or
both, during an exchange. More frequent exchanges shorten dwell
times and increase the dialysate flow rate and thus avert attaining
osmotic equilibrium. Additionally, potential exists for enhancing
ultrafiltration by measures that reduce the peritoneal reabsorption
rate. (From Mactier and coworkers [13]; with permission.)
2
3
Dwell time, h
STANDARDIZED 4-HOUR PERITONEAL EQUILIBRATION TEST
FIGURE 4-8
Standardized 4-hour peritoneal equilibration test. Dt/D0 glucosefinal to initial
dialysate glucose ratio.
1. Perform an overnight 8- to 12-h preexchange.

2. Drain the overnight exchange (drain time not to exceed 25 min) with patient in the upright position.
3. Infuse 2 L of dialysis solution over 10 min with patient in the supine position. Roll the patient from side to side after
every 400-mL infusion.
4. After the completion of infusion (0 time) and at 120 min, drain 200 mL of dialysate. Take a 10-mL sample, and
reinfuse the remaining 190 mL into the peritoneal cavity.
5. Position the patient upright, and allow patient ambulation if able.
6. Obtain a serum sample at 120 min.
7. At the end of study (240 min), drain the dialysate with the patient in the upright position
(drain time not to exceed 20 min).
8. Measure the drained volume, and take a 10-mL sample from the drained volume after a good mixing.
9. Analyze the blood and dialysate samples for creatinine and glucose concentrations.
10. Correct the serum and dialysate creatinine concentrations for high glucose level (correction factor 0.000531415).
11. Calculate the dialysate to plasma ratios for creatinine, and so on, and calculate the Dt/D0 glucose.
Correction of creatinine levels

Corrected creatinine (mg/dL)
= Observed creatinine (mg/dL) (glucose [mg/dL] x 0.000531415)
FIGURE 4-9
Equation to correct the creatinine levels in dialysate and serum.
The creatinine levels in dialysate and serum need to be corrected
for high glucose levels, which contribute to formation of noncreatinine
chromogens during the creatinine assay. The correction factor may
vary from one laboratory to another. In our laboratory at the University
of MissouriColumbia, the correction factor is 0.000531415.
Accordingly, the corrected creatinine is calculated as in the equation.
The correction in the serum is minimal due to low blood sugar levels;
however, it is significant in dialysate, especially during the early
phase of dwell (0- and 2-hour dialysate samples).
FIGURE 4-10
Equation to calculate the intraperitoneal residual volume. Residual volume is the volume
of dialysate remaining in the peritoneal cavity after drainage over 20 minutes. The residual
volume can be determined by knowing the dilution factor for solutes such as potassium, urea,
and creatinine during the next instillation. The calculation of residual volumes is based on
the assumption that the mixing of fluid in the peritoneal cavity is instantaneous and complete. This equation is used for the calculation, where Vin is instillation volume; S1 is solute
concentration in pretest exchange dialysate; S2 is solute concentration in instilled dialysis
solution; and S3 is solute concentration immediately after instillation (0 dwell time). The
residual volumes by urea, creatinine, glucose, potassium, and protein are calculated and
averaged for accuracy. The measurement of residual volumes is of limited clinical usefulness; however, it is of great value in a research setting in which accurate determination of
intraperitoneal volume is required.
Intraperitoneal residual volume

R=
Vin(S3 S2)
(S1 S3)
1.1
1.1
0.9
Dialysis to plasma ratio
Dialysis to plasma ratio
0.9
0.7
0.5
0.7
0.5
0.3
0.3
0.1
0.1
1/
2
1.1
1/
2
35
Dialysate to plasma ratio 1000
Glucose
0.9
0.7
0.5
0.3
Hours
Hours
Final to initial dialysate glucose ratio
Creatinine
Urea
Protein
30
25
20
15
10
1/
2
2
Hours
1/
2
2
Hours
FIGURE 4-11
Classification of peritoneal transport function. Based on the peritoneal equilibrium
test results, peritoneal transport function
may be classified into average, high (H),
and low (L) transport types. The average
transport group is further subdivided into
high-average (HA) and low-average (LA)
types. For the population studied by
Twardowski and coworkers [6], the transport classification is based on means; standard deviations (SDs); and minimum and
maximum dialysate to plasma ratio (D/P)
values over 4 hours for urea, creatinine,
glucose, protein, potassium, sodium, and
corrected creatinine (panels AG).
0.1
0
4.7
4.8
Potassium
1.1

The volume of drainage correlates positively
with dialysate glucose and negatively with
D/P creatinine values at 4-hour dwell times
(panel H). (From Twardowski and coworkers [6]; with permission.)
Sodium
1.00
0.9
0.7
0.5
0.3
0.70
1/
2
2
Hours
0.80
H
HA
LA
L
Max
+SD
SD
Min
0.1
0.90
1/
2
2
Hours
ADK vol05 ch p04 fig11F

3500
1.1
Max
+SD
x
SD
Min
Corrected creatinine
3000
0.9
0.7
2000
mL
2500
1500
0.5
1000
0.3
H
HA
LA
L
0.1
0
1/
2
2
Hours
500
0
CLINICAL APPLICATIONS OF THE

PERITONEAL EQUILIBRATION TEST
Peritoneal membrane transport classification
1. Choose peritoneal dialysis regimen.
2. Monitor peritoneal membrane function.
3. Diagnose acute membrane injury.
4. Diagnose causes of inadequate ultrafiltration.
5. Diagnose causes of inadequate solute clearance.
6. Estimate dialysate to plasma ratio of a solute at time t.
7. Diagnose early ultrafiltration failure.
8. Predict dialysis dose.
9. Assess influence of systemic disease on peritoneal membrane function.
Drain
volume
Residual
pre-eq
Volume
post-eq
FIGURE 4-12
In clinical practice it is customary to perform the baseline standardized peritoneal equilibrium test (PET) approximately 3 to 4 weeks
after catheter insertion. The PET is repeated when complications
occur. The standardized test for clinical use measures dialysate
creatinine and glucose levels at 0, 2, and 4 hours of dwell time
and serum levels of creatinine and glucose at any time during
the test. The extensive unabridged test, as originally proposed
by Twardowski and coworkers [6], has become a very important
research tool.
Baseline peritoneal equilibrium test

High
transporter
D/P creatinine
Low average
transporter
D/P creatinine
High average
transporter
D/P creatinine
16%
68%
Low
transporter
D/P creatinine
16%
Baseline peritoneal equilibrium test

High
High average
Low average
Low
NIPD
DAPD
NIPD
CAPD
High-dose CAPD
High-dose CCPD
High-dose CCPD
only when significant
residual renal
function is present
1.0
0.97
0.92
0.9
0.88
0.85
0.80
0.8
0.7
0.0
High
High average
Low average
Low
1.0
2.0
3.0
4.0
4.9
FIGURE 4-13
Population distribution of peritoneal membrane transport types.
Baseline peritoneal equilibrium test results of patients on long-term
peritoneal dialysis in the United States suggest that approximately
68% have average transport rates, 16% have high transport rates,
and another 16% have low transport rates [6]. Similar distributions
of transport types have been documented worldwide [1416].
D/Pdialysate to plasma ratio.
FIGURE 4-14
Using transport type to select a peritoneal dialysis regimen. Because
clearance rates continue to increase with time, patients with low
transport rates are treated with long dwell exchanges, ie, continuous cyclic peritoneal dialysis (CCPD). Owing to the low rate of
increase in the dialysate to plasma ratio (D/P), the clearance rate
per unit of time is augmented relatively little by rapid exchange
techniques such as nightly intermittent peritoneal dialysis (NIPD).
On the contrary, the clearance per exchange rate over long dwell
exchanges would be less in patients with high transport rates.
During the short dwell time, patients with high transport rates
capture maximum ultrafiltration and small solutes are completely
equilibrated. Therefore, these patients are best treated with techniques using short dwell exchanges, ie, NIPD or daytime ambulatory peritoneal dialysis (DAPD). Patients with average transport rates
can be effectively treated with either short or long dwell exchange
techniques. CAPDcontinuous ambulatory peritoneal dialysis.
FIGURE 4-15
Diagnosis of early ultrafiltration failure. The dialysate to plasma ratio (D/P) curve of sodium, during the unabridged peritoneal equilibrium test (2.5% dextrose dialysis solution),
typically shows an initial decrease owing to the high ultrafiltration rate. Because of sodium
sieving, the ultrafiltrate is low in sodium. Consequently, the dialysate sodium is lowered,
resulting in a lower D/P ratio of sodium. Later, during the dwell when ultrafiltration ceases, dialysate sodium tends to equilibrate with that of capillary blood, returning the D/P
ratio of sodium to baseline. Absence of the initial decrease of the D/P of sodium is an indication of ultrafiltration failure and is typically seen in the early phase of sclerosing encapsulating peritonitis. (From Dobbie and coworkers [17]; with permission.)
4.10
(DxV)
P
where C = clearance in mL/min:
DxV = dialysate solute removed per minute;
D = dialysate solute concentration;
V = volume of dialysate in mL/min; and
P = plasma solute concentration
C=
or
C=(D/P) x V
where C = clearance in mL/exchange at time t;
D/P = solute equilibrium rate at time t; and
V = volume of dialysate at time t
Kt/V
where K = urea clearance in mL/min;

t = minutes of therapy; and
V = volume of urea distribution or total
body water
Mass-transfer area coefficient

The diffusive mass transfer is estimated by
M=I
A
(C C )
R P D
where M = diffusive mass transfer:

A = effective membrane surface area;
I = coefficient of proportionality;
R = sum of all resistances;
Cp = solute concentration in the potential
capillary blood; and
CD = solute concentration in the dialysate
Dividing both sides of the equation by solute

concentration in peripheral blood (CB) will
yield instantaneous clearance or the MTAC;
M
A CP CD
=K=I
CB
R CB CB
If the peritoneal capillary blood flow is infinite,

Cp will equal Cb and
A
C
Ki=I
1 D
R
CB
( (
If the dialysate flow is also infinite,

then Co will equal 0, and
A
Ki=Kmax=I
R
FIGURE 4-16
Creatinine and urea clearances rates. These rates are estimated by dividing the amount of
solute removed per unit of time by the plasma solute concentration. Alternatively, clearance
also can be estimated by multiplying the solute equilibration rate per unit of time by the
volume of dialysate into which equilibration occurred over the same unit of time. By convention, the creatinine clearance rate is normalized to body surface area.
The urea clearance is normalized to total body water (volume of urea distribution in the
body) and is expressed as Kt/V. The Kt/Vvalue is a number without a unit ([mL/min min]/
mL). During intermittent dialysis, with a dialysate flow rate of 30 mL/min, the typical urea
clearance is about 18 to 20 mL/min [18]. Increasing the dialysate flow rates to 3.5 to 12
L/h by rapid exchanges increases the urea clearance rate to a maximum of 30 to 40 mL/min.
Beyond this maximum rate, the clearance rate begins to decrease owing to the loss of membrane-fluid contact time with infusion and drainage; inadequate mixing may also occur
[1922]. Clearance could be enhanced by increasing the membrane-solution contact [23].
Continuous dialysate flow techniques using either two catheters or double-lumen catheters
also have enhanced the urea clearance rate to a maximum of 40 mL/min. At these high flow
rates, poor mixing, channeling, abdominal pain, and poor drainage limit successful application. Maintaining a fluid reservoir in the peritoneal cavity (called tidal peritoneal dialysis)
and then replacing only a fraction of the intraperitoneal volume rapidly, increases clearance
rates by about 30% compared with the standard technique using the same doses owing to
maintaining fluid-membrane contact at higher dialysis-solution flow rates [2429]. During
continuous ambulatory peritoneal dialysis (CAPD) in adults, the optimum volume that
ensures complete membrane-solution contact is about 2 L [30,32]. Successful use of 2.5and 3.0-L volumes has been reported in adult patients undergoing CAPD; however, hernial
complications are increased [32,33].
FIGURE 4-17
The mass-transfer area coefficient (MTAC). The MTAC represents the clearance rate by
diffusion in the absence of ultrafiltration and when the solute accumulation in the dialysis
solution is zero [3439]. MTAC is equal to the product of peritoneal membrane permeability (P) and effective peritoneal membrane surface area (S). Thus, when both capillary
blood and dialysate flows are infinite, the clearance rate is directly proportional to the
effective peritoneal surface area and inversely proportional to the overall membrane resistance. However, infinite blood and dialysate flows cannot be achieved, and the maximum
clearance rate is unattainable. The closest measurable value, the MTAC, was introduced.
The MTAC represents an instantaneous clearance without being influenced by ultrafiltration and solute accumulation in the dialysate. The MTAC is measured over a test exchange
during which at least two blood and dialysate samples are obtained at different dwell
times. The precision of the measurement is enhanced with more data points. The MTAC
is seldom used clinically; however, it is a very useful research tool.
4.11
References
1. Clough G, Michel CC: Quantitative comparisons of hydraulic permeability and endothelial intercellular cleft dimensions in single form
capillaries. J Physiol 1988, 405:563576.
22. Tenckhoff H, Ward G, Boen ST: The influence of dialysate volume

and flow rate on peritoneal clearance. Proc Eur Dial Transplant Assoc
1965, 2:113117.
2. Pannekeet MM, Mulder JB, Weening JJ, et al.: Demonstration of

aquaporin-CHIP in peritoneal tissue of uremic and CAPD patients.
Peritoneal Dial Int 1996, 16(suppl 1):S54.
23. Trivedi HS, Twardowski ZJ: Long-term successful nocturnal intermittent

peritoneal dialysis: a ten-year case study. In Advances in Peritoneal
Dialysis. Edited by Khanna R. Toronto, Canada: Peritoneal Dialysis
Publications; 1994:8184.
3. Flessner MF, Dedrick RL, Schultz JS: Exchange of macromolecules

between peritoneal cavity and plasma. Am J Physiol 1985, 248:H15.
4. Flessner MF, Fenstermacher JD, Blasberg RG, Dedrick RL: Peritoneal
absorption of macromolecules studied by quantitative autoradiography.
Am J Physiol 1985, 248:H26.
24. Di Paolo N: Semicontinuous peritoneal dialysis. Dial Transplant

1978, 7:839842.
25. Finkelstein FO, Kliger AS: Enhanced efficiency of peritoneal dialysis
using rapid, small-volume exchanges. ASAIO J 1979, 2:103106.
6. Twardowski ZJ, Nolph KD, Khanna R, et al.: Peritoneal equilibration

test. Peritoneal Dial Bull 1987, 7:138147.
26. Twardowski ZJ, Nolph KD, Khanna R, et al.: Tidal peritoneal dialysis.
In Ambulatory Peritoneal Dialysis: Proceedings of the IVth Congress
of the International Society for Peritoneal Dialysis, Venice, Italy, June
1987. Edited by Avram MM, Giordano C. New York: Plenum;
1990:145149.
7. Ahearn DJ, Nolph KD: Controlled sodium removal with peritoneal

dialysis. Trans Am Soc Artif Intern Organs 1972, 28:423.
27. Twardowski ZJ, Prowant BF, Nolph KD, et al.: Chronic nightly tidal
peritoneal dialysis (NTPD). ASAIO Trans 1990, 36:M584M588.
8. Popovich RP, Moncrief JW: Kinetic modeling of peritoneal transport:

In Todays Art of Peritoneal Dialysis. Edited by Trevino-Bacerra A,
Boen FST. Basel, Switzerland: Karger; 1979:5972. [Contributions to
Nephrology, 1.]
28. Twardowski ZJ: Tidal peritoneal dialysis: acute and chronic studies.
Eur Dial Transplant Nurses Assoc Eur Renal Care Assoc September
1990, 15:49.
29. Twardowski ZJ: Tidal peritoneal dialysis. In Dialysis Therapy. Edited
by Nissenson AR, Fine RN. Philadelphia: Hanley & Belfus;
1993:153156.
30. Twardowski ZJ, Nolph KD, Prowant BF, et al.: Efficiency of high volume low frequency continuous ambulatory peritoneal dialysis
(CAPD). ASAIO Trans 1983, 29:5357.
31. Krediet RT, Boeschoten EW, Zuyderhoudt FMJ, et al.: Differences in
the peritoneal transport of water, solutes and proteins between dialysis with two- and with three-litre exchanges [thesis]. In Peritoneal
Permeability in Continuous Ambulatory Peritoneal Dialysis Patients.
Edited by Krediet RT. Amsterdam, Holland: University of Amsterdam;
1986:129146.
5. Wade OL, Combes B, Childs AW, et al.: The effect of exercise on the
splanchnic blood flood and splanchnic blood volume in normal man.
Clin Sci 1956, 15:457.
9. Twardowski ZJ: Physiology of peritoneal dialysis. In Clinical Dialysis.

Edited by Nissenson AR, Fine RN, Gentile DE, edn 3. Norwalk, CT:
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10. Nolph KD, Twardowski ZJ, Popovich RP, et al.: Equilibration of peritoneal dialysis solutions during long dwell exchanges. J Lab Clin Med
1979, 93:246256.
11. Twardowski ZJ: Nightly peritoneal dialysis (why? who? how? and
when?). Trans Am Soc Artif Intern Organs 1990, 36:816.
12. Nolph KD, Hano JE, Teschan PE: Peritoneal sodium transport during
hypertonic peritoneal dialysis: physiologic mechanisms and clinical
implications. Ann Intern Med 1969; 70:931.
13. Mactier RA, Khanna R, Twardowski ZJ, et al.: Contribution of lymphatic absorption to loss of ultrafiltration and solute clearances in
continuous ambulatory peritoneal dialysis. J Clin Invest 1987,
80:13111316.
14. Zabetakis PM, Krapf R, DeVita MV, et al.: Determining peritoneal
dialysis prescriptions by employing a patient-specific protocol.
Peritoneal Dial Int 1993, 13:189193.
15. Wolf CJ, Polsky J, Ntoso KA, et al.: Adequacy of dialysis in CAPD and
cycler PD; the PET is enough. Peritoneal Dial Bull 1992, 8:208211.
16. Struijk DG, Krediet RT, Koomen GCM, et al.: A prospective study of
peritoneal transport in CAPD. Kidney Int 1994, 17391744.
17. Dobbie JW, Krediet RT, Twardowski ZJ, et al.: A 39-year-old man
with loss of ultrafiltration. Peritoneal Dial Int 1994, 14:384394.
18. Nolph KD, Popovich RP, Ghods AJ, et al.: Determinants of low
clearances of small solutes during peritoneal dialysis. Kidney Int
1978, 13:117123.
19. Boen ST: Kinetics of Peritoneal Dialysis. Baltimore, MD: Medicine;
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20. Penzotti SC, Mattocks AM: Effects of dwell time, volume of dialysis
fluid, and added accelerators on peritoneal dialysis of urea. J Pharm
Sci 1971, 60:15201522.
21. Pirpasopoulos M, Lindsay RM, Rahman M, et al.: A cost-effectiveness
study of dwell time in peritoneal dialysis. Lancet 1972, 2:11351136.
32. Twardowski Z, Janicka L: Three exchanges with a 2.5 liter volume

for continuous ambulatory peritoneal dialysis. Kidney Int 1981,
20:281284.
33. Twardowski ZJ, Prowant BF, Nolph KD, et al.: High volume, low frequency continuous ambulatory peritoneal dialysis. Kidney Int 1983,
23:6470.
34. Randerson DH: Continuous ambulatory peritoneal dialysis-a critical
appraisal [thesis]. Sydney, Australia: University of New South Wales;
1980.
35. Pyle WK: Mass transfer in peritoneal dialysis [thesis]. Austin: University
of Texas; 1981.
36. Farrell PC, Randerson DH: Mass transfer kinetics in continuous ambulatory peritoneal dialysis. In Proceedings of the First International
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Legrain M. Amsterdam, Holland: Excerpta Medica; 1980:3441.
37. Pyle WK, Moncrief JW, Popovich RP: Peritoneal transport evaluation
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New York: Masson; 1981:3552.
38. Pyle WK, Popovich RP, Moncrief JW: Mass transfer in peritoneal dialysis. In Advances in Peritoneal Dialysis. Edited by Gahl GM, Kessel
M, Nolph KD. Amsterdam, Holland: Excerpta Medica; 1981:4146.
39. Garred LF, Canaud B, Farrell PC: A simple kinetic model for assessing
peritoneal mass transfer in continuous ambulatory peritoneal dialysis.
ASAIO J 1983, 6:131137.
Dialysis Access
and Recirculation
Toros Kapoian
Jeffrey L. Kaufman
John Nosher
Richard A. Sherman
ince its inception, hemodialysis has been bedeviled by problems

of vascular access. Access, from the time of creation and throughout a patients dialysis life, consumes significant time, effort, and
expense and creates much anxiety and risk for patient and family.
Vascular access complications remain the single leading cause of hospitalization and expense for dialysis patients. Some, such as infected
access sites, are potentially life threatening. It is common for an access
problem to precipitate a crisis related to the end of a patients dialysis
life. Despite the advances made in hemodialysis technology, the same
vascular access problems that plagued dialysis pioneers continue
today to confound patient care teams.
CHAPTER
5.2
Arteriovenous Dialysis Access: Evaluation and Placement

EVALUATION FOR HEMODIALYSIS VASCULAR ACCESS
History
Surgical cutdown
Multiple peripheral catheters
Asymmetry of pulse
Asymmetry of blood pressure
Peripherally inserted central catheter

line placement
Abnormal capillary refill
Transvenous pacemaker
Axillary dissection
Presence of surgical or other scars
Intravenous drug use

Obesity
Peripheral vascular disease
Atherosclerotic disease
Abnormal Allen test
FIGURE 5-1
Evaluation for hemodialysis access. The creation of optimal vascular
access requires an integrated approach among patient, nephrologist,
and surgeon. The preoperative evaluation includes a thorough history
and physical examination. A history of arterial and venous line placements should be sought. The upper extremities are examined for
edema and asymmetry of pulse and blood pressure. Access should be
placed at the wrist only after it is verified that the radial artery is not
the dominant arterial conduit to the hand. The classic study is the
Allen test, in which an observer compresses both the radial and ulnar
arteries, has the patient exercise the hand by opening and closing to
cause blanching, then releases one vessel to be certain that the fingers
become perfused. An alternative, and perhaps more precise, test is to
verify by Doppler imaging that flow to all digits is maintained despite
occlusion of the radial artery. If indicated, vascular imaging studies
should be used to delineate the vascular anatomy and rule out arterial
or venous disease. Clinically silent stenosis involving the central veins
is becoming increasingly common with the improved survival of critically ill patients for whom central vein catheters are commonplace.
FIGURE 5-2
Creation of a Brescia-Cimino (radial-cephalic) fistula. The native
vein arteriovenous fistula is the preferred choice for hemodialysis
access. This simple and effective procedure, in which an artery is
connected to an adjacent vein to provide a large volume of blood
flow into the superficial venous system, has become less common
in recent years. The ideal artery has minimal wall calcification, so
that dilation can occur with time and allow unimpeded flow. In
addition, the artery should not be affected by proximal stenosis,
the most common site being an ostial lesion in the subclavian
artery. Ideally, the outflow vein is subjected to minimal dissection
or manipulation during the surgical procedure. Forcible distension
of veins and rough handling of arteries leads to formation of
neointimal fibrous hyperplasia and localized stenosis.
The first autogenous access site described was radial-cephalic at
the level of the radial styloid process. These can be constructed endvein to side-artery, A and B, or side-to-side, C, between the two vessels. The exposure is conveniently obtained using a transverse incision at the wrist, just proximal to the radial styloid process, where
the artery and cephalic vein lie close to one another. In general, the
two vessels are just far enough apart so that an end-to-side technique is best. When the vessels overlie each other, some surgeons
prefer the side-to-side technique, which allows reversal of blood
flow into the dorsum of the hand and then via collaterals into the
forearm, theoretically leading to better flow volume over time.
Dialysis Access and Recirculation
FIGURE 5-3
The Brescia-Cimino (radial-cephalic) fistula. The radial-cephalic fistula offers many advantages. It is simple to create and preserves
more proximal vessels for future access construction. The lower
5.3
incidence of steal is likely the result of the lower flow rate associated with these accesses. Additionally, such accesses have low rates
of thrombosis and infection. The photograph shows a mature
Brescia-Cimino fistula in a patient with longstanding diabetes. The
fistula outflow vein has numerous aneurysmal segments, and,
although they are associated with some tendency toward flow stagnation, they are of no harm to the patients dialysis life. They do,
however, become obvious targets for the dialysis technical staff,
who have a tendency to puncture them repeatedly rather than to
utilize new needle insertion sites. The patients arm also demonstrates marked muscle atrophy secondary to advanced diabetic neuropathy, which particularly involves the thenar eminence and the
interosseus muscle groups. Complaints of weakness and loss of
grip strength in the arm are common and may represent symptoms
of steal. In this case, however, the symptoms are due to the intrinsic loss of muscle mass, rather than to steal.
A
FIGURE 5-4
The brachial-cephalic vein fistula. If a radial-cephalic vein fistula cannot be constructed,
the next best choice for vascular access is the brachial-cephalic vein fistula. Accesses that
utilize the brachial artery have the advantage of higher blood flow rates than those that
use the radial artery. Although this may improve the efficiency of hemodialysis, it is also
associated with increased risk of arm edema and steal. A, The native anatomy of the antecubital veins somewhat resembles the letter M. A more complete depiction is seen in B.
The medial volar venous flow enters the basilic system; lateral volar flow enters the
cephalic system; and the central connector, which includes a deep tributary, connects the
brachial (venae comitantes) system at the brachial artery bifurcation. To create an antecubital autogenous site, there are two general approaches; the surgeon either mobilizes the
cephalic vein directly into the brachial artery (C) or anastomoses the deep connector
between the median antecubital vein and the brachial veins directly to the adjacent artery.
It is also possible to prepare a native vein arteriovenous fistula in the antecubital fossa by
transposing brachial or basilic veins from the deeper compartment of the brachium to the
subcutaneous tissue.
5.4
FIGURE 5-5
Polytetrafluoroethylene (PTFE) vein graft. The most common synthetic material used for
dialysis access construction is the PTFE conduit. This material replaced bovine heterografts;
alternative materials such as the umbilical vein graft have not yet made much headway.
Because of the infection risk, Dacron bypass grafts have never functioned well for dialysis.
PTFE is an inert material that is formed into a pliable conduit. Its ultramicroscopic structure is a series of nodes connected by tiny filaments, leaving pores whose size can be varied
during manufacture. The process of healing

after implantation involves ingrowth of
fibroblasts into the pore structure, giving a
final graft-tissue amalgam that is incorporated when encountered by the surgeon for
revision. There is virtually no neovascularization through the pores, which are too
small for capillary ingrowth. In humans,
neointima grow along the graft for no more
than 3 cm from the anastomosis. In animal
models, neointima can be much more
robust, growing along most of the length of
the graft and providing it with greater resistance to thrombosis. Typical layouts for the
construction of a PTFE access site are A, the
forearm loop, and B, linear forearm graft,
respectively. Alternative sites include upper
arm loop grafts, groin grafts, axillary arteryto-vein grafts, and a variety of other constructions. The sites of choice are limited by
the requirements of hemodialysis: delivery
of a high rate of blood flow and accessibility
to the dialysis staff for cannulation with an
adequate length of graft to keep the needles
sufficiently separated and allow rotation of
cannulation sites.
FIGURE 5-6
Trends in dialysis access sites. Despite our understanding of
hemodialysis access and the advantages and disadvantages of the
various options available, there is an alarming trend away from
the use of native vein fistulas. Of even more concern is the increasing number of patients who begin dialysis without a permanent
vascular access in place and the increasing prevalence of central
vein catheters. It is not clear whether these trends are the result of
age, comorbid conditions such as diabetes and peripheral vascular
disease, or simply the untoward effect of late nephrology referral.
Although central vein catheters were initially designed for temporary use while an arteriovenous vascular access was being constructed, improvements in design have led to their being used for
permanent dialysis access. Nevertheless, central vein catheters,
while popular with patients because they obviate being stuck,
are the source of a variety of access complications, including infection, central vein stenosis, and thrombosis.
5.5
Complications of Arteriovenous Dialysis Access Placement
A
FIGURE 5-7
Arteriovenous fistula anastomotic stenosis. Arteriovenous fistulas
exhibit better long-term patency compared with polytetrafluoroethylene (PTFE) grafts. A, This arteriogram, performed by injecting
the brachial artery, demonstrates an end-to-side arteriovenous fistula involving the brachial artery and the cephalic vein. The arrow
indicates an area of narrowing adjacent to the anastomosis, the
B
most common site for a stenotic lesion in native vein fistulas.
B, Angioplasty successfully eliminated the anastomotic stenosis.
Limitations on balloon size are often encountered when treating
lesions in arteriovenous fistulas because a portion of the balloon
must often extend into the donor artery, which typically is of
smaller diameter than the outflow vein.
FIGURE 5-8
Exposed polytetrafluoroethylene (PTFE) graft. Proper placement of
a PTFE graft is crucial for its long-term survival. The graft cannot
be too short, as it will deteriorate quickly from puncture limited to
only a few sites; if it is too long, however, it will have a greater
impedance to flow and a tendency toward thrombosis. The graft
should be neither too deep to the skin nor too shallow. When the
graft is too shallow, puncture by the dialysis staff is easier, but the
skin may be eroded with scarring from repeated use. This photograph shows a linear forearm graft with a segment of exposed
PTFE. An exposed graft is a serious problem for several reasons.
First, exposure of actual puncture holes eventually leads to hemorrhage. Second, an exposed graft is, by definition, infected.
Although some cases have been treated successfully with rotational
skin flaps and a long course of antibiotics, the majority do not
heal. The ideal treatment is removal of the segment of exposed
graft, splicing a segment of new PTFE away from the site of exposure, and allowing secondary wound healing.
5.6
FIGURE 5-9
Extravasation injury to the access site. A, A relatively fresh segment of polytetrafluoroethylene graft was removed during a revision procedure. There is virtually no fibrosis or calcification (associated with repeated puncture). The luminal surface displays the
results of multiple sites of puncture and healing. Among the most
dramatic and troublesome complications of dialysis is access infiltration. In most cases the infiltration is minor and usually results
from either inadequate hemostasis at the end of dialysis or needle
perforation through the access site. Extravasation injury to the
access is more likely when a needle errantly transfixes a graft or
vein or when it accidentally becomes dislodged into the subcutaneous tissue. The venous return needle presents the biggest problem. In the face of typical pump speeds of 400 to 500 mL/min a
potentially huge volume of fluid can enter the soft tissue before
the pump stops in response to the alarm for elevated venous pressure. In many cases, the graft is unusable for weeks after such an
episode. Continued use of the access in this setting may result in
loss of the access site. B, In this example, the infiltration was composed of approximately 400 mL of priming crystalloid and blood,
located both deep and superficial to the investing fascia of the
arm. The access remained patent and was eventually restored to
function; however, a series of percutaneous drainage procedures
and open drainage were necessary. Compartment syndrome, with
loss of distal motor function or sensation in the arm, is another
concern in this setting, and drainage must be performed to treat
this surgical emergency.
FIGURE 5-10
Outflow vein stenosis. Stenotic lesions are most often found
at a polytetrafluoroethylene (PTFE) grafts venous anastomotic
site or within its outflow vein. A, Radiograph depicting an
angioplasty balloon inflated across an outflow vein with a
stenotic lesion. The waist in the balloon (arrow) indicates the
location of the stenosis. With increasing inflation pressure the
waist disappears, an indication of successful angioplasty. Failure
to eliminate the waist in the balloon indicates incomplete dilatation of the lesion. Occasionally, outflow vein stenoses are very
resistant to dilatation and require high inflation pressures. This
is not surprising given the amount of scarring and intimal hyperplasia that can develop in a dialysis access site. B, Resected
graft-venous anastomosis from a one-year-old PTFE graft. The
vein wall seen here is enormously thickened. Angioplasty of
lesions such as these is often unsuccessful, as this rigid material
is likely to rebound to its stenotic state with any manipulation.
E
FIGURE 5-11
Graft thrombosis due to outflow vein stenosis requiring use of an
atherectomy catheter. Thrombectomy of a dialysis access site involves
removal of three types of clot. A, The body of a thrombosed access
contains a red or purplish thrombus that is often gelatinous. It is easily removed with a balloon-tipped thrombectomy/embolectomy
catheter. This photograph also demonstrates the small meniscus of
firm, laminar, platelet-rich clot that usually obstructs arterial inflow.
On occasion, it is also found at the venous end. This type of clot can
be tenacious and may not be removed with thrombolytic therapy or
the balloon catheter. A cutdown at the arterial end of the graft may
5.7
be necessary to permit removal of this material under direct visualization. Failure to remove this meniscus invariably leads to rethrombosis. B, This type of clot is demonstrated in an arteriogram performed through the brachial artery following thrombolytic therapy.
The arterial end of this polytetrafluoroethylene (PTFE) graft demonstrates a residual intraluminal thrombus (arrow), which is typical of
the platelet-rich plug or arterial type thrombus. A third type of clot
(not shown) consists of a white laminar material that lines the graft
over time, especially in sites of repeated puncture. This material can
create a stenosis along the body of the graft and may be removed by
curettage at the time of thrombectomy using an atherectomy
catheter. Failure to remove this material decreases blood flow
through the graft and may lead to rethrombosis. According to
Poiseuilles law, if blood pressure remains constant, a 6-mm graft
with 1 mm of circumferential laminar clot accommodates only 20%
of the flow originally present, since flow is inversely related to the
fourth power of the radius.
Eighty percent of thrombosed accesses have an associated stenotic
lesion. C, An eccentric focal stenosis is demonstrated at the anastomosis of a PTFE forearm graft and its outflow vein (arrow), which
did not respond to percutaneous transluminal angioplasty. The lesion
was subsequently resected using a Simpson atherectomy catheter,
which consists of a concealed cutting chamber that is deflected into
contact with the stenotic lesion of the vessel wall by inflating the
associated balloon. With the lesion projecting into the cutting chamber, a high-speed cylindrical cutting blade resects tissue into a collecting chamber. This chamber is rotated sequentially until the circumference of the lesion has been treated. D, The Simpson atherectomy
catheter is placed across the stenotic lesion. E, The postprocedure
venogram shows that the lesion was successfully resected.
5.8

FIGURE 5-12
Pulse spray catheter. To increase the efficiency of drug thrombolysis,
pulse spray catheters are often used. The technique involves embedding the catheter within the clot and intentionally obstructing the
catheter end hole with a guidewire. When the fibrinolytic agent is
injected, it is forced out through the catheter sideholes in jets and
permeates the clot. With this method, a larger surface area of clot
is exposed to the fibrinolytic agent.
FIGURE 5-13
Thrombectomy brush. Several types of mechanical thrombectomy
devices have been developed as alternatives to pharmaceutical
fibrinolysis. All mechanically macerate or disrupt clot into small
fragments that embolize into the central veins and, eventually, the
pulmonary vascular bed. This photograph demonstrates a brush
attached to a motor drive that imparts high-speed rotary motion
to disrupt the thrombus. The danger of most mechanical devices
is the risk of vascular injury.
FIGURE 5-14
Outflow vein stenosis with stenting. A, Arteriography in this
patient with a Brescia-Cimino fistula demonstrates stenosis of the
outflow vein approximately 15 cm central to the fistula (arrow).
B, Percutaneous transluminal angioplasty was performed in this
patient; however, because of immediate elastic recoil, the lesion
looks no different after angioplasty. C, Following stent placement
(arrow), there is no residual stenosis, and good flow through the
stent is apparent. Stents have proven controversial in access sites.
Although they may improve patency in central vein stenoses (vide
infra), in the periphery they may be a hindrance. Some patients
develop vigorous fibrosis at the venous site of a stent. D, This

photograph demonstrates what had occurred only 1 month after
stent placement. Stents can be a problem when dealing with subsequent vascular access dysfunction. During thrombectomy, the
tiny wires of a stent can puncture balloon catheters. When stented segments restenose, it is impossible to perform open patch
angioplasty over such segments, and it becomes necessary to
jump to a different venous outflow site. It is not clear whether
stents in or adjacent to dialysis grafts are cost effective in maintaining graft patency.
FIGURE 5-15
Intragraft stenosis. A, This arteriogram demonstrates a forearm
loop polytetrafluoroethylene (PTFE) graft with an intragraft stenosis
(arrow). Stenotic lesions in this site are less common than those
involving either the venous anastomosis or the outflow vein.
B, These lesions can be treated successfully with percutaneous transluminal angioplasty (arrow). In cases where angioplasty is unsuccessful, intragraft stenoses can also be treated using percutaneous
5.9
atherectomy or surgical revision. Since this region of the access is

subject to needle cannulation, the placement of a stent would be
inadvisable. Intragraft stenoses may be located between the sites of
the arterial and venous needle placements during dialysis. If so, the
most common screening studies, namely venous pressure measurements and recirculation, do not have abnormal findings and the
lesion may remain undetected until access thrombosis develops.
B
FIGURE 5-16
Aneurysmal degeneration. Severe aneurysmal degeneration poses a significant surgical problem for both patient and surgeon. A, Photograph demonstrating an anastomotic aneurysm
in a loop forearm polytetrafluoroethylene (PTFE) graft. This aneurysm is an example of the
type of degenerative changes that occasionally occur in both arteries and veins subjected to
turbulence and high tangential wall stress. This is common in the native circulation in areas
of poststenotic dilatation. The PTFE graft with high flow volumes manifested the enlargement of the venous outflow. This bulge, which constitutes a segment of flow stagnation, is
associated with increased risk of thrombosis over time. Since this would jeopardize the
long-term function of the access, the area was revised by interposing a short segment of
PTFE to a new venous outflow adjacent to the aneurysmal segment. B, Radiograph demonstrating a pseudoaneurysm in the midportion of a forearm loop PTFE graft (arrow). This
lesion represents a communication between the graft and a confined space in the tissue surrounding the graft and is a common finding in dialysis patients. C, A pseudoaneurysm in a
patient with a 3-year-old left groin PTFE graft. Because of the patients severe phobia of
central vein catheters, this access was revised in two separate procedures to maintain dialysis continuity. The lateral area of the loop was initially replaced, and when this was healed
and functioning well the medial segment was replaced.
5.10

FIGURE 5-17
Vascular steal. Vascular steal is a common problem of dialysis access sites. The principle
of steal is related to two phenomena: 1) calcification or stenosis in the inflow arterial segment proximal to an access site (so that the native artery cannot dilate to meet the increasing demands for flow volume); 2) and an outflow arterial bed in parallel to the fistula origin
with higher net vascular resistance than the fistula conduit. If both of these are present,
blood flow is diverted to the access site in association with a drop in perfusion pressure to
the most acral tissues, the fingers. When steal is severe, trauma to the digits leads to gangrene. Several treatment strategies are available to the surgeon. The access can be banded, or purposefully stenosed at its origin to divert flow to the ischemic site. The access
can be revised using a tapered graft or the point of origin of the access can be moved more
proximally in the arterial tree, in the hope of allowing full flow without diverting distal
perfusion pressure. Additionally, one can perform a variety of bypass procedures to divert
higher-pressure proximal blood to increase distal perfusion pressure. In severe cases, either
the access or the distal digits may be sacrificed to preserve the other.
FIGURE 5-18
Vascular access screening methods. Dialysis grafts have a high incidence of thrombosis, the risk of which increases when graft flow
rates (A) fall below 600 to 700 mL/min, particularly with stenotic
lesions in or near the graft. Most often, stenoses occur just distal to
the graft-vein anastomosis (B) but they can occur proximal to the
graft-artery anastomosis (C) or within the graft itself (D). Various
screening methods may help detect grafts at high risk for thrombosis at a point where graft revision (surgical or radiologic) may
increase its longevity.
Measurement of graft blood flow (using Doppler imaging, ultrasound dilution, or another method) is increasingly available and
may be the best screening method. When graft flow declines below
dialyzer blood flow (E), blood flows between the needles (F) in a
retrograde direction. This development is called recirculation, since
it results in repeated uptake and dialysis of blood that has just been
dialyzed. Recirculation can be detected by finding evidence that
blood from the venous cannula is being taken up by the arterial
cannula. This is most often recognized by the finding of an arterial
blood urea nitrogen value below that in blood entering the graft.
A stenotic lesion in an outflow vein tends to increase the pressure
in the vein and graft (G) between the stenosis and the venous needle. This pressure usually ranges from 25 to 50 mm Hg but may
increase to more than 70 mm Hg in the presence of stenosis. This
pressure can be measured directly or can be estimated from the
venous pressure monitor on the dialysis machine at zero blood
flow (adjusting for the difference in height between the graft and
the transducer). To increase accuracy, this pressure can be normalized by dividing it by the mean arterial pressure. More commonly,
this intragraft pressure is determined indirectly by using the dialysis
machines pressure transducer and a pump speed of 200 mL/min.
In this case the measured pressure often exceeds 100 mm Hg in a
normal graft, owing to the resistance in the venous needle.
5.11
Central Venous Dialysis Access

FIGURE 5-19
Right internal jugular vein catheters. The use of central vein
catheters has grown significantly over the past several years. These
catheters were at one time used only on a temporary basis and
served as a bridge to permanent vascular access. Improvements
in catheter design and function combined with ease of insertion
have increased use of central vein catheters in dialysis units. To
minimize the risk of central vein stenosis and subsequent thrombosis, central vein catheters should be inserted preferentially into the
right internal jugular vein, regardless of whether they are being
used for temporary or more permanent purposes. The typical positioning of a double-lumen catheter, A, is with its tip at the junction
of the right atrium and the superior vena cava. The catheter has
been tunneled underneath the skin so that the exit site (large
arrow) is located just beneath the right clavicle and distant from
the insertion site (small arrow). This catheter also has a cuff into
which endothelial cells will grow and produce a biologic barrier to
bacterial migration. B, Chest radiograph showing a dialysis central
vein catheter that is composed of two separate single-lumen
catheters that have been inserted into the right internal jugular
vein. The distal tip of the venous catheter is positioned just above
the right atrium. Care must be taken, however, to ensure proper
placement of catheters with this type of design, because the two
single lumens are radiographically indistinguishable.
B
FIGURE 5-20
Central vein stenosis. A, Venogram of
the central outflow
veins performed in
a patient with a left
upper extremity
polytetrafluoroethylene graft and arm
edema, B.
(Continued on
next page)
5.12

The angiogram (Panel A) demonstrates complete occlusion of the innominate vein (arrow)
with collateral filling in the neck and the chest. The most common cause for stenosis or
thrombosis of the central venous system is previous injury from indwelling central vein
catheters. Central vein stenosis may not become apparent until an arteriovenous anastomosis
is created. This increases blood flow in the outflow veins and may overwhelm a compromised
central vein, resulting in the appearance of superficial collateral veins on the neck and chest
wall in addition to ipsilateral arm edema. In this example, the occlusion was crossed using an
angiographic catheter, and thrombolytic therapy was administered. C, Venography performed
after thrombolysis demonstrates severe stenosis of the innominate vein and the superior vena
cava (arrow).
B
FIGURE 5-21
Stent deployment. When angioplasty fails, metal stents are introduced to treat outflow vein occlusion. These stents are either balloon
expandable or self-expanding. The stages of deployment of the selfexpanding Wallstent (Schneider, Inc, Division of Pfizer Hospital
Products, Minneapolis, MN) are seen in these radiographs. A, The
radiopaque stent is positioned across the lesion to be treated. B, As
the deployment envelope is gradually withdrawn, the stent begins to
expand (arrow). These stents shorten during deployment, and this
factor must be taken into consideration for proper placement. C, An
angioplasty balloon (arrow) is placed in the proximal portion of this
completely deployed stent to achieve further expansion.
5.13

D, To improve central vein patency following angioplasty, metal stents have been
placed in the innominate vein and the superior vena cava. E, A postprocedure venogram
demonstrates no residual stenosis.
E
FIGURE 5-22
Central vein catheter complications. A, This
radiograph demonstrates the tip of this dialysis catheter abutting the wall of the left
innominate vein at its junction with the superior vena cava. To maintain adequate dialysis
flow rates and minimize fibrin sheath formation, it is important for the catheter tip to be
in the superior vena cava, near or in the right
atrium. B and C, Injection of contrast
through these dialysis catheters demonstrates
the contrast outlining the outside of the distal
portion of the catheter (arrows). This finding
is characteristic of a fibrin sheath with contrast medium trapped between the fibrin
sheath and the outer wall of the catheter.
Fibrin sheaths are associated with a reduction
(often severe) in the achievable blood flow
rate and, as a result, inadequate dialysis
delivery. They can be lysed by instilling large
doses of urokinase (typically 250,000 units)
through the catheter ports. If thrombolytic
therapy is unsuccessful, the fibrin sheath can
be stripped using a snare loop. Although
these catheters can function remarkably well,
they are prone to thrombosis.
5.14

D, The clot is typical of one that is remarkably tenacious. Before
replacement of this catheter, a variety of manipulations were performed, including attempted thrombolysis with localized infusion of
urokinase. A new catheter was placed in the same site in a same-day
procedure using local anesthesia.
D
FIGURE 5-23
Translumbar catheter placement. Patients receiving chronic hemodialysis may exhaust
potential sites for permanent vascular access. Additionally, after long-term use of central
vein catheters, these sites also develop irreversible occlusion. In most cases, these patients
are trained for peritoneal dialysis; however, some patients cannot tolerate this modality.
This patient failed all attempts at arteriovenous and central vein access placement, including those involving the vessels of the lower extremity. Peritoneal dialysis was not possible
owing to recurrent disabling pleural effusions. Translumbar placement of tunneled
catheters (arrow) into the inferior vena cava can provide a long-term solution for the
patient with no apparent remaining access sites.
The Dialysis Prescription

and Urea Modeling
Biff F. Palmer
emodialysis is a life-sustaining procedure for the treatment of

patients with end-stage renal disease. In acute renal failure the
procedure provides for rapid correction of fluid and electrolyte
abnormalities that pose an immediate threat to the patients well-being. In
chronic renal failure, hemodialysis results in a dramatic reversal of uremic
symptoms and helps improve the patients functional status and increase
patient survival. To achieve these goals the dialysis prescription must
ensure that an adequate amount of dialysis is delivered to the patient.
Numerous studies have shown a correlation between the delivered dose
of hemodialysis and patient morbidity and mortality [14]. Therefore, the
delivered dose should be measured and monitored routinely to ensure
that the patient receives an adequate amount of dialysis. One method
of assessing the amount of dialysis delivered is to calculate the Kt/V. The
Kt/V is a unitless value that is indicative of the dose of hemodialysis.
The Kt/V is best described as the fractional clearance of urea as a function of its distributional volume. The fractional clearance is operationally defined as the product of dialyzer clearance (K) and the treatment time (t). Recent guidelines suggest that the Kt/V be determined by
either formal urea kinetic modeling using computational software or
by use of the Kt/V natural logarithm formula [5]. The delivered dose
also may be assessed using the urea reduction ratio (URR).
A number of factors contribute to the amount of dialysis delivered
as measured by either the Kt/V or URR. Increasing blood flow rates
to 400 mL/min or higher and increasing dialysate flow rates to 800
mL/min are effective ways to increase the amount of delivered dialysis.
When increases in blood and dialysate flow rates are no longer effective,
use of a high-efficiency membrane can further increase the dose of
dialysis (KoA >600 mL/min, where KoA is the constant indicating the
efficiency of dialyzers in removing urea). Eventually, increases in blood
and dialysate flow rates, even when combined with a high-efficiency
membrane, result in no further increase in the urea clearance rate. At
this point the most important determinant affecting the dose of dialysis
is the amount of time the patient is dialyzed.
CHAPTER
6.2
Ultrafiltration during dialysis is performed to remove volume

that has accumulated during the interdialytic period so that
patients can be returned to their dry weight. Dry weight is
determined somewhat crudely, being based on clinical findings.
The patients dry weight is the weight just preceding the development of hypotension. The patient should be normotensive
and show no evidence of pulmonary or peripheral edema. A
patients dry weight frequently changes over time and therefore
must be assessed regularly to avoid hypotension or progressive
volume overload.
During ultrafiltration the driving force for fluid removal is the
establishment of a pressure gradient across the dialysis membrane.
The water permeability of a dialysis membrane is a function of
membrane thickness and pore size and is indicated by its ultrafiltration coefficient (KUf). During ultrafiltration additional solute
removal occurs by solvent drag or convection. Because of
increased pore size, high-flux membranes (KUf >20 mL/h/mm Hg)
are associated with much higher clearances of average to high molecular weight solutes such as 2 microglobulin. Because blood
flow rates over 50 to 100 mL/min result in little or no further
increase in the clearance of these molecules, clearance is primarily
membrane-limited. In contrast, clearance values for urea are not
significantly greater with a high-flux membrane compared with a
high-efficiency membrane because the blood flow rate, and not the
membrane, is the principal determinant of small solute clearance.
The biocompatibility of the dialysis membrane is another
consideration in the dialysis prescription. A biocompatible dialysis
membrane is one in which minimal reaction occurs between the
humoral and cellular components of blood as they come into
contact with the surface of the dialyzer [6]. One such reaction
that has been used as a marker of biocompatibility is evidence of

complement activation. Cellulosic membranes generally tend to be
bioincompatible, whereas noncellulosic or synthetic membranes
have more biocompatible characteristics. Whether any clinical
difference exists in acute or chronic outcomes between biocompatible and bioincompatible membranes is still a matter of debate.
Trials designed to address this issue have been mostly uncontrolled, limited in sample size, and often retrospective in nature.
Nevertheless, some evidence exists to suggest that bioincompatible membranes may have a greater association with 2 microglobulin-induced amyloidosis, susceptibility to infection, enhanced
protein catabolism, and increased patient mortality [59].
Another aspect of the dialysis prescription is the composition
of the dialysate. The concentrations of sodium, potassium,
calcium, and bicarbonate in the dialysate can be individualized
such that ionic composition of the body is restored toward
normal during the dialytic procedure. This topic is discussed in
detail in chapter 2.
Although hemodialysis is effective in removing uremic toxins
and provides adequate control of fluid and electrolyte abnormalities, the procedure does not provide for the endocrine or
metabolic functions of the normal kidney. Therefore, the dialysis prescription often includes medications such as erythropoietin and 1,25(OH)2 vitamin D. The dose of erythropoietin
should be adjusted to maintain the hematocrit between 33%
and 36% (hemoglobin of 11 g/dL and 12 g/dL, respectively)
[10]. Vitamin D therapy is often used in patients undergoing
dialysis to help limit the severity of secondary hyperparathyroidism. Dosages usually range from 1 to 2 g given intravenously with each treatment.
Treatment
Diffusion
Blood
Dialysate
Urea, 100 mg/dL
Urea, 0 mg/dL
Potassium, 5.0 mEq/L
Potassium, 2.0 mEq/L
Bicarbonate, 20 mEq/L
Bicarbonate, 35 mEq/L
Dialysis membrane
FIGURE 6-1
Diffusional and convective flux in hemodialysis. Dialysis is a
process whereby the composition of blood is altered by exposing it to
dialysate through a semipermeable membrane. Solutes are transported
across this membrane by either diffusional or convective flux. A, In
diffusive solute transport, solutes cross the dialysis membrane in a
direction dictated by the concentration gradient established across
the membrane of the hemodialyzer. For example, urea and potassium diffuse from blood to dialysate, whereas bicarbonate diffuses
from dialysate to blood. At a given temperature, diffusive transport
is directly proportional to both the solute concentration gradient
across the membrane and the membrane surface area and inversely
proportional to membrane thickness.
The Dialysis Prescription and Urea Modeling

Ultrafiltration
Blood
Dialysate
90 mm Hg
TREATMENT OF HEMODYNAMIC INSTABILITY
150 mm Hg
H 2O
H 2O
H 2O
6.3
Dialysis membrane

B, During hemodialysis water moves from blood to dialysate
driven by a hydrostatic pressure gradient between the blood and
dialysate compartments, a process referred to as ultrafiltration.
The rate of ultrafiltration is determined by the magnitude of this
pressure gradient. Movement of water tends to drag solute across
the membrane, a process referred to as convective transport or solvent drag. The contribution of convective transport to total solute
transport is only significant for average-to-high molecular weight
solutes because they tend to have a smaller diffusive flux.
ACCEPTABLE METHODS TO MEASURE

HEMODIALYSIS ADEQUACY*
Formal urea kinetic modeling (Kt/V) using computational software
Kt/V = -LN (R0.008 t)
+ (4-3.5 R)
Uf/wt
Urea reduction ratio
*Recommended by the National Kidney Foundation Dialysis Outcomes Quality
Initiative Clinical Practice Guidelines, which suggest a prescribed minimum Kt/V of

1.3 and a minimum urea reduction ratio of 70%.
tLN is the natural logarithm; R is postdialysis blood urea nitrogen (BUN)/predialysis
BUN; t is time in hours, Uf is ultrafiltration volume in liters; w is postdialysis weight
in kilograms.
Exclude nondialysis-related causes (eg, cardiac ischemia, pericardial effusion, infection)

Set the dry weight accurately
Optimize the dialysate composition
Use a sodium concentration of 140 mEq/L
Use sodium modeling
Use a bicarbonate buffer
Avoid low magnesium dialysate
Avoid low calcium dialysate
Optimize the method of ultrafiltration
Use volume-controlled ultrafiltration
Use ultrafiltration modeling
Use sequential ultrafiltration and isovolemic dialysis
Use cool temperature dialysate
Maximize cardiac performance
Have patients avoid food on day of dialysis
Have patients avoid antihypertensive medicines on day of dialysis
Pharmacologic prevention
Erythropoietin therapy to keep hematocrit >30%
Experimental (eg,caffeine, midodrine, ephedrine, phenylephrine, carnitine)
FIGURE 6-2
The common treatments for hemodynamic instability of patients
undergoing dialysis. It is important to begin by excluding reversible
causes associated with hypotension because failure to recognize
these abnormalities can be lethal. Perhaps the most common reason for hemodynamic instability is an inaccurate setting of the dry
weight. Once these conditions have been dealt with, the use of a
high sodium dialysate, sodium modeling, cool temperature dialysis,
and perhaps the administration of midodrine may be attempted.
All of these maneuvers are effective in stabilizing blood pressure in
dialysis patients.
FIGURE 6-3
Acceptable methods to measure hemodialysis adequacy as recommended in the Dialysis Outcomes Quality Initiative (DOQI)
Clinical Practice Guidelines. These guidelines may change as new
information on the benefit of increasing the dialysis prescription
becomes available. For the present, however, they should be considered the minimum targets.
6.4
Considerations in Choice of Membranes
KoA 900 High-efficiency

dialyzer
KoA 650
300
200
e-lim
Membran
ited
KoA 300 Conventional

dialyzer
Flo
wlim
ite
d
Urea clearance, mL/min
400
100
0
0
100
200
300
400
2000
1800
1600
KUf=60 mL/h/mm Hg
Ultrafiltration, mL/h
1400
KUf=4 mL/h/mm Hg
1200
KUf=3 mL/h/mm Hg
1000
800
600
400
200
0
0
100
500
200
300
400
Transmembrane pressure, mm Hg
600
FIGURE 6-4
Relationships between membrane efficiency and clearance and
blood flow rates in hemodialysis. When prescribing the blood flow
rate for a hemodialysis procedure the following must be considered:
the relationship between the type of dialysis membrane used, blood
flow rate, and clearance rate of a given solute. For a small solute
such as urea (molecular weight, 60) initially a linear relationship
exists between clearance and blood flow rates. Small solutes are
therefore said to be flow-limited because their clearance is highly
flow-dependent. At higher blood flow rates, increases in clearance
rates progressively decrease as the characteristics of the dialysis
membrane become the limiting factor. The efficiency of a dialyzer
in removing urea can be described by a constant referred to as
KoA, which is determined by factors such as surface area, pore
size, and membrane thickness. Use of a high-efficiency membrane
(KoA >600 mL/min) can result in further increases in urea clearance
rates at high blood flow rates. In contrast, at low blood flow rates no
significant difference exists in urea clearance between a conventional
and a high-efficiency membrane because blood flow, and not the
membrane, is the primary determinant of clearance.
FIGURE 6-5
Water permeability of a membrane and control of volumetric
ultrafiltration in hemodialysis. The water permeability of a dialysis
membrane can vary considerably and is a function of membrane
thickness and pore size. The water permeability is indicated by its
ultrafiltration coefficient (KUf). The KUf is defined as the number
of milliliters of fluid per hour that will be transferred across the
membrane per mm Hg pressure gradient across the membrane.
A high-flux membrane is characterized by an ultrafiltration coefficient of over 20 mL/h /mm Hg. With such a high water permeability value a small error in setting the transmembrane pressure can
result in excessively large amounts of fluid to be removed. As a
result, use of these membranes should be restricted to dialysis
machines that have volumetric ultrafiltration controls so that the
amount of ultrafiltration can be precisely controlled.
High-efficiency dialyzer
High-flux dialyzer
Normal kidney
Clearance, mL/min
150
100
6.5
FIGURE 6-6
High-efficiency and high-flux membranes in hemodialysis. These
membranes have similar clearance values for low molecular weight
solutes such as urea (molecular weight, 60). In this respect both
types of membranes have similar KoA values (over 600 mL/min),
where KoA is the constant indicating the efficiency of the dialyzer
in removing urea. As a result of increased pore size, use of highflux membranes can lead to significantly greater clearance rates of
high molecular weight solutes. For example, 2-microglobulin is not
removed during dialysis using low-flux membranes (KUf <10
mL/h/mm Hg, where KUf is the ultrafiltration coefficient). With
some high-flux membranes, 400 to 600 mg/wk of 2-microglobulin
can be removed. The clinical significance of enhanced clearance of
2-microglobulin and other middle molecules using a high-flux dialyzer is currently being studied in a national multicenter hemodialysis trial.
50
0
100
1000
10,000
100,000
Vit
(m amin
- w=1 B1
2 m
35 2
(m icrog 5)
w= lob
11, ulin
800
)
10
(m Urea
w=
60)
Solute molecular weight, Daltons
Patients recovering renal function, %
80
60
Polymethyl methacrylate
40
Cuprophane
20
0
0
10
15
20
25
Number of hemodialysis treatments
30
FIGURE 6-7
Effects of membrane biocompatibility in hemodialysis. Another
consideration in the choice of a dialysis membrane is whether it is
biocompatible. In chronic renal failure some evidence exists to suggest
that long-term use of biocompatible membranes may be associated
with favorable effects on nutrition, infectious risk, and possibly
mortality when compared with bioincompatible membranes [59].
In the study results shown here, the effect of biocompatibility on
renal outcome in a group of patients with acute renal failure who
required hemodialysis was examined. Patients received dialysis with
a cuprophane membrane (a bioincompatible membrane known to
activate complement and neutrophils) or a synthetic membrane
made of polymethyl methacrylate (a biocompatible membrane
associated with more limited complement and neutrophil activation).
The two groups of patients were similar in age, degree of renal failure,
and severity of the underlying disease as defined by the Acute
Physiology and Chronic Health Evaluation (APACHE) II score. As
compared with the bioincompatible membrane, those patients treated
with the synthetic biocompatible membrane had a significantly shorter
duration of renal failure in terms of number of treatments and
duration of dialysis. In the setting of acute renal failure, particularly
in patients after transplantation, a biocompatible membrane may
be the preferred dialyzer. (From Hakim and coworkers [11];
with permission.)
6.6

300
280
QD=800
260
Clearance, mL/min
240
Dialyzer
KoA=800
QD=500
220
200
QD=800
180
Dialyzer
KoA=400
FIGURE 6-8
Dialysate flow rate in hemodialysis. The clearance of urea also
is influenced by the dialysate flow rate. Increased flow rates help
maximize the urea concentration gradient along the entire length of
the dialysis membrane. Increasing the dialysate flow rate from 500
to 800 mL/min can be expected to increase the urea clearance rate
on the order of 10% to 15%. This effect is most pronounced at
high blood flow rates and with use of high KoA dialyzers. KoA
constant indicating the efficiency of the dialyzer in removing urea;
QDdialysate flow rate.
QD=500
160
140
120
100
200
250
300
350
400
450
500
Prescription for Dose Delivery
Urea concentration
1. Dialyzer urea clearance rate

KoA of membrane
Blood flow
Dialysate flow
Convective urea flux
2. Treatment time
3. Volume of distribution
1. Urea generation rate

Protein catabolic rate
2. Volume of distribution
3. Residual renal function
Dialysis
time
Time on
Time off
Interdialytic
time
Time on (next dialysis)
FIGURE 6-9
Delivering an adequate dose of dialysis in hemodialysis. Providing
an adequate amount of dialysis is an important part of the dialysis
prescription. During the dialytic procedure a sharp decrease in the
concentration of urea occurs followed by a gradual increase during
the interdialytic period. The decrease in urea during dialysis is
determined by three main parameters: dialyzer urea clearance rate
(K), dialysis treatment time (t), and the volume of urea distribution
(V). The dialyzer urea clearance rate (K) is influenced by the characteristics of the dialysis membrane (KoA), blood flow rate, dialysate
flow rate, and convective urea flux that occurs with ultrafiltration.
The gradual increase in urea during the interdialytic period depends
on the rate of urea generation that, in an otherwise stable patient,
reflects the dietary protein intake, distribution volume of urea, and
presence or absence of residual renal function.
FACTORS RESULTING IN A REDUCTION OF THE

PRESCRIBED DOSE OF HEMODIALYSIS DELIVERED
Compromised urea clearance
Access recirculation
Inadequate blood flow from the vascular access
Dialyzer clotting during dialysis (reduction of effective surface area)
Blood pump or dialysate flow calibration error
Reduction in treatment time
Premature discontinuation of dialysis for staff or unit convenience
Premature discontinuation of dialysis per patient request
Delay in starting treatment owing to patient or staff tardiness
Time on dialysis calculated incorrectly
Laboratory or blood sampling errors
Dilution of predialysis BUN blood sample with saline
Drawing of predialysis BUN blood sample after start of the procedure
Drawing postdialysis BUN >5 minutes after the procedure
6.7
FIGURE 6-10
Each of the factors listed may play a major role in the reduction of
delivered dialysis dose. Particular attention should be paid to the
vascular access and to a reduction in the effective surface area of
the dialyzer. Perhaps the most important cause for reduction in
dialysis time has to do with premature discontinuation of dialysis
for the convenience of the patient or staff. Delays in starting dialysis
treatment are frequent and may result in a significant loss of dialysis
prescription. Finally, particular attention should be paid to the correct
sampling of the blood urea nitrogen level and the site from which
the sample is drawn.
BUNblood urea nitrogen.
0.1
0.0 0
0.0 8
0.0 6
4
Increasing
ultrafiltation
1.80
0.02
0.00
Kt/v by formal urea kinetic modeling
1.60
1.40
1.20
1.00
0.80
0.60
0.40
0.50
0.60
0.70
Urea reduction ratio, %
0.80
FIGURE 6-11
Monitoring the delivered dose in hemodialysis. Use of the urea reduction ratio (URR) is the simplest way to monitor the delivered dose of
hemodialysis. However, a shortcoming of this method compared with
formal urea kinetic modeling is that the URR does not account for the
contribution of ultrafiltration to the final delivered dose of dialysis.
During ultrafiltration, convective transfer of urea from blood to
dialysate occurs without a decrease in urea concentration. As a result,
with increasing ultrafiltration volumes the Kt/V, as determined by
formal urea kinetic modeling, progressively increases at any given
URR. For example, a URR of 65% may correspond to a Kt/V as
low as 1.1 in the absence of ultrafiltration or as high as 1.35 when
ultrafiltration of 10% of body weight occurs.
6.8
45
MAJOR COMPONENTS OF DIALYSIS PRESCRIPTION

500 U/kg
40
150 U/kg
Hematocrit, %
35
30
50 U/kg
25
15 U/kg
20
15
0
12
6
8
10
Weeks of rHuEpo therapy
14
16
FIGURE 6-12
Correction of anemia in chronic renal failure. Anemia is a predictable complication of chronic renal failure that is due partly
to reduction in erythropoietin production. Use of recombinant erythropoietin to correct the anemia in patients with chronic renal
failure has become standard therapy. The rate of increase in hematocrit is dose-dependent. The indicated doses were given intravenously three times per week. Current guidelines for the initiation
of intravenous therapy suggest a starting dosage of 120 to 180
U/kg/wk (typically 9000 U/wk) administered in three divided doses.
Administration of erythropoietin subcutaneously has been shown
to be more efficient than is intravenous administration. That is, on
average, any given increment in hematocrit can be achieved with
less erythropoietin when it is given subcutaneously as compared
with intravenously. In adults, the subcutaneous dosage of erythropoietin is 80 to 120 U/kg/wk (typically 6000 U/wk) in two to three
divided doses. rHuEporecombinant human erythropoietin. Data
from Eschbach and coworkers [12]; with permission.
Choose a biocompatible membrane

Prescribe a Kt/V 1.3 or a URR 70%
Rigorously ensure that the delivered dose equals the amount prescribed
When the delivered dose is less than that prescribed do the following:
Exclude factors listed in Figure 6-10
Increase blood flow rate 400 mL/min
Increase dialysate flow rate to 800 mL/min
Use a high-efficiency dialyzer
Increase treatment time
Choose dialysate composition: sodium, potassium, bicarbonate, and calcium
Adjust ultrafiltration rate to achieve patients dry weight (assess dry weight regularly)
Adjust recombinant erythropoietin to maintain hematocrit between 33% and 36%
When indicated, use 1,25(OH)2 vitamin D for treatment of secondary
hyperparathyroidism
Use normal saline, hypertonic saline, or mannitol for treatment of intradialytic
hypotension
URRurea reduction ratio.
FIGURE 6-13
All these components are important as contributors to a successful
dialysis prescription. The Dialysis Outcomes Quality Initiative
(DOQI) recommendations should be followed to achieve an adequate
dialysis prescription, and the time on dialysis should be monitored
carefully. When the delivered dialysis dose is less that prescribed,
the reversible factors listed in Figure 6-10 should be addressed first.
Subsequently, an increase in blood flow to 400 mL/min should be
attempted. Increases in dialyzer surface area and treatment time
also may be attempted. In addition, attention should be paid to the
correct dialysis composition and to the ultrafiltration rate to make
certain that patients achieve a weight as close as possible to their
dry weight. Hematocrit should be sustained at 33% to 36%. Finally,
vitamin D supplementation to prevent secondary hyperparathyroidism
and use of normal saline or other volume expanders are encouraged
to treat hypotension during dialysis. KoAconstant indicating the
efficiency of the dialyzer in removing urea.
References
1.
2.
3.
4.
5.
6.
Owen WF, Lew NL, Liu Y, Lowrie EG: The urea reduction ratio and
serum albumin concentration as predictors of mortality in patients
undergoing hemodialysis. N Engl J Med 1993, 329:10011006.
Hakim RM, Breyer J, Ismail N, Schulman G: Effects of dose of dialysis
on morbidity and mortality. Am J Kidney Dis 1994, 23:661669.
Held PJ, Port FK, Wolfe RA, et al.: The dose of hemodialysis and
patient mortality. Kidney Int 1996, 50:550556.
Parker TF III, Husni L, Huang W, et al.: Survival of hemodialysis
patients in the United States is improved with a greater quantity of
dialysis. Am J Kidney Dis 1994, 23:670680.
Hemodialysis Adequacy Work Group: Dialysis Outcomes Quality
Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 2:S22S31.
Hakim, RM: Clinical implications of hemodialysis membrane biocompatibility. Kidney Int 1993, 44:484494.
7. Vanholder R, Ringoir S, Dhondt A, et al.: Phagocytosis in uremic and

hemodialysis patients: a prospective and cross sectional study. Kidney
Int 1991, 39:320327.
8. Gutierrez A, Alvestrand A, Bergstrom J: Membrane selection and
muscle protein catabolism. Kidney Int 1992, 42:S86S90.
9. Hornberger JC, Chernew M, Petersen J, Garber AM: A multivariate
analysis of mortality and hospital admissions with high-flux dialysis.
J Am Soc Nephrol 1992, 3:12271237.
10. Hemodialysis Adequacy Work Group: Dialysis Outcomes Quality
Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 3:S199S201.
11. Hakim RM, Wingard RL, Parker RA: Effect of the dialysis membrane
in the treatment of patients with acute renal failure. N Engl J Med
1994, 331:13381342.
12. Eschbach JW, Egrie JC, Downing MR, et al.: Correction of the anemia
of end-stage renal disease with recombinant human erythropoietin.
N Engl J Med 1987, 316:7378.
Complications of Dialysis:
Selected Topics
Robert W. Hamilton
omplications observed in end-stage renal disease may be due to

the side effects of treatment or to the alterations of pathophysiology that go with kidney failure.
CHAPTER
7.2
Complications of Hemodialysis
COMPLICATIONS OF HEMODIALYSIS
Complication
Differential diagnosis
Fever
Hypotension
Bacteremia, water-borne pyrogens, overheated dialysate

Excessive ultrafiltration, cardiac arrhythmia, air embolus, pericardial
tamponade; hemorrhage (gastrointestinal, intracranial,
retroperitoneal); anaphylactoid reaction
Inadequate removal of chloramine from dialysate, failure of dialysis
concentrate delivery system
Incomplete removal of aluminum from dialysate water, prescription
of aluminum antacids
Excessive urea clearance (first treatment), failure of dialysis
concentrate delivery system
Excessive heparin or other anticoagulant
Excessive ultrafiltration
Hemolysis
Dementia
Seizure
Bleeding
Muscle cramps
FIGURE 7-1
Complications associated with hemodialysis.
FIGURE 7-3
Thrombosis of the left innominate vein. Thrombosis can be a complication of reliance on subclavian catheters for vascular access for
hemodialysis. This was discovered during investigation of edema of
the left arm.

Dialyzer hypersensitivity. This patient was switched from a cellulose
acetate dialysis membrane to a cuprammonium cellulose one. Within
8 minutes of starting hemodialysis he developed apprehension,
diaphoresis, pruritus, palpitations, and wheezing. This eruption
was seen over the arm used for arteriovenous access for dialysis.
(From Caruana and coworkers [1]; with permission.)
FIGURE 7-4
Dilation of a stricture of the left innominate vein using balloon
angioplasty in the patient shown in Figure 7-3.
Complications of Dialysis: Selected Topics
7.3

Ischemia of the index finger. Occasionally the arteriovenous fistula results in radial-tobrachiocephalic steal, leaving inadequate blood supply to the fingers. This risk is
especially common in diabetic patients.
FIGURE 7-6
Dialysis-associated amyloidosis. Multiple carpal bone cysts without joint space narrowing
in a patient treated with dialysis for 11 years. This phenomenon has been attributed to
inadequate clearance of b-2microglobulin using low-permeability, cellulose dialysis membranes.
(From van Ypersele de Strihou and coworkers [2]; with permission.)
Complications of Peritoneal Dialysis

FIGURE 7-7
Perforation of the bladder on insertion of peritoneal catheter. Bladder perforation can be a
complication of blind insertion of a peritoneal catheter. It is recognized by the sudden
appearance of glucose-positive urine on instillation of the first bag of dialysate.
Instillation of radiographic contrast medium confirms the diagnosis.
7.4

Peritonitis. In continuous ambulatory peritoneal dialysis (CAPD)
peritonitis can easily be recognized by the fact that drained peritoneal
fluid becomes opacified. The inability to read the writing on the
opposite side of the drained bag (or a newspaper through the bag)
correlates with a peritoneal leukocyte count of more than 100 cells
per microliter.

Tunnel abscess in patient undergoing continuous ambulatory peritoneal
dialysis. Pericatheter infections are a common source of peritonitis.
Sometimes, the findings are more subtle than in this case. Prompt
treatment with antibiotics is indicated. If the infection fails to
respond, removal of the catheter is indicated.
FIGURE 7-10
Sclerosing encapsulating peritonitis. This patient had several bouts
of peritonitis during the course of her treatment on peritoneal dialysis.
She developed partial small bowel obstruction. Abdominal computed
tomography revealed a homogeneous mass filling the anterior peritoneum. At laparotomy the mesentery was encased in a marblelike fibrotic mass. The patient required long-term home parenteral
hyperalimentation for recovery. (From Pusateri and coworkers [3];
with permission.)
7.5
Complications of Renal Failure
Pericardial effusion
Ventricular septum
Right ventricle
Left ventricle
FIGURE 7-11
Pericardial tamponade. Narrow pulse pressure and a
pericardial friction rub suggest pericarditis (a frequent
complication of uremia) especially in patients with chest

Perforating folliculitis. The skin of uremic patients can be intensely
pruritic. Earlier, it was attributed to deposition of calcium and
phosphorus in the skin. Today, we know that is the result of
repeated trauma to the skin associated with scratching.
pain. Pericardial tamponade may present as dialysis-induced

hypotension. (Courtesy of T. Pappas, MD, Medical College
of Ohio.)
FIGURE 7-13
Acquired cystic disease of the kidney. Abdominal computed tomography demonstrates cystic disease in this patient, who had focal
segmental glomerulosclerosis complicated by protein C deficiency
and renal vein thrombosis. Eleven years after the initial diagnosis,
he developed renal failure requiring hemodialysis. Two years after
starting dialysis, he developed hematuria, and these cysts were
found. The appearance and clinical course are consistent with
acquired cystic disease of the kidney. These cysts carry some risk of
malignant transformation.
7.6

FIGURE 7-14
Malnutrition. Malnutrition is an important risk factor for dialysis patients, as reflected in this
graph depicting the relation of death to serum albumin values. Albumin may have antioxidant
properties. Low concentrations of serum albumin may favor oxidation of lipids, which
renders them more atherogenic. (Data from Owens and coworkers [4].
Risk of death
15
10
0
>4.5 4.04.4 3.53.9 3.03.4 2.52.9 <2.5
Serum albumin, g/dL
Radiologic Manifestations of Renal Osteodystrophy
FIGURE 7-15
Radiograph of a shoulder involved by osteoporosis. The shoulder
joint demonstrates diffuse osteoporosis. There is distal resorption
of the clavicle. A small amount of calcification can be seen on the
clavicular side of the coracoclavicular ligament. These findings are
suggestive of osteitis fibrosa cystica.
FIGURE 7-16
Diffuse bone demineralization as demonstrated in skull radiograph.
This radiograph demonstrates the generalized granular appearance that is characteristic of the diffuse demineralization seen in
renal osteodystrophy.
7.7
FIGURE 7-17
Radiograph of the hands of a patient who has renal osteodystrophy.
The hands demonstrate diffuse bilateral osteoporosis. The resorption
of the distal phalanges is best seen in the first and second digits of
the right hand. The radial side of the middle phalanges of the second
and third digits bilaterally demonstrates subperiosteal bone resorption.
Soft tissue calcification is present on the radial side of the proximal
interphalangeal joint of the second digit of the left hand.
10 min
30
30
50
1 hr
2 hr
FIGURE 7-18
Parathyroid scan. The patient was injected with 24.6 mCi of 99m
Tc Cardiolite. Hyperfunction of four parathyroid glands is seen.
This technique is often useful to determine the location and number
of parathyroid glands before performing subtotal parathyroidectomy.
At operation, diffuse hyperplasia of four parathyroid glands was
found. (From Ishibashi and coworkers [5].)
References
1.
2.
3.
Caruana RJ, Hamilton RW, Pearson FC: Dialyzer hypersensitivity syndrome: possible role of allergy to ethylene oxide. Am J Nephrol 1985,
5:271274.
van Ypersele de Strihou C, Jadoul M, Malghem J, et al.: Effect of dialysis
membrane and patients age on signs of dialysis-related amyloidosis.
The working party on dialysis amyloidosis. Kidney Int 1991,
39:10121019.
Pusateri R, Ross R , Marshall R, et al.: Sclerosing encapsulating
peritonitis: report of a case with small bowel obstruction managed
by long-term home parenteral hyperalimentation and a review of the
literature. Am J Kidney Dis 1986, 8:5660.
4.
5.
Owens WF, Lew NL, Liu L, et al.: The urea reduction ratio and serum
albumin concentration as predictors of mortality in patients undergoing
hemodialysis. N Engl J Med 1993, 329:10011006.
Ishibashi M, Nishida H, Hiromatsu Y, et al.: Localization of ectopic
parathyroid glands using technetium-99m sestamibi imaging: comparison
with magnetic resonance and computed tomographic imaging. Eur J
Nuclear Med 1997, 24:197201.
Histocompatibility Testing
and Organ Sharing
Lauralynn K. Lebeck
Marvin R. Garovoy
istocompatibility and its current application in kidney transplantation are discussed. Both theoretic and clinical aspects of
human leukocyte antigen testing are described, including antigen typing, antibody detection, and lymphocyte crossmatching. Living
related, living unrelated, and cadaveric donor-recipient matching algorithms are discussed with regard to mandatory organ sharing and
graft outcomes.
CHAPTER
8.2
Transplantation as Treatment of End-Stage Renal Disease
Chromosome 6
(short arm)
Class II
Glyoxylase DP
HLA complex
Class III Class I
DQ DR
DZ DO
Cyp21 TNF
H
G
TNF
TNF
HSP 70
BF
C2
3000
CYP 21-B
C4B
CYP 21-A
C4A
500
4000
J
A
3000
DRB
DRA
DQB2
DQA2
DQB1
DQA1
LMP 2
TAP 1
LMP 7
TAP 2
DMB
DMA
DNA
DPA1
DPA2
DPB1
DPB2
Class I
2000
X
E
Class III
1000
Class II
0
1500
FIGURE 8-1
The major histocompatibility complex (MHC) is a group of closely
linked genes that was first appreciated because it was found to
contain the structural genes for transplantation antigens. A, The
MHC, located on the short arm of chromosome 6, is now recognized to include many other genes important in the regulation of
immune responses. B, Regions of the MHC classes I, II, and III.
The MHC can be divided into three regions, of which the class I
and II regions contain the loci for the human histocompatibility
antigen or human leukocyte antigen (HLA). Genes in the class I
Specific locus
HLA
The major histocompatibility

complex in humans
Provisional
specificity
Locus
HLA
Specific antigen
Allele designation
DRB1
Corresponding antigen
04
03
Specific allele
region encode the a or heavy chain of the class I antigens, HLA-A,

B, and C. The class I region is composed of other genes, most of
which are pseudogenes and are not expressed. The MHC class II
region is more complex, with structural genes for both the a and
b chains of the class II molecules. The class II region includes four
DP genes, one DN gene, one DO gene, five DQ genes, and a varying number of DR genes (two to 10), depending on the halotype.
Many other immune response genes are coded within the class III
region. TNFtumor necrosis factor.
FIGURE 8-2
Nomenclature of human leukocyte antigen (HLA) specificities. HLA
nomenclature may be confusing to the newcomer, but the format is
logical. The prefix HLA precedes all antigens or alleles to define
the major histocompatibility complex (MHC) of the species. The
designation, A, B, C, DR, and so on, is next and defines the locus.
The locus is followed by a number that denotes the serologically
defined antigen or a number with an asterisk that denotes the
molecularly defined allele. In some cases the letter w is placed
before the serologic antigen, indicating it is a workshop designation
and the specific assignment is provisional.
Histocompatibility Testing and Organ Sharing
PRETRANSPLANTATION
TESTING FOR RENAL PATIENTS
HLA phenotype
Patient cells tested with known antisera
HLA antibody screen
Known cells tested with patient sera
HLA crossmatch
Donor cells tested with patient sera
8.3
FIGURE 8-3
In an immunogenetics and transplantation laboratory, three major types of renal pretransplantation testing are performed routinely. The human leukocyte antigen (HLA) assignments
are assigned by serologic methods (ie, complement-dependent cytotoxicity); however, molecular-based methodologies are becoming widely accepted. Most laboratories now have the
capability of reporting at least low-resolution molecular class II types.
The sera of patients awaiting cadaveric donor kidney transplantation are tested for the
degree of alloimmunization by determining the percentage of panel reactive antibodies
(PRAs). Current federal regulations require that the serum screening test use lymphocytes
as targets; however, because these same regulations no longer mandate monthly screening,
assays using soluble antigens may be used as adjuncts to the classic lymphocytotoxic assays.
The purpose of cross-match testing is to detect the presence of antibodies in the patients
serum that are directed against the HLA antigens of the potential donor. When present,
the antibodies indicate that the immune system of the recipient has been sensitized to the
donor antigens. The various test methods differ in sensitivity, including the multiple variations
of the lymphocytotoxicity text, flow cytometry, and enzyme-linked immunosorbent assay
(ELISA). The degree of acceptable risk is one factor to be considered in selecting a method
of appropriate sensitivity. For example, when the only risk considered unacceptable is that
of hyperacute rejection, a technique having lower sensitivity is adequate. A second approach
may be to consider the degree to which an individual patient or type of patient is at risk
for graft rejection. The patient having a repeat graft is at higher risk for graft rejection
than is the patient receiving a primary graft. Because patients differ in their degree of risk,
it is appropriate to use different techniques to offset that risk.
MHC I AND II CHARACTERISTICS

Class I
Class II
Composed of HLA-A, -B, and -C

Ubiquitous distribution
Autosomal codominant
Target for immune effector mechanism
Serologic and molecular detection
Heterodimer noncovalently linked
Heavy chain (a):
Contains variable regions
Confers human leukocyte antigen
specificity
Light chain (b2-microglobulin):
Invariant
Composed of HLA-DR, -DQ, and -DP

Restricted distribution
Autosomal codominant
Major role in immune response
induction
Serologic, molecular, and cellular
detection
Heterodimer noncovalently linked
a Chain:
Nonvariable in HLA-DR
Contains variable regions in HLA-DQ
and -DP
b Chain:
Contains variable regions
Confers most of HLA-DR specificity
FIGURE 8-4
Human leukocyte antigens (HLAs) are heterodimeric cell-surface
glycoproteins. HLAs are divided into two classes, according to
their biochemical structure and respective functions. Class I antigens
(A, B, and C) have a molecular weight of approximately 56,000 D
and consist of two chains: a glycoprotein heavy chain (a) and a
light chain (b2-microglobulin). The a chain is attached to the cell
membrane, whereas b2-microglobulin is associated with the a
chain but is not covalently bonded. The HLA class I molecules are
found on almost all cells; however, only vestigial amounts remain
on mature erythrocytes. Class II antigens (HLA-DR, DQ, and DP)
have a molecular weight of approximately 63,000 D and consist of
two dissimilar glycoprotein chains, designated a and b, both of
which are attached to the membrane. Each chain consists of two
extramembranous amino acid domains, and the outer domains of
each molecule contain the variable regions corresponding to class II
alleles. Although class I antigens are expressed on all nucleated cells
of the body, the expression of class II antigens is more restricted. Class
II antigens are found on B lymphocytes, activated T lymphocytes,
monocyte-macrophages, dendritic cells, and early hematopoietic
cells, and of importance in transplantation, endothelial cells.
8.4

MHC
protein
FIGURE 8-5
Biology of the major histocompatibility complex (MHC). A, The
biologic function of MHC antigens is to present antigenic peptides
to T lymphocytes. In fact, it is an absolute requirement of T-lymphocyte activation for the T cells to see the antigenic peptide
bound to an MHC molecule. This MHC restriction has been
defined on a molecular basis with the elucidation of the crystalline
structures of classes I and II MHC molecules. B, The N-terminal
domains of the MHC molecules are formed by the folding of portions of their component chains in b-pleated sheets and a helices.
C, The sheet portions form a floor, and the helices form the sides
of a peptide-binding groove.
T-cell
receptor
chain
Processed
antigen
chain
2m
Peptide
Heavy
subunit
Peptide
subunit
2m subunit
subunit
FIGURE 8-6
The structure of class I and II molecules.
Comparison of the crystalline structures of
classes I and II molecules has revealed overall
structural similarity, with a few significant
differences. A, Class I molecules have a
groove with deep anchor pockets at each
end (a pita pocket). These pockets restrict
the binding of peptides to those of eight to
nine amino acid residues in length. B, The
peptide-binding groove of class II molecules
is more flexible and relatively open at one
end, more like a hotdog bun, permitting
larger peptides from 13 to 25 amino acid
residues in length to bind.
HLA SPECIFICITIES
A
DR
DQ
DP
A1
A2
A203
A210
A3
A9
A10
A11
A19
A23(9)
A24(9)
A2403
A25(10)
A26(10)
A28
A29(19)
A30(19)
A31(19)
A32(19)
A33(19)
A34(10)
A36
A43
A66(10)
A68(28)
A69(28)
A74(19)
A80
B5
B7
B703
B8
B12
B13
B14
B15
B16
B17
B18
B21
B22
B27
B2708
B35
B37
B38(16)
B39(16)
B3901
B3902
B40
B4005
B41
B42
B44(12)
B45(12)
B46
B47
B48
B49(21)
B50(21)
B51(5)
B5102
B5103
B52(5)
B53
B54(22)
B55(22)
B56(22)
B57(17)
B58(17)
B59
B60(40)
B61(40)
B62(15)
B63(15)
B64(14)
B65(14)
B67
B70
B71(70)
B72(70)
B73
B75(15)
B76(15)
B77(15)
B7801
B81
Bw4
Bw6
Cw1
Cw2
Cw3
Cw4
Cw5
Cw6
Cw7
Cw8
Cw9(w3)
Cw10(w3)
DR1
DR103
DR2
DR3
DR4
DR5
DR6
DR7
DR8
DR9
DR10
DR11(5)
DR12(5)
DR13(6)
DR14(6)
DR1403
DR1404
DR15(2)
DR16(2)
DR17(3)
DR18(3)
DR51
DR52
DR53
DQ1
DQ2
DQ3
DQ4
DQ5(1)
DQ6(1)
DQ7(3)
DQ8(3)
DQ9(3)
DPw1
DPw2
DPw3
DPw4
DPw5
DPw6
Antigens listed in parentheses are the broad antigens, antigens followed by broad antigens in parentheses
are the antigen splits.
8.5
FIGURE 8-7
Allelic polymorphism. Allelic polymorphism
is a hallmark of the human leukocyte antigen
(HLA) system. The extreme polymorphism of
the HLA system is seen in the large numbers
of different alleles that exist for the multiple
major histocompatibility complex (MHC)
loci. At any given locus, one of several
alternative forms or alleles of a gene can
exist. Because so many alleles are possible
for each HLA locus, the system is extremely
polymorphic. The currently accepted World
Health Organization serologically defined
alleles are shown here. Established HLA
antigens are designated by a number following
the letter that denotes the HLA locus (eg,
HLA-A1 and HLA-B8). For example, by
serologic techniques, 28 distinct antigens
are recognized at the HLA-A locus, and
59 defined antigens at the HLA-B locus.
Sequencing studies of the HLA-DRB1 gene
have identified over 100 distinct alleles, and
preliminary analysis indicates that this level
of polymorphism will be as high for other
loci such as HLA-B. MHC polymorphism
ensures effective antigen presentation of
most pathogens; however, clinically, MHC
polymorphism complicates attempts to find
histocompatible donors for solid organ
transplantation.
8.6

Father
a b
A1
A3
Mother
c d
A2
A9
Cw7
B8
Cw7
B7
Cw7
B12
Cw4
B35
DR3
DR2
DR5
DR3
Stage 1
Incubate cells
and serum
30 min
RT
Wash 3
Add AHG 2 min

Stage 2
Add rabbit serum

(complement)
Children
a
A1
a
A2
A1
b
A9
A3
b
A2
A3
Cw7
B8
Cw7
B12
Cw7
B8
Cw4
B35
Cw7
B7
Cw7
B12
Cw7
B7
Cw4
B35
DR3
DR5
DR3
DR3
DR2
DR5
DR2
DR3
FIGURE 8-8
Genetic principles of the major histocompatibility complex (MHC).
The MHC demonstrates a number of genetic principles. Each person
has two chromosomes and thus two MHC haplotypes, each inherited
from one parent. Because the human leukocyte antigen (HLA) genes
are autosomal and codominant, the phenotype represents the
combined expression of both haplotypes. Each child receives one
chromosome and hence one haplotype from each parent. Because
each parent has two different number 6 chromosomes, four different
combinations of haplotypes are possible in the offspring. This
inheritance pattern is an important factor in finding compatible
related donors for transplantation. Thus, an individual has a 25%
chance of having an HLA-identical or a completely dissimilar sibling
and a 50% chance of having a sibling matched for one haplotype.
The genes of the HLA region occasionally ( 1%) demonstrate
chromosomal crossover. These recombinations are then transmitted
as new haplotypes to the offspring.
SCORING OF COMPLEMENT-DEPENDENT
CYTOTOXICITY REACTIONS
Dead cells, %
010
1120
2150
5180
80100
Unreadable
Assigned value
1
2
4
6
8
0
60 min
RT
A9
Interpretation
Negative
Borderline negative
Weak positive
Positive
Strong positive
No cells, contamination, bubble
Stage 3
Visualize membrane injury

(Eosin-y, AO/EB, etc.)
FIGURE 8-9
Complement-dependent technique. The standard technique used to
detect human leukocyte antigen (HLA)-A, -B, -C, -DR, and -DQ antigens has been the microlymphocytotoxicity test. This assay is a complement-dependent cytotoxicity (CDC) in which lymphocytes are used
as targets because the HLA antigens are expressed to varying degrees
on lymphocytes and a relatively pure suspension of cells can be
obtained from anticoagulated peripheral blood. Lymphocytes obtained
from lymph nodes or the spleen also may be used. HLA antisera of
known specificity are placed in wells on a Terasaki microdroplet
tray. A concentrated suspension of lymphocytes is added to each
well. If the target lymphocytes possess the antigen corresponding to
the antibody present in the antiserum, the antibody will affix to the
cells. Rabbit complement is then added to the wells and, when sufficient antibody is bound to the lymphocyte membranes, complement is
activated. Complement activation injures the cell membranes (lymphocytotoxicity) and increases their permeability. Cell injury is detected by
dye exclusion: cells with intact membranes (negative reactions)
exclude vital dyes; cells with permeable membranes (positive reactions) take up the dye. Sensitivity of the CDC assay is increased by
wash techniques or the use of AHG reagents prior to the addition of
complement. Because HLA-DR and -DQ antigens are expressed on
B cells and not on resting T cells, typing for these antigens usually
requires that the initial lymphocyte preparation be manipulated before
testing to yield an enriched B-cell preparation. AHGantiglobulinaugmented lymphocytotoxicity; RTroom temperature.
FIGURE 8-10
Scoring of complement-dependent cytotoxicity. In an effort to
standardize interpretation of complement-dependent cytotoxicity
(CDC) reactions, a uniform set of scoring criteria have been established. When most of the cells are alive, visually refractile on
microscopic examination, a score of 1 is assigned. Conversely,
when most of the cells are dead, a score of 8 is assigned. This
method of interpretation for CDC reactions is universally used in
cross-match testing, antibody screening, and antigen phenotyping
for serologically defined HLA-A, -B, -C, -DR, and -DQ. (Adapted
from Gebel and Lebeck [1]; with permission.)
10
8
5
11
4
8.7
FIGURE 8-11
The United Network for Organ Sharing (UNOS) regions. UNOS is
a not-for-profit corporation within the United States organized
exclusively for charitable, educational, and scientific purposes
related to organ procurement and transplantation. Its formation
established a national Organ Procurement and Transplantation
Network with the mandate to improve the effectiveness of the
nations renal and extrarenal organ procurement, distribution, and
transplantation systems by increasing the availability of and access
to donor organs for patients with end-stage organ failure. Additionally,
the UNOS maintains quality assurance activities and systematically
gathers and analyzes data and regularly publishes the results of the
national experience in organ procurement and preservation, tissue
typing, and clinical organ transplantation. Functionally, the United
States is divided into UNOS regions as detailed on this map.
Additional geographic divisions (ie, local designation) defined by
the individual organ procurement organizations and the transplantation centers they service comprise the working system for cadaveric renal allocation.
UNITED NETWORK FOR ORGAN SHARING: NUMBER OF PATIENT REGISTRATIONS

ON THE NATIONAL TRANSPLANT WAITING LIST AS OF OCTOBER 31, 1997
Kidney number
by blood type (%)
Kidney number
by race (%)
Kidney number
by gender (%)
Type O: 19,654(52.04)
Type A: 10,612(28.10)
Type B: 6579(17.42)
Type AB: 923(2.44)
Total: 37,768
White: 18,353(48.59)
Black: 13,290(35.19)
Hispanic: 3441(9.11)
Asian: 2200(5.83)
Other: 484(1.28)
Total: 37,768
Female: 16,269(43.08)
Male: 21,499(56.92)
Total: 37,768
FIGURE 8-12
The United Network for Organ Sharing (UNOS) patient waiting
list. The UNOS patient waiting list is a computerized list of
patients waiting to be matched with specific donor organs in the
hope of receiving a transplantation. Patients on the waiting list
are registered on the UNOS computer by UNOS member transplantation centers, programs, or organ procurement organizations. The UNOS Match System is an algorithm used to prioritize
Kidney number by
transplantation center region (%)
Region 1: 1738(4.60)
Region 2: 6060(16.05)
Region 3: 3844(10.18)
Region 4: 2191(5.80)
Region 5: 7361(19.49)
Region 6: 855(2.26)
Region 7: 3826(10.13)
Region 8: 1559(4.13)
Region 9: 3936(10.42)
Region 10: 3121(8.26)
Region 11: 3277(8.68)
Total: 37,768
Kidney number
by age (%)
05: 76(0.20)
610: 119(0.32)
1117: 429(1.14)
1849: 21,102(55.87)
5064: 12,942(34.27)
65+: 3100(8.21)
Tota: 37,768
patients waiting for organs. The system eliminates potential

recipients whose size or ABO type is incompatible with that
of a donor and then ranks those remaining potential recipients
according to a UNOS board-approved system. As indicated
here, nearly 40,000 patients are awaiting kidney transplantation
in the United States. (Adapted from the United Network for
Organ Sharing [2]).
8.8
POINT SYSTEM FOR KIDNEY ALLOCATION

Time of waiting
The time of waiting begins when a patient is listed and meets the minimum established criteria on the United
Network for Organ Sharing Patient Waiting List. One point will be assigned to the patient waiting for the longest
period, with fractions of points being assigned proportionately to all other patients according to their relative
time of waiting.
Quality of HLA mismatch
10 points if there are no A, B, or DR mismatches.
7 points if there are no B or DR mismatches.
5 points if there is one B or DR mismatch.
2 points if there is a total of two mismatches at the B and DR loci.
Panel reactive antibody
Patients will be assigned 4 points if they have a panel reactive antibody level of 80% or more.
Medical urgency
No points will be assigned to patients based on medical urgency for regional or national allocation of kidneys.
Locally, the patients physician has the authority to use medical judgment in assignment of points for medical
urgency. When there is more than one local renal transplantation center, a cooperative medical decision is
required before assignment of points for medical urgency.
Pediatric kidney transplantation candidates
4 points if the patient is under 11 years of age.
3 points if the patient is over 11 and under 18 years of age.
CROSSMATCH METHODS
Lymphocytotoxicity:
Autocrossmatch vs allocrossmatch
T or B cell
Short/long/wash/AHG methods
IgG vs IgM
Flow cytometry
Enzyme-linked immunosorbent assay
FIGURE 8-13
Point system for kidney allocation. Kidneys
that cannot be allocated to a human leukocyte antigen (HLA)matched patient are
distributed locally to candidates who are
ranked according to waiting time, with
additional points for degrees of HLA mismatch and antibody sensitization. Pediatric
patients, medically urgent cases, and previous
donors (living related donors, and so on)
also are given a point advantage.
FIGURE 8-14
Crossmatch methods. Early reports correlating a positive crossmatch between recipient
serum and donor lymphocytes with hyperacute rejection of transplanted kidneys led to
establishing tests of recipient sera as the standard of practice in transplantation. However,
controversy remains regarding 1) the level of sensitivity needed for crossmatch testing;
2) the relevance of B-cell crossmatches, a surrogate for class II incompatibilities; 3) the
relevance of immunoglobulin class and subclass of donor-reactive antibodies; 4) the significance
of historical antibodies, ie, antibodies present previously but not at the time of transplantation;
5) the techniques and type of analyses to be performed for serum screening; and 6) the
appropriate frequency and timing of serum screening. Despite a number of variables, when
the data from reported studies are considered collectively, several observations can be
made. Human leukocyte antigendonor-specific antibodies present in the recipient at the
time of transplantation are a serious risk factor that significantly diminishes graft function
and graft survival. Antibodies specific for human leukocyte antigen class II antigens (HLA-DR
and -DQ) are as detrimental as are those specific for class I antigens (HLA-A, -B, and -C). The
degree of risk resulting from HLA-specific antibodies varies among immunoglobulin classes,
with immunoglobulin G antibodies representing the most serious risk. AHGantiglobulinaugmented lymphocytotoxicity.
250
250
200
200
CD3 PE
SSC
150
100
150
100
R1
50
50
0
0
0
50
100
150
FSC
200
250
100
150
FSC
200
250
100
T cell
90
160
Counts
50
200
Neg (n = 508)
80
120
70
80
60
M1
Neg (n = 75)
Pos (n = 106)
Pos (n = 43)
50
40
40
0
0
R2
50
100 150 200
Human IgG-Fc-FITC
First
30
250
Regraft
6
12
0
6
12
FIGURE 8-15
Techniques of crossmatch testing. Early crossmatch testing provided a means to prevent
most but not all hyperacute rejections. These early tests were performed with a technique
of rather low sensitivity. Subsequently, more sensitive techniques were employed in an
attempt to not only prevent all hyperacute rejections but also improve graft survival
rates. Techniques that have been used include variations of the lymphocytotoxicity test
that incorporate wash steps, change in incubation times or temperatures, or both, or add
an antiglobulin reagent. Flow cytometry and an array of other methods such as antibody-
ALTERNATIVE APPROACHES TO HLA MATCHING
CREG*
Associated human leukocyte

antigen gene products
1C
2C
5C
7C
8C
12C
4C
6C
A1,3,9,10,11,28,29,30,31,32,33
A2,9,28, B17
B5,15,17,18,35,53,70,49
B7,13,22,2740,41,47,48
B8,14,16,18
B12,13,21,40,41
A24,25,32,34, Bw4
Bw6, Cw1,3,7
Approximate
epitope frequency, %
C refers to major public epitope or cross-reactive groups (CREG).
80
66
59
64
37
44
85
87
8.9
dependent cellular cytotoxicity also have

been tried. Two of the most sensitive techniques are the antiglobulin-augmented lymphocytotoxicity (AHG) and flow cytometric crossmatching. A, The use of flow
cytometry to define the lymphocyte population by light scatter parameters, followed
by a specific marker for T lymphocytes,
ie, CD3 (B) allows this technique to be
highly specific for human leukocyte antigen
(HLA) class Ipositive cells. The donor
lymphocytes have been preincubated with
recipient serum, washed, and subsequently
stained with AHG-Fluorescsin isothiocyanate (FITC), a fluorochrome-labeled
antihuman globulin. C, Results of flow
cytometric cross-matching are evaluated as
shifts in the fluorescence from negative sera
and are interpreted as positive or negative
based on independently defined cutoffs
above the negative. D, Multiple studies in
renal transplantation have shown correlations between positive AHG or flow cytometric cross-matches and decreased graft
survival at 1 year or more. The largest
differences are seen when patients are
grouped as primary grafts versus repeat
grafts. In some instances the effect of using
a more sensitive cross-match technique
only can be seen in patients having repeat
grafts or those with a higher immunologic
risk. CD3 PEmonoclonal antibody to
CD3 fluorescent labelled with phycoerythrin; FCconstant fragment of IgG molecule; FITCfluorescent labelled with fluorescein isothiocynate; FSCforward scatter; R1region 1; R2region 2; SSCside
scatter. (Panel D adapted from Cook [3];
with permission.)
FIGURE 8-16
Alternative approaches to human leukocyte antigen (HLA) matching.
Because completely mismatched kidney transplantations function
well over long periods, an alternative approach might begin with the
hypothesis that six-antigen mismatched transplantations were not
completely mismatched. Interest in reevaluating the potential roles
of cross-reactive groups (CREGs) in transplantation is one such
approach. In the early days of serologic HLA testing, a high panel
reactive antibody sera was considered to be composed of many antiHLA antibodies. It was later noted, however, that sera of highly sensitized patients awaiting solid organ transplantation were generally composed of a small number of antibodies directed at public antigens, also
called CREGs, rather than multiple antibodies, each reacting with a
specific conventional HLA antigen. Furthermore, the frequency of the
CREGs was much higher, eg, 35% to 88%, than that of even the most
common HLA-A and -B antigens. By inference, therefore, matching for
donor and recipient antigens included in the same CREG, ie, CREG
matching, could result in a higher number of matched transplantations
and a lower level of sensitization in patients having repeat grafts. In
addition, because of the inclusion of several private HLA-A and -B
antigens within a single CREG, a number of relatively rare antigens
can be matched more easily, offering the possibility of improved graft
survival for a greater number of both white and nonwhite patients.
(Adapted from Thelan and Rodey [4]; with permission.)
100
100
80
80
60
ABDR
MM
n
0
3023
1
1305
40
30
20
T 12
14
12
3736
12
6312
12
4
5
6414
11
3641
1209
11
10
Graft survival (log), %
Graft survival (log), %
8.10
White
1st cadaver
UNOS (19911996)
10
60
ABDR
MM
0
40
30
T 12
301
255
970
2459
6
6
3251
2078
739
1
2
20
Black
1st cadaver
UNOS (19911996)
10
0
3
4
5
6
7
Years after transplantation
FIGURE 8-17
The role of human leukocyte antigen (HLA) matching in the United
States in whites (A) and blacks (B). Recent large registry analyses
of the role for HLA matching in renal transplantation consistently
have shown a stepwise decrease in long-term graft survival rates
with increasing antigen mismatches. Based on these results the United
Network of Organ Sharing (UNOS) incorporated the level of HLA
match into its algorithm used nationally for kidney allocation. The
UNOS initially determined that transplantations for which all six
HLA-A, -B, and -DR antigens matched in the donor and recipient
should be performed. Each cadaveric donor type was compared by a
computer search with the HLA types of all patients awaiting kidney
transplantation. When a patient with six antigen matches was
Serology
(antibody defined)
versus
(Low
Molecular
Intermediate
High resolution)
HLA-DR13
*1301*1312 *1314*1330
HLA-DR14
*1401, *1402, *1405*1429
HLA-DR6
DR1403
DR1404
10
3
4
5
6
7
10
identified in an ABO-compatible recipient, the kidney was offered

for that patient, and if accepted by the transplantation center, was
shipped for transplantation. (Normally, kidneys from a patient
with blood type O are allocated only to patients with type O blood,
except in the case of patients with six antigen matches.) The UNOS
policy regarding mandatory sharing of HLA-matched kidneys has
been liberalized twice. The first time was in 1990 to include phenotypically matched pairs with fewer than six antigens. The policy
was changed for a second time in 1995 to include zero-mismatched
pairs in which the donor could have fewer antigens than the recipient,
provided none were mismatched. (Adapted from Cecka [5]; with
permission.)
FIGURE 8-18
Serologic testing and antigen assignment. Most of the published
transplantation outcome data is based on serologic testing and
assignment of antigens. These data include algorithm matching
based on broad human leukocyte antigen (HLA) specificities
such as HLA-DR6 that includes HLA-DR13 and HLA-DR14 and
their many alleles. The question has now become one of what level
of HLA testing is useful clinically for matching purposes in renal
transplantation. Although this issue has not been resolved, recent
data published from the European Registry upholds the positive
effect that correct HLA matching has had on renal graft outcome.
FIGURE 8-19
Classes II and I mismatches in supposed 0 mm shared renal transplantations. The effect on
graft survival of shared human leukocyte antigen (HLA) 0mm organs when defined by serologic typing and then confirmed by molecular typing. A strong effect of HLA matching is
seen at even 1 year on the graft survival. A, Eighty-six first cadaveric kidney transplantations
that were reported by serologic typing as HLA-A, -B, -DR identical-compatible were tested
by molecular methods. Sixty-four transplantations were confirmed to be HLA-DR compatible; however, mismatches were found in the remaining 22 transplantations. Transplantations
in which HLA compatibility was confirmed had a functional success rate of 90% at 1 year
compared with 68% for transplantations in which the DNA typing revealed HLA-DR mismatches (P < 0.02). B, An analysis of the influence of HLA-class I DNA typing on kidney
graft survival is shown. A total of 183 cadaveric transplantations were confirmed to be
HLA-A and B compatible after DNA typing, whereas mismatches were found in the remaining 32 cases. Transplantations in which compatibility was confirmed had a functional success
rate of 86.9% at 1 year compared with a 71.9% rate for those in which DNA typing
revealed HLA-A or -B mismatches (P = 0.033.) (Panel A adapted from Opelz and coworkers
[6]; panel B adapted from Mytilineous and coworkers [7]; with permission.)
100
Graft survival, %
90
DNA: DR 0 mm
(n = 64)
80
70
DNA: DR >0 mm
(n = 22)
60
50
40
0
6
Time, mo
100
12
DNA: A+B 0 mm
(n = 183)
90
Graft survival, %
8.11
80
70
DNA: A+B >0 mm

(n = 32)
60
50
0
0
6
Time, mo
12
100
60
90
Living donor
1988
50
70
50
40
88
89
90
91
30
20
10
n
1809
1895
2086
2385
t 12
12.5
14.3
14.9
14.6
92
93
94
95
n
2527
2828
2914
3117
t 12
17.0
16.3
17.5
8.8
30
20
10
0
0
0
1996
40
60
%
Graft survival, %
80
3
4
5
FIGURE 8-20
Living donor kidney transplantation graft survival rates (A) and
donor sources (B). The high graft survival rates reported for
recipients of living donor kidneys improved from 89% in 1988
to 93% in 1991 (P < 0.001), even though a substantial increase
has occurred in both the number of living donors and centers
performing these transplantations. Some of the increase in living
donations has been due to a growing acceptance of so-called
Parent
Offspring
Sibling
Other
relative
Spouse/other
unrelated
unconventional donors, ie, spouses and other genetically

unrelated donors, as well as distant relatives and half-siblings.
In 19881989, unrelated donors accounted for 4% of living
donor transplantations and distant relatives for 2%. These
numbers have tripled and are now at 12% and 6%, respectively.
(Panel A from Cecka [8]; panel B adapted from the United
Network for Organ Sharing [9]; with permission.)
8.12
References
1.
2.
3.
4.
5.
Gebel HM, Lebeck LK: Crossmatch procedures used in organ

transplantation. Clin Lab Med 1991, 11:609.
United Network for Organ Sharing: UNOS Bulletin 1997, 2.
Cook DJ, et al.: An approach to reducing early kidney transplant
failure by flow cytometry crossmatching. Clin Transpl 1987, 1:25.
Thelan D, Rodey G: American Society of Histocompatibility and
Immunogenetics Laboratory Manual, edn 3. Lenexa, KS: ASHI.
Cecka JM: The role of HLA in renal transplantation. Human
Immunology 1997, 56:616.
6.
7.
8.
9.
Opelz et al.: Transplantation 1998, 55:782785.

Mytilenous et al.: Tissue Antigens 1997, 50:355358.
Cecka JM: UNOS Scientific Renal Transplant Registry. In Clinical
Transplant Registry. Edited by Cecka JM, Terasaki P. Los Angeles:
UCLA; 1996:114.
United Network for Organ Sharing: UNOS Bulletin 1997, 2.
Transplant Rejection
and Its Treatment
Laurence Chan
ejection is the major cause of graft failure, and if the injury to

the tubules and glomeruli is severe, the kidney may not recover.
It is therefore important to diagnose acute rejection as soon as
possible to institute prompt antirejection therapy. Generally, the success
with which rejection can be reversed by immunosuppressive agents
determines the chance of long-term success of the transplant [1,2].
CHAPTER
9.2
Mechanisms of Renal Allograft Rejection

Immune response cascade
Allograft
CD2
TCR CD4
HLAclass II
HLAclass I
HLAclass II
APC
HLAclass I
CD58
CD4
IL-1
CD4
T cells
Cytokines IL-2R
IL-2
IFN-
etc.
CD8
T cells
TCR
CD8
CD3
CD3
CD2
TCR
CD58
CD8 TCR
CD2
CD3
CD3
T cells
B cells
NK cells
IL-2R
CD8
T cells
CD4
Clonal
expansion
HLAclass I
CD2
HLAclass II
Graft
destruction
B. OVERVIEW OF REJECTION EVENTS

Antigen-presenting cells trigger CD4 and CD8 T cells
Both a local and systemic immune response develop
Cytokines recruit and activate nonspecific cells and accumulate in graft, which facilitates
the following events:
Development of specific T cells, natural killer cells, or macrophage-mediated cytotoxicity
Allograft destruction
Indirect allorecognition
CD8+
cytotoxic cell
FIGURE 9-1
Aspects of the rejection response. A, The immune response
cascade. Rejection is a complex and redundant response to grafted
tissue. The major targets of this response are the major histocompatibility complex (MHC) antigens, which are designated as
human leukocyte antigens (HLAs) in humans. The HLA region on
the short arm of chromosome 6 encompasses more than 3 million
nucleotide base pairs. It encodes two structurally distinct classes
of cell-surface molecules, termed class I (HLA-A, -B, and -C) and
class II (-DR, -DQ, -DP).
B, Overview of rejection events. T cells recognize foreign antigens
only when the antigen or an immunogenic peptide is associated
with a self-HLA molecule on the surface of an accessory cell called
the antigen-presenting cell (APC). Helper T cells (CD4) are activated
to proliferate, differentiate, and secrete a variety of cytokines. These
cytokines increase expression of HLA class II antigens on engrafted
tissues, stimulate B lymphocytes to produce antibodies against the
allograft, and help cytotoxic T cells, macrophages, and natural killer
cells develop cytotoxicity against the graft.
C, Possible mechanisms for allorecognition by host T cells. In the
direct pathway, T cells recognize intact allo-MHC on the surface of
donor cells. The T-cell response that results in early acute cellular
rejection is caused mainly by direct allorecognition. In the indirect
pathway, T cells recognize processed alloantigens in the context of
self-APCs. Indirect presentation may be important in maintaining
and amplifying the rejection response, especially in chronic rejection.
IFN-ginterferon gamma; IL-1interleukin-1; IL-2Rinterleukin-2 receptor; NKnatural killer. (Panel A adapted from [3];
with permission; panel C adapted from [4]; with permission.)
Direct allorecognition
CD8+
cytoxic cell
Th cell
Th cell
Allogeneic
cell
Shed
allogeneic
MHC
IL-2
IL-2
II
(Class Iderived peptide

presented by responder
class II molecule)
Allogeneic (stimulator)
antigen presenting cell
Taken up and
processed by host
antigen-presenting cell
Peptide derived from

allogeneic MHC presented
on host MHC
Responder antigen-presenting cell
Class I stimulator
Class II haplotype
Class III responder
haplotype
2 microglobulin
II
9.3
Transplant Rejection and its Treatment
Classification of Rejection
A. VARIETIES OF REJECTION
Types of rejection Time taken
Cause
Hyperacute
Minutes to hours
Preformed antidonor antibodies and

complement
Accelerated
Days
Reactivation of sensitized T cells
Acute
Days to weeks
Primary activation of T cells
Chronic
Months to years
Both immunologic and nonimmunologic

factors
FIGURE 9-2
Varieties of rejection (panel A) and immune mechanisms (panel B).
On the basis of the pathologic process and the kinetics of the rejection
A
FIGURE 9-3 (See Color Plate)
Histologic features of hyperacute rejection. Hyperacute rejection is
very rare and is caused by antibody-mediated damage to the graft.
The clinical manifestation of hyperacute rejection is a failure of the
kidney to perfuse properly on release of the vascular clamps just
after vascular anastomosis is completed. The kidney initially becomes
firm and then rapidly turns blue, spotted, and flabby. The presence
B. IMMUNE MECHANISMS OF
RENAL ALLOGRAFT REJECTION
Type
Hyperacute
Accelerated
Acute
Cellular
Vascular
Chronic
Humoral
Cellular
+++
++
+
+++
++
+++
+
+?
response, rejection of renal allografts can be commonly divided

into hyperacute, accelerated, acute, and chronic types.
B
of neutrophils in the glomeruli and peritubular capillaries in the kidney
biopsy confirms the diagnosis. A, Hematoxylin and eosin stain of
biopsy showing interstitial hemorrhage and extensive coagulative
necrosis of tubules and glomeruli, with scattered interstitial inflammatory cells and neutrophils. B, Immunofluorescence stain of kidney
with hyperacute rejection showing positive staining of fibrins.
9.4
A
FIGURE 9-4
Histologic features of acute accelerated rejection. A and B, Photomicrographs showing histologic features of acute accelerated vascular
rejection. Glomerular and vascular endothelial infiltrates and swelling
are visible. An accelerated rejection, which may start on the second
or third day, tends to occur in the previously sensitized patient in
A
FIGURE 9-5
Histologic features of acute cellular rejection. A, Mild tubulitis.
B, Moderate to severe tubulitis. Acute rejection episodes may occur
as early as 5 to 7 days, but are generally seen between 1 and 4
weeks after transplantation. The classic acute rejection episode of
the earlier era (ie, azathioprine-prednisolone) was accompanied by
swelling and tenderness of the kidney and the onset of oliguria
with an associated rise in serum creatinine; these symptoms were
usually accompanied by a significant fever. However, in patients
who have been treated with cyclosporine, the clinical features of an
acute rejection are really quite minimal in that there is perhaps
some swelling of the kidney, usually no tenderness, and there may
be a minimal to moderate degree of fever. Because such an acute
rejection may occur at a time when there is a distinct possibility of
B
whom preformed anti-HLA antibodies are present. This type of
rejection occurs in patients who have had a previous graft and presents
with a decrease in renal function; the clinical picture is similar to
that for hyperacute rejection.
B
acute cyclosporine toxicity, the differentiation between the two
entities may be extremely difficult.
The differential diagnosis of acute rejection, acute tubular necrosis,
and cyclosporine nephrotoxicity may be difficult, especially in the
early posttransplant period when more than one cause of dysfunction
can occur together [2]. Knowledge of the natural history of several
clinical entities is extremely helpful in limiting the differential diagnosis. Reversible medical and mechanical causes should be excluded
first. Percutaneous biopsy of the renal allograft using real-time ultrasound guide is a safe procedure. It provides histologic confirmation
of the diagnosis of rejection, aids in the differential diagnosis of
graft dysfunction, and allows for assessment of the likelihood of a
response to antirejection treatment.
9.5
B
Hypothetical schema for
chronic rejection
C. CHRONIC ALLOGRAFT
REJECTION
Acute rejection
Antibody deposition
Oxidized LDL
Infection
Typical clinical presentation

Gradual increase in creatinine (months)
Non-nephroticrange proteinuria
No recent nephrotoxic events
Key pathologic features
Arterial fibrosis and intimal thickening
T cells
Macrophages
Platelet aggregates
Cytokines/
growth factors
Cell proliferation
Fibrosis
Vascular injury
Arteriosclerosis
Tubulointerstitial
injury
Glomerular sclerosis
Reduced nephron
mass
Graft loss
FIGURE 9-6
Features of chronic rejection. A, Arterial
fibrosis and intimal thickening. B. Interstitial
fibrosis and tubular atrophy. C, Typical
presentation and pathologic features. Chronic
rejection occurs during a span of months
to years. It appears to be unresponsive to
current treatment and has emerged as the
major problem facing transplantation [5].
Because chronic rejection is thought to be the
end result of uncontrolled repetitive acute
rejection episodes or a slowly progressive
inflammatory process, its onset may be as
early as the first few weeks after transplantation or any time thereafter.
D, The likely sequence of events in chronic
rejection and potential mediating factors for
key steps. Progressive azotemia, proteinuria,
and hypertension are the clinical hallmarks
of chronic rejection. Immunologic and
nonimmunologic mechanisms are thought
to play a role in the pathogenesis of this
entity. Immunologic mechanisms include
antibody-mediated tissue destruction that
occurs possibly secondary to antibodydependent cellular cytotoxicity leading to
obliterative arteritis, growth factors derived
from macrophages and platelets leading to
fibrotic degeneration, and glomerular hypertension with hyperfiltration injury due to
reduced nephron mass leading to progressive
glomerular sclerosis. Nonimmunologic causes
can also contribute to the decline in renal
function. Atheromatous renovascular disease
of the transplant kidney may also be
responsible for a significant number of
cases of progressive graft failure.
9.6
Diagnostic and therapeutic approach to chronic rejection

Slowly rising creatinine

E, Diagnostic and therapeutic approach to chronic rejection.
ATGantithymocyte globulin; ATNacute tubular necrosis; BP
blood pressure; CsAcyclosporine; LDLlow-density lipoprotein.
Check CsA level

High
Low
Lower CsA dose

and repeat creatinine
Improved
No improvement
Ultrasound
Obstruction
No obstruction
Biopsy
ATN Glomerulonephritis
Recurrent GN
de novo GN
Rejection
Acute
Acute
on chronic
Adjust immunosuppressant
Steroid bolus
OKT3 or ATG
Chronic
Temporizing measures
Control BP
Avoid nephrotoxins
BANFF CLASSIFICATION OF RENAL

ALLOGRAFT REJECTION
Normal
Patchy mononuclear cell infiltrates without tubulitis is not uncommon
Borderline changes
No intimal arteritis; mild tubulitis and endocapillary glomerulitis
Acute rejection
Grade I: tubulitis ++
Grade II: tubulitis with glomerulitis
Grade III: intimal arteritis, interstitial hemorrhage, fibrinoid, thrombosis
FIGURE 9-7
The Banff classification of renal allograft rejection. This schema is
an internationally agreed on standardized classification of renal
allograft pathology that regards intimal arteritis and tubulitis as
the main lesions indicative of acute rejection [6].
9.7
New techniques
Constant (but not excessive) suction
25-G needle
Transplanted kidney
Wound
Inguinal ligament
FIGURE 9-8
Fine-needle aspiration cytology technique for the transplanted kidney.
A 23- or 25-gauge spinal needle is used under aseptic conditions. A
20-mL syringe containing 5 mL of RPMI-1640 tissue culture medium
is connected to the needle. Ultrasound guidance may be used on
the rare occasions when the graft is not easily palpable [8].
Monitoring of other products of inflammation such as neopterin
and lymphokines continues to be explored. It has been shown that
acute rejection is associated with elevated plasma interleukin (IL)-1
in azathioprine-treated patients and IL-2 in cyclosporine-treated
patients. IL-6 is also increased in the serum and urine immediately
after transplantation and during acute rejection episodes. The major
problem, however, is that infection, particularly viral, can also elevate
cytokine levels. Recently, polymerase chain reaction (PCR) has also
been used to detect mRNA for IL-2 in fine-needle aspirate of human
transplant kidney [7,8]. Using the PCR approach, IL-2 could be
detected 2 days before rejection was apparent by histologic or clinical
criteria. Reverse transcriptasePCR has also been used to identify
intrarenal expression of cytotoxic molecules (granzyme B and perforin)
and immunoregulatory cytokines (IL-2, -4, -10, interferon gamma,
and transforming growth factor-b1) in human renal allograft biopsy
specimens [9]. Molecular analyses revealed that intragraft display
of mRNA encoding granzyme B, IL-10, or IL-2 correlates with
acute rejection, and intrarenal expression of transforming growth
factor (TGF)-b1 mRNA is associated with chronic rejection. These
data suggest that therapeutic strategies directed at the molecular
correlates of rejection might refine existing antirejection regimens.
Treatment
IMMUNOSUPPRESSION
PROTOCOLS
Induction protocols
Maintenance protocols
Early posttransplantation
Late posttransplantation
Antirejection therapy
FIGURE 9-9
Immunosuppressive therapy protocols. Standard immunosuppressive therapy in renal
transplant recipient consists of 1) baseline therapy to prevent rejection, and 2) short courses of
antirejection therapy using high-dose methylprednisolone, monoclonal antibodies or polyclonal antisera such as antilymphocyte globulin (ALG) and antithymocyte globulin (ATG).
Antilymphocyte globulin is prepared by immunizing rabbits or horses with human lymphoid
cells derived from the thymus or cultured B-cell lines. Disadvantages of using polyclonal
ALS include lot-to-lot variability, cumbersome production and purification, nonselective
targeting of all lymphocytes, and the need to administer the medication via central venous
access. Despite these limitations, ALG has been used both for prophylaxis against and for
the primary treatment of acute rejection. A typical recommended dose for acute rejection
is 10 to 15 mg/kg daily for 7 to 10 days. The reversal rate has been between 75% and
100% in different series. In contrast to murine monoclonal antibodies (eg, OKT3), ALS
does not generally induce a host antibody response to the rabbit or horse serum. As a
result, there is a greater opportunity for successful readministration.
9.8

FIGURE 9-10
Induction (panel A) and maintenance (panel B) immunosuppression protocols. These
immunosuppressive protocols differ from center to center. There are numerous variations,
but the essential features are 1) the prednisone dosage is high initially and then reduced to
a maintenance dose of 10 to 15 mg/d over 6 to 9 months, and 2) the cyclosporine dosage is
8 to 12 mg/kg/d given as a single or twice daily dose, and dosage is adjusted according to
trough plasma and serum blood levels. To maintain immunosuppression provided by
cyclosporine and to reduce the incidence of cyclosporine side effects, azathioprine or
mycophenolate has also been used with lower dosages of cyclosporine. The results of this
triple therapy are excellent, with first-year graft survival greater than 85% reported in most
instances and with a substantial number of patients having no rejection at all. Although
this type of regimen was the most common, there have been a number of exceptions [2,10].
Recently, mycophenolate mofetil has been approved by the US Food and Drug
Administration for prophylaxis of renal transplant rejection [11]. This agent was developed as a replacement to azathioprine for maintenance immunosuppression. FK506 is a
new immunosuppressive agent that has been approved by the FDA. FK506 is similar to
cyclosporine in its mode of action, efficacy, and toxicity profile. The drug has been used in
kidney transplantation. FK506 may be beneficial in renal transplantation as rescue therapy
in patients taking cyclosporine who have recurrent or resistant rejection episodes [1214].
A. INDUCTION PROTOCOLS
Standard induction
Corticosteroids
Azathioprine or mycophenolate
Cyclosporine or FK506
Antibody induction
OKT3 or antithymocyte gamma globulin
B. MAINTENANCE
IMMUNOSUPPRESSION
Cyclosporine or FK506
Mycophenolate
Prednisolone
ATG
OKT3
ATG
OKT3
Postantigenic
differentiation
MPA
AZA
CD4
CD4
ATG
OKT3
Class II
HLA antigen
ATG
OKT3
Prolife
ration
IL-1
TNF-
Steroids
CD4
CsA
FK506
RPM
MPA
Ant
ibod
y
IL-2
Steroids
CD8
Cy
to
k
CD8
B lymphocyte
Stimulated
macrophage
Macrophage
IL-2
ine
Allogeneic
cell
CD4
ATG
OKT3
Class I
HLA antigen
IL-1
CD8
ration
Prolife
CD8
ATG
OKT3
AZA
MPA
ATG
OKT3
A
FIGURE 9-11
Mechanism of action of immunusuppressive drugs. A, The sites of
action of the commonly used immunosuppressive drugs. Immunosuppressive drugs interfere with allograft rejection at various sites
in the rejection pathways. Glucocorticoids block the release of
ATG
OKT3
-Interferon
interleukin (IL)-1 by macrophages, cyclosporine (CsA) and FK506

interfere with IL-2 production from activated helper T cells, and
azathioprine (AZA) and mycophenolate mofetil (MPA) prevent
proliferation of cytotoxic and helper T cells.
9.9
TCR signal
IL-2R
Nucleus
TCR
signal
TCR Cyclosporin A
FK506
Nucleus
TCR
signal
TCR
T lymphocyte
LKR signal
IL-2R
LKR
signal TCR
Nucleus
Il-2
IL-2R
LKR
signal
Rapamycin
TCR
Nucleus
Cell differentiation
Cell proliferation

B, Mechanism of action of CsA, FK506, and rapamycin (RPM).
CsA and FK506 block the transduction of the signal from the Tcell receptor (TCR) after it has recognized antigen, which leads
to the production of lymphokines such as IL-2, whereas RPM
blocks the lymphokine receptor signal, eg, IL-2 plus IL-2 receptor
(IL-2R), which leads to cell proliferation.
The addition of a prophylactic course of antithymocyte globulin (ATG) or OKT3 with delay of the administration of CsA or
FK506 during the initial postoperative periods has been advocated by some groups. OKT3 prophylaxis was associated with a
lower rate of early acute rejection and fewer rejection episodes
per patient. Prophylactic use of these agents appears to be most
effective in high-risk cadaver transplant recipients, including
those who are sensitized or who have two HLA-DR mismatches
or a prolonged cold ischemia time [2,10]. IFN-ginterferon
gamma; TNF-atumor necrosis factor-a.
Treatment algorithm for acute rejection
A. ANTIREJECTION THERAPY REGIMENS
Acute rejection
Intravenous methylprednisolone, 0.5 or 1 g x 3 d
OKT3
Antithymocyte gamma globulin
Rabbit antithymocyte globulin
Humanized anti-CD25 (IL-2 receptor) intravenously every 2 wk
AntiICAM-1 and antiLFA-1 antibodies
FIGURE 9-12
Treatment of acute rejection. A, Typical antirejection therapy regimens.
B, Treatment algorithm. A biopsy should be performed whenever
possible. The first-line treatment for acute rejection in most centers
is pulse methylprednisolone, 500 to 1000 mg, given intravenously
daily for 3 to 5 days. The expected reversal rate for the first episode
of acute cellular rejection is 60% to 70% with this regimen [1517].
Steroid-resistant rejection is defined as a lack of improvement in
urine output or the plasma creatinine concentration within 3 to 4
days. In this setting, OKT3 or polyclonal antiT-cell antibodies
should be considered [18]. The use of these potent therapies should
be confined to acute rejections with acute components that are
potentially reversible, eg, mononuclear interstitial cell infiltrate with
tubulitis or endovasculitis with acute inflammatory endothelial infiltrate
[19,21]. ATGantithymocyte globulin; ICAM-1intercellular
adhesion molecule-1; LFA-1leukocyte function-associated antigen-1.
Mild
Severe
Steroid bolus
Resolves
Rising creatinine
OKT3 or polyplonal
antibodies x 10 d
Resolves
Persistent acute rejection

on repeat biopsy
Evaluate OKT3
antibody titer
Low
High
ATG or OKT3
ATG
9.10
A. MAJOR SIDE EFFECTS OF IMMUNOSUPPRESSIVE AGENTS
Nephrotoxicity
Neurotoxicity
Hirsutism
Gingival hypertrophy
?????
Hypertension
Cyclosporine
FK506
+++
+
+++
++
0
+++
++
++
0
0
+
+
Azathioprine
Mycophenolate
mofetil
++
++
+
++
+
+?
Infection
Marrow suppression
Hepatic dysfunction
Megaloblastic anemia
Hair loss
? Neoplastic
+
+
0
0
?
FIGURE 9-13
Side effects of immunosuppressive agents. A, The major side effects of several immunosuppressive agents. The major complication of pulse steroids is increased susceptibility
to infection. Other potential problems include acute hyperglycemia, hypertension,
peptic ulcer disease, and psychiatric disturbances including euphoria and depression.
B, Vasoconstriction of the afferent arteriole (AA) caused by cyclosporine. (From English
Spleen
Lymph nodes
Washed white cells
Thymus
Subcutaneous injection
Globulin
extracted
Intravenous infusion
Vial
FIGURE 9-14
The making of a polyclonal antilymphocyte preparation.
Antilymphocyte globulin (ALG) or antithymocyte globulin (ATG) are
polyclonal antisera derived from immunization of lymphocytes, lymphoblasts, or thymocytes into rabbits, goats, or horses. These agents
have been used prophylactically as induction therapy during the early
posttransplantation period and for treatment of acute rejection. Most
centers reduce concomitant immunosuppression (eg, stop cyclosporine
and lower azathioprine dose) to decrease infectious complications.
Antithymocyte gamma globulin (ATGAM) is the only FDA-approved
Horse serum
polyclonal preparation. Two rabbit immunoglobulin preparations,

raised by immunization with thymocytes or with a human lymphoblastoid line, are scheduled for phase III multicenter testing versus
ATGAM or OKT3, respectively. Potential side effects include fever,
chills, erythema, thrombocytopenia, local phlebitis, serum sickness,
and anaphylaxis. The potential for development of host anti-ALG
antibodies has not been a significant problem because of the use of
less immunogenic preparations and probably because ALG suppresses
the immune response to the foreign protein itself [2,10].

Fuse with
polyethylene glycol
Spleen cells
Myeloma cells
Assay hybrid cells
Select desired hybrids
Propagate desired clones

Grow in
mass culture
Freeze
Thaw
Produce in
animals
Antibody
A. RECOMMENDED PROTOCOL FOR OKT3 TREATMENT

Evaluation and treatment before administration
Laboratory tests including complete blood count
Monitor intake and output; record weight changes
Chest radiograph
Hemodialysis or ultrafiltration for volume overload
Premedication on day 0 and 1
Methylprednisolone, 250500 mg IV given 1 h prior to dose
Methylprednisolone or hydrocortisone sodium succinate, 250500 mg IV given
30 min after the dose
Diphenhydramine, 50 mg IV 30 min prior to dose daily
Acetaminophen, 650 mg PO 30 min prior to dose
Discontinue cyclosporine, maintain azathioprine at 25 mg/d
Administer OKT3, 5 mg/d IV, days 013
Monitor clinical course
Check CD3 level on day 3
Increase OKT3 dosage to 10 mg/d if either:
Anti-OKT3 antibody is high
OKT3 level is low
CD3 level is not low
Antibody
9.11
FIGURE 9-15
The making of a monoclonal antibody.
OKT3 is a mouse monoclonal antibody
directed against the CD3 molecule of the
T lymphocyte. OKT3 has been used either
from the time of transplantation to prevent
rejection or to treat an acute rejection episode.
It has been shown in a randomized clinical
trial to reverse 95% of primary rejection
episodes compared with 75% with high-dose
steroids in patients who received azathioprineprednisone immunosuppression. In patients
receiving triple therapy (cyclosporineazathioprine-prednisone), 82% of primary
rejection episodes were successfully reversed
by OKT3 versus 63% with high-dose
steroids. Like antilymphocyte globulin
(ALG), reduction of concomitant immunosuppression (discontinuation of cyclosporine
and reduction of azathioprine or mycophenolate mofetil dose) decreases the incidence
of infectious complications. Side effects
include fever, rigors, diarrhea, myalgia,
arthralgia, aseptic meningitis, dyspnea, and
wheezing, but these rarely persist beyond
the second day of therapy.
Release of tumor necrosis factor (TNF),
interleukin-2, and interferon gamma in serum
are found after OKT3 injection. The acute
pulmonary compromise due to a capillary
leak syndrome rarely has been seen because
patients are brought to within 3% of dry
weight before initiation of OKT3 treatment.
Infectious complications, particularly infection
with cytomegalovirus, are increased after
multiple courses of OKT3.
FIGURE 9-16
Treatment with OKT3. A, Recommended protocol for OKT3 treatment. The development of host anti-OKT3 antibodies is a potential
problem for the reuse of this drug in previously treated patients.
About 33% to 100% of patients develop antimouse antibodies
after the first exposure to OKT3, depending on concomitant
immunosuppression. Anti-OKT3 titers of 1:10,000 or more usually
correlate with lack of clinical response. If anti-OKT3 antibodies are
of low titer, retreatment with OKT3 is almost always successful. If
retreatment is attempted with antimouse titers of 1:100 or more, then
certain laboratory parameters, including the peripheral lymphocyte
count, CD3 T cells, and trough free circulating OKT3 should be
monitored. If the absolute CD3 T-lymphocyte count is greater than
10 per microliter or free circulating trough OKT3 level is not
detected, it may be indicative of an inadequate dose of OKT3. The
dose of OKT3 can be increased from 5 to 10 mg/d [21].
9.12
AntiOKT3 antibodies
80
70
%CD+cells
60
CD3
50
OKT3 treatment
40
30
CD4
20
CD8
10

B, Monitoring of peripheral blood T cells in a patient receiving
OKT3 treatment. The absence of CD3+ cells from the circulation
is the best parameter for monitoring the effectiveness of OKT3.
Failure of the CD-positive percentage to fall or a fall followed by
a rapid rise indicates the appearance of blocking antibodies.
Approximately 50% to 60% of patients who receive OKT3 will
produce human antimouse antibodies (HAMA), generally in low
titers (< 1:100). Low antibody titers do not affect the response to
retreatment (reversal rate almost 100%) if the rejection episode
occurs within 90 days after transplantation. Conversely, titers
above 1:100 or recurrent rejection beyond 90 days is associated
with a reversal rate of less than 25%. The reversal rate is essentially
zero when both high HAMA titers and late rejection are present.
POorally; IVintravenous.
0
0
13
Hours
16
22
Days
Chimeric antibody
Mouse antibody
Reshaped
antibody
Mouse determinants
} Human determinants
A
IgG1 depleting
IgG4 nondepleting
TCR/CD3
MHC/Ag
APC
Signal 1
B7-1
T-cell
CD28
X
B7-2
CTLA4
Signal 2
CTLA41g
Signal 1 without signal 2

results in:
T-cell anergy
Th2>Th1
Apoptosis
FIGURE 9-17
New immunosuppressive agents. New agents such as mycophenolate
mofetil, FK506, and rapamycin are currently under evaluation for
refractory acute rejection. In addition, both mycophenolate and
rapamycin prevent chronic allograft rejection in experimental animals.
Whether this important observation is reproducible in humans
remains to be determined by long-term study.
A, Humanized monoclonal antibodies. The development of
genetically engineered humanized monoclonal antibodies will largely
eliminate the anti-antibody response, thereby increasing the utility
of antiT-cell antibodies in the treatment of recurrent rejection.
Experimental antibody therapies are now being designed to directly
target the CD4 molecule, the interleukin-2 receptor, the CD3 molecule
by a humanized form of monoclonal anti-CD3, and adhesion molecules
such as intercellular adhesion molecule-1 or leukocyte functionassociated antigen-1 [23]. Humanized monoclonal antibodies are
essentially human immunoglobulin G (IgG), nonimmunologic with
a long half-life, and potentially can be administered intravenously
about every 2 weeks. Humanized anti-CD25 (IL-2 receptora chain)
monoclonal antibodies has been shown to be effective in lowering
the incidence of acute renal allograft rejection. Its role in the treatment of rejection, however, has not been explored. With increasing
specificity for lymphocytes, these new agents are likely to have fewer
toxicities and better efficacy.
B, Therapeutic application of CTLA41g to transplant rejection.
APCantigen-presenting cell; MHCmajor histocompatibility
complex; TCRT-cell receptor.
9.13
References
1. Terasaki PI, Cecka JM, Gjertson DW, et al.: Risk rate and long-term
kidney transplant survival. Clin Transpl 1996, 443.
2. Chan L, Kam I: Outcome and complications of renal transplantation.
In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk
CW: 1997.
3. J Clin Immunol 1995, 15:184.
4. Nephrol Dial Transpl 1997, 12 [editorial comments].
5. Shaikewitz ST, Chan L: Chronic renal transplant rejection. Am J
Kidney Dis 1994, 23:884.
6. Solez K, Axelsen RA, Benediktsson H, et al.: International standardization
of criteria for the histologic diagnosis of renal allograft rejection: the
Banff working classification on renal transplant pathology. Kidney Int
1993, 44:411.
7. Helderman JH, Hernandez J, Sagalowsky A, et al.: Confirmation of
the utility of fine needle aspiration biopsy of the renal allograft.
Kidney Int 1988, 34:376.
8. Von Willebrand E, Hughes D: Fine-needle aspiration cytology of the
transplanted kidney. In Kidney Transplantation, edn 4. Edited by
Morris PJ. 1994:301.
9. Suthanthiran M: Clinical application of molecular biology: a study of
allograft rejection with polymerase chain reaction. Am J Med Sci
1997, 313:264.
10. Halloren PF, Lui SL, Miller L: Review of transplantation 1996. Clin
Transpl 1996.
11. Sollinger HW for the US Renal Transplant Mycophenolate Mofetil
Study Group: Mycophenolate mofetil for prevention of acute rejection
in primary cadaveric renal allograft recipients. Transplantation 1995,
60:225.
12. Jordan ML, Shapiro R, Vivas SA, et al.: FK506 rescue for resistant
rejection of renal allografts under primary cyclosporine immunosuppression. Transplantation 1994, 57:860.
13. Woodle ES, Thistlethwaite JR, Gordon JH, et al.: A multicenter trial
of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection.
14. Jordan ML, Naraghi R, Shapiro R, et al.: Tacrolimus rescue therapy
for renal allograft rejection: five year experience. Transplantation
1997, 63:223.
15. Gray D, Shepherd H, Daar A, et al.: Oral versus intravenous high
dose steroid treatment of renal allograft rejection. Lancet 1978,
1:117.
16. Chan L, French ME, Beare J, et al.: Prospective trial of high dose versus
low dose prednisone in renal transplantation. Transpl Proc 1980,
12:323.
17. Auphan N, DiDonato JA, Rosette C, et al.: Immunosuppression by
glucocorticoids: inhibition of NF-kB activation through induction of
IkBa. Science 1995, 270:286.
18. Ortho Multicenter Study Group: A randomized trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants.
N Engl J Med 1985, 313:337.
19. Norman DJ, Shield CF, Henell KR, et al.: Effectiveness of a second
course of OKT3 monoclonal anti-T cell antibody for treatment of
20. Schroeder TJ, Weiss MA, Smith RD, et al.: The efficacy of OKT3 in
vascular rejection. Transplantation 1991, 51:312.
21. Schroeder TJ, First MR: Monoclonal antibodies in organ transplantation.
22. English J, et al.: Transplantation 1987, 44:135.
23. Strom TB, Ettenger RB: Investigational immunosuppressants: biologics.
In Primer on Transplantation. Edited by Norman D, Suki W.
Post-transplant Infections
Connie L. Davis
lthough the rates are markedly decreased from previous

decades, infection is the most important cause of early morbidity and mortality following transplantation. Infection is
closely linked to the degree of immunosuppression and thus to the frequency and intensity of rejection and its therapy. The potential sources
of infection in the transplant patient are multiple, including organisms
from the allograft itself and from the environment. Patients should be
advised to be sensible to possible exposures and to wash their hands
thoroughly when exposed to infected individuals or human excrement, specifically, exposures in daycare and occupational settings as
well as during gardening and pet care. In those taking immunosuppressive agents, signs and symptoms of infections are frequently blunted until disease is far advanced. Therefore, due to the unusual nature
of the infections and the lack of timely symptom development, the key
to patient survival is the prevention of infection. Infections may be
prevented by pretransplant vaccinations, along with prophylactic
medications, preemptive monitoring and behavior modification.
Currently, the most common infectious problems within the first
month following transplantation are bacterial infections of the wound,
lines, and lungs. Additionally, herpetic stomatitis is common. Beyond
1 month following transplantation, infections are related to more
intense immunosuppression and include viral, fungal, protozoal, and
unusual bacterial infections. Although hepatitis may occasionally
cause fulminate and fatal disease if acquired peritransplantation, the
manifestations of hepatitis B or hepatitis C infections occur years following transplantation.
CHAPTER
10
10.2
Conventional
CLASSIFICATION OF INFECTIONS
OCCURRING IN TRANSPLANT PATIENTS
Unconventional
Viral
CMV onset
EBV VZV papova adenovirus
HSV
CMV
chorioretinitis
Fungal TB Pneumocystis
CNS
Listeria
Aspergillus, nocardia, toxoplasma
Bacterial
Cryptococcus
Wound
Pneumonia
line-related
Hepatitis
Hepatitis B
Onset of non-A, non-B hepatitis
UTI: Relatively
benign
UTI: bacteremia, pyelitis, relapse
3
4
Time, mo
Transplant
FIGURE 10-1
Timetable for the occurrence of infection in the renal transplant
patient. Exceptions to this chronology are frequent. CMV
cytomegalovirus; CNScentral nervous system; EBVEpsteinBarr virus; HSVherpes simplex virus; UTIurinary tract infection; VZVvaricella-zoster virus. (Adapted from Rubin and
coworkers. [1]; with permission.)
Infections related to technical complications*

Transplantation of a contaminated allograft, anastomotic leak or stenosis, wound
hematoma, intravenous line contamination, iatrogenic damage to the skin,
mismanagement of endotracheal tube leading to aspiration, infection related
to biliary, urinary, and drainage catheters
Infections related to excessive nosocomial hazard
Aspergillus species, Legionella species, Pseudomonas aeruginosa, and other gramnegative bacilli, Nocardia asteroides
Infections related to particular exposures within the community
Systemic mycotic infections in certain geographic areas
Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis,
Strongyloides stercoralis
Community-acquired opportunistic infection resulting from ubiquitous saphrophytes in the environment
Cryptococcus neoformans, Aspergillus species, Nocardia asteroides, Pneumocystis carinii
Respiratory infections circulating in the community
Mycobacterium tuberculosis, influenza, adenoviruses, parainfluenza, respiratory
syncytial virus
Infections acquired by the ingestion of contaminated food/water
Salmonella species, Listeria monocytogenes
Viral infections of particular importance in transplant patients
Herpes group viruses, hepatitis viruses, papillomavirus, HIV
*All lead to infection with gram-negative bacilli, Staphylococcus species, and/or
Candida species.
The incidence and severity of these infections and, to a lesser extent, the other
infections listed, are related to the net state of immunosuppression present in
a particular patient.
FIGURE 10-2
Classifications of infections occurring in transplant patients.
(Adapted from Rubin [2]; with permission.)
50
Patients, n
40
Timing of infection
Period of prophylaxis
Bacterial (mean 60 days)

CMV (mean 70 days)
Non-CMV viral (mean 145 days)
Fungal (mean 163 days)
30
20
10
0
3
Months after transplant
46
712
FIGURE 10-3
Timing of infections following kidney/pancreas transplantation
at a single transplantation center using antiviral (ganciclovir IV
followed by acyclovir) and antibacterial (trimethoprim-sulfamethoxazole) prophylaxis. CMVcytomegalovirus. (From
Stratta [3]; with permission.)
10.3
Preventive Strategies
INFECTIOUS DISEASE HISTORY TO BE TAKEN PRIOR TO TRANSPLANTATION
FIGURE 10-4
Infectious disease history to be taken prior
to transplantation.
1. Past immunizations.
2. Past infections or exposures to infections.
A. Bacterial
Rheumatic fever, sinusitis, ear infections, urinary tract infections, pyelonephritis, pneumonia, diverticulitis, tuberculosis
B. Viral
Measles, mumps, varicella, rubella, hepatitis
3. Chronic or recurrent infections, such as pneumonia, sinusitis, urinary tract infection, or diverticulitis
4. Surgical history, such as splenectomy
5. Transfusion or previous transplant history and dates
6. Past travel history, including military service
7. Past immunosuppressive drug treatment (eg, for asthma, renal disease, or rheumatologic disease)
8. Lifestyle
A. Smoking, drinking, illicit drug use, marijuana smoking
B. Sexual partners, orientation, unprotected contact and date, safety practices used, sexually transmitted diseases,
genital warts
C. Food, consumption of raw fish or meat, consumption of unpasteurized products, such as milk, cheese, fruit juices,
or tofu
D. Avocationgardening and the use of gloves, cleaning sheds, hiking, camping, water sources, bathing pets, cleaning
pet litter and cages, hunting practices
E. Vocationjobs that require exposure to possible infectious agents, such as daycare, ministry, small closed offices,
garbage collections or dump workers, construction workers, forestry workers, health care, veterinarians, farmers
PRETRANSPLANT VACCINATIONS OR BOOSTERS TO

BE GIVEN TO ALL TRANSPLANT RECIPIENTS UNLESS
RECENT ADMINISTRATION CAN BE DOCUMENTED
FIGURE 10-5
Pretransplant vaccinations or boosters to be given to all transplant
recipients unless recent administration can be documented.
1. Td (Tetanus toxoid, diphtheria)

2. Pneumococcal vaccine
3. Hepatitis B
4. Influenza
PRETRANSPLANT VACCINATIONS TO BE GIVEN IF

SERONEGATIVE OR PAST INFECTION BY HISTORY
CANNOT BE DOCUMENTED
1. Measles-mumps-rubella vaccine
2. Polio
3. Varicella (0.5 mL subcutaneously followed by booster of 0.5 mL in 48 weeks)
4. Haemophilus influenza type B
FIGURE 10-6
Pretransplant vaccinations to be given if seronegative or past
infection by history cannot be documented.
10.4
INACTIVATED VACCINES THAT ARE CONSIDERED SAFE

AND MAY BE GIVEN AS NEEDED POST-TRANSPLANT
FOR ANTICIPATED EXPOSURE
VACCINES THAT MAY NOT BE GIVEN

(LIVE ATTENUATED VACCINES)
1. Bacille Calmette-Gurin (BCG)
2. Measles
3. Mumps
4. Rubella
5. Oral polio
6. Oral typhoid
7. Yellow fever
1. Anthrax
2. Cholera
3. Rabies vaccine absorbed
4. Human diploid cell rabies vaccine
5. Inactivated typhoid vaccine, capsular polysaccharide parenteral vaccine,
or heat phenol-treated parenteral vaccine
6. Japanese encephalitis virus vaccine
7. Meningococcal vaccine
8. Plague vaccine
FIGURE 10-8
Vaccines that may not be given include live attenuated vaccines.
FIGURE 10-7
Inactivated vaccines that are considered safe and may be given as
needed post-transplant for anticipated exposure.
A. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES
Vaccine
Dosage
Route of administration
Type
DT
Td
DTP
DTaP (Acel-Imune)
DTP-HbOC (Tetramune)
0.5 mL
0.5 mL
0.5 mL
0.5 mL
0.5 mL
IM
IM
IM
IM
IM
Toxoids
Toxoids
Diphtheria and tetanus toxoids with killed B. pertussis organisms
Diphtheria and tetanus toxoids with acellular pertussis
Diphtheria and tetanus toxoids with killed B. pertussis
organisms and Haemophilus b conjugate (diphtheria
CRM197 protein conjugate)
Haemophilus B, conjugate vaccine

ProHIBit (PRP-D), manufactured by
Connaught Laboratories
HibTITER (HbOC), manufactured by
Praxis Biologicals
PedvaxHib (PRP-OMP), manufactured
by MSD
Hepatitis B
0.5 mL
0.5 mL
IM
IM
Polysaccharide (diphtheria toxoid conjugate)
0.5 mL
IM
Oligosaccharide (diphtheria CRM protein conjugate)
0.5 mL
IM
Polysaccharide (meningococcal protein conjugate)
IM in the anterolateral thigh or in

the upper arm; SC in individuals
at risk of hemorrhage
Yeast recombinantderived inactivated viral antigen
Infants born to HBsAg-negative

mothers and children < y[ ]
Recombivax HB (MSD)
Engerix-B (SKF)
2.5 g (0.25 mL)

10 g (0.5 mL)
FIGURE 10-9
AD, General immunization guidelines. HBOChaemophilus B
influenzaediphtheria protein conjugate vaccine, oligosaccharide;
IDintradermal; IMintramuscularly; DTdiphtheria tetanus;
DTPdiphtheria tetanus pertussis; MMRmeasles mumps
rubella; MRmeasles rubella; MSDMerck Sharpe & Dohme;
PRP-Dhaemophilus Bdiphtheria toxoid conjugate vaccine,

polysaccharide; PRP-OMPhaemophilus influenzae type
bmeningococcal protein conjugate vaccine; SCsubcutaneous;
SKFSmithKline and French; Tdtetanus, diphtheria. (From
Isada and coworkers [4]; with permission.)
10.5
B. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES
Infants born to HBsAg-positive mothers (immunization and administration of 0.5 mL hepatitis B immune globulin is recommended for infants born to HBsAg mothers using different
administration sites) within 12 hours of birth; administer vaccine at birth; repeat vaccine dose at 1 and 6 months following the initial dose
Vaccine
Dosage
Recombivax HB (MSD)
Engerix-B (SKF)
Children 1119 y
Recombivax HB (MSD)
Engerix-B (SKF)
Adults > 19 y
Recombivax HB (MSD)
Engerix-B (SKF)
Dialysis patients and immunosuppressed patients
Recombivax HB (MSD)
Engerix-B (SKF)
5 g (0.5 mL)
10 g (0.5 mL)
5 g (0.5 mL)
20 g (1 mL)
10 g (1 mL)
20 g (1 mL)
<11 y, 20 g (0.5 mL); 11 y, 40 g, (1 mL) using special dialysis formulation
<11 y, 20 g (1 mL); 11 y, 40 g (2 mL), give as two 1 mL doses at different sites
C. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES
Vaccine
Dosage
Influenza
Split virus only in pediatric patients
635 mo
38 y
9 y
Measles
0.25 mL (1 or 2 doses)
0.5 mL (1 or 2 doses)
0.5 mL (1 dose)
0.5 mL
Type
IM (2 doses 4+ weeks apart in children

<9 years of age not previously immunized;
only 1 dose needed for annual updates)
Inactivated virus subvirion (split) (contraindicated

in patients allergic to chicken eggs)
SC
Live virus (contraindicated in patients with

anaphylactic allergy to neomycin)
Most areas: Two doses (1st dose at 12 months with MMR; 2nd dose at 46 years or 1112 years, depending on local school entry requirements).
High-risk area: Two doses (1st dose at 12 months with MMR; 2nd dose as above).
Children 615 months in epidemic situations: Dose is given at the time of first contact with a health care provider; children<1 year of age should receive single antigen measles vaccine.
If vaccinated before 1 year, revaccinate at 15 months with MMR. A 3rd dose is administered at 46 years or 1112 years, depending on local school entry requirements.
10.6
D. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES
Children 615 months in epidemic situations: Dose is given at the time of first contact with a health care provider;
children<1 year of age should receive single antigen measles vaccine. If vaccinated before 1 year, revaccinate at 15 months
with MMR. A 3rd dose is administered at 46 years or 1112 years, depending on local school entry requirements.
Vaccine
Dosage, mL
Type
Meningococcal
MMR
MR
Mumps
Pneumococcal
polyvalent
Poliovirus (OPV)
trivalent
Poliovirus (IPV)
trivalent
Rabies
Rubella
Tetanus (adsorbed)
Tetanus (fluid)
Yellow fever
0.5
0.5
0.5
0.5
0.5 (2 y)
SC
SC
SC
SC
IM or SC (IM preferred)
Polysaccharide
Live virus
Live virus
Live virus
Polysaccharide
0.5
Oral
Live virus
0.5
SC
Inactivated virus
1
0.5 (12mo)
0.5
0.5
0.5
IM , ID
SC
IM
IM, SC
SC
Inactivated virus
Live virus
Toxoid
Toxoid
Live attenuated virus
PRETRANSPLANT VIRAL SEROLOGIES TO CHECK

AT THE PRETRANSPLANT VISIT
Viral serology
Treatment, work-up modification or change in post-transplant treatment
Herpes simplex virus 1, 2

Epstein-Barr virus
If positive, treat early post-transplant with acyclovir, famciclovir, or ganciclovir

If negative, consider post-transplant ganciclovir. Test donor due to risk of post-transplant
lymphoma with primary infection
Consider vaccination with Oka strain live attenuated virus if negative or treatment with
acyclovir following clinical exposure
If the recipient is positive or donor positive, consider prophylactic or preemptive
antiviral treatment
If positive, check HBeAg and HBDNA and biopsy. If HBDNA positive, consider pretransplant
antiviral treatment with interferon if biopsy allows. Consult hepatologist regarding other
treatment options
If positive, check HCV RNA status by polymerase chain reaction. If positive biopsy even
with normal transaminase values and consider pretransplant treatment with interferon
Consider safety of transplantation if true positive. More data are required to make an
informed decision
Varicella-zoster virus
Cytomegalovirus
HBsAg
Hepatitis C virus
HIV
FIGURE 10-10
Pretransplant viral serologies to check at
the pretransplant visit.
FIGURE 10-11
Pretransplant bacterial serologies.
PRETRANSPLANT BACTERIAL SEROLOGIES

Serology
Modification
RPR (Rapid plasma reagin)
If positive, check with a treponemal specific testFluorescent treponemal antibody

absorbed test (FTA-ABS) or microhemagglutination assay for treponema pallidum
(MHA-TP)
If positive the general recommendation without documented previous treatment after
first evaluating a chest radiograph is isoniazid 300 mg/d to continue for 6 months or
9 to 12 months post-transplant
PPD
10.7
EFFECT AND POSSIBLE EFFECTS OF PROPHYLACTIC ANTIVIRAL STRATEGIES

No treatment
Acyclovir orally 3 3M
Ganciclovir IV acyclovir PO 3 3M
CMVIgG 3 5 doses
Ganciclovir 3 3M PO
Risk: HSV
CMV
VZV
EBV
Adenovirus
HHV6
HHV8
HSV
Slight CMV
VZV
Slight EBV
No change in adenovirus
Slight HHV6
Slight HHV8
HSV
Slight CMV
VZV
EBV
? Adenovirus
Slight HHV6
Slight HHV8
? Effect
Slight CMV
? Effect
? Effect
? Effect
? Effect
? Effect
HSV
CMV
VZV
EBV
? Slight in adenovirus
? HHV6
? HHV8
FIGURE 10-12
Effect and possible effects of prophylactic antiviral strategies. CMV
cytomegalovirus; EBVEpstein-Barr virus; HHV6human herpes
virus 6; HHV8human herpes virus 8; HSVherpes simplex; VZV

varicella zoster. Question mark indicates question as to the effect.
PROPHYLACTIC ANTIBACTERIAL AND ANTIPROTOZOAL STRATEGIES

Type of infection
Treatment perioperatively or postoperatively
Wound
Against uropathogens and staphylococci, eg, ampicillin-sulbactam, cefazolin

plus aztreonam 3 24 to 48 hours adjusted for renal function
Risk urinary leak, hematoma, lymphocele
Common choices
Trimethoprim sulfamethoxazole
Ciprofloxacin
Cephazolin
Ampicillin
Duration of treatment varies
An important factor is the presence of the urinary catheter
Urinary tract
Legionella
Pneumocystis
Toxoplasmosis
Nocardia
Listeria monocytogenes
FIGURE 10-13
Prophylactic antibacterial/
antiprotozoal strategies.
10.8
Prevention Strategies
PREVENTION OF RESPIRATORY INFECTIONS IN THE IMMUNOSUPPRESSED PATIENT
Infection
Options for prevention
Pneumococcal pneumonia
Influenza illness
Haemophilus influenzae
Tuberculosis
Mycobacterium avium complex illness
Pneumocystis carinii pneumonia
CMV pneumonia
Pneumococcal vaccination; oral penicillin prophylaxis; passive prophylaxis with immune globulin
Annual influenza vaccination; amantadine or rimantadine prophylaxis (for influenza A virus only)
H. influenza type B vaccination
Case finding and early treatment; infection control procedures; preventive therapy with isoniazid
Rifabutin prophylaxis
Prophylaxis with oral trimethoprim-sulfamethoxazole or aerosolized pentamidine
Use of CMV-seronegative organs and blood products for CMV-seronegative recipients; passive prophylaxis with
CMV immune globulin; prophylaxis with antiviral agents (acyclovir, ganciclovir)
Identification of source; institution of control measures associated with potable water, such as hyperchlorination,
maintenance of hot water temperature above 50C (122F)
Use of HEPA filter to minimize airborne spores; avoidance of decaying leaves and vegetation
Prophylaxis with antifungal agents
Avoidance of pigeons and pigeon droppings; prophylaxis with antifungal agents
Complete travel history to identify patients at risk; avoidance of areas of high exposure to Histoplasma; formalin
treatment of infected soil
Complete travel history to identify patients at risk; avoidance of areas of high exposure to Coccidioides immitis
Complete travel history to identify patients at risk; ova and parasite analysis of stool specimen in patients at risk;
thiabendazole prophylaxis
Legionella pneumonia
Aspergillosis
Candida illness
Cryptococcosis
Histoplasmosis
Coccidioidomycosis
Strongyloidiasis
FIGURE 10-14
Prevention strategies for the prevention of pulmonary infection. CMVcytomegalovirus;
HEPAhigh-efficiency particulate air. (Adapted from Maguire and Wormser [5]; with permission.)
10.9
PASSIVE IMMUNIZATION AGENTSIMMUNE GLOBULINS

Immune globulin
Hepatitis B (H-BIG*)
Percutaneous inoculation
Perinatal
Sexual exposure
Immune globulin (IG)
Hepatitis A prophylaxis
Hepatitis B
Hepatitis C
Measles
Rabies
Tetanus (serious, contaminated, wounds;
<3 previous tetanus vaccine doses)
Varicella-zoster (VZIG)
Dosage
Route
IM
0.06 mL/kg/dose (within 24 h) (5 mL max)

0.5 mL/dose (within 12 h of birth)
0.06 mL/kg/dose (within 14 d of contact) (5 mL max)
IM*
0.02 mL/kg/dose (as soon as possible or within 2 wk after exposure)
(single exposure)
0.06 mL/kg/dose (>3 mo or continuous exposure) repeat every 46 mo
0.06 mL/kg/dose (H-BIG should be used)
0.06 mL/kg/dose (percutaneous exposure)
0.25 mL/kg/dose (max 15 mL/dose) (within 6 d of exposure)
0.5 mL/kg/dose (max 15 mL/dose) (immunocompromised children)
20 IU/kg/dose (within 3 d)
250500 units/dose
Within 48 hours but not later than 96 hours after exposure
010 kg
125 units = 1 vial
10.120 kg
250 units = 2 vials
20.130 kg
375 units = 3 vials
30.140 kg
500 units = 4 vials
>40 kg
625 units = 5 vials
IM
IM
*Deep IM in the gluteal region for large doses only. Deltoid muscle or the anterolateral aspect of the thigh are preferred sites for injection. No greater than 5 mL/site in adults or large
children; 13 mL/site in small children and infants. Maximum dose: 20 mL at one time.
IG prophylaxis may not be indicated in a patient who has received IGIV within 3 weeks of exposure.
1/2 of dose used to infiltrate the wound with the remaining 1/2 of dose given IM Rabies immune globulin is not
recommended in previously HDCV immunized patients.
No greater than 2.5 mL of VZIG/one injection site. Doses >2.5 mL should be divided and administered at different sites.
FIGURE 10-15
Passive immunization agents for prevention postexposure.
HBIGhepatitis B immune globulin; HDCVhuman diploid
cell rabies vaccine; IGimmune globulin; IGIVintravenous
immune globulin; IMintramuscularly; VZIGvaricella

zoster immune globulin. (From Isada and coworkers [4];
with permission.)
10.10

FIGURE 10-16
Live virus vaccinations generally not given to
transplant patients. IGimmune globulin;
OPVpoliovirus vaccine live oral. (From
Isada and coworkers [4]; with permission.)
GUIDELINES FOR SPACING THE ADMINISTRATION OF

IMMUNE GLOBULIN (IG) PREPARATIONS AND VACCINES
Immunobiologic combinations
Recommended minimum interval between doses
Simultaneous administration
None. May be given simultaneously at different sites or at any time
between doses.
Should generally not be given simultaneously. If unavoidable to do so,
give at different sites and revaccinate or test for seroconversion in
3 months. Example: MMR should not be given to patients who have
received immune globulin within the previous 3 months.
IG and killed antigen

IG and live antigen
Nonsimultaneous administration
First
IG
Killed antigen
IG
Live antigen
Second
Killed antigen
IG
Live antigen
IG
None
None
6 wk, and preferably 3 mo
2 wk
*The live virus vaccines, OPV, and yellow fever are exceptions to these recommendations. Either vaccine may be
administered simultaneously or any time before or after IG without significantly decreasing antibody response.
O
N
N
H2N
HN
CH3COO
CH3COO
H 2N
HN
HO
Valacyclovir
Acyclovir
HN
N
HO
Acyclovir
OH
Ganciclovir
77%
54%
15%
2%7%
100% liver/GI
100%* R
91% unchanged urine
Plasma t1/2:
23 h
23 h
23 h
23 h
Intracellular t1/2:
720 h
0.71 h
0.71 h
6 h3 wk
HSV/V2V/EBV
HSV/V2V/EBV
HSV/V2V/EBV
HHV8, CMV, adeno, HBV
Antiviral spectrum:
NH2
3Na
O
O
P C
6H2O
O O
N
O
Phosphonoformicacid
Foscarnet
O
O
OCH2P(OH)22H2O
OH
HOCH2
Cidofuvir
Lamivudine
86% oral bioavailability
IV
IV
26 h
34 h
57 h
Tissue t1/2:
87.541.8 h
1765 h
1015 h
Metabolism:
100% renal excretion
85% renal excretion
70%90% renal excretion
Administration:
t1/2:
N
O
100%* R
Oral bioavailability:
O
N
HN
H 2N
N
H O
(CH3)CH C C O
NH+3Cl
Famciclovir
Penciclovir
Excretion:
O
N
FIGURE 10-17
Antiviral agents. Asterisk indicates excreted unchanged
in the urine; all antivirals are subject to changes in t1/2
with changing renal function. Adenoadenovirus;
CMVcytomegalovirus; EBVEpstein-Barr virus;

HHV8human herpesvirus 8; HSVherpes simplex virus;
VZVvaricella-zoster virus.
Acyclovir
Valacyclovir
Famciclovir
R1
viral
thymidine
kinase
Drug-P1
cell
kinase
Drug P2
cell
kinase
cell
kinase
GP3
R2
R1
Ganciclovir
Cidofovir
cell
car v UL97
GP1
kinase
gene product
autophosphorylating
protein kinase
cellular
enzymes
GP2
viral
DNA
Polymerase
Drug P3
cell
kinase
R2
viral
DNA
Polymerase
CP2 (no viral enzymes needed)
DRUG INTERACTIONS BETWEEN ANTIVIRALS, ANTIFUNGALS,

ANTIBACTERIALS, ANTIMYCOBACTERIALS, AND ANTIPROTOZOALS
WITH CYCLOSPORINE AND FK506
Drug
Effect on CSA/FK506
Antifungals
Amphotericin B
Clotrimazole troches (more in FK506)
Ketoconazole (keto>itra>fluconazole)
Griseofulvin
Antibacterial
Clarithromycin
Doxycycline
Erythromycin
Gentamicin
Nafcillin
Rifampin
Rifabutin
Sulfamethoxazole/trimethoprim
Ticarcillin
Antimycobacterial
Isoniazid
Pyrazinamide
Antiparasitic
Chloroquine
FIGURE 10-18
Antiviral activation and action (acyclovir, valacyclovir, famciclovir, ganciclovir). Resistance
(R) to antivirals has been found at the level
of viral thymidine kinase (R1) and DNA polymerase (R2). Ganciclovir is monophosphorylated in cytomegalovirus (CMV)-infected cells
by the CMV UL97 gene product. Acyclovir,
valacyclovir, and famciclovir are not easily
phosphorylated in CMV-infected cells.
Cidofovir does not require viral enzymes to be
phosphorylated to the active diphosphonate.
FIGURE 10-19
Drug interactions between antivirals,
antifungals, antibacterials, antimycobacterials, and antiprotozoals with cyclosporine
and FK506. (From Lake [6] and Yee [7];
with permission.)
Nephrotoxicity of combination
FIGURE 10-20
Infections transmitted to transplant recipients
via the donor organ.
INFECTIONS TRANSMITTED TO TRANSPLANT RECIPIENTS

VIA THE DONOR ORGAN
Virus
10.11
Bacteria
HIV, cytomegalovirus,
Aerobe (gram positive),
herpes simplex virus,
aerobe (gram negative),
Epstein-Barr virus,
anaerobes, Mycobacterium
hepatitis B virus,
tuberculosis, atypical
hepatitis C virus,
mycobacteria
hepatitis D virus, ?
hepatitis G virus,
adenovirus (?), parvovirus (?),
papillomavirus, rabies,
Creutzfeldt-Jakob
Fungi
Parasitic
Candida albicans,
Malaria toxoplasmosis,
Histoplasma capsulatum,
trypanosomiasis,
Cryptococcus neoformans,
strongyloidiasis
Marosporium apiospermum
10.12
Cytomegalovirus
Envelope
Tegument
Attachment and
penetration
Capsid
Egress
Cytoplasm
Nucleus
IE
E
L
Uncoating
Release of
viral DNA
Transcription
Protein synthesis
Replication
DNA
Scaffold
Assembly
Packaging
FIGURE 10-21
The lifecycle of cytomegalovirus (CMV). The envelope binds with
the cell membrane, and the DNA is uncoated and transferred into
the nucleus, where cell protein synthesis machinery is used to manufacture new DNA and capsid. The DNA is packaged into the capsid and returns to the cytoplasm, where the tegument and envelope
are assembled around the capsid and the whole virus transported
to the cellular surface and released.
CMV is a double-stranded DNA virus that causes disease following transplantation after primary infection, reinfection, or reactivation of latent infections. CMV disease is seen most frequently
within the first 4 to 6 months of transplantation if no antiviral
prophylaxis is used; however, in the presence of antiviral prophylaxis and new immunosuppressive agents, the onset of CMV disease may be shifted to longer intervals from transplantation. There
also may be a slight increase in the occurrence of CMV enteritis
with the use of some of the newer combinations of immunosuppressive agents. When the recipient is CMV positive and receives
an organ from a CMV-positive donor, reactivation of the latent
infection in the recipient is responsible for 15% to 30% of the
infections seen, and reinfection with the virus from the donor is
responsible for 70%.
CMV disease prevention may be accomplished by administering
prophylactic antiviral agents or by the use of routine surveillance
testing. Variables to be considered in an individuals risk of CMV
disease development are the use of antilymphocyte medications,
and the donor and recipient, CMV serostatus. The highest risk
group for CMV disease is the group at risk for primary CMV
exposure and those given antilymphocyte preparations. Specifically,
increased CMV disease is seen during situations that trigger viral
replication. High levels of tumor necrosis factor alpha, such as
levels occurring during infections or after OKT3 administration,
activate the CMV promoter, thus stimulating the conversion from
the latent to the reactivated state.
All of the prophylactic strategies for the prevention of CMV
disease have shown some benefit in different studies; currently,
however, the most effective approach is oral ganciclovir. A more
bioavailable oral ganciclovir may even increase the effectiveness
and is now under investigation. Oral ganciclovir is started when
the patient is able to take oral medications within the first week
following transplantation and is administered at a dose of 1 g 3
times a day for 3 months following transplantation adjusted for
renal function. The protective effect is also seen in those who have
received antilymphocyte preparations. The most desirable solution
would be a vaccine that induced natural immunity mechanisms.
Vaccines targeted against the structural glycoproteins of CMV are
currently continuing under development but are not yet available;
their ultimate effectiveness is not known at this time. As patients
who already have had natural infections are not immune to reinfection or reactivation, a vaccine solution may not be possible.
MANIFESTATIONS OF CMV DISEASE IN RENAL

TRANSPLANT RECIPIENTS
10.13
FIGURE 10-22
Manifestations of cytomegalovirus (CMV) disease in renal
transplant recipients.
CMV disease
A. Syndrome: fever, leukopenia, malaise, lack of another cause
B. Organ specific: hepatitis, enteritisduodenum, colon; pancreatitis; pneumonitis;
interstitial nephritis, retinitis
C. Risk of CMV disease by donor
Recipient serostatus without antiviral prophylaxis
D/R
D+RD+R+
D-R+
D-R-
Infection*
70%100%
50%80%
Disease
56%80%
27%39%
0%27%
<5%
*Infection determined by new anti-CMV antibody development or a greater than

fourfold rise in anti-CMV titers.

Endoscopic aspects of cytomegalovirus
(CMV) infection. A, CMV esophageal
ulcers. B, CMV duodenal ulcers.
B
Histologic lesion in cytomegalovirus infection.
10.14
RANDOMIZED TRIALS EVALUATING CMV PROPHYLACTIC STRATEGIES

ADMINISTERED DURING THE TIME OF GREATEST RISK FOR CMV DISEASE
Control
Treated
Drug
Author
Induction or Rejection
Antilymphocyte
Serostatus
CMV Disease
CMV Disease
IgG
Metsellar
Steinmuller
Teuschert
Snydman*
Boland
ATG-rej
ALG/OKT3
None
Some
None
All patients
R+
D+RD+RD+R-
20
18
18
35
11
30%
39%
100%
60%
18%
19
16
18
24
11
37%
13%
20%
21%
27%
AcyclovirPO
Balfour
ALG
All patients
51
29%
53
8%
7
8
100%
38%
6
9
17%
11%
Subgroups
D+RD+R+
Ganciclovir
Valacyclovir
Rondeau
ATG/OKT3
D+R-
15
73%
17
47%
Conti
Antilymphocyte
R+
18
56%
22
9%
Hibberd
OKT3
R+
49
33%
64
14%
Brennan
ATG
D+or R+
23
61%
19
21%
Squillet
NA
R+
204
10.8%
204
0%
Dosing
Cytotec, 6 doses
Sandoglobulin, 5 doses
Cytotec, 11 doses
Cytotec
Cytotec, 5 doses
Acyclovir
800 mg po qid x 3 months
Ganciclovir 5 mg/kg bid

IV d1428
Ganciclovir with antilymphocyte
drug 2.5 mg/kg/IV bid
Ganciclovir 2.5 mg/kg/d
during ALG
Oral ganciclovir 1 g tid
2 g qid
*Antilymphocyte serum was given to two globulin and eight control patients as induction therapy and four globulin and seven control patients as antirejection therapy.
FIGURE 10-25
Randomized trials evaluating cytomegalovirus (CMV) prophylactic strategies
administered during the time of greatest risk for CMV disease.
FIGURE 10-26
The prevention of cytomegalovirus (CMV)
disease. This figure shows the different strategies for the management of CMV-positive
transplant recipients or recipients of CMVpositive organs.
The "prevention" of CMV disease

CMV D+
CMV R+
Preemptive treatment
CMV antigenemia
testing or PCR
testing weekly starting
the third or fourth
postoperative week
()*
or low titer
positive-depending
on the laboratory
threshold
(+)
Treat with
IV ganciclovir
5 mg/kg bid adjusted
for renal function
1014 d
Antiviral prophylaxis
For all CMV D+ R,
D+ R+, D R+ the following
have been employed
a. po ganciclovir
1 g tid 3 months
b. IV ganciclovir post
transplant only or followed
by oral acyclovir for 3
months
c. Oral high dose acyclovir
800 mg po qid 3 months
d. Pooled IV IgG or CMV
hyperimmune globulin
10.15
No testing or
antiviral therapy
Wait for infection
* Different laboratories have different thresholds for clinically significant positive tests.
Continue
surveillance
The most costly approach.

The most convenient and effective. Both ganciclovir and acyclovir are adjusted for
renal function.
DETECTION OF CMV DISEASE AND INFECTION

Antibodies: the development of IGM anti-CMV antibodies, a four fold or greater increase in IgG titers
Culture:
A. Standard culture in a fibroblast monolayer
Results may require up to 6 wk
B. Shell vial culturesthe buffy coat is centrifuged onto fibroblasts increasing fibroblast infection. Viral infection
is detected by applying a monoclonal antibody directed against the 72-Kd major immediate early protein of
CMV. RBCs in the buffy coat may be toxic to the monolayer resulting in a false-negative test. Urine and BAL
specimens may be positive without predicting disease. Results are available in 16 to 36 h.
Other:
A. AntigenemiaGranulocytes and monocytes are isolated and stained with a monoclonal antibody against a
matrix, tegument protein pp65 (structural late protein). Culture is not required, granulocytes and monocytes from the buffy coat are stained, testing results are available in 4 to 6 h. It may be argued that the
positivity may not be due to replicating virus in the WBCs but due to exogenous acquisition from infected
endothelial cells. The number of antigen positive cells per unit number of WBC counted that determines
the onset of symptomatic diseases depends upon the individual laboratory; however, usually over 10 positive cells per 105 WBC precede the onset of symptoms by approximately 1 week.
B. Polymerase chain reactionFor the detection of CMV DNA in whole blood or serum. CMV DNA is amplified
from whole blood or serum. The sensitivity and predictive value depend on the laboratory.
FIGURE 10-27
Detection of cytomegalovirus (CMV) disease
and infection. BALbronchoalveolar
lavage; RBCred blood cell;
WBCwhite blood cell.
10.16
Tuberculosis
SOME ANTITUBERCULOSIS DRUGS
Drug
Primary antituberculous therapy
Isoniazid* (I.N.H., and others)
Rifampin*(Rifadin, Rimactane)
Pyrazinamide
Ethambutol(Myambutol)
Other Drugs
Capreomycin (Capastat)
Kanamycin (Kantrex, and others)
Streptomycin**
Cycloserine (Seromycin, and others)
Ethionamide (Trecator-SC)
Ciprofloxacin (Cipro)
Ofloxacin (Floxin)
Adult dosage (daily)
Pediatric dosage (daily)
Main adverse effects
300 mg
600 mg
1530 mg/kg
15 mg/kg (about 1 g)
1020 mg/kg (max. 300 mg)

1020 mg/kg (max. 600 mg)
same as adult
same as adult
Hepatic toxicity
Hepatic toxicity, flu-like syndrome
Hepatic toxicity, hyperuricemia
Optic neuritis
15 mg/kg IM or IV
15 mg/kg IM
250500 mg bid
250500 mg bid
500750 mg bid
200400 mg q12h or
400800 mg/day
1530 mg/kg
1530 mg/kg
2040 mg/kg IM
1520 mg/kg
1520 mg/kg
Not recommended
Not recommended
Auditory and vestibular toxicity, renal damage

Auditory toxicity, renal damage
Vestibular toxicity, renal damage
Psychiatric symptoms, seizures
Gastrointestinal and hepatic toxicity
Nausea
Nausea
*Rifamate (containing rifampin 300 mg plus isoniazid 150 mg) is also available
Can be given orally or parenterally. Pyridoxine should be given to prevent neuropathy in malnourished or pregnant patients and those with alcoholism or diabetes. For intermittent use
after a few weeks to months of daily dosage, the dosage is 15 mg/kg twice/wk (max. 900 mg).
Available orally or intravenously. For intermittent use after a few weeks to months of daily dosage, the dosage is 600 mg twice/wk.
For intermittent use after a few weeks to months of daily dosage, the dosage is 4050 mg/kg twice/wk (max. 3 g).
Daily dosage should be 25 mg/kg/d if organism isoniazid-resistant or during first 1 to 2 months; decrease dosage if renal function diminished. For intermittent use after a few weeks to
months of daily dosage, the dosage is 50 mg/kg twice/wk.
**Temporarily not available in the United States.
For patients > 40 years old, 500 to 750 mg/d or 20 mg/kg twice/wk; decrease dosage if renal function is diminished. Some clinicians change to lower dosage at 60 rather than
40 years of age.
Some authorities recommend pyridoxine 50 mg for every 250 mg of cycloserine to decrease the incidence of adverse
psychiatric effects.
FIGURE 10-28
The treatment of tuberculosis (TB) depends on the clinical presentation. Pretransplant prophylaxis for a positive purified protein
derivative, if given, is with isoniazid 300 mg/d up to, or following,
transplantation. Post-transplant treatment is more accepted, but
due to the possible high rate of hepatotoxicity, many centers have
chosen not to administer prophylaxis. Treatment of pulmonary
disease should include at least two to three drugs (depending on
resistance patterns in the area) for 6 to 9 months. Treatment of
disseminated disease or extrapulmonary disease should include

three or four drugs for 12 to 18 months. When starting treatment
with isoniazid and rifampicin, care should be taken to increase the
glucocorticoid dose twofold and the cyclosporine by threefold to
fivefold. This is because rifampicin (and somewhat isoniazid)
induces the metabolism of steroids and cyclosporine and FK506
through the P450 cytochrome system. (Adapted from Med Lett
Drugs Ther [8]; with permission.)
10.17
Protozoal/Parasitic Infections
DIAGNOSTIC TECHNIQUES FOR PNEUMOCYSTIS CARINII INFECTION
Technique
Yield
Complications
Comments*
Routine sputum
Induced sputum
Transtracheal aspiration
Gallium scan
Bronchoalveolar lavage (BAL)
BAL/brushing
BAL/transbronchial biopsy
Open lung biopsy
Poor
30%75%
Fair (with experience)
Nonspecific
>50% (>95% in AIDS)
As for BAL alone
Over 90% (all patients)
Over 95% (all patients)
Needle aspirate
Up to 60%
Rare
Rare
Common: bleeding; subcutaneous air
Injection site
Bleeding, aspiration fever, bronchospasm
As for BAL
See BAL; pneumothorax
Anesthesia, air leakage, altered respiration,
wound infection
Pneumothorax, bleeding
Cultures needed
First choice; excellent in AIDS
Rarely worthwhile
Positive in >95% of infected patients
Wedged terminal BAL with immunofluorescence
Not useful for P. carinii
Impression smears; cultures/pathology
Gold standard noninfectious/infectious processes;
large sample
Best in localized disease
*All samples should be cultured and stained for bacteria (including mycobacteria), fungi, viruses, and examined for protozoa. Optimal procedures depend on the locally available expertise.
FIGURE 10-29
Diagnostic techniques for Pneumocystis carinii infection.
(Adapted from Fishman [9]; with permission.)
FIGURE 10-30
The treatment of Pneumocystis carinii
infection. (Adapted from Fishman [9];
with permission.)
THE TREATMENT OF PNEUMOCYSTIS CARINII
Agent(s) (route)
Dose
Options
Trimethoprim
and sulfamethoxazole
(TMP-SMZ) (IV/po)
Pentamidine
isethionate (IV)
Dapsone (po) with
TMP (po/IV)
Clindamycin (IV/po)
and primaquine
Trimetrexate (IV) with
folinic acid (po)
(leucovorin)
Pyrimethamine (po)
15 mg/kg/d TMP (to 20)

75 mg/kg/d SMZ (to 100)
Treat through rash: reduce TMP or SMZ by

one half; desensitize
4 mg/kg/d
300 mg/d maximum
100 mg/d
1520 mg/kg/d (900 mg)
600900 mg q 6 h
1530 mg base po qd
3045 mg/m2/d
80100 mg/m2/d
Lower dose (23 mg/kg); IM not advised
Load 50 mg bid x 2 d,
then 2550 mg qd
Load 75 mg/kg, then
100 mg/kg/qd
750 mg po tid
Not studied fully
with sulfadiazine
Atovaquone (po)
Methemoglobinemia; G6PD;
may be tolerated in sulfadiazine allergy
Methemoglobinemia; diarrhea
(pyrimethamine for primaquine)
Leukopenia, anemia;
thrombocytopenia; relapse common
Maximum 4 g in two doses; up to 8 g

Variable absorbance, improved
with fatty food; rash
*Adjunctive therapies (see text); corticosteroids (high dose with rapid taper); possibly interferon gamma;
granulocyte-macrophage colony-stimulating factor.
Based on clinical judgment of physicians; some agents are not approved by the Food and Drug Administration
for this indication.
10.18
ANTIBIOTIC THERAPY FOR TOXOPLASMA GONDII INFECTION

Drug
Dose
Duration
Comments
Pyrimethamine
100 mg po x 2
(then) 25 mg50 mg
po, qd, or qod
Sulfadiazine 4 g po
(then 11.5 g po qid
or tri-sulfapyridine;
(75100 mg/kg/d)
6001200 mg IV or
600 mg po q6h
1 g po tid or qid
Load
36 wk
Bone marrow suppression;

may give folinic acid 5 mg po/im
qod except leukemia
36 wk
Decrease dose for neutropenia;

sulfa allergy common
36 wk
Slower resolution than

with sulfa; C. difficile colitis
In pregnancy or sulfa allergy with
pyrimethamine; CNS data limited
Sulfonamide
Clindamycin
Spiramycin
36 wk
FIGURE 10-31
Antibiotic therapy for Toxoplasma gondii
infection. (Adapted from Fishman [9];
with permission.)
*Active infection: twice weekly blood counts are necessary to detect bone marrow suppression resulting from therapy.
Lifelong prophylaxis after acute infection is recommended in transplant and AIDS patients.
Investigational: trimetrexate, atovaquone, macrolides, gamma interferon.
Yeast and Fungal Infections

FIGURE 10-32
(see Color Plate)
Candida esophagitis
seen on esophagogastroduodenoscopy.
FIGURE 10-33
(see Color Plate)
Endoscopic view of
severe esophagitis.
10.19

Displayed are Aspergillus as fungus balls, which are proliferating
masses of fungal hyphae. The hyphae are septute, 5 to 10 m
thick, and branch at acute 40 angles. Aspergillus frequently
invades blood vessels, causing hemorrhage and necrotizing
inflammation with downstream infarction. This image shows
three fungus balls in the lung (Gomori-Ammon stain for fungi).
TREATMENT OF FUNGAL INFECTIONS IN THE SOLID-ORGAN

TRANSPLANT RECIPIENT BY CATEGORY OF INFECTION
Category of infection
Prophylactic
Mucocutaneous candidiasis
Candiduria
Nystatin (oral)
Preemptive
Definitive
Fluconazole*
Fluconazole
Amphotericin B bladder irrigation;
Fluconazole
Invasive candidiasis
Life-threatening
Catheter-associated
Less-ill, sensitive organism
Aspergillosis
Mucormycosis,
Phaeohyphomycosis,
Hyalohyphomycosis
Cryptococcosis
Histoplasmosis,
Coccidioidomycosis,
Blastomycosis
Pneumocystis carinii
Itraconazole
Fluconazole
?Itraconazole
TMP/SMX
Itraconazole
Amphotericin B (0.51.0 mg/kg)

+/ flucytosine
Amphotericin B
Fluconazole in selected cases
Fluconazole
Amphotericin B (1.01.5 mg/kg)**
Amphotericin B (1.0-1.5 mg/kg)**
Amphotericin B + flucytosine x 2 wk,

then Fluconazole x 410 wk if
clinical and microbiologic response
Amphotericin B;
itraconazole may be useful as
primary therapy
TMP/SMX
*Asymptomatic candiduria in renal transplant recipients

Not T. glabrata or other resistant species
Removal of catheter
Less ill, sensitive organism, nephrotoxicity owing to amphotericin B and proven microbiologic and clinical response
Pulmonary colonization immediately before or after transplantation
**Surgical dbridement where possible
Excision of focal pulmonary nodule due to C. neoformans or H. capsulatum
For coccidioidomycosis in endemic areas
FIGURE 10-35
Treatment of fungal infections in the solidorgan transplant recipient by category of
infection. TMP/SMXtrimethoprimsulfamethoxazole. (Adapted from Hadley
and Karchmer [10]; with permission.)
10.20
Hepatitis B
31
100
24
22
12
19
18
80
20
17
90
70
15
60
Dialysis
13
13
Transplant
50
40
1
11
9
9
6
30
20
10
0
0
4
6
8
Years following detection of HBsAg
10
FIGURE 10-36
Survival of hepatitis B virus (HBV)infected patients with end-stage
renal disease treated with either dialysis or transplantation. Patients
infected with HBV (hepatitis B surface antigen [HBsAg] positive)
on hemodialysis were matched for age with 22 previously transplanted HBsAg-positive patients. This study shows the reason for
concern and investigation as to the safety of transplantation in
HBV-infected patients. Although there are other studies showing a
significantly decreased survival in patients transplanted with HBV
infection, most currently show equivalent survival of over 10 years.
The cause of death in the HBV-infected group, however, may more
often be from infection and liver failure than from cardiac disease.
The safety of transplantation in HBsAg-positive patients has

been debated for over 25 years. Increased mortality, if seen, is usually
seen beyond 10 years following transplantation and is often secondary to liver failure or sepsis. The acquisition of hepatitis B infections post-transplant, however, does carry a worse prognosis.
Virtually all patients with severe chronic active hepatitis, and 50%
to 60% of those with mild chronic active hepatitis on liver biopsy
prior to transplantation, will progress to cirrhosis. Patients with
chronic persistent hepatitis usually do not show histologic progression over 4 to 5 years of follow-up, although mild lesions do not
guarantee preservation of hepatic function over longer periods. The
complete natural history of hepatitis B following transplantation is
not known, as biopsies have been performed largely in those who
have abnormal liver function tests; however, one recent study, that
included analyses of all individuals who were HBsAg positive
around the time of transplantation, has shown histologic progression in 85.3% of those who were rebiopsied with the development
of hepatocellular carcinoma in eight of 35 patients who developed
cirrhosis. A key to management of patients who were HBsAg positive following transplantation is to periodically monitor the liver by
ultrasound and to perform a serum alpha-fetoprotein level to detect
hepatocellular carcinoma at the earliest possible stage. The key to
minimizing the effects of hepatitis B infections following transplantation, however, is to administer the hepatitis B vaccine as early as
possible in the treatment for end-stage renal disease. It is noted that
60% will develop antihepatitis B titers when vaccinated while on
dialysis compared with only 40% of those who have already been
transplanted. Co-infection with hepatitis C may result in more
aggressive liver disease but so far has not led to a marked decrease
in patient survival. Because of the high risk of acute renal failure or
rejection with the use of interferon post-transplant, treatment of
hepatitis B with interferon following renal transplantation is not
advised. Lamivudine or other experimental antihepatitis agents may
be used pretransplant for patients with hepatitis B infection. (Figure
adapted from Harnett and coworkers. [11]; with permission.)
10.21
POST-TRANSPLANT SURVIVAL IN HEPATITIS BINFECTED PATIENTS

Patients evaluated, n
1 y, %
3 y, %
Author
Year
HBsAg +
HBsAg
HBsAg +
HBsAg
Pirson
Hillis
Touraine
Dhar
Roy
Pfaff
1977
1979
1989
1991
1994
1997
61
16
140
51
85
781
60
149
869
541
172
13,287
94
55
94
92
100
88.8
95
90
93
98
100
91.8
5 y, %
HBsAg + HBsAg
28
HBsAg +
10 y, %
HBsAg
60
80
91
88
75
77.6
88
93
75
80.6
HBsAg +
HBsAg
80
87
82
66
61.6
68 (8 y)
65.8
+HBsAg positive; HBsAg negative.

Later studies have usually shown comparable patient and graft survival in HBsAg-positive patients compared with HBsAg-negative patients. There may only be a slight 3% to 4% difference
overall in long-term graft and patient survival in favor of HBsAg-negative patients.
FIGURE 10-37
Post-transplant survival in hepatitis Binfected patients. Later studies have shown comparable patient and graft survival in hepatitis B
surface antigen (HBsAg)positive patients compared with HBsAgnegative patients. There may only be a slight 3% to 4% difference
overall (in favor of HBsAg-negative patients) in long-term graft and

patient survival. (Data from Pirson and coworkers [12], Hillis and
coworkers [13], Touraine and coworkers [14], Dhar and coworkers
[15], Roy and coworkers [16], and Pfaff and Blanton [17].)
CHRONIC HEPATITIS B INFECTION IN HBsAg-POSITIVE RENAL

TRANSPLANT RECIPIENTS: RESULTS OF LIVER BIOPSIES PERFORMED
PERITRANSPLANT AND A MEDIAN OF 66 MONTHS LATER
First Biopsy
n = 131
Histology
Normal
Chronic persistent
Chronic active
Cirrhosis
Miscellaneous
%
39%
25%
25%
0%
11%
Second biopsy
n = 101
66 months
%
6%
18%
42%
28%
6%
Histologic deterioration was seen in 85.3% of those rebiopsied with hepatocellular carcinoma seen in 8/35 with
cirrhosis. Patients had not been treated with anti-HBV agents. 151 patients were HBsAg positive, median age 46,
35 females, 116 males. Immunosuppression in 124 was prednisone and azathioprine and in 27 cyclosporine,
azathioprine, and prednisone. The median follow-up was 125 months (range 1 to 320). Median time of HBsAg
positively was 176 months with 20% acquiring HBV infection post-transplant.
FIGURE 10-38
Chronic hepatitis B infection in hepatitis B
surface antigen (HBsAg)positive renal
transplant recipients. Results of liver biopsies performed peritransplant and a median
of 66 months later in 131 of 151 HBsAg+
patients. Histologic determination was seen
in 85.3% of patients rebiopsied, with hepatocellular carcinoma seen in eight of 35
patients with cirrhosis. Patients had not
been treated with anti-hepatitis B virus
agents. With a median age of 46, 151
patients were HBsAg positive (35 female,
116 male). Immunosuppression in 124
patients was with prednisone and azathioprine, and in 27 patients was with
cyclosporine, azathioprine, and prednisone.
(From Fornairon and coworkers [18];
with permission.)
10.22
CHRONIC HEPATITIS B INFECTION: CAUSES OF DEATH

IN 151 HBSAG-POSITIVE PATIENTS OVER 125 MONTHS
Liver related (n = 15)
Spontaneous bacterial peritonitis
Hepatocellular carcinoma
Liver failure
Fibrosing cholestatic hepatitis
Not liver related (n = 26)

6
4
5
2
Cancer
Sepsis
Cardiovascular
Stroke
Other
FIGURE 10-39
Chronic hepatitis B infection. Causes of death in 151 hepatitis B
surface antigen (HBsAg)positive patients over 125 months. Death
following transplantation is more frequently due to sepsis and liver
failure in patients with hepatitis than in patients without chronic
hepatitis. (From Fornairon and coworkers [18]; with permission.)
6
8
5
3
4
Death following transplantation in patients with hepatitis is more frequently caused

by sepsis and liver failure than in patients with chronic hepatitis.
Hepatitis B virus screening in renal transplant candidates
()No further testing
(+) eAg
HBV DNA
() DNA
indicates lack of
viral replication
? Biopsy
? Use antiviral
Consult hepatology
except by routine
dialysis schedule
(+) DNA/eAg (+)
Hepatitis B virus
Screen by HBsAg
1.0
0.9
0.8
0.7
HCV+HBV (n=189)
HCV+HBV+ (n=46)
0.6
0.5
0
Biopsy
Cirrhosis
Mild to
severe hepatitis
(CPH, CAH)
No renal transplant alone

Referral to Liver transplant
center (if appropriate)
that transplants
HBV DNA(+) candidates
Consider
treatment
FDA approved
interferon
Lamividine
Famacyclovir
Labucovir
Adefovir
In trials
FIGURE 10-40
Hepatitis screening in renal transplant candidates. CAH
chronic active hepatitis; CPHchronic persistent hepatitis;
HBsAghepatitis B surface antigen; HBVhepatitis B virus.
12
24
36
48
60
72
Months
84
96
108
120
FIGURE 10-41
Patient survival in 235 hepatitis C virus (HCV)-positive patients.
Patients coinfected with HCV and hepatitis B virus (HBV) had
comparable survival 12 years after transplant as those infected
with HCV alone although fibrosis was more common in dually
infected patients. Results were based on 27 biopsies in patients
who were both HCV positive and HBV positive and 81 biopsies
in patients who were both HCV positive and HBV negative. Over
time, liver failure occurred more frequently in patients who were
both HCV and HBV positive (17%) than in patients who were
both HCV positive and HBV negative (7%). (From Pouteil-Noble
10.23
Hepatitis C
Other high risk 30%
16% Drug-related
4% STD history
1% Prison
9% Low SES
Injection
drug use 43%
Sexual 15%
Transfusions 4%
Occupation/hemodialysis 4%
Unknown 1%
Household 3%
FIGURE 10-42
Risk factors associated with reported cases of acute hepatitis C in the United States (1991 to
1995). Hepatitis C transplant infection prior to transplantation has not been definitively
shown in most studies to markedly affect survival for at least 5 years following renal transplantation. Furthermore, hepatitis Cpositive individuals who are otherwise good transplant
candidates appear to have increased survival when transplanted, compared with staying on
dialysis. Liver biopsies performed prior to transplantation have usually shown mild histological changes or chronic persistent hepatitis, but sequential biopsies have not been performed
for a long enough period of time and compared with survival to outline the natural history.
Transaminase levels do not help to predict histology or outcome. Death in hepatitis Cpositive
individuals is more often related to infection than in hepatitis Cnegative transplant recipients.
Post-transplant treatment with interferon alpha has led to an unacceptably high rate of both
rejection and acute renal failure secondary to severe interstitial edema without tubulitis.
Additionally, except for a few individuals, interferon has not resulted in long-term viral clearance. Most studies show the return of hepatitis C viremia within 1 month following cessation
of interferon. At this point it appears that hepatitis G infections (also caused by an RNA
virus) in renal transplant recipients, although occasionally associated with slight increases in
chronic hepatitis, are not associated with decreased survival.
E2/NS1 glycoprotein
Hepatitis C virus screening in renal transplant candidates

Hepatitis C virus
Screen for HCV by EIA-2 or 3
HCV (Ab) (+)

55 nm
RNA
33 nm core
PCR
Liver biopsy
E1 glycoprotein
FIGURE 10-43
Proposed structure of the hepatitis C virus.
Referral for liver

and kidney
transplant
Cleared infection
Repeat PCR in high-risk
group in 6 months
Lipoprotein
envelope
Cirrhosis
HCV Ab ()
no further testing
unless high-risk behavior
Mild changes
CPH (mild hepatitis)
CAH (moderate to
severe hepatitis)
Transplant
Monitor clinically
for the onset of
cirrhosis
Monitor carefully
for infection
Referral for
Interferon treatment
Currently unknown
sustained response
Transplant
FIGURE 10-44
Hepatitis screening in renal transplant candidates. CAHchronic
active hepatitis; CPHchronic persistent hepatitis; HCV(ab)
hepatitis C virus antibody; PCRpolymerase chain reaction.
10.24

FIGURE 10-45
The survival of hepatitis C virus (HCV)infected patients after
transplant group 1 or while awaiting transplantation group 2.
Patients who are transplanted have an increased survival. A small
biopsy study of dialysis (n = 14) and transplant (n = 14) patients
showed no difference in histologic progression in transplant recipients. The amount of fibrosis, however, was slightly increased.
(Adapted from Knoll and coworkers. [20]; with permission.)
Fraction of patients surviving
1.0
0.9
Group I
0.8
Group II
0.7
0.6
0.5
0
12
100
24
Time, mo
36
48
FIGURE 10-46
Five-year patient (panel A) and graft (panel B) survival in hepatitis C
virus (HCV)positive and HCV-negative patients from recent reports
from United States centers. There is no significant difference over
5 years in patient or kidney graft survival. MCWMedical College
of Wisconsin; MiamiUniversity of Miami; NEOBNew England
Organ Bank; UCSF CAD University of California, San Francisco
with cadaveric donors; UCSF LRDUniversity of California, San
Francisco, with living related donors; UWUniversity of Washington.
HCV +
HCV
Survival, %
80
60
40
20
0
100
MCW
Miami
UCSF
LRD
UCSF
CAD
NEOB
UW
3 yr
Miami
UCSF
LRD
UCSF
CAD
NEOB
UW
3 yr
HCV +
HCV
Survival, %
80
60
40
20
0
MCW
RENAL AND HEPATIC OUTCOME IN PATIENTS TREATED WITH INTERFERON

ALPHA FOLLOWING RENAL TRANSPLANT FOR HCV INFECTION
Author
Year
Number treated
HCV + HBV +
Dose mU, SC, TIW
Normalization of ALT
Discontinued treatment
Number with cirrhosis
PCR +PCR
RelapsePCR +
Acute renal failure
Rejection
Lost transplant
New proteinuria
Thervet
1994
13
4
35
1
7
8
NA
NA
2
0
0
NA
Magnone
1995
11
1
1.55
NA
7
NA
NA
NA
0
7
6
NA
Rostaing
1995
14
0
3
10
7
1
4
4
5
0
1
2
Rostaing*
1996
16
NA
3
NA
9
NA
NA
NA
6
0
3
NA
Yasumura
1997
6
0
6
6
0
0
2
0
0
1
0
1
10.25
FIGURE 10-47
Renal and hepatic outcome in patients
treated with interferon alpha post-renal
transplant for hepatitis C virus (HCV)
infection. Interferon treatment results in a
high rate of transplant acute renal failure or
rejection. Transplant biopsies in those with
acute renal failure show severe diffuse
edema. Acute renal failure is not very
responsive to steroids. Virologic clearing is
rare, as HCV-RNA is detectable, on average, 1 month after discontinuing interferon
if the polymerase chain reaction (PCR)
became negative during treatment. ALT
alanine aminotransferase; SCsubcutaneously; TIWthree times a week. (Data
from Thervet and coworkers [21],
Magnone and coworkers [22], Rostaing
and coworkers [23,24], and Yasumura and
coworkers [25].)
*Most are overlapping patients with the 1995 study.
Hepatitis G
HEPATITIS G VIRUS IN RENAL TRANSPLANTATION:
PREVALENCE OF INFECTION AND ASSOCIATED FINDINGS
Author
Year
Location
% infection
% with HCV infection
% with chronic ALT elevation
Rejection rate
% with HBsAg
Survival versus HGV negative
Dussol
1997
Marseille
28%
12.5%
12.5%
Unchanged
8%
NA
Murthy*
1997
NEOB
18%
28%
35%
Unchanged
NA
Unchanged
Fabrizi
1997
Milan
36%
91%
18%
NA
18%
NA
*One patient may have acquired HGV through the donor organ. Five of 10 pretransplant
positive patients became HGV RNA negative post-transplant.
FIGURE 10-48
Hepatitis G virus (HGV) in renal transplantation: prevalence of
infection and associated findings. Hepatitis G virus is an RNA
virus of the flaviviridae family. Hepatitis G virus was isolated independently by two different groups of investigators and called
hepatitis GB viruses by Simmons and colleagues, and hepatitis G
virus by Lenin and colleagues. It now appears that GB virus-A and
GB virus-B are tamarin viruses and GBV-C is a human virus with
sequence homology of more than 95% with the hepatitis GV

sequence. The virus has been shown to be transmitted by transfusions, including plasma products, by frequent parenteral exposure,
including intravenous (IV) drug abuse, by sexual exposure, and by
mother to child transmission. In the United States, the prevalence
of hepatitis G virus is 1.7% among healthy volunteer blood
donors, 8.3% among cadaveric organ donors, and 33% among IV
drug abusers. Among chronic hemodialysis patients, the prevalence
of hepatitis G virus RNA has been variable, ranging from 3.1% in
Japan to 55% in Indonesia and some areas in France. Likewise, the
reported incidence of co-infection with hepatitis B virus (HBV) and
hepatitis C virus (HCV) is extremely variable.
Hepatitis G virus RNA is detected by reverse transcriptase polymerase chain reaction (PCR). The development of reliable serologic
assays for hepatitis G has been difficult due to the lack of linear
epitopes expressed by hepatitis G virus. The risk for pretransplant
hepatitis G infection is associated with increasing numbers of
blood transfusions and with longer duration of dialysis. Post-transplantation, most patients with hepatitis G virus remain viremic;
however, patients have been shown to clear the virus post-transplant. At this time, hepatitis G virus does not appear to invoke a
poor outcome after transplantation, either in the form of severe
liver disease or increased mortality; however, the long-term studies
needed to provide a firm conclusion about this have not been performed. The question of transmission of hepatitis G virus via transplantation is still under investigation. NAnot available; NEOB
New England Organ Bank. (Data from Dussol and coworkers [26],
Murthy and coworkers [27], and Fabrizi and coworkers [28].)
10.26

FIGURE 10-49
Kaplan-Meier estimate of graft survival among recipients with
GBV-C RNA and without GBV-C RNA before transplantation.
Death with a functioning graft is included as a cause of graft loss.
The relative risk of graft loss among recipients with pretransplantation GBV-C RNA (and 95% CI of the risk) was calculated using a
proportional hazards model. The number of patients at risk at the
beginning of each 12-month interval is provided. (Adapted from
Murthy and coworkers [27]; with permission.)
Probability of graft survival
1.0
0.8
0.6
0.4
Relative risk: 0.88 (0.37, 2.09)
GBV-C negative
GBV-C positive
0.2
0.0
0
12
24
36
48
60
Time, mo
72
84
96
108
GBV-C neg. 79
GBV-C pos. 16
63
12
58
10
54
10
50
10
35
9
26
9
14
4
0
0
46
10
Value of Pretransplant Liver Biopsy

HEPATITIS MARKERS AND HISTOPATHOLOGIC DIAGNOSIS FROM LIVER BIOPSIES PRIOR TO TRANSPLANT
HbsAg (+)
Anti-HCV (+)
HBsAg and anti-HCV (+)
Anti-HBs and anti-HCV (+)
Anti-HBs (+)
Total
CAH
CPH
CIRH
Normal
HSTAS
Other
Total
2
11
1
8
22
2
4
1
10
1
9
13
34
1
3
7
30
2
22
13
74
FIGURE 10-50
Liver biopsy in the evaluation of hemodialysis patients who are
renal transplant candidates. Seventy-four patients were biopsied.
Forty-six percent of patients had normal or nonspecific changes in
their liver biopsies, 30% CAH, 11% CPH, and 3% cirrhosis. Liver
enzymes are poor predictors of histology in ESRD. Although with
current management HBV-positive and HCV-positive recipients can
enjoy comparable 10-year survival to noninfected patients, those
with moderate to severe hepatitis more frequently progress histologically and may develop sepsis or liver failure. Liver biopsy aids in
the long-term plan for the individual patients immunosuppression
and hepatic and infection monitoring. Furthermore, pretransplant
antiviral medications may be beneficial, especially interferon, where
post-transplant administration is not advisable because of markedly
increased rates of acute renal failure and rejection.(Adapted from
zdogan and coworkers. [29]; with permission.)
Hepatitis A infections are associated with acute hepatitis

and, on occasion, with acute renal failure. Hepatitis A infections can be prevented by either using immunoglobulin injections or, more currently, a hepatitis A vaccine that is given as
a two-dose series. This is an inactivated virus that is produced
in human fibroblast cell culture and is given to adults as an
initial and second dose 6 to 12 months later. The effectiveness
of this vaccination has not yet been tested in renal transplant
recipients, nor are there specific guidelines on the administration prior to transplantation, but given the lack of toxicity, it
may very well be advised in the future to give this to patients
with end-stage renal disease and, specifically, to patients who
are considering transplantation. CAHchronic active hepatitis;
CPHchronic persistent hepatitis; CIRHcirrhosis; HSTAS
hepatic steatosis.
10.27
Viral Interstitial Nephritis

FIGURE 10-51
Viruses that cause interstitial nephritis in renal transplant recipients. Consider this condition when nonspecific inflammation is
seen on biopsy or unexplained rejection occurs. Viruses may cause
renal disease by direct infection of the glomerular and/or tubular
cells or by the immune response directed against virally infected
cells. Most commonly nonspecific interstitial inflammation is seen
but severe tubular injury by mononuclear cells, peritubular inflammation, and interstitial fibrosis may also be seen. The presentation
of virally mediated interstitial nephritis may be acute or subacute.
In addition to routine light microscopy, occasionally evaluation by
immunofluorescence, electron microscopy, or special stains for light
microscopy are necessary to make the diagnosis.
VIRAL INTERSTITIAL NEPHRITIS

Adenovirus
BK virus
Cytomegalovirus
Epstein-Barr virus
Herpes simplex virus 1, 2, 6
Varicella-zoster virus
Hantavirus
Hepatitis C viruspossible
HIV
Proportion of patients with AIDS
HIV
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
No cyclosporine treatment (n=13)

Cyclosporine treatment (n=40)
P=0.001
6
12 18 24 30 36 42 48 54 60
Months since transplantation-related HIV-1 infection
66
FIGURE 10-52
The occurrence of AIDS in HIV-infected transplant recipients
according to immunosuppressive treatment. Immunosuppression
included cyclosporine in 40 individuals and no cyclosporine in
13 individuals.
The precise natural history of HIV infection following renal
transplantation is still not well delineated. The largest single series
from Pittsburgh analyzed 11 patients who were HIV positive prior
to transplantation and 14 patients who developed HIV infections
following transplantation. Of the 11 patients infected before transplantation, six were alive an average of 3.3 years following transplantation. Five patients had died, however; three of AIDS-related
complications. Of the 14 patients infected peritransplantation,
seven patients were alive at follow-up an average of 4.8 years later.
There had been seven deaths, three due to AIDS. Complications
seemed to correlate with increased immunosuppression for rejec-
tion. Another report evaluating 53 patients infected with HIV

around the time of transplantation found that patients treated with
cyclosporine appeared to have a better long-term prognosis than
those who were treated with prednisone and azathioprine.
In summary, although there are no firm conclusions, it appears
that there is not much difference between pre- or post-transplant
acquisition of HIV infection, although some authors, based on
small numbers of patients, have concluded that the age of the
patient and the duration of the infection are both prognostic factors. It also appears that approximately 25% of HIV-infected individuals do poorly within the first 6 months of transplantation,
especially following antirejection treatment (Rubin, unpublished
data). Another 25% of individuals appear to do very well 6 years
and beyond following transplantation. The remainder of the individuals seem to develop AIDS within 3 to 3.5 years after transplantation, with an average survival of about 3 months after the onset
of AIDS. It has also been noted that cytomegalovirus or other
infections that may increase HIV proliferation may influence this
outcome, and that prophylactic antimicrobial strategies may alter
the natural history.
Currently, it is advised that all transplant candidates be
screened for the presence of HIV antibody and counseled about
the possible consequences of further immunosuppression, but
not be categorically denied transplantation if they are otherwise
asymptomatic. Patient management following transplantation
should be focused on the avoidance of large increases in immunosuppression and opportunistic infections, with special attention to
the viral, pneumocystic, and mycobacterial infections that these
individuals may develop. Antiretroviral strategies in transplantation require study. (Adapted from Schwarz and coworkers [30];
with permission.)
10.28
Herpes Simplex Virus

Linear esophageal ulcers caused by herpes simplex virus (HSV) and
Candida. Infection with HSV-1 and -2 leads to stomatitis and
esophagitis post-transplantation without acyclovir prophylaxis.
Additionally, paronychia, corneal ulcers, encephalitis, genital
lesions, disseminated involvement of the gastrointestinal tract, pancreas, and liver, and interstitial nephritis has been seen. HSV-6
causes exanthem subitum in children, mononucleosis, and hepatitis. There has been some evidence that reactivation infections may
be associated with rejection in transplant recipients. Both reactivation and reinfection may occur. HSV-8 is associated with Kaposis
sarcoma. Prevention of these infections has been achieved using
prophylactic acyclovir following transplantation. If clinical symptoms occur from HSV, they usually are treated with acyclovir
adjusted for renal function.

Varicella-zoster virus (VZV) infection. Primary VZV infections usually result in typical vesicular eruptions of generalized onset without dermatomal localization. Reactivation infection of the virus
from the dorsal root ganglion usually causes a dermatomally localized vesicular eruption. By the time of renal transplantation, over
94% of adults have evidence of a prior VZV infection. In those

patients previously infected, antibody titers increase following
transplantation. Pretransplant screening is recommended to advise
the patient on treatment of post-transplant exposures. Post-transplant exposures to zoster or chickenpox in the nonimmune individual should be treated with acyclovir, famcyclovir, or varicella-zoster
immune globulin. Immune globulin is rarely required at this time.
Patients with the new onset of varicella infection following transplantation or with diffuse zoster should be treated with intravenous acyclovir, 10 mg/kg, three times per day, or famcyclorir
depending on renal function. Infection in the transplant recipient,
particularly in those who are primarily infected, can result in
encephalitis, disseminated intravascular coagulation, pneumonia,
bowel involvement, pancreatitis, dermatitis, and hepatitis.
The attack rate in nonimmune individuals of household contacts
with varicella infections is 80% to 90%. Therefore, if individuals
have not previously had varicella infections at the time of transplant
evaluation, vaccination with a live attenuated strain could be considered. Recently this strategy has been used in children prior to renal
transplantation. Attack rates in vaccinated individuals may be up to
31%, but the disease that develops is much milder compared with
those susceptible individuals not previously vaccinated. Should resistant strains of varicella develop, foscarnet has been effective.
Foscarnet is associated with a renal decline in renal function.
(Adapted from Friedman-Kien [31]; with permission.)
FIGURE 10-55
Adenovirus infection of the colon. Adenovirus infections normally
cause asymptomatic infections, coryza, or pharyngitis. Infection in the
first decade of life usually protects individuals from future infection as
long as the immune system is intact; however, in transplant recipients,
adenovirus types 11, 34, and 35 have been shown to cause interstitial
pneumonia, conjunctivitis, hemorrhagic cystitis, hepatitic necrosis,
interstitial nephritis and gastroenteritis, and disseminated disease.
Adenovirus infection may be latent prior to transplant and reactivate post-transplant, or a primary infection may be acquired.
Adenovirus has been shown to infect the bladder, uroepithelial

cells, renal tubular cells (distal greater than proximal), the
endothelium of the glomeruli and peritubular capillaries, and,
occasionally, mesangial cells. The outcome of adenovirus infection
is related to the type of immunosuppression and the recipient age.
The death rate during active infection in renal transplantation may
be as high as 18% but may be even higher in younger patients.
The onset of disease after transplantation is usually within 6
months of the transplant.
Clinically, the most frequent symptoms of an adenovirus infection involve difficult micturition, including gross hematuria, fever,
and, occasionally, renal dysfunction. The diagnosis is suspected
when bacterial cultures are negative but there is gross hematuria.
The urinary symptoms usually last 2 to 4 weeks. The diagnosis is
made by urine culture or by electron microscopy or light
microscopy, where adenoviruses are seen as intranuclear
basophilic viral inclusions with a narrow halo between the inclusions and the nuclear membrane. Treatment has been somewhat
successful using ganciclovir. Interferon therapy is difficult because
of the risk of acute renal failure or rejection in transplant recipients. Furthermore, efficacy is questionable because of the virus
ability to inhibit the mode of action of interferon. Ribavirin has
successfully cleared the virus in several immunosuppressed
patients. The use of IVIG has not been associated with reliable
results. In the future, cidofovir may also be used for the treatment
of adenovirus infections, but renal insufficiency and proteinuria
may limit use.
CENTRAL NERVOUS SYSTEM INFECTION IN THE TRANSPLANT RECIPIENT

Incidence 5%; mortality up to 85% for CNS infections
Acute to subacute
L. monocytogenes
Subacute to chronic
Cryptococcus neoformans
Mycobacterium tuberculosis
Coccidiodes immitis
Focal brain infection
Aspergillus
L. monocytogenes
T. gondii
N. asteroides
Candida albicans
Cryptococcus
Progressive dementia
Polyomavirus, HSV, CMV, HIV
Symptoms
Headachemay be mild, may have little meningismus
Fevermay be mild
altered consciousness
Cerebrospinal fluid
Lymphocytic pleocytosis
(viral/fungal/MTB)
Hypoglycorrhaia
Neutrophilic pleocytosis (bacterial)
10.29
Over three-fourths of central nervous system infection

is accounted for by
L. monocytogenes
C. neoformans
A. fumigatus
Timing
Early
Listeria
Nocardia
Toxoplasma
Aspergillus
Lateas above and due to chronic enhanced immunosuppression plus Cryptococcus and tuberculosis
Diagnosis
CT scan identifies hypodense ring-enhancing lesions
CSF examination
Directed lesional aspirates
FIGURE 10-56
Central nervous system infection in the
transplant recipient. CNScentral nervous
system; CSFcerebrospinal fluid; MTB
mycobacterium tuberculosis.
10.30
CAUSES OF HEADACHE IN THE TRANSPLANT RECIPIENT

Medications
OKT3 (aseptic meningitis)
ATG
IVIgG
Cyclosporine
Tacrolimus
Antihypertensives
ACE inhibitors
Nitrates
Hydralozine
Minoxidil
Hypertension
Neck tension, muscle pulls, ligamental irritation
Sinusitis
Ocular abnormalities
Excessive vomiting
Migraine headaches exacerbated by cyclosporine, tacrolimus, and
Stroke
Infection of the central nervous system
FIGURE 10-57
Causes of headache in the transplant recipient. ACEangiotensinconverting enzyme; CNScentral nervous system; ATGantithymocyte globulin.
WORK-UP OF AN UNEXPLAINED HEADACHE

History
Character, pattern, positional relationships
Fever, duration of headache and fever
Location of headache
Visual, movement, sensory impairment
Bowel or bladder incontinence
Trauma
Medications old and new
Time of medications and relationships to headache
Eye
Neurological
Complete the rest of the examination
If no papilledema or focal neurological deficitlumbar puncture
If papilledema or focal deficitCT first if no mass lesionlumbar puncture
Cerebrospinal fluid is sent for
Cell count and differential
Protein
Glucose
Grams stain
Fungal stains
Acid fast stain
Fungal culture
Mycobacterial cultures
Bacterial cultures
Cryptococcal antigen
Save cerebrospinal fluid in addition for other tests including
Histoplasma capsulatum or Coccidiodes immitis antibody titers
FIGURE 10-58
Work-up of an unexplained headache.
FIGURE 10-59
Epstein-Barr virus (EBV). EBV is associated with asymptomatic infection, mononucleosis,
hepatitis, and, rarely, interstitial nephritis. In transplant recipients, posttransplant lymphoproliferative disorder (PTLD) is also associated with EBV. EBV promotes B-cell proliferation, if left unchecked by immunosuppressive agents targeting the T-cell system. This chest
radiograph shows multiple pulmonary nodules of PTLD. Symptoms vary from no symptoms to diffuse organ involvement causing dysfunction. Any area of the body may be
involved, with frequent sites being the gums, chest, abdomen, and central nervous system.
PTLD occurs during the first posttransplant year in approximately 50% of those developing PTLD. It is seen in 1% to 2% of renal transplant recipients. Primary EBV infection
following transplantation and antilymphocyte agent use is associated with an increased
risk. Increasing quantitative blood EBV DNA levels may predict the onset of PTLD.
10.31
Viral Meningitis
VIRAL MENINGITIS
Causal agents
Enterovirus
Coxsackie*
ECHO*
Poliovirus
Adenovirus
Mumps
Arbovirus
Herpes group
Cytomegalovirus*
Herpes simplex virus 1 and 2*
HHV-6*
HHV-8*
Varicella-zoster virus*
Epstein-Barr virus*
Coronavirus
HIV
Influenza A, B
Lymphocytic choriomeningitis virus
Parainfluenza virus
Rabies virus
Rhinoviruses
Rotavirus
Japanese encephalitis virus*
Tick borne encephalitis virus
PML (JC) virus (in development)*
BK virus (in development)*
FIGURE 10-60
Viruses causing meningitis in transplant
recipients. The presentation is usually with
fever and headache alone or in conjunction
with headache may be the initial symptom.
Nuchal rigidity is rare in the transplant
patient. Cerebrospinal fluid samples should
be saved for viral analysis and analysis
should be requested if the diagnosis is not
rapidly available from standard studies.
* Cerebrospinal fluid polymerase chain reaction available to make the diagnosis but locations vary
Increased in transplant patients
Black Hairy Tongue

Black hairy tongue is the result of hypertrophy of filiform papillae
of the tongue, often seen in transplant patients after antibiotic
treatment. The origin is unknown but is associated with topical or
systemic antibiotics, poor oral hygiene, smoking, alcohol, and the
use of mouthwashes. Most often there are no symptoms; however,
nausea, gagging, taste alteration, or halitosis are reported by some
patients. Treatment includes brushing with a soft brush and, occasionally, topical vitamin B, salicylic acid, gentian violet, or surgical
removal. This entity is not to be confused with hairy leukoplakia,
which is composed of white corrugated plaques on the lateral surface of the tongue. These lesions may be small and flat or extensive and hairy. Microscopic evaluation shows epithelial cells with
herpetic viral inclusions, specifically Epstein-Barr virus. Treatment
is oral acyclovir.
10.32
Tinea Versicolor
Tinea versicolor (pityriasis versicolor) is a chronic superficial fungal
disease caused by Malassezia furfur, a yeast normally found on the
skin. It is in yeast form in the unaffected skin areas and in the
mycelial phase on affected skin. The disease usually is located on
the upper trunk, neck, or upper arms. Symptoms may include scaling, erythema, and pruritis. It may appear as slightly scaly brown
macules or whitish macules. Treatment options include oral or topical terbinafine (1% cream or gel), oral or topical ketoconazole, oral
fluconazole, or topical treatments, such as ciclopiroxolamine, piroctoneolamine, zinc pyrithione, or sulfur-containing substances, such
as selenium sulfide; the most common treatment is selenium.
Patients are asked to wet themselves in the shower, turn off the
water, apply the selenium and let it sit for 10 minutes, and then
rinse. Also, oral fluconazole, 200 mg, once or repeated once a week
later is a simple and effective treatment. Of note, oral terbinafine,
250 mg, daily for 12 weeks is associated with slightly decreased
cyclosporine levels. Terbinafine is an allylamine that binds to a
small subfraction of hepatic cytochrome P450 in a type I fashion.
Side effects seen during terbinafine use include gastrointestinal distress in up to 5% of patients and skin rashes in 2% of patients.
Kaposis Sarcoma
Kaposis sarcoma of the lower leg in a male transplant recipient.
Kaposis sarcoma is a tumor, perhaps of lymphatic endothelial origin,
that presents as purple papules or plaques that advance to nodules of
the extremities, oral mucosa, or viscera. In transplant recipients it presents on average by 21 months post-transplant, with the largest number (46%) within the first post-transplant year. It is seen most often in
men (3:1) and in those of Arabic, black, Italian, Jewish, and Greek
ancestry. It accounts for 5.7% of the malignancies reported to the
Cincinnati Transplant Tumor Registry (nonmelanoma skin cancers
and in situ carcinomas of the uterine cervix excluded). Transplant
programs in Italy and Saudi Arabia have reported higher rates of
post-transplant Kaposis sarcoma. Visceral involvement is less common in the transplant recipient than in the AIDS patient, but it must
be remembered that it may be seen in the liver, lungs, gastrointestinal
tract, and nodes. Mortality is increased with visceral involvement
(57% versus 23%). HHV-8 has been proposed as the causal agent
of this tumor; however, not all investigators feel the evidence is conclusive. Of note, the occurrence in AIDS patients is decreased in those
who receive foscarnet, cidofovir, and ganciclovir, but not acyclovir.
Treatment includes decreasing immunosuppression, local radiation,
excision, interferon, or chemotherapy.
10.33
Mucormycosis
FIGURE 10-64
Mucormycosis is caused by fungi of the order Mucorales, including
Rhizopus, Absidia, and Mucor. Mucorales are ubiquitous saprophytes found in the soil and on decaying organic material, including
bread and fruit. Human infection is believed to be caused by the
inhalation of spores that initially land on the oral and nasal
mucosa. Direct inoculation into tissues, however, has been reported.
Most of the spores, once in the tissue, are contained by the phagocytic response. If this fails, as it often does in patients with diabetes
mellitus and those otherwise immunosuppressed, germination
begins and hyphae develop. The hyphae, as shown in the micrograph, are large, nonseptate, rectangular, and branch at right angles.
Infection begins with the invasion of blood vessels, which causes
necrosis and dissemination of the infection. The most common site
of involvement is the rhino-orbital-cerebral area, accounting for
approximately 70% of cases; however, pulmonary, cutaneous, gastrointestinal, and disseminated infection may be seen. The chest
radiograph during pulmonary infections may show an infiltrate,
nodule, cavitary lesion, or pleural effusion. Gastric involvement may
range from colonization of peptic ulcers to infiltrative disease with
vascular invasion causing perforation. Although classic for
mucormycosis, a black eschar of the skin, nasal mucosa, or palate is
present in only about 20% of patients early in the course of the disease and cannot be relied on for assistance in early diagnosis.
Survival is dependent on early diagnosis. Diagnosis is by biopsy
with classic histologic findings and by culture of tissue. Treatment
includes amphotericin B, surgical removal of the lesion, packing of
the sinus areas with amphotericin Bsoaked packs, and perhaps
hyperbaric oxygen. Liposomal amphotericin B has also been effective. Treatment must include both surgery and amphotericin B.
Condyloma Acuminata
A
FIGURE 10-65
Condyloma acuminata (anogenital/venereal warts) are caused by
infection with human papillomavirus 6 or 11. In transplant recipients they may become extremely extensive. Treatment has included
fluorouracil, podophyllin, podophyllotoxin, intralesional interferon, topical interferon, systemic interferon, and, more recently,
imiquimod, which causes the induction of cytokines, especially
B
interferon alpha. Lesions have responded in 50% of nontransplant
patients receiving the 5% cream. Invasive treatments have included
surgical excision, cryotherapy, electrocautery, and carbon dioxide
laser. Recurrences are common. A, Condyloma acuminata in a
male transplant recipient. B, Condyloma acuminata in a female
transplant recipient.
10.34
Verruca Vulgaris
B
FIGURE 10-66
Verruca vulgaris (common warts) are caused by human papillomaviruses 1, 2, 3, 4, 5, 8, 11, 16, and 18, as well as others, with
the highest percentage by type 4. Warts are found most often on
the fingers, arms, elbows, and knees and are much more numerous
in the immunosuppressed patient. Treatment modalities have been
the same as for condyloma acuminata, with the addition of topical
cidofovir and hyperthermia. Therapy should be planned based on
the location, extent, and size of the lesions. Not all lesions need
treatment. Early dermatologic referral is needed for those lesions
that appear to be advancing rapidly as certain papilloma viruses
(16, 18, 31, 51, 52, 56) have been associated with squamous cell
carcinomas of the skin and cervix. A and B, Verruca vulgaris of the
finger and knee. Note the large size and multiple warts. C, Verruca
planae, flat warts at multiple locations of the hand, also often seen
on the face.
10.35
Molluscum Contagiosum
FIGURE 10-67
Molluscum contagiosum is an infection of
the skin caused by the molluscum contagiosum virus, a member of the pox virus family.
Molluscum does not grow in culture or
infected laboratory animals. Manifestations
are pearly, pink, dome-shaped, glistening,
firm lesions; in immunosuppressed patients,
however, they may be over 1 cm in diameter
and multiple lesions may occur together. The
infection usually lasts up to 2 months in
immunocompetent patients, but a chronic,
recalcitrant, and disfiguring infection may
occur in immunosuppressed patients. The
virus is contracted and spreads via close contact with an infected person, fomites, or via
autoinoculation. The incubation period is 2
weeks to 6 months. The diagnosis is made
visually or by direct examination of curettings from the center of the lesion showing
molluscum intracytoplasmic inclusion bodies. Treatment is started for the prevention of
spreading, to relieve symptoms, and for cosmetic reasons. Treatment includes cryotherapy, curettage, podophyllin, cantharidin,
trichloroacetic acid, phenol, salicylic acid,
strong iodine solutions, lactic acid, tretinoin,
silver nitrate, and interferon alpha topical or
intralesional, and possibly oral cimetidine,
with adhesive tape occlusion. None of the
available treatments result in a rapid or definite clearance in the immunosuppressed
patient. Treatment of the underlying retrovirus infection has been shown to help in
AIDS patients, and perhaps reviewing the
degree of immunosuppression in the transplant patient will help. A, Molluscum contagiosum papule. Note pearly umbilicaled
appearance. B, Histologic slide of molluscum
showing a cross section of the papule.
C, Close-up view of the molluscum bodies.
10.36
Intestinal Protozoa
SIMILARITIES AMONG THE INTESTINAL SPORE-FORMING PROTOZOA
History
Identified as human pathogens in recent decades
Once considered rare pathogens; now known to commonly cause infections
The AIDS epidemic increased awareness and recognition
Biology
Protozoa
Intracellular location in epithelial cells of the intestine
Spore or oocyst form is shed in stool
Pathogenesis of diarrhea
Unknown; possible abnormalities of absorption, secretion, and motility
Intense infection of small bowel associated with dense inflammatory infiltrate
May be associated with villus blunting and crypt hyperplasia
Nonulcerative and noninvasive*
Gut function and morphology related to number of organisms
Epidemiology
Common in tropical regions and places with poor sanitation
Transmission is through fecal-oral route, person-to-person contact, and
water or food
Endemic disease of children
Common source of epidemics in institutions and communities
May cause travelers diarrhea
Clinical manifestations
Asymptomatic infection
Self-limited diarrhea, nausea, and abdominal discomfort in healthy children and adults
Prolonged (subacute) diarrhea in some immunocompetent patients
Chronic diarrhea in immunodeficient patients
Diagnosis
Microscopic stool examination should be initial approach
Detection of cysts or spores in stool requires expertise and proper stains
Antibiotic treatment
Not usually indicated in healthy persons with acute infection
Indicated for chronic infection in immunodeficient patients
*Septata intestinalis may invade the mucosa.

Probably true for all; conclusively shown only for cryptosporidia.
Not proven for microsporidia.
FIGURE 10-68
Cryptosporidia, Isospora, cyclospora, and microsporidia are
intestinal spore-forming protozoa that infect enterocytes predominately of the small intestine. Infection occurs by ingesting the
spores (oocytes) by person-to-person contact or ingesting contaminated food or water, including city or swimming pool water [32].
Infections in immunocompetent individuals may be asymptomatic
or self-limited and associated with mild to moderate diarrhea and,
less frequently, nausea, abdominal cramping, vomiting, and fever.
In immunodeficient patients, especially those with T-cell impairment, the infections may cause severe persistent diarrhea. The most
common infection among the intestinal protozoas is cryptosporidium. The general prevalence of cryptosporidia in stool specimens in
Europe and North America is 1% to 3%, and in Asia and Africa is
5% to 10%. Antibodies to cryptosporidia, however, have been
found in 32% to 58% of adults. (Adapted from Goodgame [33];
with permission.)
10.37
Histoplasmosis
FIGURE 10-69
Histoplasmosis is caused by the thermal dimorphic fungus
Histoplasma capsulatum that exists in its mycelial phase in nature
and in the yeast form in the human body. It is found in the soil
enriched with bird or bat droppings in the Ohio and Mississippi
River Valleys and in Texas, Virginia, Delaware, and Maryland.
Disease is caused by primary infection or by reactivation of latent
infection. Primary infection is acquired by inhalation of infectious
microconidia, by direct inoculation into the skin, or via an infected
allograft. Once the microconidia is lodged in the alveolar and
interstitial spaces, it becomes a yeast, multiplies intracellularly, and

disseminates until cell-mediated immunity develops (2 to 10 weeks).
Organisms that disseminate concentrate in the reticuloendothelial
system. Disseminated disease is marked by fever, weight loss, weakness, fatigue, and mild respiratory symptoms. There may also be
organ-specific symptoms, including those of urinary tract obstruction. Histoplasma may be found in the glomerular capillary macrophages or macrophages within the interstitium and be associated
with focal medullary necrosis or papillary necrosis. The most common symptom of infection is fever, and often there are skin lesions,
as shown in this figure, but central nervous system involvement is
rare in transplant patients, as are abnormal chest radiographs.
When present, chest radiographic findings include diffuse, nodular,
patchy, or miliary infiltrates; hilar adenopathy is uncommon.
Diagnosis is made by identification of the yeast on a smear,
histopathologic detection of intracellular organisms in viable pulmonary tissue, a fourfold rise in antibody titers (only seen in about
50% of immunosuppressed patients), culture of the blood or tissue,
or a urine antigen assay. Identification of the organism causing
culture growth of a white, fuzzy mold (Histoplasma, Blastomyces,
Coccidioides) is now performed by DNA hybridization. The bone
marrow may be the most reliable source for sampling and staining
for organisms. Treatment is amphotericin B occasionally, with
long-term oral intraconazole after completing amphotericin.
Resolution of infection may be monitored by following the
Histoplasma urinary antigen.
Cryptococcosis
FIGURE 10-70
Cutaneous cryptococcosis, multiple lesions on the arm. Cryptococcus
neoformans is an encapsulated yeast that exists worldwide, predominately in the soil contaminated by bird and other animal
droppings. Infection is through inhalation with dissemination to
the central nervous system (CNS), skin, mucous membranes, bone,
bone marrow, and genitourinary tract. Infection has also occurred
through the renal allograft. The most common disease site is the
CNS, where patients present with headache, fever, mental confusion, seizures, papilledema, long tract signs, or, uncommonly,
meningismus. The onset of infection is anywhere from 6 months
to years following transplantation. The onset may be very insidious, with nausea and headache occurring for weeks to months
before the fever develops. Pulmonary involvement presents asymptomatically or with dyspnea and cough. The chest radiograph
shows wide variability in that circumscribed pulmonary nodules,
alveolar infiltrates, interstitial infiltrates with or without effusions,
and cavitation may be seen. Cutaneous disease may be the first
sign of dissemination in up to 30% of cases. Diagnosis is made by
the identification of the yeast in the cerebrospinal fluid (CSF) or
pulmonary secretions, the detection of cryptococcal antigen in the
CSF or blood, or culture. Amphotericin B is the most common
agent used for treatment, with some also favoring the use of flucytosine and perhaps azole therapy for maintenance to prevent
relapse. Specific patients may be treated with fluconazole alone.
Serial determinations of the serum cryptococcal antigen, which is
positive in over 95% of patients with cryptococcal meningitis, may
help to follow and modify the course of therapy. Patients should
be treated until the cryptococcal antigen is negative, and then for
another 2 to 4 weeks for added safety.
10.38
Herpes Simplex
Primary oral herpes simplex, mucosal membrane showing vesicles
and ulceration.

Primary herpes simplex stomatitis.
FIGURE 10-73
Cutaneous herpes simplexherpetic whitlow. This condition may be
confused with a bacterial infection.
10.39
Central Nervous System Infections

CEREBROSPINAL FLUID FINDINGS BY TYPE OF MENINGITIS
Type
Viral
Fungal
Tuberculous
Bacterial
WBC Count (per mm)
Differential, %
Protein Level, mg/dL
Glucose level, mg/dL
Stain used
5.500
40400
1001000
400100,000
>50 lymphocytes
>50 lymphocytes
>80 lymphocytes
>90 PMNs
30150
40150
40150 (may exceed 400)
80500
Normal to low
Normal
Normal to low
<35
Grams
India ink and cryptococcal antigen
Acid-fast
Grams
FIGURE 10-74
Cerebrospinal fluid findings in patients with bacterial meningitis.
(Adapted from Maxon and Jacobs [34]; with permission.)
References
1. Rubin RH, Wolfson JS, Cosimi AB, et al.: Infection in the renal transplant recipient. Am J Med 1981, 70:405411.
2. Rubin RH: Infectious disease complications of renal transplantation.
Kidney Int 1993, 44:221236.
3. Stratta R: International Congress on Immunosuppression, Orlando,
FL, 1998.
4. Isada CM, Kastan BL, Goldman MD, et al.: Infectious Disease
Handbook, edn. 2. Lexi Comp, Inc., 19971998.
5. Maguire GP, Wormser GP: Preventing infections in the immunocompromised: Part 2. Journal of Respiratory Diseases 1994, 15:408.
6. Lake KD: Management of drug interactions with cyclosporine.
Pharmacotherapy 1991, 11:110S118S.
7. Yee GC: Pharmacokinetic interactions between cyclosporine and other
drugs. Transplant Proc 1990, 22:12031207.
8. Drugs for tuberculosis [letter]. Med Lett Drugs Ther 1992, 24:1012.
9. Fishman JA: Pneumocystis carinii and parasitic infections in transplantation. Infect Dis Clin North Am 1995, 9:10051044.
10. Hadley S, Karchmer AW: Fungal infections in solid organ transplant
recipients. Infect Dis Clin 1995, 19:10451074.
11. Harnett JD, Zeldis JB, Parfrey PS, et al.: Hepatitis B disease in dialysis
and transplant patients: further epidemiologic and serologic studies.
12. Pirson Y, Alexandre GPJ, van Ypersele de Strihou C: Long-term effect
of HBs antigenemia on patient survival after renal transplantation.
N Engl J Med 1977, 296:194196.
13. Hillis WD, Hillis A, Walker WG: Hepatitis B surface antigenemia in renal
transplant recipients: increased mortality risk. JAMA 1979, 242:329.
14. Touraine JL, Traeger J: Renal TX at the University of Lyon. Clin
Transpl 1989, 5:229238.
15. Dhar JM, Al-Khader AA, Al-Sulaiman MH, Al-Hasani MK: The significance and implications of hepatitis B infection in renal transplant
recipients. Transplant Proc 1991, 23:1785-1786.
16. Roy DM, Thomas PP, Dakshinamurthy KV, et al.: Long-term survival
in living related donor renal allograft recipients with hepatitis B infection. Transplantation 1994, 58:118119.
17. Pfaff WW, Blanton JW: Hepatitis antigenemia and survival after renal
transplantation. Clin Transplant 1997, 11:476479.
18. Fornairon S, Pol S, Legendre C, et al.: The longterm virologic and
pathologic impact of renal transplantation on chronic hepatitis B virus
infection. Transplantation 1996, 62:297299.
19. Pouteil-Noble C, Tardy JC, Chossegros P, et al.: Co-infection by
hepatitis B virus and hepatitis C virus in renal transplantation: morbidity and mortality in 1098 patients. Nephrol Dial Transplant 1995,
10 (suppl 6):122124.
20. Knoll GA, Tankersley MR, Lee JY, et al.: The impact of renal transplantation on survival in hepatitis Cpositive end-stage renal disease
patients. Am J Kidney Dis 1997, 29:608614.
21. Thervet E, Pol S, Legendre C, et al.: Low-dose recombinant leukocyte
interferon-a treatment of hepatitis Cpositive end-stage renal disease
patients: a pilot study. Transplantation 1994, 58:625627.
22. Magnone M, Holley JL, Shapiro R, et al.: Interferon-a-induced acute
23. Rostaing L, Izopet J, Baron E, et al.: Treatment of chronic hepatitis C
with recombinant interferon alpha in kidney transplant recipients.
24. Rostaing L, Modesto A, Baron E, et al.: Acute renal failure in kidney
transplant patients treated with interferon alpha 2b for chronic
hepatitis C. Nephron 1996, 74:512516.
25. Yasumura T, Nakajima H, Hamashima T, et al.: Long-term outcome
of recombinant INF-a treatment of chronic hepatitis C in kidney
transplant recipients. Transplant Proc 1997, 29:784786.
26. Dussol B, Charrel R, De Lamballerie X, et al.: Prevalence of hepatitis
G virus infection in Kidney transplant recipients. Transplantation
1997, 64:537539.
27. Murthy BVR, Muerhoff AS, Desai SM, et al: Impact of pretransplantation GB virus C infection on the outcome of renal transplantation.
J Am Soc Nephrol 1997, 8:11641173.
28. Fabrizi F, Lunghi G, Bacchini G, et al.: Hepatitis G virus infection in
chronic dialysis patients and kidney transplant recipients. Nephrol
10.40
29. Histopathological impacts of hepatitis virus infection in hemodialysis

patients: Should liver biopsy be performed before renal transplantation? Artif Organs 1997, 21:355358.
30. Schwartz A, Offermann G, Keller F, et al.: The effect of cyclosporine
on the progression of human immunodeficiency virus type 1 infection
transmitted by transplantation: data on four cases and review of the
literature. Transplantation 1993, 55:99-103.
31. Friedman-Kien AE: Cutaneous manifestations. In Atlas of Infectious
Diseases, vol 1 (edn 2): AIDS. Philadelphia: Current Medicine;
1997:5.15.18.32.
32. Lemon JM, McAnulty JM, Bawden-Smith J: Outbreak of cryptosporidiosis linked to an indoor swimming pool. Med J Aust 1996, 165:613616.
33. Goodgame RW: Understanding intestinal spore-forming protozoa:
cryptosporidia, microsporidia, isosporidia, and cyclospora. Ann
Intern Med 1996, 124:429441.
34. Maxson S, Jacobs: Viral meningitis: tips to rapidly diagnose treatable
causes. Postgrad Med 1993, 93:153166.
Immunosuppressive
Therapy and Protocols
Angelo M. de Mattos
he 1990s have seen major steps in the dissection of basic mechanisms of allorecognition, and renal graft survival has achieved
unprecedented clinical results. Transplantation has turned into a
widespread modality of therapy for patients with chronic renal failure
that benefits thousands worldwide. Combinations of immunosuppressive agents have proved to be an effective strategy to inhibit diverse
pathways of the multifaceted immune system, allowing the reduction of
both dosage and adverse effects of each individual drug. As understanding of the molecular basis of the immune response has expanded
rapidly, so have the possibilities for designing therapeutic interventions
that are more effective, more specific, and safer than are current treatment options. As we reach the end of the century, several different and
innovative approaches will add to this fascinating and complex therapy.
CHAPTER
11
11.2
Ca
Tac/FK-BP
Csa/Cyp
Calcineurin
IL-2
X
P
NF-ATc
RNA
NF-AT box
DNA
FIGURE 11-1
Mechanism of action for cyclosporine (Csa) and tacrolimus (Tac).
The common cytoplasmic target for cyclosporine and tacrolimus is
calcineurin. After binding to cyclophillin (Cyp), cyclosporine interacts with calcineurin, inhibiting its catalytic domain. Thus dephosphorylation of transcription factors is prevented, as exemplified by
the nuclear factor of activated T lymphocyte (NF-AT). Despite having a different ligand called FK-binding protein (FK-BP), tacrolimus
inhibits calcineurin in a similar way. Because phosphorylated transcription factors cannot cross the nuclear membrane, the production
of key factors for lymphocyte activation and proliferation (ie, interleukin-2, tumor necrosis factor-, interferon, c-myc, and others) is
inhibited [1]. NF-ATcnuclear factor of activated T-lymphocytecytoplasmic form; Pphosphorus; Cacalcium.
DNA
IL-2
IL-2 receptor
p
m-TOR
PHAS-1
PHAS-1
eIF-4F
Rapa/FKBP
G1
S
G0
M
G2
FIGURE 11-2
Proposed mechanism of action for rapamycin (rapa). Rapamycin
binds to FK-binding protein (FK-BP). However, the immunosuppressive properties of rapamycin are not due to inhibition of calcineurin. Rapamycin blocks the activating signal delivered by
growth factors (exemplified by the interleukin-2 [IL-2] receptor)
by blocking the translation of the coding of messenger RNA
(mRNA) for key proteins required for progression through the
G1 phase of the cell cycle. In this model the mammalian target of
rapamycin (m-TOR, also called FRAP or RAFT1), phosphorylates
the translational repressor PHAS-I. Arrest of the cell cycle results,
and the proliferation of lymphocytes is thereby inhibited. The full
understanding of the mechanism(s) of action of rapamycin is the
focus of intense research at this time [2]. elF-4translation initiation factor belonging to the Ets family; G(0,1, and 2)quiescent;
Mmitosis; Ssynthesis.
Immunosuppressive Therapy and Protocols
Azathioprine
PRPP
HGPRT
TIMP
6-MP
6-m-MP
Allopurinol
Thiouric acid
HGPRT
IMP
Mycophenolate, mizoribine
D
IMP
PRPP + Adenine
AMP
GMP
ATP
GTP
Energy
Hypoxanthine + PRPP
RNA, DNA
Csa or FK-506
HGPRT
Guanine + PRPP
Energy, signaling
Glycoproteins
Monotherapy
Dual therapy
Triple therapy
Csa or FK-506
Steroid
Csa or FK-506
Aza or MMF
Csa or FK-506
Steroid
Aza or MMF
Antilymphocytic
Csa or FK-506
Steroid
Aza or MMF
Antilymphocytic
Quadruple
therapy
(induction versus
sequential)
Csa or FK-506
Steroid
Aza or MMF
1 week
1 month
11.3
FIGURE 11-3
Mechanism of immunosuppression of
azathioprine and mycophenolate mofetil
(MMF). Azathioprine and MMF prevent
lymphocyte proliferation by way of inhibition of purine base synthesis, thus resulting
in decreased production of the building
blocks of nucleic acids (ie, DNA and RNA).
Azathioprine is metabolized to 6-mercaptopurine (6-MP), which is further converted
to 6-ionosine monophosphate. This molecule inhibits key enzymes in the de novo
pathway of purine synthesis (adenosine
monophosphate [AMP] and guanosine
monophosphate [GMP]). MMF is metabolized to mycophenolic acid, which is a noncompetitive inhibitor of the enzyme that
converts inosine monophosphate (IMP) to
GMP. The depletion of GMP may have
effects other than inhibition of nucleic acid
production. Some events of T-lymphocyte
activation are independent of guanosine
triphosphate (GTP), as is the assembling of
certain adhesion molecules. ATPadenosine
triphosphate; HGPRThypoxanthine-guanine phosphoribosyl transferase; IMPD
inosine-monophosphate dehydrogenase;
PRPPphosphoribosyl pyrophosphate;
6-m-MP6-methyl-mercaptopurine; TIMP
thioinosine monophosphate. (Adapted from
de Mattos and coworkers [3,4].)
FIGURE 11-4
Summary of strategies for combining immunosuppressive agents.
Currently, monotherapy (usually cyclosporine [Csa]) is not used in
the United States. Dual therapy (involving cyclosporine or tacrolimus)
is used commonly in Europe. Most centers in the United States use
triple or quadruple therapy (induction or sequential). Some centers
continue the induction with the antilymphocytic biologic agent for
a predetermined period (usually 1014 days), overlapping with the
initiation of cyclosporine (or tacrolimus). Alternatively, the biologic
agent is discontinued and cyclosporine (or tacrolimus) begun as soon
as the graft function reaches a determined threshold, resulting in no
overlap of these two agents. In living donor transplants, azathioprine
(Aza) is commonly begun a few days before surgery. [5]. FK-506
tacrolimus; MMFmycophenolate mofetil.
11.4
Murine
Monoclonal
antibody
Muromonab OKT3
Anti-Tac
SDZ-CHIB
T10B9
BMA 031
WT 32
Anti-ICAM 1
33B3-1
Humanized-chimeric
Humanized-grafted
Type
Target
Murine
Murine
Murine/Human
Murine
Murine
Murine
Murine
Rat
FIGURE 11-5
Evolution of monoclonal antilymphocytic antibodies. Monoclonal
antibodies are the result of complex genetic engineering techniques.
A, Differences among murine, chimeric, and humanized antibodies. Attempts to reduce side effects, improve efficacy, and decrease
xenosensitization are the main reasons for development of these
modifications on the murine molecule. B, The different monoclonal
antibodies, their classification regarding the molecular structure, and
their targets. Muromonab OKT3 (Ortho Pharmaceutical, Raritan,
NJ) is the only monoclonal antibody commercially available at this
time [6]. CD3 monomorphic membrane co-receptor present in
T-lymphocytes; IL-2Rinterleukin-2R; TCRT-cell receptor.
CD3
IL-2R (CD25)
IL-2R (CD25)
TCR
TCR
CD3
CD54
IL-2R (CD25)
FIGURE 11-6
Experimental model of the vasoconstrictive
effect of cyclosporine. Some of the acute
nephrotoxicity of cyclosporine is due to the
significant yet reversible vasoconstrictive
effect of the drug. A, Scanning electron
micrograph of glomerulus of a rat not
exposed to cyclosporine. Arrow indicates
glomerular capillary loop. AAafferent
artery. B, After 14 days of cyclosporine
treatment, the entire length of an afferent
arteriole shows narrowing (magnification
500). Arrow indicates afferent artery. (From
English and coworkers [7]; with permission.)
11.5
AGENTS USED IN RENAL TRANSPLANTATION

Drug
Dosage
Adverse reactions
Cost
Cyclosporine
Sandimmune
(Sandoz Pharmaceuticals, East Hanover, NJ)
Neoral
(Sandoz Pharmaceuticals, East Hanover, NJ)
Starting dose: 710 mg/kg/d in

2 divided doses
Maintenance: based on blood levels
Starting dose: 710 mg/kg/d in
2 divided doses
IV Csa equals one third of oral Csa; IV
cyclosporine is given by continuous
infusion over 24 h
Starting and maintenance dose:
13 mg/kg/d; IV dose equals half of oral dose
Decrease dose by half for 50% decrease
in leukocyte count
Hold dose for leukocyte count of <3000
Nephrotoxicity, hypertension, gingival overgrowth, hirsutism, hepatotoxicity, neurotoxicity,

hypomagnesia, hyperkalemia
Same
Gelcaps: $1.61/25 mg;

$6.42/100 mg
Liquid: $6.41/100 mg, orally
Gelcaps: $1.44/25 mg;
$5.77/100 mg
Liquid: $6.38/100 mg, orally
$113.32/100 mg, IV
Leukopenia, anemia, thrombocytopenia,

hepatitis, pancreatitis, alopecia, skin cancer,
aplastic anemia (rare)
$1.29/50-mg tablet
$101.18/100-mg vial, IV
Azathioprine
Imuran
(Glaxo Wellcome, Research Triangle Park, NC)
Azathioprine
(Roxane Laboratories, Columbus, OH)
Azathioprine sodium (injectable)
(Bedford Laboratories, Bedford, OH)
OKT3
(Ortho Pharmaceutical, Raritan, NJ)
Muromonab-cd3
Antithymocyte globulin
Atgam
(Upjohn Co, Kalamazoo, MI)
Prednisone
(various manufacturers)
Deltasone
(Upjohn Co, Kalamazoo, MI)
FK-506, tacrolimus
Prograf
(Fujisawa USA, Inc, Deerfield, IL)
Mycophenolate mofetil
CellCept
(Roche Laboratories, Nutley, NJ)
Daclizumab
(Roche Laboratories, Nutley, NJ)
Simulect
(Novartis Pharmaceuticals Inc.,
East Hanover, NJ)
$1.16/50-mg tablet
$81.60/100-mg vial, IV
Induction: 2 mg/d (low-dose)

5 mg/d (standard)
Rejection treatment: 5 mg/d
Hold (delay) dose for weight gain >3% or
temperature >39C
Increase dose based on CD3+ cell count
and CD3 density (suggested)
Discontinue if anti-OKT3 antibody titer
>1:1000
Starting dose: 1530 mg/kg/d
Decrease (or hold) dose for leukocytes
<3000 or platelets <100,000
Starting dose: 500 to 1000-mg infusion
for 35 d
Maintenance: taper schedule (variable)
Starting dose: 0.150.3 mg/kg/d in

2 divided doses
Avoid IV (0.050.1 mg/kg/d as a
continuous infusion over 24 h)
Starting dose: 23 g/d orally in 2 divided
doses (IV preparation in clinical trials)
Maintenance: based on GI and bone
marrow toxicities
1 mg/kg/d every 2 wk for a total of 5 doses
20 mg/d, given on days 0 and
4 post transplant
Cytokine release syndrome: fever, chills, chest

pain, dyspnea, wheezing, noncardiogenic
pulmonary edema, nausea, vomiting, diarrhea,
headache, aseptic meningitis, seizures, skin rash
$672.00/5-mg vial
Leukopenia, thrombocytopenia, fever, chills, skin

rash, back pain, headache, nausea, vomiting,
diarrhea, horse serum sickness
Fat redistribution, increased appetite, weight gain,
hyperlipidemia, hypertension, peripheral edema,
hyperglycemia, skin atrophy, poor healing, acne,
night sweats, insomnia, mood changes, blurred
vision, cataracts glaucoma, osteoporosis
Nephrotoxicity, hypertension, hepatotoxicity,
pancreatitis, diabetes, seizures, headache,
insomnia, tremor, paresthesia
$262.24/250-mg vial
$0.02$0.05/5-mg tablet
Methylprednisolone, IV
$17.88$35.50/500-mg vial
$2.39/1-mg caplet
$11.97/5-mg caplet
$222.00/5-mg ampule, IV
Nausea, vomiting, diarrhea, leukopenia,

anemia, thrombocytopenia
$2.04/250-mg caplet
$4.08/500-mg tablet
$102.00/500-mg, IV
Reported same as placebo
$418.20/25 mg, IV
Reported same as placebo
$1224.00/20mg, IV
Cost to the pharmacist based on the average wholesale price listing in Red Book, 1997 [8].
CD3monomorphic membrane co-receptor present in T-lymphocytes; Csacyclosporine; GIgastrointestinal.
Adapted from de Mattos and coworkers [3,4].
FIGURE 11-7
A summary of the immunosuppressive agents currently used in human renal
transplantation is given. Dosages and costs are subject to local variation.
11.6
CLINICALLY RELEVANT DRUG INTERACTIONS WITH IMMUNOSUPPRESSIVE DRUGS

Drug
Cyclosporin A and tacrolimus
Diltiazem
Nicardipine
Verapamil
Erythromycin
Clarithromycin
Ketoconazole
Fluconazole
Itraconazole
Methylprednisolone (high dose only)
Carbamazepine
Phenobarbital
Phenytoin
Rifampin
Aminoglycosides
Amphotericin B
Cimetidine
Lovastatin
Azathioprine
Allopurinol
Warfarin
ACE inhibitors
Mycophenolate mofetil
Acyclovir-ganciclovir (high doses only)
Antiacids
Cholestyramine
Effect
Mechanism
Increased blood levels
Decreased metabolism (inhibition of cytochrome P-450-IIIA 4)

Decreased blood levels
Unknown
Increased metabolism (inhibition of cytochrome P-450-IIIA 4)
Increased renal dysfunction
Additive nephrotoxicity
Increased serum creatinine

Decreased metabolism
Competition for tubular secretion

Myositis, increased creatine phosphokinase, rhabdomyolysis
Increased bone marrow toxicity

Decreased anticoagulation effect
Increased bone marrow toxicity
Inhibiting xantine oxidase

Increased prothrombin synthesis or activity
Not established
Increased levels of acyclovir-ganciclovir

and mycophenolate mofetil
Decreased absorption
Decreased absorption
Competition for tubular secretion

Binding to mycophenolate mofetil
Interferes with enterohepatic circulation
ACEangiotensin-converting enzyme.
Adapted from de Mattos and coworkers [3,4].
FIGURE 11-8
Clinical relevant drug interactions with immunosuppressive agents.
Close monitoring of drug levels is required periodically with concomitant use of drugs with potential interaction. Drug level monitoring is
clinically available for cyclosporin A and tacrolimus. Monitoring of

non-immunosuppressive drug level is also important when used with
potential interacting immunosuppressive agents.
NEW IMMUNOSUPPRESSIVE AGENTS UNDERGOING CLINICAL TRIALS

Agent
Mechanism of action
Rapamycin
Leflunomide
Inhibition of cytokine action (downstream of interleukin-2 receptor and other growth factors)
Inhibition of cytokine action (expression of or signaling by way of interleukin-2 receptor)
Inhibition of DNA and RNA synthesis (pyrimidine pathway)
Inhibition of DNA and RNA synthesis (pyrimidine pathway)
Unknown (related to heat-shock proteins?)
Unknown (stimulation of suppressor cells?)
Inhibition of DNA and RNA synthesis (de novo purine pathway)
Blockage of T-cell co-stimulatory pathway
Brequinar
Deoxyspergualin
SKF-105685
Mizoribine
CTLA-4Ig
11.7
FIGURE 11-9
Proposed mechanisms of action of new
immunosuppressive drugs currently undergoing clinical or preclinical trials in organ
transplantation [9].
Acknowledgments
The author would like to thank Ali Olyaei, Pharm D., for his assistance with the
preparation of this manuscript.
References
1.
Clipstone NA, Crabtree GR: Calcineurin is the key signaling enzyme

in T lymphocyte activation and the target of the immunosuppressive
drug.Ann NY Acad Sci USA 1993, 696:2030.
6.
2.
Brunn GJ, Hudson CC, Sekulic A, et al.: Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin.Science
1997, 277:99101.
7.
3.
de Mattos AM, Olyaei AJ, Bennet WM: Pharmacology of immunosuppressive medications used in renal diseases and transplantation.Am
J Kid Dis 1996, 28:631637.
8.
4.
de Mattos AM, Olyaei AJ, Bennet WM: Mechanism and risks of

immunosuppressive therapy. In Immunologic Renal Disease. Edited
by Neilson EG, Couser WG. Philadelphia: Lippincott-Raven;
1996:861885.
5.
9.
Barry JM: Immunosuppressive drugs in renal transplantation: a review

of the regimens. Drug 1992, 44:554566.
Powelson JA, Cosimi AB: Antilymphocyte globulin and monoclonal
antibodies. In Kidney Transplantation: Principles and Practice, edn 4.
Edited by Morris PJ. Philadelphia: WB Saunders Co; 1994.
English J, Evan A, Houghton DC, Bennett WM: Cyclosporineinduced acute renal dysfunction in the rat.Transplantation 1987,
44:135141.
Red Book: Drug Topics. Montvale, NJ: Medical Economics
Company, Inc., 1998.
First MR: An update on new immunosuppressive drugs undergoing
preclinical and clinical trials: potential applications in organ transplantation.Am J Kid Dis1997, 29:303317.
Evaluation of Prospective
Donors and Recipients
Bertram L. Kasiske
ll patients should be considered for transplantation when it is

determined that renal replacement therapy will someday be
required. In some cases, the evaluation can be completed and the
patient can receive transplantation before initiating chronic maintenance
dialysis. Prospective candidates for transplantation must be carefully
screened for potentially fatal cancers and infections that are made worse
by immunosuppression. Hepatic, pulmonary, cardiovascular, and gastrointestinal disorders all may increase the risks of surgery and chronic
immunosuppression. Patients must be carefully screened for these disorders. In many cases, intervention before transplantation may help reduce
the recipients risks of transplantation. Detailed guidelines have been
established to evaluate prospective candidates for transplantation [1].
Living donors offer the recipient optimal graft survival, reduced waiting time, and an opportunity for preemptive transplantation (ie, before
initiating dialysis). The evaluation of prospective living donors must
ensure that the donation is safe for both donor and recipient. However,
the primary focus of this evaluation must always be on protecting the
well-being of the prospective donor. Both the short-term surgical risks
and the long-term risks of having a single kidney must be carefully
defined. The evaluation also must ensure the donor has no disease that
could be transmitted with the kidney. Guidelines have been developed
for the evaluation of living prospective donors [2].
When no suitable living donors are available, the prospective recipient
can be placed on the waiting list for a cadaveric kidney. Unfortunately,
because the number of patients needing cadaveric kidneys has grown
much faster than has the number of available kidneys, the median
waiting time is now over 2 years. This shortage has led many transplantation centers to use cadaveric kidneys, which are associated with
reduced graft survival. In particular, graft survival is affected by the
age of the kidney donor. Many centers are expanding the age limits of
acceptability to reduce waiting times. A detailed discussion of the
selection, retrieval, preservation, and allocation of cadaveric kidneys
is beyond the scope of this review.
CHAPTER
12
12.2
Evaluation of Prospective Transplantation Recipients

Initial evaluation of recipients
Irreversible
renal failure
Currently on
dialysis?
Monitor rate
GFR decline
No
Yes
Dialysis likely in
6 months?
No
Yes
Prospective
living donor?
FIGURE 12-1
Initiating the evaluation. Before transplantation it must be clearly
established that renal failure in the patient is irreversible. When the
prospective recipient is not already on chronic maintenance dialysis,
however, preemptive transplantation (ie, transplantation before
initiating dialysis) should be considered. Because the waiting time
for a cadaveric kidney is generally long, preemptive transplantation
usually is possible only when a prospective living donor is available.
In any case, the rate of decline in the glomerular filtration rate (GFR)
must be monitored closely in patients with progressive renal disease.
The evaluation process should begin when it is anticipated that
transplantation may be required within 6 months. (From Kasiske
and coworkers. [1]; with permission.)
Yes
No
Evaluate prospective
living donor
Evaluate potential
recipient
Cancer screening in recipients

Screen for cancer
Current or past
evidence of cancer?
Yes
No
Appropriate
disease-free
interval?
Proceed with
evaluation
FIGURE 12-2
Screening for cancer. An active malignancy is an absolute contraindication to transplantation.
Effective screening measures for patients at risk include chest radiograph, mammogram,
PAP test, stool Hemoccult, digital rectal examination, and flexible sigmoidoscopy examination. Patients who have had a life-threatening malignancy but are potentially cured may
be candidates for transplantation when there has been an appropriate disease-free interval.
This interval generally is at least 2 years, and longer in the case of some malignancies.
(From Kasiske and coworkers [1].)
12.3
Evaluation of Prospective Donors and Recipients
Screening for infection in recipients

Yes
Active infection?
100
90
Appropriate treatment
and disease-free interval
80
No
HIV positive?
Discourage transplantation
No
History of TB or
positive PPD
without adequate
therapy?
Yes
Consider prophylactic
treatment
Graft survival, %
70
Yes
60
50
40
CMV r/d
n/n
n/p
p/n
p/p
30
No
20
Assess risk for
other infections
n
4670
5970
7299
11,257
10
0
FIGURE 12-3
Screening for infection. An active potentially life-threatening infection
is a contraindication to transplantation. Patients with human immunodeficiency virus (HIV) are usually not candidates for transplantation.
Patients with a history of tuberculosis (TB) or a positive purified
protein derivative (PPD) skin test who have not been adequately
treated should generally receive prophylactic therapy. (From
Kasiske and coworkers [1].)
Assessment for recurrent renal

disease in recipients
Renal disease
with potential
to recur?
No
Yes
Wait until
quiescent
Yes
Risk acceptable?
No
Proceed with
evaluation
Avoid
transplantation
FIGURE 12-4
Assessing the risks of cytomegalovirus (CMV) infection after transplantation. CMV is a major cause of morbidity and mortality after
transplantation. The incidence and severity of CMV are associated
with the serologic status of the donor (d) and recipient (r), the risks
generally being the following: recipient negativedonor negative
less than recipient positivedonor negative less than recipient negative
donor positive less than recipient positivedonor positive. As shown
in these data from the United Network for Organ Sharing Scientific
Registry, the rate of graft survival tends to be less in recipients of
kidneys from donors who test positive for CMV infection. The
serologic status of both the donor and recipient is often used to
determine which patients are candidates for prophylactic or preemptive anti-CMV therapy after transplantation. (From Cecka [3];
with permission.)
FIGURE 12-5
Assessing the risk of renal disease recurrence. Although the risk for recurrence of the
underlying renal disease is rarely great enough to preclude transplantation, patients and
physicians must be aware of this risk. In some cases it may be prudent to delay transplantation until the underlying disease is quiescent. (From Kasiske and coworkers [1].)
12.4
100
90
Cannot
recur
411
Can recur in transplant organ

685
3072
31
80
1058
3-year graft survival, %
70
39
134
41
5421
HSP
Diabetes
type II
101
60
50
40
30
20
10
0
Alport's
syndrome
PKD
FSGS
MPGN
HUS
IgA
Scleroderma Oxalosis
Evaluation for liver disease in recipients

Symptoms or
enzymes
suggesting liver
disease?
Evaluation for viral hepatitis in recipients

Consider
cholecystectomy
for gallstones
Yes
No
Yes
Discontinue
Toxic drug or
alcohol
No
Consider biopsy
and treatment
Measure HBsAg
and HCV antibody
Yes
FIGURE 12-6
The influence of underlying renal disease on
graft survival. As shown in these data from
the United Network for Organ Sharing
Scientific Registry, 3-year graft survival rates
in groups of patients with different underlying causes of renal failure vary substantially.
The 3-year graft survival rates for recipients
with renal diseases that do not recur (eg,
Alports syndrome and polycystic kidney disease [PKD] were about 80%. Graft survival
rates for patients with diseases that may recur
in the transplanted kidney varied from 60%
to 83%. Of course, most of these differences
in graft survival may be due to factors associated with the underlying cause of renal failure
(eg, cardiovascular disease) and not disease
recurrence itself. Focal segmental glomerulosclerosis (FSGS), hemolytic uremic syndrome (HUS), Henoch-Schnlein purpura
(HSP), and hereditary oxalosis can cause graft
failure relatively soon after transplantation.
(MPGN), scleroderma, IgA nephropathy, and
diabetes generally cause graft failure only
after several years. Numbers above bars indicate number of patients who had that disease.
(From Cecka [3]; with permission.)
Elevated TIBC
or ferritin
No
Positive HBeAg
or HCV?
Antibody or
HBeAg?
Yes
Yes
No
No
Yes
Elevated
enzymes?
No
Elect Yes
biopsy?
Severe disease
on biopsy?
Yes
Consider
avoiding
transplantation
Yes
Acceptable
risk?
No
No
No
FIGURE 12-7
Evaluation of patients with signs and symptoms of liver disease.
Patients with cholecystitis should be considered for cholecystectomy.
For other patients with signs and symptoms of liver disease, potential hepatic toxins should be considered. The incidence of liver disease from iron deposition has declined with the diminishing use of
blood transfusions in dialysis patients, but may be seen occasionally
in patients with a high total iron binding capacity (TIBC) or ferritin.
All prospective candidates for transplantation must be screened for
hepatitis B and C by testing for the presence of hepatitis B surface
antigen (HBsAg) and hepatitis C virus (HCV) antibodies. Both
viruses can cause potentially fatal liver disease after transplantation.
Fortunately, the incidence of hepatitis B is declining among patients
with renal disease, largely as a result of the use of effective vaccination programs. (From Kasiske and coworkers [1]; with permission.)
Proceed with
evaluation
No
Moderate
disease on
biopsy?
FIGURE 12-8
Viral hepatitis. Patients whose test results are positive for antibodies or hepatitis e-antigen (HBeAg) are at high risk for succumbing to liver disease and most likely are not candidates for transplantation. A liver biopsy should be considered for all patients with
hepatitis C virus (HCV) antibodies or hepatitis B surface antigen.
Patients with severe chronic active hepatitis or cirrhosis on biopsy
generally are not candidates for renal transplantation unless simultaneous liver transplantation is being considered. Whether antiviral
therapy before transplantation can increase the number of patients
who are candidates for transplantation is unclear. (From Kasiske
12.5

1.0
78
59
52
47
45
34
20
1.0
69
67
62
57
45
29
22
17
15
12
11
0.8
Patient survival, %
Graft survival, %
0.8
79
0.6
0.4
21
16
13
10
Relative risk: 1.27 (0.62, 2.60)
0.2
0.6
0.4
Relative risk: 3.33 (1.40, 7.93)
AntiHCV positive
AntiHCV negative
0.2
AntiHCV positive
AntiHCV negative
0
0
FIGURE 12-9
Effects of pretransplantation hepatitis C virus (HCV) serology
results on survival of the graft (A) and patient (B). Numbers
above (antiHCV negative) and below (antiHCV positive)
survival curves indicate the number of patients at risk during
that time interval. The relative risk after transplantation associated with the patient testing positive for HCV antibodies before
Past
history of
IHD?
Yes
Active
angina?
Smoking
cessation
program
No
High
risk for
IHD?
Yes
Stress test
positive?
No
No
Severe lung
disease on
function tests?
Yes
Risk factor
intervention
Wait until adequate

resolution with therapy
FIGURE 12-10
Lung disease. Few studies exist that address the effects of cigarette
smoking on outcome after renal transplantation. Because the risks of
transplantation surgery no doubt are increased by cigarette smoking,
candidates for transplantation should be referred to smoking cessation programs. (From Kasiske and coworkers [1]; with permission.)
Yes
No
Yes
Imaged coronary
lesions severe?
Yes
Revascularization
successful?
No
No
Proceed with
evaluation
Yes
No
No
No
Yes
Evaluation of IHD in recipients
Yes
Currently
smoking?
transplantation also is shown, along with 95% confidence intervals. Although no statistically significant effect of HCV on graft
survival was seen, patient survival was significantly diminished
among those who tested positive for HCV after transplantation.
Not all investigators have confirmed these findings. (From Periera
Evaluation of effects of smoking in recipients

Dyspnea on
exertion or
smoking history?
4
Evaluate
for CHF
Reconsider
transplantation
candidacy
FIGURE 12-11
Ischemic heart disease (IHD). The incidence of IHD is several fold
higher in renal transplantation recipients compared with the general
population. Patients with IHD before transplantation are at high risk
to develop IHD events after transplantation. Therefore, angiography
should be considered in candidates for transplantation who have
angina pectoris. Candidates with currently asymptomatic IHD and
those at high risk for IHD should undergo a stress test. Patients with
severe coronary artery disease on angiography must be considered
for a revascularization procedure before transplantation. Aggressive
management of risk factors is appropriate for all patients, with or
without IHD. (From Kasiske and coworkers [1]; with permission.)
12.6

100
(13)
Free of cardiac events, %
90
(9)
Revascularized
80
(7)
(10)
70
60
50
40
(4)
30
Medically treated
20
(2)
10
0
0
12
15
18
21
24
Follow-up, mo
Evaluation of CHF in recipients

Signs and
symptoms of
CHF?
Yes
Exclude secondary
causes
Yes
Adequate response
to medical
management?
No
Proceed with
evaluation
No
Reconsider
transplant
candidacy
Evaluation of CVD in recipients

History of
stroke or TIA?
Yes
Recent
symptoms?
No
Yes
Consider carotid
ultrasonography
No
Carotid bruit?
Yes
Refer to
neurologist
No
High-risk
ADPKD patient?
No
Yes
Large
intracranial
aneurysm on
imaging?
No
Risk factor
intervention
Yes
Consider prophylactic
surgery
Proceed with evaluation
FIGURE 12-12
Effects of surgical versus medical management of coronary disease
before renal transplantation in candidates who have insulin-dependent diabetes. In this study, 26 patients with insulin-dependent diabetes who were found to have over 75% stenoses in one or more
coronary arteries were randomly allocated to either medical management or a revascularization procedure before transplantation.
Ten of the 13 patients who were managed medically and 2 of the
13 who had revascularization performed had a cardiovascular disease end point within a median of 8.4 months after transplantation
(P < 0.01). These findings suggest that transplantation candidates
who have diabetes should be screened for silent coronary artery
disease because revascularization decreases morbidity and mortality
after transplantation. The numbers in parentheses indicate the number of patients being followed at that time. (From Manske and
FIGURE 12-13
Congestive heart failure (CHF). Myocardial performance has
been shown to improve in some patients after renal transplantation. Thus, a low ejection fraction alone does not automatically
exclude patients from transplantation. In contrast, patients with
severe irreversible myocardial disease may not be good candidates
for transplantation. Occasionally, patients may be candidates for
simultaneous heart and kidney transplantation. (From Kasiske
FIGURE 12-14
Cerebral vascular disease (CVD). Patients must not undergo
surgery within 6 months of a stroke or transient ischemic attack
(TIA). Asymptomatic patients with a carotid bruit should be considered for carotid ultrasonography because patients with severe
carotid disease may be candidates for prophylactic surgery. Patients
with autosomal dominant polycystic kidney disease (ADPKD) and
either a previous episode or a positive family history of a ruptured
intracranial aneurysm must be screened with computed tomography or magnetic resonance imaging. Patients found to have an
aneurysm over 7 mm in diameter may benefit from prophylactic
surgery. (From Kasiske and coworkers [1]; with permission.)
Evaluation of PVP in recipients

PVD unresponsive
to conservative
management?
Yes
Consider
invasive
intervention
No
Aortoiliac vascular
disease?
Yes
12.7
FIGURE 12-15
Peripheral vascular disease (PVD). Peripheral vascular disease is commonly associated
with coronary artery disease, cerebral vascular disease, or both. However, PVD itself may
require intervention before transplantation to prevent infection and sepsis after transplantation. In addition, some patients may have aortoiliac disease severe enough to require
intervention before transplantation. Rarely, vascular disease is severe enough to make it
difficult to find an artery suitable for the anastomosis of the allograft renal artery. (From
Kasiske and coworkers [1]; with permission.)
Consider repair
before or at
transplantation
No
Proceed
with
evaluation
Psychosocial evaluation of recipients

Psychosocial
evaluation
Free of limiting
cognitive
impairment?
No
Yes
Recent alcohol or
drug abuse?
No
Yes
Yes
Free of limiting No
psychiatric illness?
Supervised
abstinence?
No
Yes
History of limiting
medication
noncompliance?
Yes
Refer until
resolved
No
Proceed with
evaluation
FIGURE 12-16
Psychosocial evaluation. Patients must be free of cognitive impairments and able to give
informed consent. Most transplantation centers require patients with a history of alcohol
or drug abuse to demonstrate a period of supervised abstinence, generally 6 months or
more [6]. Similarly, patients with a past history of medication adherence poor enough
to suspect that the immunosuppressive regimen will be compromised may need to delay
transplantation until reasonable adherence can be demonstrated [6]. (From Kasiske and
12.8

FIGURE 12-17
Assessing the medical risks of transplantation surgery. Obesity
increases the risks of surgery, and a weight reduction program
before transplantation must be considered for very obese patients.
Older age is a relative contraindication to transplantation; however,
it is difficult to precisely define an upper age limit for all patients.
Rather, age and overall medical condition must be considered
together. Hypertension should be controlled before transplantation.
When control of hypertension is difficult, bilateral nephrectomy
should be considered before transplantation. BMIbody mass
index. (From Kasiske and coworkers [1]; with permission.)
Assessment of the medical risks to recipients

Yes
BMI >35 kg/m2

No
Consider weight
reduction
program
Yes
Age >65?
No
Yes
No
Additional risk
acceptable?
Hypertension
unresponsive to
medical
management?
No further
evaluation
Native kidney
nephrectomy
Yes
No
Proceed with
evaluation
90
80
70
60
50
40
30
20
10
0
100
90
80
70
*
0
Obese patients
Nonobese patients
Obese patient grafts
Nonobese patient grafts
12
15
18
21
24
Time, mo
Graft survival, %
Survival, %
100
60
50
40
Age
05
618
1945
4660
>60
30
20
FIGURE 12-18
Effects of obesity on patient and graft survival. In this case-control
study, 46 obese (body mass index > 30 kg/m2) recipients of cadaveric renal transplantation were compared with nonobese controls
matched for the following after transplantation: age, gender, diabetes, panel reactive antibody status, graft number, cardiovascular
disease, date of transplantation, and immunosuppression. Survival
of patients and grafts was significantly less among obese patients
compared with controls (P < 0.01 and P < 0.05, respectively). The
following occurred more often in obese versus nonobese patients:
delayed graft function, postoperative complications, wound complications, and new-onset diabetes. (From Holley and coworkers
10
n
198
1144
14994
10933
3908
t1/2
15.1
8.7
9.4
9.9
8.0
0
0
FIGURE 12-19
Effects of the recipients age on renal allograft survival. Data from the
United Network for Organ Sharing Scientific Registry indicate that
recipients over the age of 60 have slightly less allograft survival compared with younger recipients. t1/2graft survival half-life (in years)
the first year after transplantation. (From Cecka [3]; with permission.)
12.9

Evaluation of diabetes and hyperparathyroidism in recipients
84.7
Consider simultaneous
kidney-pancreas
transplantation
Yes
Pancreas graft survival, %
Difficult to
control
diabetes?
100
No
Symptomatic
hyperparathyroidism
or uncontrolled
hypercalcemia?
Yes
Consider
parathyroidectomy
80
73.5
77.4
73.2
69.0
71.4
52.5
46.0
39.4
40
27.7
27.7
20
22.6
Previous kidney
transplantation (n=273)
0.25
Proceed with
evaluation
Yes
History of
recurrent
UTIs?
No
No
Yes
Yes
Proceed with
evaluation
No
Indications for
native kidney
nephrectomy?
No
No
Consider ureteral
diversion or
intermittent
self-catheterization
Yes
Yes
Consider native
kidney
nephrectomy
3.0
4.0
5.0
FIGURE 12-22
Urologic evaluation of transplantation
recipients. Patients without signs and symptoms of bladder dysfunction generally do not
need additional urologic testing. However,
patients with bladder dysfunction must be
evaluated to ensure that the bladder is functional after transplantation and that potential sources of urinary tract infection (UTI)
are eliminated. Such patients can be screened
initially with voiding cystourethrography
(VCUG). (From Kasiske and coworkers [1];
with permission.)
No
Ultrasonography,
cystoscopy, and/or
retrograde
pyelogram normal?
2.0
FIGURE 12-21
Pancreas graft survival in recipients of pancreatic transplantation
with simultaneous, no previous, and previous kidney transplantation.
Survival rates of pancreatic grafts are best when pancreatic and
kidney transplantations are performed at the same time. (Data from
the United Network for Organ Sharing Scientific Registry [8].)
Urologic evaluation in recipients

Signs or
symptoms of
bladder
dysfunction?
1.0
FIGURE 12-20
Diabetes and hyperparathyroidism. Patients with difficult to control
diabetes may be candidates for simultaneous kidney-pancreas transplantation. However, patients with diabetes who have a living donor
are generally better off undergoing transplantation with the living
donor kidney alone. Patients with symptomatic hyperparathyroidism
or uncontrolled hypercalcemia should be considered for parathyroidectomy before transplantation. Medications that interfere with
the metabolism of immunosuppressive agents such as cyclosporine
should be substituted with appropriate alternatives, if possible, before
transplantation. (From Kasiske and coworkers [1]; with permission.)
VCUG
normal?
No previous kidney
transplantation
39.2
Discontinue or
reduce risk
Yes
No
Yes
61.8
54.4
60
No
Need for
medication that
may jeopardize
recipient or graft?
Simultaneous kidney
transplantation (n=3336)
Bladder
insufficiency?
12.10

PUD and pancreatitis
Evaluation of active colonic disease in recipients

Signs or symptoms
of active PUD?
Yes
History of
diverticulitis?
Yes
No
Severe diverticular
disease on barium
enema?
No
Yes
Consider partial
colectomy
Endoscopic or
radiographic
confirmation?
No
No
Yes
Other active colonic

disease?
Yes
Adequate response
to medical
management?
Defer transplantation
until quiescent
FIGURE 12-23
Diverticulitis and inflammatory bowel disease. Patients with a history
of symptomatic diverticulitis must be evaluated for partial colectomy
before transplantation. Inflammatory bowel disease generally
should be quiescent at the time of transplantation. (From Kasiske
No
Consider
cadaveric
donor
Yes
Blood and tissue
typing
ABO compatible?
No
Yes
T-cell CDC
X-match negative?
No
Assess
likelihood of
false-positive
results
Yes
Yes
HLA identical?
Presence of
autoantibodies?
No
Yes
No
Proceed with
evaluation
Transplantation
History of
pancreatitis?
Yes
Delay transplantation
until evaluation and
treatment
No
Proceed with
evaluation
FIGURE 12-24
Peptic ulcer disease (PUD) and pancreatitis. Patients with PUD
or pancreatitis must undergo evaluation and treatment before
transplantation. Both conditions may be exacerbated by corticosteroids used after transplantation. (From Kasiske and coworkers
FIGURE 12-25
Immunologic evaluation for living donor transplantation. Generally,
transplantation donors and recipients must have compatible blood
groups. Tissue typing is also carried out, and the degree of human
leukocyte antigen (HLA) matching may be taken into account in
selecting the best living donor when more than one donor is available.
Just before transplantation, the recipients serum is tested against
donor cells to be certain no preformed antibodies are present in the
recipient that may cause a hyperacute rejection. A positive crossmatch (X-match) generally precludes transplantation from that
donor. CDCcell-dependent cytotoxicity. (From Kasiske and
Evaluation of transplantation from a living donor

Potential living
donor?
Consider
pretransplantation
surgical treatment
Yes
No
Proceed with
evaluation
No
Consider other
donor
12.11

Donor-specific transfusions in recipients
100
1y
P= 0.02
2444
40
3303
Transplantation
No
P= 0.04
50
15,087
X-match negative?
Yes
60
20,461
Yes
3164
Negative X-match, flow

cytometry, or antiglobulin?
Consider DST
76.4%
70
4172
No
19,187
Yes
84%
80
26,585
No
5 y>1 y
90
Adjusted graft survival, %
First transplantation?
Consider other
donor
1-5
6-10
>10
1-5
6-10
>10
FIGURE 12-26
Donor-specific transfusion (DST). When the living donor is non
human leukocyte antigen identical and it is the recipients first transplantation, some centers use donor-specific blood transfusions before
transplantation to enhance graft survival. Unfortunately, donor-specific transfusions may induce the formation of antibodies against the
donor that will preclude the transplantation. Most centers have
abandoned the use of random blood transfusions as part of the
preparation of recipients for cadaveric transplantation. X-match
cross-match. (From Kasiske and coworkers [1]; with permission.)
Immunologic evaluation for cadaveric transplantation

No living
donor
No
First
transplantation?
Review typing from

previous grafts
Yes
PRA 11%
No
Autologous
X-match positive?
Yes
No
Yes
PRA after DTT or

analogous cell
adsorption
Identify HLA
specificities
Waiting list
Periodic
antibody
screening
Yes
Increasing
PRA?
No
No
Final CDC
X-match
negative?
Yes
Transplantation
Number of pretransplantation transfusions
FIGURE 12-27
Effects of random blood transfusions on first cadaveric renal allograft survival. Blood transfusions before transplantation had a
small but statistically significant beneficial effect on 1-year graft
survival. However, a small reduction occurred in 5-year graft survival (among patients who survived at least 1 year with a functioning kidney) that was attributable to random donor blood transfusions before transplantation (From Gjertson [9]; with permission.)
FIGURE 12-28
Immunologic evaluation for cadaveric transplantation. Donors and
recipients must have compatible blood groups. Tissue typing is carried out, and the degree of matching is used in the allocation of
cadaveric organs. Some data suggest that the presence of human
leukocyte antigen (HLA) mismatches that were also mismatched in
a previous graft (especially at the DR locus) may lead to early graft
loss. Thus, it may be wise to avoid these mismatches. When the
percentage of panel reactive antibodies (PRA) is over 10%, tests
may be carried out to determine whether some of the antibodies
are autoreactive rather than alloreactive. Autoreactive antibodies
may not increase the risk for graft loss as do alloreactive antibodies.
The presence of high titers of alloreactive antibodies usually is due
to previous pregnancies, transplantations, and blood transfusions.
Determining antibody specificities may be useful in avoiding certain
HLA antigens. In the highly sensitized patient (PRA > 50%) it may
be difficult to find a complement-dependent cytotoxicity (CDC)
cross-matched (X-match) negative donor. Avoiding blood transfusions may help the titer decrease over time. DTT1, 4-dithiothreitol (DTT). (From Kasiske and coworkers [1]; with permission.)
12.12
100
100
90
80
90
70
80
60
HLA-identical sibling donor (n= 1984)

Spousal donor (n= 368)
Parental donor (n= 3368)
Living unrelated donor (n=129)
Cadaveric graft (n= 43,341)
Cadaveric graft, urine flow 1st day, no dialysis (n=32,281)
Cadaveric graft, no urine 1st day, dialysis required
in 1st week (n= 11,060)
50
40
30
20
10
0
0
70
Graft survival, %
Graft survival, %
Evaluation of Prospective Living Donors
1
2
P< 0.025
60
50
40
30
Graft:
HLA-identical
1-haplotype
Zero-haplotype
20
FIGURE 12-29
Effects of donor source on renal allograft survival. Data from the
United Network for Organ Sharing Scientific Registry were used to
compare 3-year graft survival rates between recipients of kidneys
from different donor sources. The best graft survival was seen in
recipients of human leukocyte antigen (HLA)identical sibling
donors. Grafts from spouses and other living unrelated donors,
however, survived just as well as did grafts from parental donors
and better than grafts from cadaveric donors. These data have
encouraged centers to use emotionally related donors to avoid
the long waiting times for cadaveric kidneys. (From Terasaki and
Candidate for renal

transplantation
Yes
Willing and available

ABO-compatible
living related donor?
No
Yes
No
Evaluate for cadaveric
transplantation
No
No
Willing and available

ABO-compatible
emotionally related donor?
Cross-match
negative?
t1/2
25.5
16.0
11.9
0
0
FIGURE 12-30
Effects of human leukocyte antigen (HLA) matching on living related
graft survival. Graft survival is best for HLA-identical grafts from siblings and next best for one-haplotype mismatched grafts. Importantly,
the half-life (t1/2) of grafts that survived at least 1 year is proportional
to the degree of matching. This information can be used along with
other factors to select the most suitable among two or more living
prospective donors. (From Cecka [3]; with permission.)
FIGURE 12-31
Use of living donors. A suitable living donor is better than a cadaveric
donor because graft survival is better and preemptive transplantation
is possible. The best donor usually is a family member. Psychosocial
and biological factors must be taken into account when choosing
among two or more living prospective donors. Every effort must
be made to ensure that the donation is truly voluntary. Caregivers
should tell prospective donors that if they do not wish to donate,
then friends and relatives will be told the donor was not medically
suitable. (From Kasiske and coworkers [2]; with permission.)
Choice of living donor versus cadaveric transplantation
Willing to
accept living
donor?
10
n
2288
3082
808
Yes
Yes
Proceed with
evaluation
12.13

Preliminary evaluation for a living donor
Yes
Economic risk
acceptable?
Risk assessment for living donor
Psychosocial
evaluation
No
No
Age and renal

function
acceptable?
Yes
No
Voluntarism
reasonably
certain?
No
Yes
Yes
Yes
Surgical risk
acceptable?
Financial
incentive?
Preliminary
medical
evaluation
No
No
Long-term risk
acceptable?
Yes
Yes
Yes
Consider
alternative
donor
Consider
alternative
donor
No
No
Risk
acceptable?
Risk of
recurrent
disease?
HIV, hepatitis,
or pregnancy
test positive?
No
Risk
acceptable?
Yes
CMV titer
positive or
history of
tuberculosis?
Yes
Yes
Proceed with
evaluation
FIGURE 12-32
Preliminary evaluation of a living prospective donor. The
prospective donor must be made aware of the possible costs
associated with donation, including travel to and from the
transplantation center and time away from work. The prospective
donor must undergo a psychological evaluation to ensure the
donation is voluntary. A preliminary medical evaluation should
assess the risks of transmitting infectious diseases with the kidney, eg, infection with human immunodeficiency virus (HIV)
and cytomegalovirus (CMV). (From Kasiske and coworkers [2];
with permission.)
27
Transplantation centers, %
22
20
15
13
13
10
6
3
No age
exclusion
55
60
65
70
No
Screening for
diabetes
negative?
Yes
Proceed with
evaluation
FIGURE 12-33
Assessing risks. Older age may place the living prospective donor at
greater surgical risk and may be associated with reduced graft survival for the recipient. The prospective donor must be informed of
both the short-term surgical risks (very low in the absence of cardiovascular disease and other risk factors) and the long-term consequences of having only one kidney. With regard to long-term risks,
it should be considered whether there is a familial disease that the
living donor may be at risk to acquire and whether having only one
kidney would alter the natural history of renal disease progression.
These questions are often most pertinent for relatives of patients
with diabetes. (From Kasiske and coworkers [2]; with permission.)
FIGURE 12-34
Donor age restrictions used by transplantation centers. Results of
an American Society of Transplantation survey of the United
Network for Organ Sharing centers showed that many centers
either use no specific age exclusion criteria or have no policy.
Among those that use an upper age limit, there appears to be a
bell-shaped curve, with 65 years of age at the median. (From Bia
30
Risk of
diabetes?
No
Yes
No
No
7580
Exclude if age in years is greater than:
No policy
or do not
know
12.14

100
90
90
Progressive effect
(each 10 y)
(0.3) (1.4) (2.5)
Static effect
(20.2) (17.1) (14.0)
88
80
-20
-15
70
61
60
(52)
50
Progressive effect (each 10 y)

(76)
(101)
46
40
25
30
50
Proteinuria, mg/d
75
Static effect
(2.4)
(0.3)
20
100
(5.1)
Progressive effect (each 10 y)

(0)
(1.1)
(2.2)
10
0
Mildly
elevated
FBS
Normal FBS
but abnormal
GTT
Mild type
II diabetes
< 50y
Mild type
II diabetes
< 30y
FIGURE 12-35
Screening living prospective donors for diabetes. Results of the survey of the United Network for Organ Sharing centers showed that
most centers exclude patients with a mildly elevated fasting blood
sugar (FBS) and patients with normal FBS but an abnormal glucose
tolerance test (GTT). Most centers exclude donors with mild type
II diabetes. (From Bia and coworkers [11]; with permission.)
64
54
50
40
30
20
20
12
10
0
Persistently
130/90 mm Hg
2.0
3.0
4.0
5.0
FIGURE 12-37
Blood pressure (BP) criteria for excluding
living prospective donors. Results of the
survey of the United Network for Organ
Sharing centers showed that most exclude
prospective donors who require antihypertensive medication or whose BP is persistently elevated over 130/80 mm Hg. However,
most centers do not exclude living prospective donors who occasionally have BP readings over 130/80 mm Hg or patients with
so-called white coat hypertension. (From
Bia and coworkers [11]; with permission.)
60
Controlled
on one BP
medication
1.0
FIGURE 12-36
Long-term risks of kidney donation. In a meta-analysis combining
48 studies of the long-term effects of reduced renal mass in humans,
no evidence was found of a progressive decline in renal function
after a 50% reduction in renal mass. Indeed, a small but statistically
significant increase occurred over time in the glomerular filtration
rate. A small increase in urine protein excretion occurred; however,
the rate of increase per decade was less than that generally considered
an abnormal amount of protein excretion, eg, 150 mg/d. A small
increase in systolic blood pressure was noted; however, it was not
enough to lead to an increase in the incidence of hypertension. Thus,
it appears that the long-term risks of kidney donation are very small.
Shown are multiple linear regression coefficients and 95% confidence
intervals. Failure of the confidence interval to include zero indicates
P < 0.05. (From Kasiske and coworkers [12]; with permission.)
70
-10
-5
Glomerular filtration rate, mL/min
Occasionally
130/90 mm Hg
130/90 mm Hg
in doctor's
office only
No policy
or do not
know
12.15

Evaluation of prospective donors with
proteinuria, hypertension, or kidney stones
Evaluation of donor risks in recipients

with familial renal diseases
No
Proteinuria
or pyuria?
Relative with
ADPKD?
Yes
Yes
Evaluation
indicates low risk?
Yes
Yes
No
Normal renal
imaging and low
risk for ADPKD?
Hypertension?
Blood pressure
high normal?
Yes
No
Yes
Female with
acceptable low
risk?
Yes
Proceed with
evaluation
Evaluate
Yes
Risk acceptable?
FIGURE 12-38
Proteinuria, hypertension, or kidney stones in living prospective
donors. Prospective donors with pyuria must be evaluated for possible
infection and other reversible abnormalities. Proteinuria is generally
a contraindication to donation. Hypertension also must be considered
at least a relative contraindication to donation. Patients with a history
of nephrolithiasis but no current or recent stones may be considered
for donation after first undergoing urologic and metabolic evaluations
for stones. (From Kasiske and coworkers [2]; with permission.)
Final evaluation of prospective living donors

No
Yes
Angiography
results
acceptable?
Yes
No
Yes
Schedule
transplantation
surgery
Consider
alternative
donor
No
Yes
Proceed with
evaluation
Yes
No
Yes
Cross-match
negative?
Male with no
hematuria?
No
No
History of
kidney stones
No
Male with No
hematuria?
No
Donor-specific
transfusion?
No
Yes
Risk acceptable?
No
Relative with
hereditary
nephritis?
Yes
No
No
Consider alternative
donor
Consider
alternative
donor
No
Evaluation indicates
low risk?
No
Yes
Isolated
hematuria
FIGURE 12-39
Risks to the related donor when the recipient has familial renal disease. Donors for relatives with autosomal dominant polycystic kidney
disease (ADPKD) may be permitted to donate if over 25 years old and
results on renal imaging are negative for cysts. Some younger persons
may be permitted to donate if genetic studies indicate that the risk for
subsequent ADPKD is very low. Male relatives of individuals with
hereditary nephritis can be donors if they do not have hematuria.
Male relatives with hematuria cannot be donors. Female relatives
without hematuria may donate; however, women of child-bearing age
who might be carriers must consider the possibility of someday donating a kidney to a child of their own with the disease. Female relatives
with hematuria should not donate when other evidence of renal disease exists; however, in the absence of such evidence the exact risk of
donation is unknown. Occasionally, donors with isolated microhematuria (not hereditary) and a negative evaluation may be suitable
donors. (From Kasiske and coworkers [2]; with permission.)
FIGURE 12-40
Final steps in evaluating a living prospective donor. Renal artery
angiography is performed to define the anatomy of the renal artery
system and exclude other previously undetected abnormalities.
Recent studies have shown that spiral computerized tomography
can replace angiography without loss of sensitivity or specificity
and with less risk and inconvenience to the prospective donor.
(From Kasiske and coworkers [2]; with permission.)
12.16
Use of Marginal Cadaveric Donor Kidneys

FIGURE 12-41
Donor age. When there are no suitable living donors, recipients are
placed on the cadaveric waiting list. The transplantation center
must always decide whether a particular cadaveric kidney being
offered for transplantation is suitable for the individual recipient.
The shortage of organs and long waiting times have caused many
centers to accept kidneys from older donors and kidneys that may
be damaged. Data from the United Network for Organ Sharing
clearly demonstrate the decreased graft survival rates of kidneys
from older donors. As a compromise, some advocate using kidneys
from older donors for older recipients. In any case, so-called marginal
kidneys should be offered to recipients with appropriate informed
consent. (From Cecka [3]; with permission.)
100
90
80
Graft survival, %
70
60
50
40
Age
618
1930
3145
4660
>60
30
20
10
n
6652
7354
7532
6476
1928
t1/2
10.9
11.7
9.8
6.9
5.2
0
0
References
1.
2.
3.
4.
5.
6.
7.
Kasiske BL, Ramos EL, Gaston RS, et al.: The evaluation of renal
transplant candidates: clinical practice guidelines. J Am Soc Nephrol
1995, 6:134.
Kasiske BL, Ravenscraft M, Ramos EL, et al.: The evaluation of living
renal transplant donors: clinical practice guidelines. J Am Soc Nephrol
1996, 7:22882313.
Cecka JM: The UNOS Scientific Renal Transplant Registry. In Clinical
Transplants 1996. Edited by Cecka JM, Terasaki PI. Los Angeles:
UCLA Tissue Typing Laboratory, 1997:114.
Periera BJG, Wright TL, Schmid CH, Levey AS: The impact of pretransplantation hepatitis C infection on the outcome of renal transplantation. Transplantation 1995, 60:799805.
Manske CL, Wang Y, Rector T, et al.: Coronary revascularisation in
insulin-dependent diabetic patients with chronic renal failure. Lancet
1992, 340:9981002.
Ramos EL, Kasiske BL, Alexander SR, et al.: The evaluation of candidates for renal transplantation: the current practice of U.S. transplant
centers. Transplantation 1994, 57:490497.
Holley JL, Shapiro R, Lopatin WB, et al.: Obesity as a risk factor following cadaveric renal transplantation. Transplantation 1990, 49:387389.
8. 1996 Annual Report of the U.S. Scientific Registry for Transplant

Recipients and the Organ Procurement and Transplantation Network
Transplant Data: 19881995. UNOS, Richmond, VA, and the Division
of Transplantation, Bureau of Health Resources Development, Health
Resources and Services Administration, U.S. Department of Health
and Human Services; 1996.
9. Gjertson DW: A multi-factor analysis of kidney graft outcomes at one
and five years posttransplantation: 1996 UNOS Update. In Clinical
Transplants 1996. Edited by Cecka JM, Terasaki PI. Los Angeles:
UCLA Tissue Typing Laboratory. 1997: 343360.
10. Terasaki PI, Checka M, Gjertson DW, Takemoto S: High survival
rates of kidney transplants from spousal and living unrelated donors.
N Engl J Med 1995, 333:333336.
11. Bia MJ, Ramos EL, Danovitch GM, et al.: Evaluation of living renal
donors. the current practice of US transplant centers. Transplantation
1995, 60:322327.
12. Kasiske BL, Ma JZ, Louis TA, Swan SK: Long-term effects of reduced
renal mass in humans. Kidney Int 1995, 48:814819.
Medical Complications of
Renal Transplantation
Robert S. Gaston
ith long-term function of allografts increasingly the norm,

detection and management of medical complications
assume greater importance in the care of renal transplantation recipients. At least two trends in transplantation seem likely to
make medical surveillance even more crucial. First, better control of
adverse immunologic events early after transplantation has significantly reduced graft loss caused by rejection; the impact of later events
(especially death with a functioning organ and chronic rejection) on
graft and patient survival is proportionately larger. Second, with successful transplantation now fairly routine, it is being offered to a
broader spectrum of candidates, including increasingly older patients
with multiple coexisting medical problems. Because more patients
with immunosuppression are now being cared for over increasingly
longer periods of time, the impact of comorbid events on outcomes
must be reduced.
Medical complications in the renal allograft recipient represent the
often overlapping impact of several variables. At the time of transplantation, significant comorbidity may already be present and can be of
immediate concern. Other problems may have originated in the milieu
of chronic renal failure, such as hyperparathyroid bone disease or
hypertension, but may evolve differently after transplantation. Finally,
new complications may result from specific toxicities of pharmaceutical
agents, reflecting the overall impact of immunosuppression. In many
cases, all of these elements contribute to overt clinical illness. For
instance, cardiovascular disease is now the most common cause of death
in renal allograft recipients [1]. Coronary disease may have predated
transplantation (indeed, coronary disease is a common cause of death
among all patients with end-stage renal disease). After transplantation,
hypertension and hyperlipidemia, perhaps exacerbated by administration
of cyclosporine and corticosteroids, result in accelerated atherosclerosis,
further potentiating preexisting cardiac problems. To intervene appropriately requires a comprehensive understanding of all the variables involved:
any decision to lessen the impact of one risk factor (eg, withdrawing
steroids) may result in unintended consequences (eg, acute rejection).
CHAPTER
13
13.2
An obvious prerequisite to caring for transplant recipients is a

thorough understanding of immunosuppressive therapies [2].
Although acute rejection can occur at any time, the greatest risk
is during the first 90 days after transplantation. Accordingly,
immunosuppression is most intense during this time, and the
chances of suffering its consequences are great (eg, drug toxicities, infection, and some malignancies [lymphoma]). In general,
tapering to a less arduous regimen over time is done, with
resulting reduction in the risks of toxicity and infection. With
long-term survival, however, the duration rather than the intensity of immunosuppression becomes more critical and strongly
influences the risks of other complications, including malignancies (skin), bone disease, and atherosclerosis.
Current maintenance immunosuppressive therapy involves
multidrug regimens (including azathioprine or mycophenolate
mofetil [MMF] and corticosteroids) built around a cornerstone,
the calcineurin-inhibitor (either cyclosporine or tacrolimus) [2].

Therapeutic considerations in treating patients on either of the
calcineurin inhibitors are remarkably similar in terms of both
adverse effects and drug interactions (Figs. 13-1 and 13-2)
[35]. Common azathioprine toxicities include bone marrow
suppression and alopecia. Because azathioprine is metabolized
by xanthine oxidase, concomitant use with allopurinol is problematic. MMF causes less bone marrow suppression than does
azathioprine and does not interact with allopurinol, facilitating
therapy of gout. However, gastrointestinal complaints (usually
dose-related nausea, bloating, or diarrhea) are common. In
addition, MMF may exacerbate the gastrointestinal toxicity of
tacrolimus. Corticosteroid toxicities are well described; protocols
designed to minimize corticosteroid exposure of transplantation
recipients remain the ideal pursued by many physicians who
treat these patients.
ADVERSE EFFECTS OF CYCLOSPORINE AND TACROLIMUS

Renal
Gastrointestinal
Hypertension
Hepatotoxicity (abnormal
transaminase levels)
Nephrotoxicity
(azotemia)
Nausea, vomiting, diarrhea
(FK > CyA)
Metabolic
Cosmetic
Glucose intolerance (FK > CyA)
Gingival hypertrophy Headache

(CyA only, especially Paresthesias
in combination with Seizures
calcium antagonists)
Tremor
Hirsutism (CyA > FK)
Hyperkalemia
Hyperlipidemia (CyA > FK)
Hyperuricemia
Hypomagnesemia
COMMON DRUG INTERACTIONS

WITH CYTOKINE INHIBITORS
Drugs that commonly increase blood levels of
cyclosporine and tacrolimus
Bromocryptine
Cimetidine
Clarithromycin
Clotrimazole
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Mefredil
Methylprednisolone
Nicardipine
Verapamil
Drugs that commonly decrease blood levels of
cyclosporine and tacrolimus
Carbamazepine
Phenobarbital
Phenytoin
Rifampin
Neurologic
FIGURE 13-1
Despite differing structures, both
cyclosporine and tacrolimus bind to intracellular receptors in T cells, forming a combination that then inhibits calcineurindependent pathways of cell activation.
Although slight differences exist in sideeffect profiles between the two drugs, their
overall impact is remarkably similar. In
many cases, dose reduction may ameliorate
the toxic effect; however, the benefit of dose
reduction must be weighed against increasing the risk of acute rejection in each
patient. CyAcyclosporine; FKtacrolimus.
FIGURE 13-2
Cyclosporine and tacrolimus are subject to remarkably similar interactions, owing in part
to a common pathway of metabolic degradation, the cytochrome P-450 enzyme system.
Although the drugs listed here predictably alter blood levels of the calcineurin inhibitors,
other interactions may also occur.
Medical Complications of Renal Transplantation
FIGURE 13-3
Risk of acute rejection in cadaver kidney transplantation. This graph, derived from the parametric analysis techniques of Blackstone and coworkers [6], depicts the risk of acute rejection over time. Using an immunosuppressive protocol including cyclosporine, mycophenolate mofetil, and prednisone, the risk of acute rejection is greatest during the first 2 months
after transplantation, diminishing significantly afterward. Because the risk of rejection is
greatest, immunosuppressive therapy is most intense during this period. Correspondingly,
complications related to immunosuppressive therapy (including infections and specific
drug toxicities) also are most likely during this time.
1.0
0.8
Risk month
13.3
0.6
0.4
0.2
0.0
0
2
4
6
8
10
Months posttransplant
12
Incidence rate
1.0
Rejection
Toxicity
0.8
0.6
0.4
0.2
0
5
7.5
10
12.5
15
17.5
20
Tacrolimus level (whole blood), ng/mL
22.5
25
FIGURE 13-4
Relationship between blood levels of tacrolimus, immunosuppressive
efficacy, and toxicity [7]. As tacrolimus levels diminish, particularly
during the early period after transplantation, the risk of toxicity is
reduced accordingly. However, the risk of acute rejection increases.
Toxicity still can occur at very low drug levels, as can rejection at
high levels. The relationship between these variables beyond the
first 6 to 12 months after transplantation is not well established.
A similar plot could be constructed for cyclosporine. (Adapted
from Kershner and Fitzsimmons [7].)
Complications of Immunosuppression
Malignancy
Kaposi's
(6%)
Other
(36%)
Lymphomas
(24%)
Skin and lip

(34%)
FIGURE 13-5
Types and distribution of malignancies among renal transplant recipients in the current era of
cyclosporine use. In these patients the risk of malignancy is increased approximately fourfold
when compared with the general population [8]. Malignancies likely to be encountered in the
transplantation recipient differ from those most common in the general population [9,10].
Lymphomas and Kaposis sarcoma may evolve as a consequence of viral infections. Women
are at an increased risk for cervical carcinoma, again related to infection (human papilloma
virus). Surprisingly, the solid tumors most commonly seen in the general population (eg, of
the breast, lung, colon, and prostate) do not occur with significantly greater frequency among
transplant recipients. Nonetheless, long-term care of these patients should involve standard
screening for these malignancies at appropriate intervals. (From Penn [9]; with permission.)
13.4
FIGURE 13-6
Primary basal cell carcinoma. Cutaneous carcinomas (primarily
basal cell and squamous cell) comprise the greatest percentage
of tumors in transplant recipients. They tend to be most problematic in fair-skinned persons whose lifestyle includes significant sun exposure; the risk increases with duration of immunosuppression. In immunocompetent patients the risks of these
lesions usually are limited; however, in transplant recipients
these lesions can be very aggressive and metastasize locally or
even systemically. The best management is aggressive prevention:
exposure to ultraviolet radiation from the sun should be minimized through diligent use of protective clothing, hats, and
sunscreen. When suspicious lesions develop, early recognition
and removal are of utmost importance.
FIGURE 13-7
Posttransplantation lymphoproliferative disease (PTLD): histologic
appearance of a renal allograft infiltrated by a monoclonal proliferation
of B lymphocytes. Non-Hodgkins lymphomas, of which PTLD is
a variant, occur in 1% to 3% of transplant recipients and in many
cases are linked to an infectious cause. PTLD can be of either
polyclonal or monoclonal B-cell composition, with lymphocytes
driven to proliferate by infection with the Epstein-Barr virus
[1113]. Development of PTLD is strongly linked to the intensity
of immunosuppression and may regress with its reduction.
However, most often in the setting of splanchnic involvement
and monoclonal proliferation, as depicted, PTLD can follow a
more aggressive unrelenting course despite withdrawal of immunosuppressive therapy.
Hematologic Complications
Serum erythropoietin level, U/L
200
1st peak
2nd peak
150
100
50
25
0
10
20
30
40
50
60
Days after transplantation
70
80
FIGURE 13-8
The course of normal erythropoiesis after renal transplantation
showing mean serum erythropoietin levels of 31 recipients [14].
An initial burst of erythropoietin (EPO) secretion at the time of
engraftment does not result in erythropoiesis. As excellent graft
function is achieved, a second burst of EPO secretion is normally
followed by effective production of erythrocytes. The hatched area
is the range of serum erythropoietin levels in normal persons without anemia.

Anemia is a common complication. Many patients leave the dialysis population with diminished iron stores and are unable to respond
to erythropoietin produced by the successful allograft. Iron replacement therapy successfully restores erythropoiesis in these patients.
Another common cause of anemia after transplantation is bone
marrow suppression owing to drug therapy with azathioprine or
mycophenolate mofetil (MMF), an effect that is usually dose-related [15,16]. Other drugs, notably angiotensin-converting enzyme
inhibitors and angiotensin receptor antagonists, may also inhibit
erythropoiesis [17].
Neutropenia also is a common complication after transplantation.
It can reflect dose-related bone marrow suppression owing to drug
therapy with azathioprine or MMF or an idiosyncratic response to a
number of drugs commonly used in this population (acyclovir, ganciclovir, sulfa-trimethoprim, H2 blockers). Alternatively, neutropenia
can be a manifestation of systemic viral, fungal, or tubercular infections. The approach to the patient with neutropenia usually involves
reducing the dose or discontinuing the potential offending agents,
along with a careful search for infections. In some settings of refractory neutropenia, administration of filgrastim (granulocyte colonystimulating factor, Neupogen) reduces the duration and severity of
neutropenia. (From Sun and coworkers [14]; with permission.)
Hematocrit, %

62
60
58
56
54
52
50
48
46
44
42
40
PRE
2
3
4
5
6
9
Months on enalapril (mean 74.5 mo)
12
15
13.5
FIGURE 13-9
Posttransplant erythrocytosis (PTE). PTE (a hematocrit of >0.52)
affects 5% to 10% of renal transplantrecipients, most commonly
male recipients with excellent allograft function [17]. PTE usually
occurs during the first year after transplantation. Although it may
resolve spontaneously in some patients, PTE persists in many. It has
been linked to an increased risk of thromboembolic events; however, our own experience is that such events are uncommon. Previous
management involved serial phlebotomy to maintain the hematocrit
at 0.55 or less (dashed line). More recently, hematocrit levels have
been found to normalize in almost all affected patients with a small
daily dose of angiotensin-converting enzyme inhibitor (ACEI) or
angiotensin II receptor antagonist. The pathogenetic mechanisms
underlying PTE and its response to these therapies remain poorly
understood; although elevated serum erythropoietin levels decrease
with ACEI use, other pathways also appear to be involved.
Death rate per 1000 patient years
Cardiovascular Complications
8
Diabetic
Nondiabetic
7
6
5
4
3
2
1
0
FIGURE 13-10
Causes of death in renal allograft recipients. Cardiovascular diseases are the most common cause of death, largely reflecting the
high prevalence of coronary artery disease in this population [1].
The risks are particularly high among recipients who have diabetes, as many as 50% of whom, even if asymptomatic, may have
significant coronary disease at the time of transplantation evaluation [18]. Effective management of cardiac disease after transplantation mandates documentation of preexisting disease in patients
at greatest risk [19].
Malignancy
Cardiac
Infectious
Stroke
Cause of death in patients with functioning transplants
DEMOGRAPHIC VARIABLES HIGHLY PREDICTIVE OF CORONARY DISEASE

IN RENAL TRANSPLANTATION CANDIDATES WITH INSULIN-DEPENDENT
DIABETES MELLITUS
Age > 45 y
Electrocardiographic abnormality: nonspecific ST-T wave changes
History of cigarette smoking
Duration of diabetes > 25 y
FIGURE 13-11
Demographic variables highly predictive of coronary disease in renal transplantation candidates
with insulin-dependent diabetes mellitus. Most transplant centers screen potential candi-
dates, particularly persons with diabetes, for

coronary disease before transplantation. In
patients with diabetes who have end-stage
renal disease with none of the demographic
characteristics listed, the risk for coronary
disease is low. Conversely, in patients who
are insulin-dependent and have any of these
risk factors, the prevalence of coronary disease
is sufficiently high to justify angiography.
A randomized study of medical therapy
versus revascularization in transplantation
candidates who have insulin-dependent
diabetes and coronary disease showed superior
outcomes with prophylactic revascularization,
even in the absence of overt symptomatology [20]. (Adapted from Manske and
coworkers [18].)
13.6
75
50
n=591
n=429
60
40
45
30
30
20
74%
15
63%
10
0
100
200
300
400
70
Cholesterol, mg/dL
130
190
310
LDL, mg/dL
75
40
n=588
250
n=430
60
32
45
24
30
16
15
FIGURE 13-12
Hypercholesterolemia and hypertriglyceridemia. Hypercholesterolemia and hypertriglyceridemia are common after kidney
transplantation. Approximately two thirds
of transplant recipients have low density
lipoprotein (LDL) or total cholesterol levels
signifying increased cardiac risk; 29% have
elevated triglyceride levels 2 years after
transplantation (Kasiske, Unpublished
data). Not only is hyperlipidemia a clear
risk factor for coronary disease (see Figs.
13-13 and 13-14), but it may also contribute
to the progressive graft dysfunction associated
with chronic rejection [21,22]. HDLhigh
density lipoprotein. (From Bristol-Myers
Squibb [23]; with permission.)
10%
29%
0
100
200
300
400
Triglycerides, mg/dL
35
50
65
80
95
HDL, mg/dL
RISK FACTORS FOR CORONARY MORBIDITY

IN RENAL ALLOGRAFT RECIPIENTS
GUIDELINES FOR LIPID-LOWERING THERAPY

Diet therapy
Positive
Negative
Age:
Male 45 y
Female 55 y or premature menopause
Family history of premature coronary
heart disease
Smoking
Hypertension
HDL cholesterol < 35 mg/dL
Diabetes mellitus
HDL cholesterol 60 mg/dL
FIGURE 13-13
Risk factors for coronary morbidity in renal allograft recipients. In
addition to elevated low density lipoprotein (LDL) cholesterol levels,
risk factors known to contribute to coronary morbidity often are
present in renal allograft recipients. About 40% of recipients are
over 45 years old, and 23% have diabetes. Smoking, hypertension,
and hyperlipidemia are among the risk factors most amenable to
long-term modification. (For guidelines in instituting lipid-lowering
therapy see Figure 13-14 [24].)
LDL cholesterol, mg/dL
Initiation
Goal
No CHD and <2 risk factors

No CHD and 2 risk factors
CHD
160
130
100
<160
<130
100
Diet plus drug therapy

LDL cholesterol, mg/dL
Initiation
Goal
No CHD and <2 risk factors

No CHD and 2 risk factors
CHD
190
160
130
<160
<130
100
FIGURE 13-14
The indications for lipid-lowering therapy and its goals are based
on the clinical history, risk factor profile (see Fig. 13-13), and low
density lipoprotein (LDL) cholesterol level in individual patients.
CHDcoronary heat disease. (From Grundy [24]; with permission.)
Lipid level, mg/dL
Prograf
CyA
p<0.001
229.8
250
P<0.05
198.6
193.9
13.7
FIGURE 13-15
Cyclosporine (CyA) and corticosteroid therapies clearly contribute to hyperlipidemia in
renal allograft recipients. Although dose reduction can reduce lipid levels, it may also
increase the risk of acute rejection. As depicted, early experience in a large multicenter
trial indicates that tacrolimus may have a less adverse impact on lipid metabolism than
does cyclosporine [25]. (From Fujisawa USA [26]; with permission.)
165.4
125
Cholesterol
Triglycerides
THERAPEUTIC OPTIONS IN LIPID-LOWERING THERAPY

HDL cholesterol Cholesterol LDL cholesterol Triglycerides
Control groups
Diet
HMG CoA
inhibitors
Fibrates
Fish oil
Probucol
Niacin
CAUSES OF HYPERTENSION AFTER TRANSPLANTATION

Intrinsic
Extrinsic
111
-2814
-569
16
-2115
-516
-1522
-5925
-4918
24
58
3.54.5
Delayed graft function
Native kidneys
Acute rejection
-3812
2343
-6621
-4828
-369
-6924
-8680
36
Cyclosporine nephropathy, chronic
Immunosuppression:
Cyclosporine
Tacrolimus
Corticosteroids
-49
-13.512
1010
Chronic rejection
Recurrent primary renal disease
(glomerulonephritis, hemolytic uremic
syndrome, and so on)
Transplantation renal artery stenosis

Hypercalcemia
mg/dL changes 95% CI.
FIGURE 13-16
A recent meta-analysis of published trials in renal transplant
recipients demonstrated these benefits of the various treatments.
Pharmacologic therapy should be instituted at low doses with
cautious surveillance for potential adverse effects, especially liver
dysfunction or rhabdomyolysis. These adverse events may occur
more frequently in transplant recipients owing to the effect of
cyclosporine on drug disposition. Levels of 3-hydroxy-3-methylglutaryl
coenzyme A (HMG CoA) reductase inhibitors are substantially higher
in patients receiving both drugs [27]. HDLhigh density lipoprotein;
LDLlow density lipoprotein. (Adapted from Massy and coworkers
FIGURE 13-17
In the current era of immunosuppressive therapy, hypertension
affects roughly two thirds of transplant recipients. Unlike hypertension in the general population, posttransplant hypertension often
reflects the impact of readily definable (and potentially treatable)
factors on systemic blood pressure [2830]. These may be grouped
conveniently into those originating within the allograft (intrinsic)
and those originating elsewhere (extrinsic).
13.8

Diagnosis and treatment of hypertension
in the renal transplant recipient
Blood pressure 140/90

Stable GFR?
Yes
Evaluate allograft function

No
Optimal blood levels

of cyclosporine
or tacrolimus?
Yes
No
Reduce dose of
cyclosporine or
tacrolimus
ECF volume status

acceptable?
Yes
No
Consider salt restriction

and/or diuretic
Administer
antihypertensive agent
(CA, ACEI, or other)
Intervention fails to
normalize BP
Adequate response
to therapy?
Multidrug regimen:
add agents of different
classes as necessary
No
Yes
Acceptable side
effect profile?
Yes
Continue
antihypertensive therapy
Reassess periodically
Yes
Adequate response
to therapy?
No
Re-evaluate allograft
function and drug therapy
Consider TRAS
FIGURE 13-18
Hypertension in the renal transplant recipient. In these patients
it may be possible to approach diagnosis and therapy in a fairly
standardized fashion. In transplant recipients with blood pressure
readings consistently over 140/90 mm Hg, intervention is warranted.
The initial approach includes assessment of allograft function,
extracellular fluid volume (ECF) status, and immunosuppressive
dosing. If these variables are stable, it is reasonable to proceed with
antihypertensive therapy. Calcium antagonists (CA) are effective
agents and may offer the added benefit of attenuating cyclosporineinduced changes in renal hemodynamics. Verapamil, diltiazem,
nicardipine, and mibefradil increase blood levels of cyclosporine
and tacrolimus and should be used with caution. Common problems
with CAs that may limit their use include cost, refractory edema,
and gingival hyperplasia. Angiotensin antagonists (ACEIs and
receptor antagonists) are also effective; their use requires close
monitoring of renal function, serum potassium levels, and hematocrit
levels. Diuretics frequently are useful adjuncts to therapy in recipients
owing to the salt retention that often accompanies cyclosporine
use. Other antihypertensive medications offer no particular benefits
or drawbacks and can be employed as needed. The rationale of
multidrug therapy is to employ agents that block hypertensive
responses via interruption of differing pathogenetic pathways.
As antihypertensive drugs are added, this consideration should
remain paramount [31,32]. GFRglomerular filtration rate;
TRAStransplanted renal artery stenosis.
FIGURE 13-19
Transplant renal artery stenosis (TRAS). TRAS accounts for less than 5% of cases of
hypertension after transplantation. Nonetheless, TRAS should always be considered in
patients with refractory hypertension who develop renal insufficiency after addition of an
ACEI to the therapeutic regimen. Although noninvasive studies (such as a renal scan with
captopril) may be helpful in diagnosing TRAS, angiography remains the gold standard for
diagnosis. Revascularization of the allograft by either surgical or angioplastic techniques
may improve renal function and ameliorate hypertension [33,34].
13.9
Gastrointestinal Complications
GASTROINTESTINAL TRACT COMPLICATIONS IN
RENAL TRANSPLANTATION RECIPIENTS
Drug
Cyclosporine
Tacrolimus
MMF
Azathioprine
Nausea and
vomiting
Diarrhea
4
30
20
12
3
32
31
Rare
Other complications
Hepatotoxicity, constipation
Hepatotoxicity, constipation
Constipation, dyspepsia
Hepatotoxicity, pancreatitis
FIGURE 13-20
Complications affecting the gastrointestinal (GI) tract remain relatively common in transplant recipients. Both tacrolimus and
mycophenolate mofetil (MMF) cause bloating, nausea, vomiting,
and diarrhea in a dose-dependent manner, particularly when used
in combination [15,16,25]. Some authors have noted that this rather
nonspecific GI toxicity occurs more commonly with Neoral than
with Sandimmune (both from Sandoz Pharmaceuticals, East
Hanover, NJ).
FIGURE 13-21 (See Color Plate)

Endoscopic image of candida esophagitis
with diffuse white exudate (panel A) and
colitis induced by cytomegalovirus infection
with submucosal hemorrhage, ulcers, and
diffuse mucosal edema (panel B). The availability and common use of effective prophylaxis against acid-peptic disease (eg, H2 blockers, omeprazole, and antacids) have significantly reduced the frequency of upper
gastrointestinal bleeding. However, infectious
agents such as cytomegalovirus and candida
continue to be problematic, particularly in
the setting of the more intense immunosuppression afforded by drugs such as mycophenolate mofetil (MMF) and tacrolimus.
FIGURE 13-22
Histologic image of chronic active hepatitis secondary to infection
with the hepatitis C virus (HCV). Note the periportal distribution
of the lymphocytic infiltrate. Recent identification of HCV has caused
intense reevaluation of the causes, frequency, and natural history of
liver disease in renal allograft recipients. As the percentage of patients
with end-stage renal disease who are infected with the hepatitis B
virus has diminished, HCV has become the most problematic cause
of liver disease. In recipients with HCV antibodies, immunosuppressive therapy may potentiate liver injury from the virus and
accelerate the course of time over which cirrhosis develops.
Nonetheless, in patients who desire transplantation and have wellpreserved liver function, little evidence exists of better longevity on
dialysis. HCV can be transmitted easily from donor to recipient in
solid organ transplantation. Because kidney transplantation is not a
life-saving procedure, most transplant centers choose not to use
kidneys from donors who are infected with HCV.
Previously, liver disease was thought to be a common cause of
death in renal allograft recipients. As blood transfusions have
become less common in the dialysis population and hepatitis B
virus less prevalent, the risk of death owing to hepatic disease
seems to have diminished. Unfortunately, therapies for HCV-related
hepatitis (interferon-) have proved to be of questionable efficacy
and may stimulate rejection of the renal allograft [3537].
13.10
Musculoskeletal and Metabolic Complications
Change in density, %
Males
Females
Both genders
3
*
*
*
*
*
*
12
18
0
6
FIGURE 13-23
Mean percentage changes in bone mineral
density of the lumbar spine after transplantation. Substantial bone loss can occur quite
early after transplantation. Metabolic bone
disease in this setting is usually multifactorial.
Most often, patients who had end-stage
renal disease before transplantation already
have some degree of renal osteodystrophy,
exacerbated in some cases by the impact of
aluminum toxicity or 2-microglobulin
amyloidosis. Patients with diabetes are
particularly at risk for low-turnover bone
disease. Administration of corticosteroids
and cyclosporine also contributes to bone
loss. Although biochemical evidence of
secondary hyperparathyroidism usually
resolves during the first year after transplantation, some patients may have persistent
parathyroid-driven bone resorption, with
or without hypercalcemia, and may require
surgical parathyroidectomy. Asterisk
values significantly different from those at
the time of transplantation. (From Julian
FIGURE 13-24
Bone densitometry. Bone densitometry
offers a noninvasive method to quantitate
bone mass. Here, a renal transplant
recipient demonstrates marked osteoporosis,
with bone density greater than 2 standard
deviations below age- and gender-matched
controls. In recent years, new therapeutic
options (including bisphosphonates, estrogens,
and thiazides) have offered hope of preserving
or even increasing bone mass [38,39].
BMDbone mass density.
FIGURE 13-25
Magnetic resonance imaging of osteonecrosis.
Osteonecrosis most commonly affects the
femoral head but can affect any weightbearing bone. The most debilitating complication of renal transplantation, its incidence
seems to be decreasing (<10% of transplant
recipients). This decrease reflects better
management of calcium and bone homeostasis
during long-term dialysis and less intense
steroid use after transplantation. The
pathogenesis of osteonecrosis remains poorly
understood, and therapeutic options are
limited (pain management while awaiting
progression to the need for joint replacement).
Magnetic resonance imaging is a sensitive
diagnostic method, allowing detection of
osteonecrosis at a very early stage [39].
FIGURE 13-26
Photograph of gouty inflammation of joints (tophus). Gout is
the clinical manifestation of hyperuricemia. After transplantation,
cyclosporine can exacerbate hyperuricemia, and severe gout can
be problematic even in the presence of chronic immunosuppression.
Management of gouty arthritis usually involves some combination
of colchicine and judicious use of short courses of nonsteroidal
anti-inflammatory drugs. Concomitant administration of allopurinol
and azathioprine can cause profound bone marrow suppression
and is avoided by most physicians who treat transplant recipients.
Because the metabolism of mycophenolate mofetil (MMF) is not
dependent on xanthine oxidase, use of allopurinol in patients
treated with MMF is relatively safe [39,40].
13.11
INCIDENCE OF POST-TRANSPLANT
DIABETES MELLITUS
PTDM (defined as requiring insulin 30 d)
Initial
At 1 year
At 18 mo
Prograf *
(n=151)
%
n
CyA
(n=151)
%
n
30
25
18
8
5
0
15.9
18.5
12.0
4.0
3.3
3.3
P value
>0.001
>0.001
*Patients without history of diabetes.
FIGURE 13-27
Photograph of gingival hyperplasia. Gingival hyperplasia occurs
in approximately 10% of transplant recipients treated with
cyclosporine. Its severity reflects the interaction of effective dental
hygiene, cyclosporine dose, and concomitant administration of calcium
antagonists (particularly dihydropyridines). This complication does
not seem to occur with use of tacrolimus, and complete resolution
of gingival hyperplasia has been noted with conversion from
cyclosporine-based therapy [25,41].
FIGURE 13-28
Post-transplantation diabetes mellitus (PTDM). PTDM complicates
the course of treatment in 5% to 10% of patients on cyclosporinebased immunosuppressive therapy. It is more common in blacks
and in patients with a family history of glucose intolerance.
PTDM often reflects the substantial steroid-related weight gain
that sometimes occurs after transplantation. The severity of PTDM
can be attenuated by weight loss and corticosteroid withdrawal,
although the latter may not be advisable owing to the risk of
rejection. In a multicenter trial, PTDM occurred with greater
frequency among patients treated with tacrolimus, particularly
blacks. Although PTDM resolved over time in almost half of
affected patients (as doses of tacrolimus and corticosteroids were
gradually reduced), PTDM remained more common in patients
receiving tacrolimus [25,42,43]. CyAcyclosporine. (From
Fujisawa USA [26]; with permission.)
Acknowledgments
The author thanks his colleagues at the University of Alabama at
Birmingham for contributing many of the illustrations used in this
chapter: Drs. Ralph Crowe, Bruce Julian, Catherine Listinsky,

Brendan McGuire, Klaus Monckemuller and Colleen Shimazu.
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11. Randhawa PS, Jaffe R, Demetris AJ, et al.: Expression of Epstein-Barr

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12. Cockfield SM, Preiksaitis JK, Jewell LD, Parfrey NA: Post-transplantation lymphoproliferative disorder in renal allograft recipients.
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virus transformation-associated genes in tissues of patients with EBV
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14. Sun CH, Ward HJ, Wellington LP, et al.: Serum erythropoietin levels
after renal transplantation. N Engl J Med 1989, 321:151157.
15. Tricontinental Mycophenolate Mofetil Renal Transplantation Study
Group: A blinded, randomized clinical trial of mycophenolate mofetil
for the prevention of acute rejection in cadaveric renal transplantation.
16. Sollinger HW, US Renal Transplantation Mycophenolate Mofetil Study
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19. Manske CL, Thomas W, Wang Y, Wilson RF: Screening diabetic
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20. Manske C, Wang Y, Wilson RF, et al.: Coronary revascularization in
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21. Kasiske BL: Risk factors for accelerated atherosclerosis in renal transplantation recipients. Am J Med 1988, 84:987992.
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Technical Aspects of
Renal Transplantation
John M. Barry
enal transplantation is the preferred treatment method of endstage renal disease (ESRD). It is more cost-effective than is
maintenance dialysis [1] and usually provides the patient with
a better quality of life [2]. Adjusted mortality risk ratios indicate a significant reduction in mortality for kidney transplantation recipients
when compared with that for patients receiving dialysis and patients
receiving dialysis who are on a waiting list for renal transplantation
(Fig. 14-1) [3].
The indication for renal transplantation is irreversible renal failure
that requires or will soon require long-term dialytic therapy. The evaluation of candidates for renal transplantation is discussed in Chapter
12. Generally accepted contraindications are noncompliance, active
malignancy, active infection, high probability of operative mortality,
and unsuitable anatomy for technical success [4]. The technical
aspects of kidney transplantation are discussed, primarily through the
illustrations of kidney preparation and of a living donor renal transplantation.
Kidneys from living donors require little preparation by the transplantation team because most of the dissection has already been done
during the nephrectomy. Further separation of the renal artery or
arteries from the renal vein(s) will allow separation of the arterial and
venous suture lines in the recipient and will prevent the technical
inconvenience of side-by-side anastomoses. The right kidney from a
living donor usually has a cuff of the inferior vena cava attached to
the renal vein. This provides the recipient team with maximum renal
vein length and a wide lumen for anastomosis. The renal arteries in a
kidney graft from a living donor are not attached to aortic patches as
they usually are in the cadaveric kidney. The technical aspects of livingdonor harvesting are not illustrated here.
CHAPTER
14
14.2
ADJUSTED MORTALITY RISK RATIOS FOR END-STAGE

RENAL DISEASE BY TREATMENT MODALITY
Treatment modality
Risk ratio
All patients on dialysis
1.0
Patients on dialysis who are on a waiting list
0.48
Cadaveric kidney transplantation recipients
0.32
Living-donor related kidney transplantation recipients
0.21
TECHNICAL CONSIDERATIONS FOR RECIPIENTS

OF KIDNEY TRANSPLANTATION
Kidney graft
Recipient
Right or left
Gross appearance and size
Arterial anatomy
Venous anatomy
Ureteral anatomy
Abdominal wall anatomy

Size
Arterial anatomy
Venous anatomy
Urinary tract anatomy and function
Gender
Data from US Renal Data System [3].
FIGURE 14-1
The adjusted mortality risk ratio for patients on dialysis placed on
the renal transplantation waiting list is greater than that for kidney
transplantation recipients, suggesting transplantation itself results
in a reduced mortality risk for patients with end-stage renal disease
who are treated [3].
FIGURE 14-2
A number of factors concerning the kidney graft and recipient
determine the technique of renal transplantation in each recipient.
Placement of the kidney graft in the contralateral iliac fossa is
preferable because the renal pelvis becomes the most medial of the
vital renal structures and thus readily available for future reconstruction if ureteral stenosis occurs. Areas of previous abdominal
surgery such as ileostomy, colostomy, renal transplantation, or a
peritoneal dialysis exit site are avoided, if possible. A kidney too
large for the recipients iliac fossa is usually placed in the right
retroperitoneal space and revascularized with the aorta or common
iliac artery and interior vena cava or common iliac vein. Pelvic vascular disease and previous renal transplantation determine whether
the aorta or internal iliac, external iliac, common iliac, native renal
or splenic artery will be selected for renal artery anastomosis. The
use of both internal iliac arteries in serial renal transplantations in
men is avoided to prevent impotence [5]. The method of urinary
tract reconstruction depends primarily on the status of the recipients bladder, continent reservoir, or incontinent intestinal conduit.
Cadaveric Kidney Graft

FIGURE 14-3
Instrument setup for cadaveric kidney graft preparation. The towel
prevents renal movement during dissection.
Technical Aspects of Renal Transplantation

FIGURE 14-4
Preparation of a left
cadaveric kidney
graft. The kidney
and its vital structures are surrounded by other tissues.
The cadaveric
kidney graft can
require an hour of
preparation time
because the specimen
usually includes a
portion of the inferior
vena cava, an aortic
cuff, the adrenal
gland, variable
amounts of perinephric tissue,
sometimes pieces of
muscle, and occasionally damaged
renal vessels.
FIGURE 14-6
Renal artery dissection. In this posterior view, the aortic patch and
main renal artery have been separated from the surrounding tissues.
14.3
FIGURE 14-5
Renal vein dissection. The adrenal and gonadal veins have been
isolated. They will be divided between ligatures.
FIGURE 14-7
Left cadaver kidney
graft after preparation. The adrenal
gland and excess
perinephric tissue
have been removed.
Fibrofatty tissue is
left around the renal
pelvis and ureter to
ensure blood supply
to the ureter. The
aortic patch, renal
vein, and ureter will
be further modified
to provide a best
fit in the recipient.
14.4
Preparation of Kidney Graft Vessels

FIGURE 14-8
Venoplasties for
right renal vein
extension of a
cadaveric kidney
graft [68]. AC,
Use being made of
the inferior vena
cava. D,Use being
made of the external
iliac vein of the
cadaveric donor.
C
E
or
FIGURE 14-9
Preparation of the
renal allograft with
multiple renal arteries
[9]. A and B, The
use of aortic patches
when the kidney is
from a cadaveric
donor is demonstrated. C and D,
The possibilities that
exist when an aortic
patch is not part of
the specimen, such
as when the kidney
is from a living
donor. E, The
segmental renal
artery also can be
anastomosed to the
inferior epigastric
artery using an endto-end technique.
The Kidney Transplantation Operation

DIVISION OF OPERATING ROOM RESPONSIBILITIES
FOR RECIPIENTS OF KIDNEY TRANSPLANTATION
Anesthesiologist
Surgeon
Anesthetic induction
Placement of central venous access line
Administration of antibiotics
Administration of immunosuppressants
Administration of heparin
Assurance of conditions for diuresis
Patient position
Bladder catheterization
Initial skin preparation
Incision and exposure of operative site
Renal revascularization
Urinary tract reconstruction
Wound closure
FIGURE 14-10
After the induction of anesthesia, the anesthesia team places a double- or triple-lumen central venous access catheter, usually via the
internal jugular vein. While that is taking place, the surgical team
places a retention catheter (usually 20F with a 5-mL balloon), fills
the bladder to 30 cm H2 pressure or 250 mL (whichever occurs
first), connects the catheter to a three-way system or clamped urinary drainage system, and places the clamp(s) within reach of the
anesthesiologist for control during the operation. The preoperative
antibiotic is administered by the anesthesia team. The surgical team
shaves both sides of the patients abdomen from just above the
umbilicus to the distal edge of the mons pubis. The skin is wiped
with alcohol, and the nursing team completes the skin preparation.
The skin over both iliac fossae is prepared in the event an unexpected vascular contraindication is detected on the chosen side. If
immunosuppressant therapy has not been administered, the anesthesia team begins that protocol.
14.5
Adult Recipient
FIGURE 14-11
Surgeons view of the right iliac fossa operative site. In this procedure,
a 40-year-old man will be receiving his brothers left kidney, which
has a single artery, single vein, and single ureter. The renal vessels
will be anastomosed to his right external iliac artery and vein, and
urinary tract reconstruction will be by extravesical ureteroneocystostomy [10,11]. The patient is positioned with the head slightly
down, supine, and rotated toward the surgeon, who is standing
on the patients left side.

Exposure of the right iliac fossa. The contents of the iliac fossa are
exposed by incising the skin, subcutaneous tissues, anterior rectus
sheath, external and internal oblique muscles, and the transversalis
muscle and fascia. The inferior epigastric artery is divided between
ligatures, the spermatic cord is preserved (in women, the round ligament is divided between ligatures), and the rectus muscle and
peritoneum are retracted medially. This exposes the genitofemoral
nerve (white umbilical tape), the external iliac vein (blue tape), and
the external and internal iliac arteries (red tapes).
FIGURE 14-13
Determining best fit. The kidney graft is placed in the wound
and the renal vessels stretched to the recipient vessels to determine
the best sites for the arterial and venous anastomoses.
FIGURE 14-14
Isolation of the arteriotomy site. Heparin (3050 U/kg) is administered intravenously, and vascular clamps are placed on the external
iliac artery. The distal clamp is applied first so that the arterial
pressure will distend the targeted artery. The external iliac artery is
incised longitudinally, the lumen is irrigated with heparinized
saline, and fine monofilament vascular sutures are placed in four
quadrants to receive the spatulated renal artery. When the recipient
artery has significant arteriosclerosis, an endarterectomy can be
done or a 5- or 6-mm aortic punch can be used to create a smooth
round arteriotomy.
14.6
FIGURE 14-15
Completed end-to-side renal arterytoexternal iliac artery anastomosis. Many surgeons perform the arterial anastomosis first because
it is smaller than is the venous anastomosis. Thus, the kidney can
be moved about more easily to expose the arterial anastomosis
when it is not tethered by a previously completed venous anastomosis. An ice-cold electrolyte solution is periodically dripped onto
the kidney graft to keep it cold during vascular reconstruction.
FIGURE 14-16
Isolation of the right external iliac vein. The kidney is retracted
medially, and a segment of the external iliac vein is isolated
between Rumel tourniquets. The cephalad tourniquet is applied
first so that increased venous pressure will dilate the vein.
FIGURE 14-17
Renal vein anastomotic setup. The renal vein is anastomosed to the
side of the external iliac vein with the same suture technique that
was used for the arterial anastomosis.
FIGURE 14-18
Completed venous and arterial anastomoses.
14.7
FIGURE 14-19
Revascularized kidney transplantation. The usual clamp release
sequence is as follows: proximal vein, distal artery, proximal artery,
and distal vein. Arterial spasm is treated by subadventitial injection
of papaverine.
FIGURE 14-20
Urinary tract reconstruction [1011]. Unstented parallel incision
extravesical ureteroneocystostomy requires a bladder full of antibiotic
solution, clearance of fat from the superolateral surface of the bladder,
and placement of the ureter under the spermatic cord to prevent
ureteral obstruction. Parallel incisions are made 2 cm apart in the
seromuscular layer of the bladder to expose the bladder mucosa.
FIGURE 14-21
Submucosal tunnel creation. A right-angle clamp is used to develop
the tunnel and to pull the transplantation ureter through it.
FIGURE 14-22
Bladder mucosa incision. After the ureter is spatulated on its ventral
surface, single-armed 5-0 absorbable sutures are placed in the heel
and in each of the dog-ears of the ureter. A double-armed horizontal mattress suture of the same material is placed in the toe
of the ureter so that the needles exit on the mucosal side. The bladder
is drained by unclamping the catheter tubing, and the bladder
mucosa is incised.
14.8
FIGURE 14-23
Partially completed ureteral anastomosis. The heel and dog-ears
of the spatulated ureter have been sutured to the bladder mucosa.
The horizontal mattress suture will be passed through the full thickness of the bladder wall and tied distal to the seromuscular incision.
This will close the toe and anchor the ureter to the bladder.
FIGURE 14-24
Completed ureteroneocystostomy. The distal seromuscular incision has
been closed over the ureter, which now lies in a submucosal tunnel.
FIGURE 14-25
Deep wound closure. A suction drain has been placed around the
kidney graft deep in the wound, and the musculofascial interrupted
sutures are ready to be tied.
FIGURE 14-26
Completed wound closure. Scarpas fascia has been closed over the
musculofascial sutures, and the skin has been closed with a 4-0
absorbable subcuticular suture. This procedure accurately approximates
the skin and eliminates subsequent staple or skin suture removal.
14.9
DIURESIS ENHANCEMENT IN
Living-donor kidney transplantation
Cadaveric kidney transplantation
Maintain CVP 510 cm H2O

Maintain MAP 60 mm Hg
Maintain SBP 90 mm Hg
Mannitol, 0.20 g/kg, IV over 1 h, start
with first vascular anastomosis
Furosemide, 0.20 mg/kg, IV during second
half of second vascular anastomosis
Same
Same
Same
Increase mannitol dose to 1 g/kg
(maximum 50 g) IV
Increase furosemide dose to 1 mg/kg IV
Albumin, 1 g/kg (to 50 g), IV over 23 h
Verapamil, 010 mg, into renal artery
based on blood pressure and weight
FIGURE 14-27
Artists depiction of the completed kidney transplantation.
CVPcentral venous pressure; IVintravenous; MAPmean arterial pressure;

SBPsystemic blood pressure.
Modified from Dawidson and ArRajab [12].
FIGURE 14-28
Maneuvers for diuresis enhancement [12]. Several intraoperative
maneuvers can be used to promote diuresis.
Child Recipient
FIGURE 14-29
Transplantation of a kidney from an adult
into a small child. The technique is modified for transplantation of a large kidney
into a small recipient. The renal artery is
anastomosed to the distal aorta or common
iliac artery, and the shortened renal vein is
anastomosed to the interior vena cava or
common iliac vein.
14.10
Postoperative Care
FIGURE 14-30
Postoperative clinical pathway.
POSTOPERATIVE CARE DURING HOSPITALIZATION

AFTER KIDNEY TRANSPLANTATION
Remove on 5th postoperative day, administer dose of antibiotic
Remove 612 wk postoperatively in clinic
Remove when 30 mL/24 h or in 3 wk if volume > 30 mL/24 h
Discontinue in 2448 h (check intraoperative culture results first)
Patient-controlled analgesia
Living donor: fixed rate of 125200 mL/h of D5W in 0.45%
normal saline
Cadaveric donor: replace insensible loss with D5W, replace
urine output mL for mL with 0.45% normal saline
Immunosuppressants Protocol (covered in Chapter 11)
Protocol (covered in Chapter 10)
Infection prevention
Peptic ulcer prevention Protocol (covered in Chapter 12)
Foley catheter
Ureteral stent, if used
Suction drain(s)
Antibiotics
Pain control
Intravenous fluids
IVintravenous.
Urologic Complications
Evaluation of kidney transplantation hydronephrosis
Hydronephrosis
Radioisotope venogram
+
furosemide wash-out
T1/2 < 1020 min
T1/2 1020 min
T1/2 > 1020 min
Percutaneous nephrostomy
Percutaneous nephrostomy
Nephrostogram
Nephrostogram
Nephrostomy drainage
plus serial serum
creatinine levels
No
No repair
or
Obstruction ?
Whitaker test
Yes
Repair
FIGURE 14-31
Algorithm for evaluation of kidney transplantation hydronephrosis [9]. The generally
accepted criterion for exclusion of upper
urinary tract obstruction is a washing out
of half of the radioisotope from the renal
pelvis in less than 10 minutes. Obstruction
is considered to be present when this value is
over 20 minutes. Percutaneous nephrostomy
allows anatomic definition of the obstruction
and temporary drainage of the hydronephrotic
kidney. A generally accepted criterion for
the diagnosis of obstruction with the percutaneous pressure-flow Whitaker test is fluid
infusion into the pelvis at the rate of 10
mL/min, resulting in a renal pelvic pressure
over 20 cm H2O.
FIGURE 14-32
Causes of renal transplantation ureteral obstruction. Hydronephrosis owing to ureteral
obstruction is one of the two most common urologic complications for which invasive
therapy is required, the other being perigraft fluid collection. Early causes of ureteral
obstruction are usually apparent within the first few days after renal transplantation.
Late causes become apparent weeks to years later.
CAUSES OF KIDNEY
TRANSPLANTATION
URETERAL OBSTRUCTION
Cause
Early
Blood clot
Edema
Technical error
Lymphocele
Ischemia
Stone
Tumor
X
X
X
X
Late
X
X
X
X
X
Evaluation of treatment of perigraft fluid collection

Perigraft fluid collection
> 50 mL ?
Hydronephrosis ?
Decreased renal function ?
Ipsilateral leg swelling ?
Fever ?
Pain ?
"No" to all
"Yes" to any
Aspirate
Serum
Lymph
Urine
Blood
Pus
Repeat ultrasound
No
Significant recurrence ?
Yes
Restudy as necessary
14.11
Serum
Lymph
Repair
Urine
Blood
Explore
Drain
FIGURE 14-33
Algorithm for evaluation and treatment of
perigraft fluid collection [9]. Perigraft fluid
collection is one of the two most common
urologic complications for which invasive
therapy is required, the other being hydronephrosis owing to ureteral obstruction.
Serum, urine, lymphatic fluid, blood, and
pus can be differentiated by creatinine and
hematocrit determinations and by microscopic examination of the fluid. Urine has a
high creatinine level, serum and lymphatic
fluid have low creatinine levels, and blood
has a relatively high hematocrit level.
Lymphocytes are present in lymphatic fluid,
and polymorphonuclear leukocytes with or
without organisms are present in pus. Open
surgical drainage is usually necessary for
fluid collections showing infection. Significant
lymphoceles have been successfully treated
with percutaneous sclerosis or by marsupialization into the peritoneal cavity by either
a laparoscopic or open surgical technique.
Persistent urinary extravasation often
requires open surgical repair. Significant
bleeding requires exploration and control
of bleeding.
14.12
Results of Renal Transplantation

US KIDNEY GRAFT SURVIVAL RATES FOR
TRANSPLANTATIONS DONE FROM 1991 TO 1995
Donor
Number
1 y, %
5 y, %
10 y (projected), %
Cadaver
Living
36,417
13,771
84
92
60
75
43
62
Data from Cecka [13].
FIGURE14-34
The 5-year patient survival rates for recipients of cadaveric and livingdonor kidney transplantations were 81% and 90%, respectively
[13]. Kidney transplantation survival rates have steadily improved
since the 1970s because of the following: careful recipient selection
and preparation, improvement in histocompatibility techniques and
organ sharing, contributions from our colleagues in government
and the judiciary, improvements in immunosuppressive therapy and
infection control, careful monitoring of recipients, and refinement of
surgical techniques. What we accomplish today as a matter of routine
was only imagined by a few just decades ago.
References
1.
2.
United Network for Organ Sharing: The UNOS Statement of

Principles and Objectives of Equitable Organ Allocation. UNOS
Update 1994, 10:20.
Evans RW, Manninea DL, Garrison LP, et al.: The quality of life of
patients with end-stage renal disease. N Engl J Med 1985, 312:553.
3.
US Renal Data System, USRDS 1997 Annual Data Report, National

Institutes of Health, Bethesda, MD: National Institute of Diabetes and
Digestive and Kidney Diseases, 1997:7273.
4.
Nohr C: Non-AIDS immunosuppression. In Care of the Surgical

Patient, Vol. 2. Edited by Wilmore DW, Brennan MF, Harken AH,
et al. New York: Scientific American; 1989:118.
5.
Gittes RF, Waters WB: Sexual impotence: the overlooked complication

of a second renal transplant. J Urol 1979, 121:719.
Barry JM, Fuchs EF: Right renal vein extension in cadaver kidney
transplantation. Arch Surg 1978, 113:300.
6.
7.
Corry RJ, Kelly SE: Technique for lengthening the right renal vein of
cadaver donor kidneys. Am J Surg 1978, 135:867.
8. Barry JM, Hefty TR, Sasaki T: Clam-shell technique for right renal vein
extension in cadaver kidney transplantation. J Urol 1988, 140:1479.
9. Barry JM: Renal transplantation. In Campbells Urology. Edited by
Walsh PC, Retik AB, Vaughan ED, Wein AJ. Philadelphia: WB
Saunders Co, 1997:505530.
10. Barry JM: Unstented extravesical ureteroneocystostomy in kidney
transplantation. J Urol 1983, 129:918.
11. Gibbons WS, Barry JM, Hefty TR: Complications following unstented
parallel incision extravesical ureteroneocystostomy in 1000 kidney
transplants. J Urol 1992, 148:38.
12. Dawidson IJA, ArRajab A: Perioperative fluid and drug therapy
during cadaver kidney transplantation. In Clinical Transplants 1992.
Edited by Terasaki PI, Secka JM. Los Angeles: UCLA Tissue Typing
Laboratory; 1993:267284.
13. Cecka JM: The UNOS Scientific Renal Transplant Registry. In Clinical
Transplants 1996. Edited by Terasaki PI, Cecka JM. Los Angeles:
UCLA Tissue Typing Laboratory; 1997:114.
Kidney-Pancreas
Transplantation
John D. Pirsch
Jon S. Odorico
Hans W. Sollinger
n the United States, diabetes mellitus is the third most common

disease and fourth leading cause of death from disease. Diabetes is
the leading cause of blindness, the number one cause of amputations and impotence, and one of the most frequently occurring chronic childhood diseases. Diabetes is also the leading cause of end-stage
renal disease in the United States, with a prevalence rate of 31% compared with other renal diseases. Diabetes is also the most frequent
indication for kidney transplantation, accounting for 22% of all
transplantation operations.
Increasingly, pancreas transplantation is being offered to patients
who would benefit from kidney transplantation (called simultaneous
pancreas-kidney transplantation) or who have had a previously successful kidney transplantation (called sequential pancreas after kidney
transplantation). Relatively few transplantation centers are performing
pancreas transplantation alone in patients with severe life-threatening
complications of diabetes. Pancreas transplantation has been criticized
because of the increased morbidity associated with the procedure and lack
of controlled trials demonstrating significant benefit to the secondary
complications of diabetes. However, many of these criticisms have
been overcome with improvement in surgical techniques and pancreas
transplantation preservation and with more potent immunosuppressive
regimens. The relative frequency of pancreas transplantation, common
surgical procedures, and outcomes of patients undergoing pancreas
transplantation are discussed.
CHAPTER
15
15.2

Urologic
2%
Unknown
6%
Unknown
6%
Other
11%
PCKD
5%
Other
18%
Nephritis
8%
GN
19%
PCKD
8%
DM
31%
GN
26%
HTN
12%
HTN
26%
Diabetes
22%
FIGURE 15-1
Disease prevalence resulting in end-stage renal disease (ESRD)
from the United States Renal Data Service (1993 to 1995). In the
continental United States at the end of 1995, 257,266 patients had
ESRD. Diabetes mellitus (DM) accounts for nearly one third of all
patients newly diagnosed with ESRD who require kidney transplantation. GNglomerulonephritis; HTNhypertensive
nephropathy; PCKDpolycystic kidney disease.
1200
Total
US
NonUS
FIGURE 15-2
Kidney transplantations by diagnosis (October 1987 through
December 1994). Approximately 10,000 patients receive kidney
transplantations in a given year. Of the primary renal diseases
requiring transplantation, diabetes accounted for 22% of all kidney
transplantations performed in the United States. GNglomerulonephritis; HTNhypertensive nephropathy; PCKDpolycystic
kidney disease.
n=9012
n=6640
n=2372
157
774
1000
800
201
528
181
530
90
91
201
417
600
400
200
32
66
6
9
11
8
78
79
19
20
30
24
36
38
80
81
82
85
50
112
51
111
112
147
170
218
146
130
1027
115
1022
95
96
167
842
200
557
213
249
0
Pre78
83
84
85
86
87
88
89
Year
FIGURE 15-3
Pancreas transplantations per year. The number of pancreas transplantations performed per year in
the United States has been increasing. In 1995 and 1996, over 1000 pancreas transplantations were
performed in the United States. A smaller number were performed outside of the United States.
92
93
94
15.3
Kidney-Pancreas Transplantation
8000
INCLUSION CRITERIA FOR

PANCREAS TRANSPLANTATION
7000
Recipient number
6000
Type I diabetes mellitus

Ability to undergo the procedure
Emotional and psychological stability
Age less than 60 y
Secondary complications of diabetes
Financial resources
5000
4000
3000
2000
1000
0
1988
1989
1990
1991
1992
1993
1994
1995
Year
FIGURE 15-4
Relative proportion of simultaneous pancreas-kidney (SPK) transplantations versus cadaveric
kidney transplantations in the United States. Despite an increasing number of SPK transplantations over the past 7 years, pancreas transplantation is a less common procedure than is
cadaveric kidney transplantation alone.
1000
EXCLUSION CRITERIA FOR

PANCREAS TRANSPLANTATION
Number of transplants
800
Significant cardiac disease
Substance abuse
Psychiatric illness
History of noncompliance
Extreme obesity
Active infection or malignancy
No secondary complications of diabetes
FIGURE 15-5
The inclusion criteria for pancreas transplantation are relatively few. Patients usually have
type I diabetes mellitus and must have the
physical stamina to undergo a major abdominal operation. The patients age is important,
with 60 years of age usually being the cutoff.
In some transplantation centers, the cutoff
age is 50 years. The patient should demonstrate emotional and psychological stability,
and significant secondary complications of
diabetes must be present. Because Medicare
does not pay for pancreas transplantations,
recipients must use either private insurance or
personal funds.
SPK
PTA
PAK
600
400
200
FIGURE 15-6
The exclusion criteria for pancreas transplantation include significant cardiac disease,
substance abuse, psychiatric illness, and a
history of noncompliance. Extreme obesity,
active infection, and malignancy are relative
contraindications to transplantation. Patients
with few or very mild secondary complications of diabetes may be candidates for kidney
transplantation alone.
0
1988
1989
1990
1991
1992
1993
1994
1995
1996
Year
FIGURE 15-7
Types of pancreas transplantation procedures and relative frequency per year (January 1988
through December 1996). Three different indications for pancreas transplantation exist.
Patients with type I insulin-dependent diabetes who require kidney transplantation may
undergo a simultaneous pancreas-kidney (SPK) transplantation or receive a kidney transplantation followed by a pancreas transplantation during a separate operation (called pancreas
after kidney [PAK] transplantation). Patients without significant renal disease may undergo
pancreas transplantation alone (PTA). The relative proportion of the types of transplantations
is shown. Most pancreas transplantations performed in the United States are of the SPK type,
followed by PAK transplantations. Presently, few PTA transplantations are performed.
15.4
Transplantation Operation
FIGURE 15-8
Simultaneous pancreas-kidney allograft procedure. Most pancreas
transplantations performed in the United States are whole organ
pancreaticoduodenal allografts from cadaveric donors transplanted
simultaneously with the kidney from the same donor [1]. Because
the pancreas from a patient with diabetes still subserves digestive
function, it is not removed. Therefore, the pancreaticoduodenal
allograft is transplanted to an ectopic location, usually the right
iliac fossa. Similarly, the kidney allograft is transplanted ectopically
to the contralateral iliac fossa. The reconstructed arterial supply to
the pancreas, as shown in Figure 15-9, is anastomosed to the common
or external iliac artery. The portal vein of the allograft is anastomosed

to the common iliac vein or distal inferior vena cava. Likewise, on the
left side the renal artery and vein are anastomosed to the common
iliac artery and vein, respectively. To restore the continuity of the
urinary tract, a standard ureteroneocystostomy is constructed to the
dome of the bladder.
Because the pancreas has dual endocrine and exocrine functions,
it is necessary to perform another anastomosis to handle exocrine
secretions. A variety of techniques to manage pancreatic exocrine
secretions have been proffered over the years with less than satisfactory results. These include duct occlusion, open drainage into the
peritoneal cavity, and creation of a button of duodenum and anastomosing this or the pancreatic duct directly to the bladder. Currently,
the most commonly performed technique in the United States is
drainage of pancreatic exocrine secretions into the bladder (bladder
drainage, BD), as depicted [1]. The BD technique involves fashioning
a short segment of donor duodenum, which is transplanted along
with the pancreas. Then the donor duodenum is anastomosed to
the dome of the recipient bladder in a side-to-side manner. In this
way exocrine secretions, including enzymes, proenzymes, water,
and sodium bicarbonate, are diverted into the urinary tract. This
technique is safe, reliable, and well tolerated; however, it is associated
with a number of specific urinary tract complications.
As a consequence of implantation into the iliac fossa, the pancreatic
allograft is drained into the systemic venous circulation, as depicted.
This results in systemic venous, rather than portal venous, insulin
release and peripheral hyperinsulinemia. An alternative approach
practiced by some surgeons is portal venous drainage. In this
approach the portal vein of the allograft is anastomosed to the superior mesenteric vein of the recipient in an end-to-side fashion. This
technique establishes drainage of insulin into the portal venous
blood flow, perhaps a more physiologic situation (procedure not
shown). The results of the two techniques are largely comparable.
Fortunately, patients have suffered no adverse effects of systemic
venous drainage and hyperinsulinemia.
Solitary pancreaticoduodenal allografts are implanted into either
iliac fossa, at whichever point the iliac vessels permit vascular anastomoses. This procedure is done, usually and preferentially, on the
right side. Otherwise, the operative sequence duplicates that of the
combined procedure.
Ligated
splenic A and V
Splenic A
15.5
Iliac Y graft
Ligated CBD
SMA
Ligated SMA and SMV
FIGURE 15-9
Preparation of the pancreaticoduodenal allograft and arterial reconstruction. The donor pancreas, duodenum, and spleen are perfused in
situ with cold University of Wisconsin solution and harvested en bloc
with the liver. The pancreaticoduodenal graft is separated from the
liver graft and prepared on the surgical back table at 4oC. The spleen
is first removed by ligating the splenic artery and vein. The duodenal
segment is shortened to approximately 10 cm, and the suture lines are
reinforced. The common bile duct (CBD) and the superior mesenteric
artery and vein (SMA and SMV) have been ligated previously in the
donor. A variety of techniques exist to reconstruct the dual arterial
blood supply to the pancreas. In our experience, the most favorable
approach entails using an iliac artery bifurcation graft harvested from
the same donor. As shown, the external iliac arterial limb of the graft
is anastomosed to the SMA, and the hypogastric arterial limb is anastomosed to the splenic artery. This technique is reliable and associated
with a very low thrombosis rate. The venous anastomosis (portal vein
to iliac vein or inferior vena cava) can be performed without tension
by complete mobilization of both the donor portal vein and the recipient iliac vein. A venous extension graft is rarely necessary and probably increases the risk of thrombosis.
FIGURE 15-10
Enteric drainage (ED) technique. An alternative approach to bladder
drainage, ED is, perhaps, a more physiologic method of handling
pancreatic exocrine secretions. ED is the preferred method in Europe
and is rapidly gaining popularity in the United States [1]. Most
commonly, it is performed as depicted without a Roux-en-Y
anastomosis. The donor duodenal segment is anastomosed in a
side-to-side fashion to the ileum or distal jejunum. Long-term graft
survival, thrombosis rates, and primary nonfunction rates are no
different when comparing the two techniques [13]. Performed
with expertise, both techniques should yield excellent results.
Several significant advantages of the ED technique over bladder
drainage make ED our technique of choice.
15.6
COMPARISON OF BLADDER DRAINAGE VERSUS ENTERIC DRAINAGE TECHNIQUES

Bladder drainage (BD)
Enteric drainage (ED)
Advantages
Ability to monitor urinary amylase levels as an indicator of rejection [6]
?Decreased risk of perioperative intra-abdominal infections
Advantages
No need for enteric conversion in up to 25% of patients who have urologic
complications
Less metabolic acidosis and chronic dehydration [3]
Shorter length of hospital stay secondary to less dehydration
Early removal of urinary catheter and fewer UTIs
Ability to perform portal venous drainage, if desired
Disadvantages
?Increased risks of perioperative peripancreatic infections
Difficult to diagnose pancreatic enzyme leaks
Disadvantages
Risks of developing urologic complications in up to 25% of patients, including urethritis,
urethral disruption, and hematuria
Risk of recurrent UTIs greater for BD than for ED [3]
Prolonged urinary catheter drainage needed to decompress bladder anastomosis
for healing
Frequent postoperative admissions for dehydration and metabolic acidosis and need for
bicarbonate replacement
UTIsurinary tract infections.
FIGURE 15-11
Early attempts using enteric drainage (ED) techniques resulted in
prohibitively high rates of intra-abdominal abscesses, wound infections,
and mycotic aneurysms threatening both graft and patient. Thereafter,
bladder drainage (BD) via a duodenocystostomy evolved in the
United States as the safest and most frequently performed exocrine
drainage procedure. It has been suggested that BD affords the ability
to monitor urinary amylase levels as an indicator of rejection, which
may be useful in the setting of a solitary pancreas transplant. However,
in recipients of simultaneous pancreas-kidney (SPK) transplant in
whom kidney function serves as a marker of rejection monitoring of
urinary amylase levels is not necessary to achieve excellent long-term
graft survival.
As experience grew with BD, however, it was found that up to
25% of patients with BD developed a significant urologic or metabolic
complication requiring surgical conversion of exocrine secretions to
ED [4,5]. Renewed interest in primary ED has resulted. Several
recent retrospective studies have compared BD pancreas transplants

to ED transplants. These studies have demonstrated equivalent
short-term graft survival rates without increased risks of infectious
complications and pancreatic enzyme leaks [13]. ED is associated
with fewer urinary tract infections (UTIs) and no hematuria.
Patients who have ED experience less dehydration and metabolic
acidosis and, as a result, a reduced need for fluid resuscitation and
bicarbonate supplementation [3]. Finally, in patients who have ED
the Foley catheter can be removed within several days, whereas
patients who have BD require prolonged drainage (up to 14 days)
to permit healing of the duodenocystostomy. Consequently, with
ED, patients are able to leave the hospital sooner. ED has proved
to be more physiologic and results in less morbidity compared
with BD. Therefore, ED is rapidly gaining popularity as the
method of choice for handling graft exocrine secretions in
pancreas transplantation.
15.7
Immunosuppression and Monitoring

IMMUNOSUPPRESSIVE PROTOCOLS
SPK
PAK and PTA
ATGAM (20 mg/kg/d for 10 d)

MMF (3 g/d)
Neoral (8 mg/kg/d)
Prednisone (500 mg intraoperatively; 250
mg on postoperative days 1 and 2; 30
mg/d thereafter)
ATGAM (20 mg/kg/d for 10 d) or

OKT3 (510 mg/d for 10 d)
MMF (2 g/d)
FK506 (8 mg/d)
Prednisone (500 mg intraoperatively; 250
mg on postoperative days 1 and 2; 30
mg/d thereafter)
ATGAMantithymocyte globulin, polyclonal serum; FK506 tacrolimus, Prograf

(Fujisawa USA, Inc., Deerfield, IL); MMFmycophenolate mofetil, RS-61443, CellCept
(Roche Laboratories, Nutley, NJ); OKT3muromonab, murine antihuman CD3 monoclonal antibody; PAKpancreas after kidney transplantation; PTApancreas transplantation alone; SPKsimultaneous pancreas-kidney transplantation.
FIGURE 15-12
Because the best treatment of rejection is prevention, the most efficacious regimen of immunosuppressive drugs should be used first.
Quadruple-drug immunosuppressive regimens, including the use
of antithymocyte globulin (ATGAM) or OKT3, have been accepted
as standard at most pancreas transplant centers. Recent data from
the United Network for Organ Sharing and several smaller retrospective comparative trials provide evidence that antiT-cell antibody
induction therapy may lessen the severity and delay the onset of
rejection and may improve short-term graft survival in recipients of
simultaneous pancreas-kidney (SPK) transplants [1,7,8]. This is the
current practice. The development of newer more specific immunosuppressive agents, however, recently has changed the face of modern immunosuppression in solid organ transplantation and raises
the possibility of successful pancreas transplantation without
induction therapy. Mycophenolate mofetil (MMF) has recently
replaced azathioprine (AZA) as maintenance immunosuppressive
therapy in kidney transplantation alone, SPK, and pancreas transplantation alone. MMF is a potent noncompetitive reversible
inhibitor of inosine monophosphate dehydrogenase (IMPDH).

IMPDH is an essential enzyme in the de novo purine synthetic
pathway upon which lymphocyte DNA synthesis and proliferation
are strictly dependent. Compared with AZA, MMF has no association with pancreatitis and has less association with leukopenia.
Moreover, whereas AZA is not useful in treating ongoing rejection,
MMF can salvage refractory acute renal allograft rejection in up to
half of patients. By virtue of this mechanism of action, MMF provides
more effective and specific immunosuppression with less risk compared with AZA.
Similarly, Neoral, a microemulsified formulation of cyclosporine
(CsA) has replaced standard CsA therapy with Sandimmune (both
drugs from Sandoz Pharmaceuticals, East Hanover, NJ). Because of
gastroparesis and autonomic dysfunction, patients with diabetes exhibit
unpredictable absorption of CsA. The new formulation of CsA
has an increased rate and extent of drug absorption with lower
inter- and intra-individual pharmacokinetic variability than does
Sandimmune, particularly in patients with diabetes. Improved
bioavailability and more reliable pharmacokinetics may translate
into fewer rejection episodes and improved graft survival. Experience
with tacrolimus (FK506) in pancreas transplantation for induction,
maintenance, and rescue therapy has demonstrated that it is safe,
well tolerated, and has a low risk of glucose intolerance. Moreover,
particularly for solitary pancreas transplants, strikingly improved
short-term graft survival results have been reported [9,10]. The
mechanism of action of FK506 as a calcineurin inhibitor is similar
to that of CsA. FK506 has a better side-effect profile compared
with CsA, causing less hirsutism, less hyperlipidemia, but somewhat more neurotoxicity. Unlike CsA, FK506 can rescue patients
with refractory rejection and treat ongoing rejection. One caveat
when using FK506 in combination with MMF is the risk of overimmunosuppression. Several studies have highlighted the fact that
FK506 may increase blood levels of the active metabolite of MMF,
mycophenolic acid, in a clinically relevant manner [11]. By reducing
the incidence of rejection, these modern immunosuppressants have
resulted in improved short- and long-term graft survival. Fewer
rejection episodes will likely translate into an overall reduction in
the glucocorticoid dosage being given in the perioperative period.
This reduction may favorably impact short-term infectious complications and long-term steroid-related adverse side effects.
15.8

Pancreas transplantation biopsy. Pancreas allograft biopsy is the
gold standard for evaluating pancreas allograft dysfunction and for
diagnosing acute rejection. In a pancreas transplantation recipient,
indications for the need of a biopsy to rule out rejection include
elevated amylase or lipase levels, unexplained fever, and glucose
intolerance. In patients with simultaneous pancreas-kidney (SPK)
transplantation, pancreas rejection most commonly (about 90%)
occurs simultaneously with kidney rejection. As a result, a diagnosis
of rejection relies almost entirely on serum creatinine, b2-microglobulin,
and renal allograft biopsy. However, in the setting of sequential
pancreas after kidney transplantation or pancreas transplantation
alone (PTA) in which isolated pancreas rejection occurs, predicting
rejection with a serologic or urinary marker is more difficult. To date,
no marker has been identified that can predict rejection accurately
enough to warrant treatment without first performing a biopsy. Thus,
the ability to perform pancreas allograft biopsy is essential in the
postoperative care of recipients of PTA. In addition to a biopsy, radiologic evaluation of the allograft with ultrasonography (to evaluate
vascular flow) and computed tomography (CT) scan (to rule out pancreatic enzyme leaks and fluid collections) are complementary studies
that deserve consideration for all episodes of allograft dysfunction.
Percutaneous core biopsies of the pancreas allograft with realtime ultrasonography or CT guidance have been shown to be safe
and reliable [1214]. A and B, After the gland is assessed for vascular patency an appropriate portion of the pancreas is identified that
is free of major vessels and overlying viscera (usually the body or
tail). C, A 20-gauge automated biopsy needle is advanced into the
pancreas graft under real-time ultrasonography, and a biopsy is
obtained. In pancreaticoduodenal grafts with bladder drainage (BD)
a cytoscopic transduodenal biopsy offers the opportunity to obtain
biopsy specimens from both the pancreas and duodenum. Success
rates for obtaining tissue for pathologic review in both techniques
are 85% to 95%. Firm adherence of the pancreas to surrounding
structures and use of real-time ultrasonography reduce the risks of
complications related to biopsy. Overall, complications occur in 5%
to 10% of patients, which can include bleeding, pancreatic duct
leak, hematuria (in BD pancreas transplants), and asymptomatic
transient hyperamylasemia. Rarely does a complication require a
repeat operation or result in graft loss.
15.9
Management of Complications
C
FIGURE 15-14
Pancreas allograft rejection. Rejection occurs with greater frequency
after pancreas and simultaneous pancreas-kidney (SPK) transplantation than after kidney transplantation alone, predictably in 75%
to 85% of patients. This difference requires a strategically different
approach that balances aggressive immunosuppression against risks

of infection. A diagnosis of rejection is dependent on biopsy of
either the kidney or pancreas allograft in recipients of SPK transplantation or of the pancreas allograft in pancreas transplantation
alone. Because of the double-edged sword of aggressive antirejection
treatment, an episode of graft dysfunction should not be treated
without biopsy-proven histopathologic evidence of immunologic
graft injury. Ruling out infectious and anatomic causes of graft
dysfunction with appropriate radiologic studies is equally important.
Drachenberg and coworkers [15] and Nakhleh and Sutherland [16]
have defined histologic criteria for grading pancreas allograft rejection
that are practical from the standpoint of being able to prognosticate
outcome and response to therapy. Serial histologic studies of pancreas
rejection (as in this case) have shown that lymphocytic infiltrates
initially involve the exocrine portion of the gland and that islet cell
tissue becomes involved later [12]. As a result, exocrine dysfunction
is frequently the first clinical sign of rejection (manifested by either
elevated serum amylase or decreased urinary amylase levels).
Consequently, early rejections without evidence of islet cell involvement usually can be treated successfully. On the contrary, the success
of antirejection treatment is far less successful when initiated after
the development of hyperglycemia [17].
A, Normal pancreas allograft core biopsy demonstrating an acinar
lobule and preserved individual islet of Langerhans without inflammatory infiltrate (magnification 3 200). B, Needle core biopsy
demonstrating glandular architecture with fibrous septae interdigitating between acinar lobules. An infiltrate is present that can be
described as mononuclear, predominantly lymphocytic, perivascular,
and septal. Endothelialitis is seen in a medium-sized vein at the
upper central edge of the biopsy specimen. These features are consistent with mild acute cellular rejection (magnification 3 200).
C, Needle core biopsy demonstrating intense septal inflammation
with activated lymphocytes. Early acinar inflammation is present
in the right upper lobule. Eosinophils also are present in the dense
septal infiltrate. These findings also are consistent with mild acute
cellular rejection (magnification 3 200). Moderate rejection is
characterized by significant acinar inflammation and arteritis.
Severe rejection is suggested when, in addition to the features listed
above, confluent acinar necrosis with extensive acinar inflammation
and ductal epithelial necrosis are present.
Features indicating a poor prognosis include arteritis, confluent
acinar necrosis, islet inflammation and necrosis, ductal epithelial
necrosis, and fibrosis. Mild acute rejection usually is reversible
with bolus corticosteroid therapy. In contrast to renal allograft
rejections, however, most mild pancreas allograft rejections are
somewhat recalcitrant to bolus steroid immunotherapy. Steroids
may worsen potentially compromised glycemic control, thus complicating treatment. Therefore, significant rejection of the pancreas
allograft may be best treated with antibody therapy, although a
randomized control trial comparing the two treatment options
has not been carried out. FK506 is commonly employed as rescue
therapy in pancreas transplant episode recipients who are experiencing a significant acute rejection episode while on cyclosporine
or Neoral (Sandoz Pharmaceuticals, East Hanover, NJ). Irreversible
allograft rejection was a frequent occurrence several years ago.
Today, it is unusual, occurring in less than 5% of patients.
15.10
Indications for enteric conversion

Metabolic
acidosis
2%
Reflux
pancreatitis
Recurrent
3%
urinary
Hematuria
19%
Urethritis
23%
tract
infections
11%
Leak
42%
FIGURE 15-15
Indications for enteric conversion (EC). A set of complications unique to pancreas transplantation arise as a consequence of urinary diversion of graft exocrine secretions. The
development of one of these complications is the most frequent cause for re-admission to
the hospital after pancreas transplantation with BD. These include the following: persistent
gross hematuria, recurrent or chronic urinary tract infections (UTIs), urethritis, urethral
stricture or disruption, urinary or pancreatic enzyme leak, graft (reflux) pancreatitis, and
excessive bicarbonate loss and acidosis [18]. Surgical conversion to ED is indicated when these
complications are incapacitating or refractory to conservative therapy. Except for leaks
and pancreatitis, these complications are largely avoided in ED pancreas grafts.
Hematuria in the immediate postoperative period is usually mild and self-limited, occasionally requiring irrigation, cytoscopic fulguration, or both. Hematuria occurring late
after transplantation (ie, months to years) may be caused by UTIs, suture granulomas,
bladder stones, or ulceration of the duodenal segment. In total, hematuria occurs in 17%
of patients. Conversion to ED is indicated when hematuria persists despite appropriate therapy
and is required in up to a third of patients who present with late or chronic hematuria.
Pancreatic enzyme or urinary leaks also can occur in the early postoperative period or as
late as several years after transplantation. Early leaks usually occur at the bladder-duodenum
suture line, whereas late leaks occur most commonly at the lateral duodenal staple line or
at the location of a duodenal ulcer. The cause is unclear. Whereas some early leaks may be
technically related, late leaks are more likely a result of rejection, cytomegalovirus infection,
ischemia, or a combination of all these. Patients usually present with sudden-onset lower
abdominal pain, fever, leukocytosis, increased serum amylase and slightly increased creatinine.
Diagnosis is confirmed by cystogram (see Fig. 15-17). Fortunately this complication is
unusual, occurring in 10% to 15% of patients.
The most common infectious complication after pancreas transplantation is UTI, occurring
in 63% of pancreas transplant recipients with BD. These recipients may be more predisposed
to UTIs than are kidney transplant recipients because of the additive effect of several factors.
These factors include alkalinization of the urine secondary to bicarbonate exocrine secretion,
presence of a diabetic neurogenic bladder with incomplete emptying, mucosal injury at the
bladder anastomosis, and prolonged catheter drainage. Occasionally, a cause for therapyresistant or recurrent infections is found on cystoscopy and study of the upper tracts also
is indicated. When no source is found, EC is indicated.
If persistent, urethritis may result in urethral stricture, disruption, or both. Although its
exact cause is unclear, urethritis is most likely caused by the digestive action of pancreatic
enzymes on the urothelium. Urethritis usually is manifested as perineal pain and discomfort
during urination and seems to occur almost exclusively in males. Initially, conservative
treatment with Foley catheter drainage for several weeks is recommended. When perforation
occurs, it usually is in the membranous portion of the urethra and presents with perineal
and testicular swelling. To avoid complications of urethral stricture and disruption, early
enteric conversion is recommended when urethritis fails to respond to an initial short
course of conservative treatment. Fortunately, these complications are unusual, occurring
in only 5% of simultaneous pancreas-kidney (SPK) transplantation recipients.
Early postoperative hyperamylasemia, thought to be caused by preservation injury, is not
uncommon and, fortunately, usually is asymptomatic and improves rapidly. Persistent or
marked elevations of amylase indicate possible technical errors, including ductal ligation
or leak. Graft pancreatitis (sometimes referred to as reflux pancreatitis) presents in a manner
similar to that of a leak. Graft pancreatitis is further defined by absence of a leak on radiologic study; evidence of gland edema on CT scan, without evidence of abscess or fluid
collections; and; most important, resolution of symptoms within 48 hours of Foley catheter
drainage. Treatment with Foley catheter drainage for several days is usually successful. When
an infection is found in the patients urine at this time, appropriate parenteral antibiotics
may be beneficial.
Metabolic acidosis is present postoperatively in about 80% of patients after pancreas
transplantation with BD and usually is due to excessive urinary loss of bicarbonate-containing
exocrine fluids. Because urinary bicarbonate loss is accompanied by an obligate loss of
fluid, low serum levels are associated with dehydration. Oral fluid replacement should be
instituted to maintain a serum bicarbonate level of at least 20 to 25 mg/dL, and dehydration
is treated appropriately. Fortunately, this problem usually stabilizes over time and infrequently
requires conversion from bladder to enteric drainage.
1.0
0.9
Percent
Fraction of patients converted
0.8
0.7
0.6
0.5
Time to EC
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.4
15.11
4 5
Years
0.3
0.2
Duodenum
Side to side
duodenoenterostomy
0.1
Kaplan-Meier rate = 28%
0.0
0
7 8
Years
10 11 12 13 14 15
FIGURE 15-16
Incidence and procedure in enteric conversion (EC). A, Surgical
conversion of pancreatic exocrine secretions from bladder drainage
to enteric drainage is necessary in many patients. Whereas half of
patients receive EC within the first postoperative year, a significant
percentage must undergo EC up to 5 years after transplantation.
B, EC involves taking down the duodenocystostomy, repairing the
bladder, and performing a simple side-to-side duodenoenterostomy.
In our experience of performing 95 ECs over a 14-year period in
Bladder
480 simultaneous pancreas-kidney (SPK) transplant recipients, only

one graft was lost within 3 months of EC [5]. No differences were
found in patient, kidney, or pancreas graft survival when comparing SPK transplant recipients who underwent EC with those who
did not. The frequency of urologic complications and need for EC
have prompted a changing trend toward performing primary
enteric drainage; however, neither of these problems appears to
impact negatively on graft survival.
FIGURE 15-17
Pancreatic enzyme and urinary leaks. A leak of urine, activated pancreatic enzymes, or both,
is one of the most devastating and life-threatening infectious complications after pancreas
transplantation. Patients exhibit sudden-onset lower abdominal pain, fever, leukocytosis,
increased serum amylase levels, and increased serum creatinine levels. Diagnosis is confirmed
by cystogram. When no leak is identified, voiding cystourethrography (VCUG) with gastrograffin (panel A) or a VCUG using technetium (Tc99m) in normal saline is performed (panels BE).
15.12

In our opinion, a Tc99m-VCUG is the most sensitive test, because
extravasation may occur only during the high-pressure phase of voiding [19]. B, This gastrograffin-VCUG demonstrates duodenal segment
and anastomosis in the region of the dome of the bladder in an
oblique anteroposterior projection. A leak of contrast is identified at
the lateral duodenal segment staple line. B and C, Normal Tc99mVCUG scintigraphy is shown. Radioactive tracer is seen within the
confines of the intact urinary tract, refluxing into the duodenal segment (large black arrow) and renal transplantation collecting system (small black arrow). D and E, Tc99m-VCUG demonstrates spill
of radioactive tracer outside of the bladder and duodenal segment
(large white arrowhead). Later, radioactive tracer is also present in
the pelvis and between loops of bowel throughout the peritoneal
cavity (small white arrowheads).
For small leaks that are contained early, treatment consists of
bladder decompression with a urinary catheter for 2 to 3 weeks.
Large leaks and those that recur after conservative therapy require
exploration, repair of the involved suture line, and enteric conversion.
Careful inspection of the duodenal segment is essential, and biopsy

of the duodenal mucosa to search for rejection or cytomegalovirus
pathology may be revealing in determining the cause. In most cases,
however, the exact cause remains enigmatic despite careful investigation. In some cases, simultaneous diversion of the fecal stream
with a Roux-en-Y anastomosis or proximal ileotransverse colostomy is advocated. Rarely is a urinary leak secondary to disruption
of the ureteroneocystostomy. Enzyme leaks are more difficult to
diagnose in enterically drained pancreata. A diagnosis in this setting
relies on contrast-enhanced computed tomography (CT) scan, which
usually demonstrates peripancreatic fluid collections. When drained
percutaneously, these fluid collections reveal infection with enteric
organisms and an elevated fluid amylase level. Surgical treatment
of leaks in ED pancreata requires an individualized approach that
usually involves repair, drainage, and diversion of the fecal stream.
An expeditious diagnosis, depending on a high index of suspicion,
and aggressive surgical intervention are essential to manage these
life-threatening complications.
15.13
FIGURE 15-18
Urethral disruption. When left untreated, urethritis usually progresses to urethral disruption.
Retrograde urethrography in a recipient of a simultaneous pancreas-kidney transplant with
bladder drainage demonstrates perforation of the membranous urethra with extensive
extravasation of contrast. Immediate treatment is placement of a suprapubic cystostomy
or, if possible, a Foley catheter. Enteric conversion follows, which is 100% successful.
Sequelae of this process include stricture and bladder outlet obstruction.
FIGURE 15-19
Patient and graft survival rates for simultaneous pancreas-kidney
(SPK) transplantations in the United States. The survival rates have
improved over the past 10 years. The current 1-year patient survival
rate for SPK is 94% (panel A), with an 89% kidney graft survival
rate (panel B) and 82% pancreas graft survival rate (panel C). The
differences over time are highly significant between all eras.
SPK patient survival by era

US cadaveric pancreas transplantations 10/1/19877/31/1997
100
90
80
70
Years
8789
9091
9293
9497
60
50
n Txs
532
908
1125
2387
1 Yr surv.
90%
91%
92%
94%
P = 0.002
40
0
12
18
24
30
36
42
Months posttransplantation
48
54
60
SPK pancreas graft function by era

100
80
60
Years
8789
9091
9293
9497
40
20
n Txs
532
908
1125
2387
1 Yr surv.
74%
75%
79%
82%
P = 0.0001
0
0
12
18
24
30
36
42
48
54
60
SPK kidney graft function by era

100
90
80
70
Years
8789
9091
9293
9497
60
50
n Txs
532
908
1125
2387
1 Yr surv.
86%
84%
86%
89%
P = 0.004
40
0
12
18
24
30
36
42
48
54
60
15.14
100
PAK patient survival by era
PTA graft function by era
100
90
80
60
70
Years
8789
9091
9293
9497
60
50
n Txs
77
76
84
209
1 Yr surv.
90%
96%
90%
95%
12
20
P = NS
18
24
30
36
42
48
54
P 0.0001
0
0
60
12
Years
8789
9091
9293
9497
80
n Txs 1 Yr surv.
77
56%
76
51%
84
52%
209
70%
%
20
70
Years
8789
9091
9293
9497
50
P 0.008
0
6
12
18
24
30
36
42
48
54
EFFECTS OF PANCREAS TRANSPLANTATION ALONE

ON SECONDARY COMPLICATIONS OF DIABETES
Beneficial
Stabilization and improvement
Beneficial
Major
None
Minimal
n Txs
46
49
72
92
1 Yr surv.
93%
90%
90%
93%
P = NS
40
0
60
FIGURE 15-20
Patient (panel A) and graft (panel B) survival rates for sequential
pancreas after kidney (PAK) transplantations. For patients with
PAK, the survival rate is similar to simultaneous pancreas-kidney
transplantations but graft survival has been poorer until very
recently. The 1-year PAK graft survival rate has improved from
52% to nearly 70%. NSnot significant.
Maintenance of normoglycemia
Neuropathy
Prevention of recurrent nephropathy
Quality of life
Retinopathy
Vascular disease
60
80
60
54
90
40
48
100
60
18
24
30
36
42
PTA patient survival by era
PAK graft function by era

100
1 Yr surv.
46%
51%
56%
74%
40
40
n Txs
46
49
72
92
Years
8789
9091
9293
9497
80
12
18
24
30
36
42
48
54
60
FIGURE 15-21
Graft (panel A) and patient (panel B) survival rates for pancreas
transplantation alone (PTA). A much smaller number of PTAs
have been performed in the United States compared with sequential
pancreas after kidney (PAK) transplantations and simultaneous
pancreas-kidney (SPK) transplantations. The patient survival rate
for PTA is similar to those of SPK and PAK transplantation; however, the PTA graft survival rate has been closer to that of the PAK rate
until the most recent transplantation era. Advancements in immunosuppressive therapy have improved the 1-year graft survival rate of
PTA transplantations from 56% to 74%. NSnot significant.
FIGURE 15-22
Multiple studies have been performed on the effects of pancreas
transplantation on the secondary complications of diabetes.
Unfortunately, most of these studies were performed with small
numbers of patients and were not randomized controlled studies.
There are four major benefits of pancreas transplantation for the
secondary complications of diabetes: 1) Normoglycemia has been
demonstrated for an extended period of time as long as the pancreas is functioning; 2) nephropathy has been shown to improve;
3) pancreas transplantation appears to prevent recurrent diabetic
nephropathy in the transplanted kidney; and 4) quality of life.
Complete freedom from insulin injections, appears to be the
major benefit of pancreas transplantation. Unfortunately, pancreas
transplantation does not appear to reverse established diabetic
nephropathy in patients with their own kidneys, and established
retinopathy and vascular disease do not appear to improve.
Hemoglobin A1,
% of total hemoglobin
FIGURE 15-23
Glycosylated hemoglobin before and after pancreas transplantation. All patients have an
abnormal hemoglobin A1 value before pancreas transplantation. Most patients, however,
maintain a normal hemoglobin A1C after successful pancreas transplantation. (From
Morel and coworkers [20]; with permission).
16
14
12
10
8
6
4
Before
transplantation
124 mo
266 mo
After
transplantation
100
Motor index
1.0
1.5
2.0
2.5
0.5
Percent eyes with stable

retinopathy grade
0.5
15.15
75
50
25
Pancreas transplant
Control
0
0
12
24
42
12
24
36
48
60
Time following pancreas transplantation, mo
72
Sensory index
1.0
1.5
2.0
2.5
Autonomic index
0.5
12
24
42
Kidney pancreas
Control
1.0
1.5
2.0
2.5
0
12
24
Months
42
FIGURE 15-24
Effects of pancreas transplantation on diabetic neuropathy. Careful
studies of motor index (panel A), sensory index (panel B), and
autonomic index (panel C) show a general trend of improvement
over 42 months in patients who received pancreas transplantation
compared with patients in the control group. In patients with pancreas transplantation, 70% had improved results on motor nerve
tests, nearly 60% on sensory tests, and 45% on autonomic tests.
In patients in the control group, only 30% had improved results
on motor and sensory tests, 12% had improved autonomic tests,
and nearly 50% had deterioration of neurologic function. (From
Kennedy and coworkers [21]; with permission).
FIGURE 15-25
Effects of pancreas transplantation on diabetic retinopathy.
Retinopathy does not appear to improve after pancreas transplantation. A similar rate of deterioration was observed in both
patients who had successful pancreas transplantation compared
with patients with diabetes who had kidney transplantation alone.
(From Ramsay and coworkers [22]; with permission).
15.16
0.5
2p = 0.02
4
3
2
1
0
0.2
0.0
Kidney alone
Kidney/ pancreas
0.7
Kidney alone
FIGURE 15-26
Effects of pancreas transplantation on
recurrent diabetic nephropathy. Pancreas
transplantation appears to prevent the
subsequent development of diabetic
nephropathy in renal allografts [23]. Both
mean glomerular volume (panel A) and
mesangial volume (panel B) were significantly lower in patients with successful
pancreas transplantation compared with
recipients with diabetes who had unsuccessful pancreas transplantation.
Kidney/ pancreas
0.5
0.4
0.3
0.2
0
1.8
Total mesangium per glomerulus, 106 m3
Mean glomerular volume, 106 m3
3.5
0.6
Mesangial fractional volume
0.3
0.1
2p = 0.004
0.4
Mesangium volume
Glomerular volume
3.0
2.5
2.0
1.5
1.0
Baseline 5 y
Comparison group
1.2
0.9
0.6
0.3
0
0
Baseline 5 y
Pancreas transplant
recipients
1.5
Baseline 5 y
Pancreas transplant
recipients
FIGURE 15-27
Effects of pancreas transplantation on established diabetic
nephropathy. Although there appears to be a benefit in the
prevention of diabetic nephropathy, there does not appear to be
a benefit in patients who undergo pancreas transplantation in
reversing established diabetic glomerular lesions. In this study,
Baseline 5 y
Comparison group
Baseline 5 y
Pancreas transplant
recipients
Baseline 5 y
Comparison group
mesangial fractional volume increased (panel A) and mean

glomerular volume decreased (panel B) in pancreas transplantation
recipients but no significant change in total mesangial volume
(panel C) occurred over a 5-year follow-up. (From Fioretto and
coworkers [24]; with permission).
Effects of pancreas transplantation on
microvascular disease. The benefits of
pancreas transplantation on vascular
disease have been variable. A, In this study,
thermography demonstrated a clear-cut
improvement in diabetic microvascular
disease after successful pancreas transplantation [25]. B, However, no evidence exists
that successful pancreas transplantation
results in the regression of established
macrovascular disease.
15.17
References
1. Gruessner A, Sutherland DER: Pancreas transplantation in the United
States (US) and Non-US as reported to the United Network for Organ
Sharing (UNOS) and the International Pancreas Transplant Registry
(IPTR). In Clinical Transplants 1996. Edited by Cecka JM, Terasaki
PI. Los Angeles: UCLA Tissue Typing Laboratory; 1996:4767.
2. Kuo PC, Johnson LB, Schweitzer EJ, Bartlett ST: Simultaneous pancreas/
kidney transplantation: a comparison of enteric and bladder drainage
of exocrine pancreatic secretions. Transplantation 1997, 63:238243.
3. Odorico JS, Becker YI, Van der Werf WJ, et al.: Advances in pancreas
transplantation: the University of Wisconsin experience. In Clinical
Transplants 1997. Edited by Terasaki PI, Cecka JM. Los Angeles:
UCLA Tissue Typing Laboratory; 1998:157166.
4. Sollinger HW, Messing EM, Eckhoff DE, et al.: Urological complications
in 210 consecutive simultaneous pancreas-kidney transplants with
bladder drainage. Ann Surg 1993, 218:561570.
5. Van der Werf WJ, Odorico JS, DAlessandro AM, et al.: Enteric
conversion of bladder drained pancreas allografts: experience in 95
patients. Transplantation Proc 1998, 30:441442.
6. Prieto M, Sutherland DER, Fernandez-Cruz L, et al.: Experimental and
clinical experience with urine amylase monitoring for early diagnosis of
rejection in pancreas transplantation. Transplantation 1987, 43:7379.
7. Brayman KL, Egidi MF, Naji A, et al.: Is induction therapy necessary
for successful simultaneous pancreas and kidney transplantation in the
cyclosporine era? Transplantation Proc 1994, 26:25252527.
8. Wadstrom J, Brekke B, Wramner L, et al.: Triple versus quadruple
induction immunosuppression in pancreas transplantation.
Transplantation Proc 1995, 27:13171318.
9. Bartlett ST, Schweitzer EJ, Johnson LB, et al.: Equivalent success of
simultaneous pancreas kidney and solitary pancreas transplantation.
A prospective trial of tacrolimus immunosuppression with percutaneous biopsy. Ann Surg 1996, 224:440449.
10. Gruessner RW, Burke GW, Stratta R, et al.: A multicenter analysis of
the first experience with FK506 for induction and rescue therapy after
pancreas transplantation. Transplantation 1996, 61:261273.
11. Zucker K, Rosen A, Tsaroucha A, et al.: Augmentation of mycophenolate mofetil pharmacokinetics in renal transplant patients receiving
Prograf and CellCeptin combination therapy. Transplantation Proc
1997, 29:334336.
12. Allen RDM, Wilson TG, Grierson JM, et al.: Percutaneous biopsy
of bladder-drained pancreas transplants. Transplantation 1991,
51:12131216.
13. Gaber AO, Gaber LW, Shokouh-Amiri MH, Hathaway D: Percutaneous

biopsy of pancreas transplants. Transplantation 1992, 54:548550.
14. Bernardino M, Fernandez M, Neylan J, et al.: Pancreatic transplants:
CT-guided biopsy. Radiology 1990, 177:709711.
15. Drachenberg CB, Papadimitriou JC, Klassen DK, et al.: Evaluation of
pancreas transplant needle biopsy. Transplantation 1997, 63:15791586.
16. Nakhleh RE, Sutherland DER: Pancreas rejection: significance of
histopathologic findings with implication for classification of rejection.
Am J Surg Pathol 1992, 16:10981107.
17. Stratta RJ, Taylor RJ, Weide LG, et al.: A prospective randomized
trial of OKT3 vs. ATGAM induction therapy in pancreas transplant
recipients. Transplantation Proc 1996, 28:927928.
18. Sollinger HW, Odorico JS, Knechtle SJ, et al.: Experience with 500
simultaneous pancreas-kidney transplants. Ann Surg 1998, 228:
284296.
19. Rayhill SC, Odorico JS, Heisey DM, et al.: A comparison of the sensitivities of contrast and isotope voiding cystourethrograms for the
detection of pancreas transplant bladder leaks. Transplantation Proc
1995, 27:31433144.
20. Morel P, Goetz FC, Moudry-Munns K, et al.: Long-term glucose
control in patients with pancreatic transplants. Ann Intern Med 1991,
115:694699.
21. Kennedy WR, Navarro X, Goetz FC, et al.: Effects of pancreatic
transplantation on diabetic neuropathy. N Engl J Med 1990,
322:10311037.
22. Ramsay RC, Goetz FC, Sutherland DER, et al.: Progression of diabetic
retinopathy after pancreas transplantation for insulin-dependent diabetes
mellitus. N Engl J Med 1988, 318:208214.
23. Bilous RW, Mauer SM, Sutherland DER, et al.: The effects of pancreas
transplantation on the glomerular structure of renal allografts in patients
with insulin-dependent diabetes. N Engl J Med 1989, 321:8085.
24. Fioretto P, Mauer SM, Bilous RW, et al.: Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic
patients with their own kidneys. Lancet 1993, 342:11931196.
25. Abendroth D, Landgraf R, Illner W-D, Land W: Evidence for
reversibility of diabetic microangiopathy following pancreas transplantation. Transplantation Proc 1989, 21:28502851.
Transplantation
in Children
Jeanne A. Mowry
enal transplantation in children has been considered the treatment of choice for end-stage renal disease for many years [1].
Successful transplantation allows for improved physical,
social, and psychological rehabilitation, enabling a child to have a
quality of life that usually is not attainable with dialysis.
Improvements in technology in pediatric transplantation have been
significant in the 1990s; however, owing to the inherent potential risks
and benefits, the optimal timing for transplantation needs to be individualized to the child. Currently, dialysis and transplantation need to
be viewed as complementary parts of each childs lifelong treatment
plan. Renal transplantation in children carries with it special issues
and problems that vary somewhat from those in adult transplantation. Because children are constantly growing and developing, technical, metabolic, immunologic, and psychological factors exist that are
unique to children and must be considered.
The current status of pediatric renal transplantation is reviewed,
summarizing immunosuppressive regimens, outcomes, and complications. Because of the low incidence of end-stage renal disease in children, much of the information available about current practices and
trends regarding pediatric renal transplantation has been collected by
national registries. To supplement the United States Renal Data
Source, the North American Pediatric Renal Transplant Cooperative
Study (NAPRTCS) was initiated in 1987 in an effort to capture information to improve the care of pediatric renal allograft recipients.
Current NAPRTCS data include information collected voluntarily
from 123 centers on 3066 children who received renal transplantation
on or after January 1, 1987 [2]. This registry has been helpful in providing a mechanism through which the clinical course of a large number of children can be evaluated.
CHAPTER
16
16.2
End-Stage Renal Disease

Frequency
FIGURE 16-1
The incidence of pediatric end-stage renal disease per million
population by age and gender and adjusted for race is depicted,
as reported by the United States Renal Data Source. This graph
shows the average rate per year, 1993 to 1995. (From United
States Renal Data System [3]; with permission.)
Rate per million population

per year
30
Male
Female
25
24
21
20
15
12
10 11
10
7
4
10
6
4
0
04
59
1014
1519
Age, y
Total 019
Etiology
DISEASES CAUSING END-STAGE RENAL DISEASE
Disease category
Children <18 years, %*
Urologic malformations
Renal dysplasia
Other congenital causes
Other glomerulonephritides and
immunologic diseases
Hypertensive nephropathy
All other causes
Adults 2064 years, % ,
26
17
15
11
14
4
0.3
5
2
17
0
0.1
17
22
40
10
FIGURE 16-2
Different diseases causing end-stage renal
disease in children and adults. The leading
causes of chronic renal failure in young
children are inherited disorders or congenital abnormalities of the urinary tract, especially obstructive uropathy and reflux
nephropathy. Focal segmental glomerulosclerosis and other glomerular disorders
are seen more often in older children.
Almost no children develop end-stage renal
disease as a result of diabetic nephropathy
and hypertension, the leading causes of
end-stage renal disease in adults. (From
Harmon [4]; with permission.)
*Data from North American Pediatric Renal Transplant Cooperative Study.

Data fromUnited States Renal Data Source.
Each age group, %
50
Age group 04 (n = 715)

Age group 519 (n = 4052)
44
40
37
30
20
10
17
21
15
13 13
11
5
13
0
GlomeruloCystic,
Interstitial Hypertension Collagen Other and
nephritis hereditary, nephritis and
and vascular unknown
and
pyelonephritis
disease
diseases
congenital
diseases
FIGURE 16-3
Data from the United States Renal Data Source of the incident
pediatric cases by disease group and age group (04 vs 519 years),
as a percentage of total pediatric end-stage renal disease within
each age group. The numbers on top of the bars indicate the percentage within each age group over 5 years, 1991 to 1995. (From
Transplantation in Children
FIGURE 16-4
Voiding cystourethrogram in a child with
posterior urethral valves showing gross
dilation of the posterior urethra with an
abrupt change in caliber at the level of the
external sphincter. Obstructive uropathy
is reported to be the cause of end-stage
renal disease in 16.5% of pediatric transplantation recipients (the primary cause
along with aplastic, hypoplastic, and dysplastic kidneys) in the North American
Pediatric Renal Transplant Cooperative
Study 1995 Annual Report. (Courtesy of
Philip Silberberg, MD.)
FIGURE 16-5
Voiding cystourethrogram in grade 5 reflux
nephropathy showing gross dilation of the
collecting system and blunting of the fornices.
Renal parenchymal scarring and destruction
usually occur before the age of 5 years but
may occur in older age groups. Intrarenal
reflux extends the vesicoureteric reflux into
the collecting tubules and nephrons, allowing
urinary access to the renal parenchyma that
can lead to renal scarring. (Courtesy of Philip
Silberberg, MD.)
16.3
FIGURE 16-6
Plain radiograph of a child with prune-belly
syndrome showing a markedly protuberant
abdomen. This syndrome, also referred to as
Eagle-Barrett syndrome or triad syndrome,
occurs almost exclusively in males. The three
classic physical findings are the deficiency of
the abdominal wall musculature, urinary
tract anomalies characterized by an extremely
dilated urinary tract, and bilateral intraabdominal testes. A wide spectrum in the
severity of abnormalities is seen, with most
children having some degree of renal dysplasia, along with bladder and ureteric dysplasias (partial or complex lack of smooth
muscle). (Courtesy of Philip Silberberg, MD.)
Rate of pediatric renal transplantations

per 100 dialysis patient-years
Transplantation Rates
FIGURE 16-7
Data from the United States Renal Data Source showing the 1995
rates of pediatric renal transplantations per 100 dialysis patientyears by recipient age. The rate of kidney transplantation varies
inversely with recipient age group. Emphasis is placed on living
related donors in the pediatric group with end-stage renal disease.
(From United States Renal Data System [3]; with permission.)
50
43
40
30
28
28
Living related donor

Cadaveric donor
33
31
22
20
24
27 26
16
11
10
0
04
59
1014
1519
Recipient age
Total
019
2044
(adult)
16.4

FIGURE 16-8
The national renal transplantation waiting list as of September
30, 1997. (From United Network for Organ Sharing Bulletin [6];
with permission.)
NUMBER OF PATIENTS ON
TRANSPLANTATION WAITING LIST
Age groups, y
Number, %
05
78
0.21
124
0.33
421
1.13
20,971
56.07
12,784
34.18
3026
8.09
37,404
610
1117
1849
5064
65+
Total
Renal Allograft Outcome

100
60
40
80
60
40
Primary
First repeat
20
Living donor
Cadaveric donor
20
100
Living donors
Graft survival, %
80
Graft survival, %
Graft survival, %
100
10
20
30
40
Follow-up, mo
50
60
FIGURE 16-9
The estimated graft survival probabilities by
allograft source from the 1995 North
American Pediatric Renal Transplant
Cooperative Study Annual Report. The overall median follow-up for patients with functioning grafts is 29 months. The estimated
graft survival probabilities have improved by
approximately 1 percentage point for cadaveric donor grafts compared with the data in
the 1994 report. For living related donor
grafts the estimated graft survival probabilities
are similar to those in the previous report at 1
and 2 years, and 1 percentage point higher at
4 years. (From Warady and coworkers [5];
with permission.)
12
24
36
48
Time posttransplantation, mo
80
60
40
Primary
First repeat
20
Cadaveric donors
60
12
24
36
48
60
FIGURE 16-10
Graft loss in young infants and children often caused by irreversible acute rejection
episodes. Rejection is, perhaps, a result of heightened immune response in this age group
[7]. Despite an improvement in graft survival in children over the past 5 years, the half-life
of renal grafts in pediatric patients remains around 10 years [8]. This half-life means that
many of these children will need a second transplantation in their lifetime. Depicted are the
North American Pediatric Renal Transplant Cooperative Study data stratifying the analysis
of the percentage of graft survival by donor source. A, Graft survival rates for living donor
transplantations, primary and first repeat. B, Survival rates for cadaveric donor source
transplantations. Graft survival rates for repeat transplantations did not correlate with
early or late failure of the primary graft. (From Tejani and Sullivan [9]; with permission.)
16.5
Factors Affecting Outcome

Donor Age and Source
Living donors
0 1 years
25 years
612 years
>12 years
110
100
Calculated clearance, mL/min per 1.73m2
90
80
FIGURE 16-11
Data from the North American Pediatric Renal Transplant Cooperative Study for pediatric kidney allograft function, measured as calculated creatinine clearance values for
both cadaveric and living donors. Regardless of the donor source, younger recipients
begin with higher calculated creatinine clearance values with a more rapid decline in
function. Older recipients have more stable calculated creatinine clearance values with
less of a decline in function.
70
60
50
Cadaveric donors
110
100
90
80
70
60
50
6 12 18 24 30 36 42 48 54 60
Follow-up, mo
0.0
RISK FACTORS ASSOCIATED WITH GRAFT FAILURE

In (relative risk)
0.2
Cadaveric donor
0.4
0.6
0.8
1.0
0
10
20
30
40
Cadaveric donor age, y
50
FIGURE 16-12
The relationship between cadaveric donor
age and the logarithm of the relative risk
of graft loss from all causes for pediatric
recipients of cadaver-donor renal transplantations. The perfect donor is 21 years of
age. The risk of graft loss is higher when the
grafts used are from either younger or older
donors. An equivalent risk of graft loss exists
from donors who are 6 and 55 years of age.
(From Harmon [10]; with permission.)
Recipient age (<2 y)

Donor age (<6 y)
Previous transplantation
ATG, ALG, OKT3 early administration (none)
More than 5 lifetime transfusions
No DR matches
Annual cohort (1992 vs 1987)
Relative risk increase
2.03
1.47
1.36
1.36
1.37
1.23
1.29
0.001
0.001
0.004
0.001
0.001
0.01
0.04
1.4
1.9
1.7
0.08
<0.001
<0.001

Recipient age <2 y
Black race
More than 5 previous transfusions
FIGURE 16-13
Risk factors associated with graft failure in a proportional hazards model for recipients of
donor grafts. ATGantithrombocytic globulin; ALGantilymphocytic globulin. (From
Warady and coworkers [5]; with permission.)
16.6
Recipient Age
FIGURE 16-14
Relationship between recipient age and the relative risk of graft loss for children who
receive cadaveric donor transplantation. A strong inverse relationship exists between the
risk of graft loss and recipient age, particularly in the group under 2 years of age. (From
1.0
0.9
Relative risk
0.8
0.7
0.6
0.5
0.4
0
6 8 10 12 14 16 18
Recipient age, y
Human Leukocyte Antigen Matching

No A, no B, no DR
No A, no B, DR match
A and B match, no DR
A and B and DR match
100
Graft survival, %
90
80
70
60
50
0
0.5
1.5
Time, y
2.5
FIGURE 16-15
Results of 4 years of experience monitoring outcomes by the North American Pediatric
Renal Transplant Cooperative Study. These results suggest a statistically significant beneficial effect of donor-related matching (P 0.05) when analyzing this allele with other
effects unique to pediatric patients with regard to age. This figure displays the subgroup
with a match at both the A and the B locus, or at neither, and compares that with the
effect of adding a donor-related (DR) antigen on the percentage of renal allografts
surviving after transplantation. Owing to the relatively short follow-up, small sample
size (1558 patients), and nonimmunologic factors pertinent to pediatric transplantation,
it is difficult to determine separate time-varying effects of class I versus class II matching.
However, it does seem clear that no antigen matching has a worse prognosis at 1 year
(72% graft survival) versus 1 or more antigen matching at each locus (1-year 81%
survival, 2-year 69% survival). (From McEnery and Stablein [11]; with permission.)
Preparation for Transplantation

Preemptive versus Previous Dialysis
100
Living donor
90
90
80
80
Graft survival, %
Graft survival, %
100
70
60
50
70
60
50
Preemptive
Prior dialysis
40
Preemptive
Prior dialysis
40
30
30
0
Cadaveric donor
10
20
30
40
50
10
20
30
40
50
FIGURE 16-16
Percentage of graft survival of initial living
(panel A) and cadaveric donor (panel B)
grafts in recipients with and without (preemptive) dialysis, indicating better survival
rates in those who did not receive dialysis
previously. The survival probabilities in the
preemptive group are significantly better
until adjustments are made for recipient
age (01 years vs others) and number of
previous transplantations (>5 vs 05) in
a proportional hazards model. (From Fine
16.7
Vaccinations
Hepatitis B (Hep B)
Hep B-1
Hep B-3
Hep B-2
Diptheria tetanus
pertussis (DPT)
H. influenzae
type b (Hib)
Polio
DTaP
or DTP
DTaP
or DTP
DTaP
or DTP
Hib
Hib
Hib
Polio
Polio
Hep B
DTaP or DTP
DTaP
or DTP
Hib
Polio
Polio
Measles-mumpsrubella (M-M-R)
M-M-R or
M-M-R
Var
Varicella (Var)
Birth
6
Age, mo
FIGURE 16-17
Infection remains a major cause of morbidity and mortality in pediatric transplantation recipients. Many infections can be successfully
prevented by immunization. The recommended US immunization
schedule for children (JanuaryDecember 1997) before transplantation is outlined. Diphtheria-tetanus-pertussis vaccine, Haemophilus
influenza type b vaccine, inactivated poliovirus vaccine, and hepatitis
B immunizations can be given after transplantation but their efficacy
may be suboptimal. The live attenuated vaccines, oral polio vaccine
(OPV), measles-mumps-rubella (M-M-R) vaccine, and varicella virus
vaccine, usually are recommended to be given only after immunosuppressive therapy has been discontinued for 3 months. Influenza A vaccines also should be administered yearly in the fall to pediatric transplantation recipients. The advent of the varicella virus vaccine may
decrease the chances of pediatric transplantation recipients developing
severe chickenpox and the incidence of zoster [13]. A recent survey
by the North American Pediatric Renal Transplant Cooperative Study
found that almost 90% of centers recommend the use of influenza
vaccine, whereas only 60% of centers recommend pneumococcal
Td
12
15
M-M-R
Var
18
4-6
11-12
14-16
Age, y
vaccine for children with renal disease. Between 5% and 12% of

centers recommend live viral vaccines, including OPV, M-M-R vaccine,
and varicella virus vaccine, for immunosuppressed patients after renal
transplantation. (From Furth and coworkers [14]; with permission.)
Vaccines are listed under the routinely recommended ages. Bars indicate the range of acceptable ages for vaccination. Shaded bars indicate
catch-up vaccination: at 11 to 12 years of age, hepatitis B vaccine
should be administered to children not previously vaccinated, and varicella virus vaccine should be administered to children not previously
vaccinated who lack a reliable history of having had chickenpox. This
schedule indicates the recommended age for routine administration of
currently licensed childhood vaccines. Some combination vaccines are
available and may be used whenever administration of all components
of the vaccine is indicated. Providers should consult the manufacturers
package inserts for detailed recommendations. Approved by the
Advisory Committee on Immunization Practices (ACIP), American
Academy of Pediatrics (AAP), and American Academy of Family
Physicians (AAFP). (See Red Book [13] for more information.)
16.8
Immunosuppression
IMMUNOSUPPRESSIVE THERAPY AND FUNCTIONING GRAFTS
Month 6 (n = 2999)
Month 12 (n = 2606)
Month 24 (n = 1915)
Month 36 (n = 1358)
Month 48 (n = 890)
Month 60 (n = 543)
Treated, % MMD*
Treated, % MMD*
Treated, % MMD*
Treated, % MMD*
Treated, % MMD*
Treated, % MMD*
Prednisone
Living donor
Cadaveric donor
Cyclosporine
Living donor
Cadaveric donor
Azathioprine
Living donor
Cadaveric donor
96
96
97
93
90
95
88
87
89
0.28
0.27
0.29
6.81
6.94
6.73
1.69
1.69
1.69
95
94
97
92
90
94
88
86
90
0.22
0.21
0.22
6.15
6.26
6.06
1.67
1.67
1.66
95
94
96
90
87
93
88
87
90
0.19
0.18
0.19
5.49
5.37
5.58
1.66
1.69
1.62
95
95
95
89
86
92
88
87
89
0.17
0.17
0.17
4.99
4.88
5.08
1.64
1.67
1.58
95
96
94
88
85
90
89
89
87
0.16
0.16
0.16
4.69
4.28
4.89
1.68
1.73
1.64
96
97
95
87
81
92
88
86
90
0.15
0.15
0.16
4.52
4.29
4.65
1.64
1.76
1.57
*MMDmedian daily doses, in mg/kg.
FIGURE 16-18
Data from the North American Pediatric Renal Transplant
Cooperative Study on immunosuppressive therapy and functioning grafts at selected times. The median daily dose of prednisone
decreased from 0.28 mg/kg at 6 months to 0.17 mg/kg at
36 months, and then to 0.15 mg/kg at 5 years after transplantation. Alternate-day prednisone was prescribed to 9% of recipients at 6 months, 17% at 12 months, 24% at 24 months, and
27% at 48 months after transplantation. The daily dose of

azathioprine did not change over time. The mean dose of
cyclosporine has increased over the years in the most recent
reported study: the mean 1-year dosages after transplantation
were 6.5, 7.0, 7.7, and 8.0 mg/kg/d for transplantations occurring in 1987, 1989, 1991, and 1993, respectively. (From Warady
Cyclosporine
20
Mean ( upper 95% CI)
Recipient age, y
Cadaveric donor
18
01
25
612
>12
16
14
12
10
8
6
4
2
0
1
12
18
24
30
FIGURE 16-19
Data from the North American Pediatric Renal Transplant Cooperative
Study of the maintenance dose of cyclosporine by donor source, recipient age, and time after transplantation. The dosage for the first month
36
42
48
for 0- to 1-year-old cadaveric donor graft recipients (panel A) is

15.0 mg/kg/d, which is similar to the 14.4 mg/kg/d the living related
donor graft recipients (panel B) receive.
16.9
20
18
Recipient age, y
01
25
612
>12
Mean (+upper 95% CI)
16
14
12
10
8
6
4
2
0
1
12
18
24
30
36
42
48

By 4 years after transplantation the mean doses of all age groups are similar
(mean and upper 95% CIs). (From Tejani and Sullivan [15]; with permission.)
LATE FIRST REJECTION RATES

Mean year-1 CsA dosage, mg/kg/d
CsA dosage, mg/kg/d*
0
>0 and 4.0
>4.0 and 5.9
>5.9 and 8.6
>8.6
80
185
186
188
184
Number of rejections Rejecting, %

9
41
44
46
29
11.3
22.2
23.7
24.5
15.8
Rejection
(SD)
Nonrejection
(SD)
0.0
2.9(0.8)
4.9(0.6)
6.9(0.8)
11.7(2.7)
0.0
3.1(0.7)
5.0(0.6)
7.3 (0.8)
12.6(4.1)
*Chi-squared test of percentage rejecting among four nonzero dose groups (P = 0.163).
FIGURE 16-20
Data from the North American Pediatric
Renal Transplant Cooperative Study on late
first rejection rates by quartiles of maintenance cyclosporine dose at 1 year. The first
acute rejection occurred over 1 year after
transplantation. Patients not receiving
cyclosporine (human leukocyte antigenidentical or those receiving tacrolimus [FK-506])
form a small group. The difference between
the rejection rates for the other four groups
are not statistically significant. The lowest
rate of late first rejection, however, is
observed in those patients receiving dosages
of cyclosporine over 8.6 mg/kg/d. CsA
cyclosporine; SDstandard deviation. (From
Tejani and Sullivan [15]; with permission.)
16.10
Tacrolimus
COMPARISON OF TACROLIMUS AND CYCLOSPORINE
Major advantages of tacrolimus
Steroid sparing
Less hypertension
Rescue of cyclosporine-resistant
rejections
Minor advantages of tacrolimus
Better graft survival
Less hirsutism
Less gingival hypertrophy
Less neurologic dysfunction
Less metabolic acidosis
Less hyperlipidemia
Major disadvantages of tacrolimus

Increased viral infections
Cytomegalovirus
Epstein-Barr virus
Increased lymphoproliferative disease
Minor disadvantages of tacrolimus
Increased acute rejection?
More diabetogenic?
Hyperkalemia?
Hypomagnesemia?
Similarities of tacrolimus and
cyclosporine
Nephrotoxicity
FIGURE 16-21
The experience at Childrens Hospital of Pittsburgh using
tacrolimus has been that 14% of 43 pediatric patients managed
with tacrolimus for a mean period of 25 months developed posttransplantation lymphoproliferative disease (PTLD). This occurrence is very high compared with PTLD reported by the North
American Pediatric Renal Transplant Cooperative Study in only
six of 1550 (0.39% or 0.10%/y) children managed with various
cyclosporine regimens [16]. Epstein-Barr virus (EBV) has a primary
role in the development of PTLD, and an even higher rate of EBVrelated PTLD has been reported in children receiving tacrolimus
for liver transplantation or rescue [17,18]. Children seem to have a
greater predisposition to PTLD than do adults. Therefore, children
need closer monitoring for this disorder when being managed with
tacrolimus. The major advantages of tacrolimus over cyclosporine
are a reduced severity of hypertension and an improved cosmetic
appearance that, in turn, may improve patient compliance with
medications. (From Ellis [19]; with permission.)
Mycophenolate Mofetil
Acute rejection episode, %
50
48%
40
30
26%
19%
20
10
0
Living
donor
Cadaveric Mycophenolate
donor
mofetil
Azathioprine
FIGURE 16-22
Initial studies at the University of California, Los Angeles Medical Center (UCLA), using
mycophenolate mofetil along with cyclosporine and prednisone, instead of azathioprine.
In 37 pediatric renal transplantation recipients, an overall incidence of first acute rejection
of just 19% was found (only 13% were clinically significant). This is a decrease compared
with the historical incidence at UCLA (19871994) of acute rejection episodes in living
related and cadaveric donor transplantations, which is 26% and 48%, respectively. The
researchers saw a moderate increase in the incidence of infection after transplantation
(mostly caused by cyclomegalovirus) and gastrointestinal side effects. (From Ettenger and
16.11
Growth in End-Stage Renal Disease
Growth rate, cm/y
Transplantation versus Dialysis

10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
Kidney
transplantation
(n = 724)
US general population
Dialysis
(n = 578)
P< 0.01
10
Age, y
1.0
Height Z
Average follow-up for calculating

ESRD growth rate = 10.4 mo
0.5
0
0 12 18 24 30 36 42 48 54 60
Follow-up, mo
Sample sizes for height Z at
follow-up months:
Age group, y 6
24 48
0 1 years
155 99 48
25 years
441 312 160
612 years 1023 716 374
1317 years 1112 625 235
12
14
16
Average age, 12.7 y
18
FIGURE 16-23
Chronic renal insufficiency and end-stage renal disease (ESRD)
resulting in physical growth and sexual development well below
the potential for age and gender [21]. One of the benefits of transplantation in children has been to improve the growth rate; however,
this may not occur in all patients [16,22,23]. Depicted is the overall
comparison between adjusted annualized growth rates by age for
prevalent pediatric transplantation and dialysis patients (1990
USRDS data) [24] and the US general population (19761980 data
from the National Center for Health Statistics) [25]. Shown are the
results of a linear regression analysis of growth rates for 578 patients
on dialysis and 724 transplantation recipients. Growth rates were
adjusted to reflect the average characteristics of patients with ESRD
at each age with regard to gender, race, ethnicity, baseline height,
and duration of ESRD. At almost all ages, growth rates were higher
for transplantation recipients compared with patients on dialysis;
however, the degree of advantage declined with age. No pubertal
growth spurt was seen in either treatment group. Although growth
rates in adolescents between 15 and 18 years of age were higher than
expected for both the dialysis and transplantation groups, the average height achieved at the end of the study was still lower than
expected. (From Turenne and coworkers [26]; with permission.)
FIGURE 16-24
Data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)
on the mean change from baseline in standardized height scores in patients with graft
function. The height standard deviation score (SDS), or Z score, is the current accepted
measurement used to evaluate accelerated growth. The Z score is an attempt to standardize
the height deficit of children with renal failure to the height of healthy children. A positive
change in Z score (+ Z), for example, indicates a reduction in height deficit (ie, an acceleration of growth). At transplantation the mean height deficit (Z score or SDS) for all patients
was -2.16 standard deviations (SD) below the appropriate age- and gender-adjusted levels.
Recipients under 6 years of age at the time of transplantation showed acceleration in linear
growth after transplantation at 4 years follow-up. Children 6 years of age or older at time
of transplantation showed no improvement in height deficit at 4 years follow-up. Z score
patients height - height at 50% for age and standard deviation of height for age. (From
Warady and coworkers [5]; with permission.)
16.12
Alternate-Day Corticosteroids
Change in height SDS
0.8
Daily
Alternate day
* Significant difference between daily and
alternate day group
0.6
*
*
0.4
FIGURE 16-25
Corticosteroids are an integral part of pediatric renal transplantation immunosuppressive protocols. In addition to hypertension and
hyperlipidemia, one of the main adverse effects of daily steroid dosing in children is growth retardation. A review of North American
Pediatric Renal Transplant Cooperative Study data, looking at the
change in the height standard deviation score (SDS) from 30 days
after transplantation to 12 to 60 months after transplantation analyzed the difference between the 1477 children treated continuously
on a daily or alternate-day steroid regimen. The mean change in
SDS was significantly greater for the alternate-day group at each
12-month interval (P < 0.05). Of note is the fact that at 12 months,
those children on alternate-day steroids had a mean serum creatinine of 1.06 0.04 mg/dL as compared with 1.28 0.02 mg/dL for
those on daily steroids (P < 0.001). Alternate-day therapy also was
more common in children without a rejection episode in the first
12 months after transplantation, recipients of living donor grafts,
white recipients, and children 2 to 12 years of age at the time of
transplantation. (From Jabs and coworkers [27]; with permission.)
0.2
0
0.2
12
100
24
36
48
100
Living donor
Graft survival, %
80
70
80
70
Daily
Alternate day
60
Daily
Alternate day
60
50
50
10
Cadaveric donor
90
90
Graft survival, %
60
20
30
40
50
Time, mo
60
10
20
30
40
50
Time, mo
60
FIGURE 16-26
Renal Transplant Cooperative Study
(NAPRTCS) evaluating the effects of
alternate-day steroids on graft survival.
Patients receiving alternate-day steroids
at 12 months were compared with those
receiving daily steroids. The NAPRTCS
found that the survival of living donor
(panel A) and cadaveric (panel B) grafts
subsequent to 12 months did not differ
between the steroid treatment groups.
Because a number of factors contribute
to graft survival and the patients were not
randomly delegated to steroid treatment
groups, a proportional hazards regression
model for graft survival after 12 months
also was developed. Again, the use of
alternate-day steroids had no adverse effect
on graft survival for recipients of either
living or cadaveric donor grafts. (From
Jabs and coworkers [27]; with permission.)
16.13
Recombinant Human Growth Hormone After Transplantation

HEIGHT VELOCITY AND HEIGHT STANDARD DEVIATION SCORES
Change in height SDS
Change in height velocity, cm/y

Pubertal status
Control
Treated
Control
Treated
Prepubertal
0.3 1.6
(n = 30)
0.6 1.8
(n = 11)
0.7 2.1
(n = 18)
3.7 1.6*
(n = 28)
4.9 3*
(n = 9)
4.3 2.2*
(n = 29)
+0.1 0.3
(n = 30)
0.1 0.4
(n = 11)
+0.1 0.5
(n = 18)
+0.6 0.3*
(n = 28)
+0.6 0.6*
(n = 9)
+0.7 0.5*
(n = 29)
Entering puberty
Pubertal
*P < 0.0001 compared with control groups.
FIGURE 16-27
Because growth often remains poor despite a functioning renal graft, a large multicenter
controlled study was initiated to evaluate the effectiveness of recombinant human growth
hormone in stimulating growth in children with a kidney allograft. In all three groups a
Mean semiquantitative score (06)

0
Interstitium
Focal inflammation (lymphocytes)
Diffuse inflammation
Focal fibrosis
Diffuse fibrosis
Growth hormone
treated recipients
Nontreated recipients
Mean score
Growth hormone Nontreated
treated (SD)
(SD)
1.6(1.7)
1.1(1.9)
2.6(1.8)
1.7(1.7)
1.4(0.8)
0.9(0.9)
2.1(0.4)
0.7(1.0)
Glomeruli
Mesangial cell proliferation
Mesangial matrix increase
1.3(1.5)
1.7(1.4)
1.4(0.8)
2.7(1.0)
Arterioles
Endothelial swelling
Endothelial proliferation
Intimal proliferation
0.3(0.8)
0.6(1.0)
1.6(1.6)
0.6(1.1)
0.3(0.8)
0.9(1.1)
1.0(0.8)
2.1(0.7)
1.1(1.2)
1.1(1.2)
0.7(0.8)
0.4(0.5)
Proximal tubules
Dilation
Atrophy
Casts
P < 0.05 between groups
significantly different growth velocity

and change in height SDS occurred during
the first year of treatment with growth
hormone (P < 0.0001) compared with a
control group. Preliminary data from the
second year of treatment also show a continued improvement in growth velocity
compared with baseline; however, not of
the magnitude seen during the first year.
The mean glomerular filtration rate did
not change significantly in the group
receiving growth hormone. Acute rejection
episodes were noted more frequently
during treatment with growth hormone,
especially for patients with a history of
more than one episode. However, other
factors, such as noncompliance with
immunosuppressive medications, were
not analyzed and cannot be excluded.
Values are expressed as mean standard
deviation. SDSstandard deviation score.
(From Broyer [28]; with permission.)
FIGURE 16-28
A Finnish study investigating the possible
association between growth hormone treatment and acceleration of chronic rejection
and late allograft dysfunction in prepubertal
children. The most common histologic findings between the eight growth hormone
treated and eight nontreated renal transplantation recipients are scored and compared
(matched for age, donor age, human leukocyte antigen, immunosuppression, and renal
function) 36 months after transplantation.
Improvement in growth was clear during
administration of growth hormone, without
a negative influence on allograft survival.
No significant difference in the amount of
lymphocyte infiltration of the allografts
between patients and the control group was
seen. No acute rejection episodes occurred
in the recipients treated with growth hormone but one occurred in the control group.
SDstandard deviation. (From Laine and
16.14
SAFETY AND EFFICACY OF GROWTH HORMONE TREATMENT

mL/min/1.73 m2*
Reference
Patients, n
Bartosh et al.
Benfield et al.
Fine et al.
Ingulli and Tejani
Tonshoff et al.
5
11
13
17
10
Van Dop et al.

Van Es et al.
9
17
Prepubertal
Pubertal
19
Serum creatinine,
mg/dL
Before
After
Before
After
51 + 6.8
75 + 20
67 + 27
58 + 29
60 + 18
63 + 25
1.4 + 0.1
1.6 + 0.6
1.5
1.6*
59
(23 - 118)
49
(19 - 102)*
1.6 + 0.6
2.1 + 0.9*
71
(25 - 150)
72
(4.4 - 172)
67
(29 - 152)
83
(24 - 121)
*P value significant.
Median values.
FIGURE 16-29
Analysis of the safety and efficacy of growth
hormone in pediatric renal transplantation
recipients. Overall, a catch-up in growth
was reported in each study, with changes in
height standard deviation score from 0.2 to
1.0. These results were not as favorable as
those reported when growth hormone was
used in patients with chronic renal failure,
perhaps owing to the use of corticosteroids
after transplantation. In three studies, renal
function was significantly decreased after
administration of growth hormone. Twelve
acute rejection episodes and four graft losses
occurred; however, a causal relationship is
unclear [30]. A controlled trial using growth
hormone after transplantation is currently
underway by the North American Pediatric
Renal Transplant Cooperative Study to help
establish the efficacy and safety of growth
hormone in pediatric transplantation recipients. Calculated clearance according to the
Schwartz formula, except for Tonshoff
(inulin clearance) [31]. (From Tonshoff
Complications after Transplantation

Acute Rejection
DIAGNOSIS OF ACUTE REJECTION
Clinical picture
Fever, weight gain, enlargement and tenderness of graft, hypertension, reduced urinary output, decreased renal
function, reduced urinary sodium excretion, and increased proteinuria
Cyclosporine trough blood level
When these levels are higher than expected, cyclosporine nephrotoxicity is suspected; however, this does not rule out
rejectionvery low levels, in the presence of elevated serum creatinine, suggest acute rejection, perhaps as a result of
noncompliance
Radionuclide renal studies
Provide information about blood flow and the excretion index, and aid in excluding extravasation and obstruction
Renal sonography with Doppler ultrasonography
Provides information about kidney size, renal blood flow, corticomedullary differentiation, pyramid shape, and the collecting system; establishes the diagnosis of obstruction, extravasation, and renal artery stenosis
Renal arteriogram
Establishes the diagnosis of major renal vessel stenosis or occlusion
Magnetic resonance imaging
Establishes the diagnosis of obstruction, renal vessel stenosis, or occlusion; aids in evaluating the corticomedullary junction and pyramid shape
Fine-needle aspiration biopsy
Identifies inflammatory cells in the graft, tubular damage, cyclosporine toxicity, and cytomegalovirus infection; aids in
differentiating rejection, acute tubular necrosis, cytomegalovirus infection, and cyclosporine nephrotoxicity
Renal biopsy
Remains the gold standard for determining rejection and cyclosporine nephrotoxicity
FIGURE 16-30
When impaired graft function occurs in
pediatric renal transplantation recipients,
rejection is the most common cause. A number of other conditions exist that also can
result in an increase in serum creatinine and
blood urea nitrogen, a decrease in urine output, or both, which must be differentiated
from rejection. In small children with large
allografts, the most sensitive indication of
rejection is hypertension. It is important to
remember that in small children, a small
increase in serum creatinine can reflect a significant decrease in the glomerular filtration
rate. Several methods to establish the cause
of renal allograft dysfunction are described;
however, the diagnostic gold standard is the
allograft core biopsy. Biopsy can easily be
performed percutaneously in most children
and should not be postponed once other
variables have been eliminated and rejection
is likely. (From Yadin and coworkers [32];
with permission.)
FIGURE 16-31
Data from the 1995 North American Pediatric Renal Transplant Cooperative Study showing
that the cumulative risk for first rejection is similar for living donor (LD) and cadaveric
donor (CD) recipients in the first few weeks after transplantation. After the first month,
however, the cumulative risk for a first rejection is higher for recipients of a CD graft. By the
end of the 48th month, 56% of LD recipients and 71% of CD recipients have had at least
one rejection episode. Rejections were completely reversed (return to baseline creatinine) in
53% of LD graft recipients, partially reversed (improved graft function but no return to
baseline creatinine) in 40%, and resulted in graft failure or death in 4% of cases. In CD,
rejection episodes were completely reversed in 49%, partially reversed in 45%, and resulted
in graft failure or death in 6%. (From Warady and coworkers [5]; with permission.)
100
Rejection, %
80
60
40
20
Living donor
Cadaveric donor
0
0
12
16.15
24
36
Follow-up, mo
48
60
Chronic Rejection
PREDICTORS OF GRAFT FAILURE
FROM CHRONIC REJECTION
Relative risk
increase
P value
3.1
4.3
2.3
1.6
1.6
<0.001
<0.001
<0.001
0.001
0.003
Acute rejection
2 acute rejections
Late (>365 d) initial acute rejection
Cadaveric donor source
Black recipient
FIGURE 16-32
Multivariate analysis of data from the North American Pediatric
Renal Transplant Cooperative Study evaluating predictors of graft
failure from chronic rejection. A proportional hazards analysis of
time to chronic rejection failure, eliminating other failures, is used
to evaluate predictors of graft failure from chronic rejection. A 3.1fold increased risk of failure from chronic rejection was seen after
a single rejection episode. A second rejection increased the risk to
over 13 times that of children who did not experience rejection.
(From Tejani and coworkers [33]; with permission.)
CAUSES OF GRAFT FAILURE

Index graft failures
Second graft failures*
Total graft failures
n = 881 (%)
n = 104 (%)
n = 985 (%)
28(3.2)
107(12.2)
16(1.8)
9(1.0)
26(3.0)
167(19.0)
239(27.1)
10(1.1)
17(1.9)
9(1.0)
4(0.5)
18(2.0)
9(1.0)
56(6.5)
98(9.0)
67(7.6)
2(1.9)
20(19.2)
2(1.9)
2(1.9)
5(4.8)
16(15.4)
28(26.9)
0(0.0)
2(1.9)
0(0.0)
2(1.9)
1(1.0)
1(1.0)
10(9.6)
9(8.7)
4(3.8)
30(3.0)
127(12.9)
18(1.8)
11(1.1)
31(3.1)
183(18.6)
267(27.1)
10(1.0)
19(1.9)
9(0.9)
6(0.6)
19(1.9)
10(1.0)
67(6.8)
107(10.9)
71(7.2)
Cause
Primary nonfunction
Vascular thrombosis
Miscellaneous technical
Hyperacute rejection, <24 h
Accelerated rejection, 27 d
Acute rejection
Chronic rejection
Infection/discontinued medication
De novo kidney disease
Patient discontinued medication
Malignancy
Recurrence of original disease
Death
Other
*Four patients have had three graft failures.
FIGURE 16-33
Renal Transplant Cooperative Study showing causes of graft failure. Chronic rejection
has become the most common cause of
graft failure (27.1%). Acute rejection causes
up to 18.6% of graft failures. Recurrence
of primary disease (focal segmental glomerulosclerosis) accounts for 6.8% of all failures. Vascular thrombosis continues to
cause a significant number of graft failures
(12.9%). (From Warady and coworkers
16.16
Vascular Thrombosis
Day after transplantation
All thrombosis, %
100
Day > 15
Day 614
Day 35
Day 2
Day 1
Day 0
80
60
40
FIGURE 16-34
Data from the North American Pediatric Renal Transplant Cooperative Study showing
vascular thrombosis is the third most common cause of graft failure in pediatric transplantation recipients. The incidence varies between centers and has been reported to be as high
as 20% in children under 2 years of age [34]. This figure depicts the timing of thrombotic
graft failure by donor source. Most of the thromboses occurred soon after transplantation.
(From Singh and coworkers [35]; with permission.)
20
0
Living donor Cadaveric donor
n = 38
n = 100
UNIVARIATE ANALYSIS OF RISK FACTORS
All
Recipient age
01 y
25 y
612 y
>12 y
Donor age
05 y
510 y
>10 y
Cold ischemia time
<24 h
>24 h
Day 0/1
Antilymphocyte therapy
No
Yes
Day 0/1 cyclosporine therapy
No
Yes
Previous transplantation
No
Yes
Native nephrectomy
No
Yes
Previous dialysis
No
Yes
Persistent ATN with >7 d of
function
No
Yes
*P < 0.01, test for trend.
P = 0.01, test for trend.
Living donor, n
Cadaveric donor, n
38/2060
1.8
100/2334
4.3
6/172
12/341
5/732
15/783
3.5*
3.4
0.7
1.9
7/78
19/343
36/827
38/1086
9.0
5.5
4.4
3.5
32/386
11/245
54/1667
8.3*
4.5
3.2
44/1363
51/909
3.2*
5.6
28/1187
10/873
2.4
1.2
61/990
39/1344
6.2*
2.9
29/1115
9/945
2.6*
1.0
66/1682
34/652
3.9
5.2
30/1886
8/174
1.6*
4.6
66/1723
34/611
3.8
5.6
26/1440
12/617
1.8
1.9
82/1790
18/540
4.6
3.3
11/680
27/1380
1.6
2.0
13/319
87/2015
4.1
4.3
10/1929
3/79
0.5*
3.8
22/1844
13/365
1.2*
3.6
FIGURE 16-35
Recent univariate analysis of risk factors
by the North American Pediatric Renal
Transplant Cooperative Study. Although
the mechanisms that lead to thrombosis are
unclear, numerous factors have been implicated, whether they be by direct or indirect
means. In cadaveric donor kidney recipients,
children less than 2 years of age had a significantly higher rate of thrombosis, as did
children who received kidneys from donors
who were under 5 years of age. Recipients
of cadaveric donor kidneys with prolonged
cold ischemia time had a higher rate of
thrombosis than did those with a cold
ischemia time under 24 hours. ATNacute
tubular necrosis. (From Singh and coworkers
16.17
Hypertension
EVALUATING HYPERTENSION
Pretransplantation
Patients, n
Significant hypertension, %
Severe hypertension, %
230
11
23
12
24
264
14
26
262
16
13
261
16
10
257
9
9
FIGURE 16-36
Cooperative Study evaluating hypertension. Hypertension is common in children after renal transplantation. The definition of
hypertension used was taken from the Report of the Second Task
Force on Blood Pressure Control in Children [15]. The percentage
of children exceeding age-adjusted blood pressure standards
decreased considerably over the 2-year period. (From Baluarte and
CYCLOSPORINE DOSAGES IN RECIPIENTS WITH AND

WITHOUT HYPERTENSION
1 mo
Degree of hypertension
Normotensive
Significant
Severe
2y
CsA dosage, mg/kg
161
36
69
8.2
9.4
10.0
P = 0.11
FIGURE 16-37
North American Pediatric Renal Transplant
Cooperative Study evaluating cyclosporine
dosages in recipients with and without hypertension. CsAcyclosporine. (From Baluarte
CsA dosage, mg/kg
213
22
22
3.9
4.8
4.7
P = 0.23
Recurrent Disease
GRAFT FAILURE FROM RECURRENT DISEASE
Disease
FSGS
MPGN type I
MPGN type II
SLE
HSP
HUS
Classical
Atypical
Recurrence rate, %
Clinical severity
Those with recurrence whose graft failed, %
2530
70
100
540
5585
High
Mild
Low
Low
Low to mild
4050
1230
1020
5
520
1220
25
Moderate
High
010
4050
FIGURE 16-38
Recurrence rates and graft failure from
recurrent disease. Some primary renal diseases may recur in the allograft, making the
underlying disease an important consideration when evaluating a child for renal transplantation. Focal segmental glomerular sclerosis and atypical hemolytic uremic syndrome recur in roughly 25% of cases.
These diseases are severe clinically and lead
to the highest percentage of graft failures,
ie, 40% to 50%. In contrast, membranoproliferative glomerulonephritis type II
recurs in all cases; however, it is not very
severe clinically and leads to graft failure in
only 10% to 20% of patients. FSGSfocal
segmental glomerulosclerosis; HSP
Henoch-Schnlein purpura; HUShemolytic-uremic syndrome; MPGNmembranoproliferative glomerulonephritis; SLE
systemic lupus erythematosus. (From Fine
and Ettenger [37]; with permission.)
16.18
Other Causes of Renal Allograft Loss

100
100
90
90
Graft survival, %
Graft survival, %
80
70
60
Congenital and structural
Glomerulonephritis
Congenital nephrotic syndrome
50
40
0
10
20
30
Months
40
70
60
40
30
50
90
90
80
80
Graft survival, %
100
Graft survival, %
100
70
60
50
30
20
30
Months
40
50
60
Hemolytic uremic syndrome
Renal infarction
Cystinosis
Familial nephritis
40
30
10
70
50
Congenital and structural

Glomerulonephritis
Congenital nephrotic syndrome
40

Renal infarction
Cystinosis
Familial nephritis
50
30
80
10
20
30
Months
40
50
10
20
30
Months
40
50
FIGURE 16-39
Data from the North American Pediatric Renal
Transplant Cooperative Study showing that
those patients receiving living donor kidneys
who have congenital nephrotic syndrome
(CNS), focal segmental glomerulosclerosis (FSG)
(panel A) or hemolytic uremic syndrome (HUS)
(panel B) had the lowest 2-year graft survival
rates. These rates range from 74.3% to 80.6%.
In patients with focal segmental glomerular
sclerosis, graft failure was attributed to disease
recurrence in 13 of 39 (33%) patients who
received kidneys from living related donors.
B, The patients with familial nephritis or cystinosis had the highest graft survival rates (88.9%
and 92.9%, respectively). (From Kashton and
FIGURE 16-40
Data from the North American Pediatric Renal
Transplant Cooperative Study for cadaveric
donor renal allografts showing that the lowest
graft survival rates occurred in children with
focal segmental glomerular sclerosis or congenital nephrotic syndrome (panel A), or hemolytic
uremic syndrome (panel B). These rates range
from 40% to 58.9%. In patients with focal
segmental glomerular sclerosis, graft failure
was attributed to disease recurrence in 14 of
81 (17%) patients who received cadaveric
donor kidneys. A, The highest graft survival
rate correlated with the diagnosis of congenital
and structural disease and glomerulonephritis
(72.2% and 73.5%, respectively). (From
Kashton and coworkers [38]; with permission.)
Mortality in Recipients
FIGURE 16-41
Data from the United States Renal Data Source on pediatric patient 1-year death rates by
age group and treatment mortality. Survival follow-up began on day 91 after onset of endstage renal disease for patients on dialysis incident in 1994, and from the date of transplantation for patients receiving transplantations in 1994 [3]. CD Txcadaveric donor
transplant; LRD Txliving related donor transplant. (From United States Renal Data
System [3]; with permission.)
1-year Kaplan-Meier death rates, %
15
Dialysis
10
5
CD Tx
LRD Tx
0
04
59
1014
Age groups
1519
FIGURE 16-42
Data from the United States Renal Data
Source regarding distribution of causes of
death in children aged 0 to 19, 1993 to
1995. (From United States Renal Data
System [3]; with permission.)
30
Deaths, %
Total deaths = 290

Percentages add to 100
25
24
20
13
12
10
16.19
0
Cardiac
Acute
arrest myocardial
infarction
Other
cardiac
causes
Cardiovascular
disease
Infection Malignancy Hemorrhage Other

known
causes
CAUSES OF DEATH BY AGE GROUP

Recipient age
01
Cause of death
All causes
Viral infection
Bacterial infection
Other infections
Malignancy
Cardiopulmonary
Hemorrhage
Recurrence of original disease
Dialysis-related complications
Other
Unknown
25
1317
n (%)
n (%)
n (%)
n (%)
27(100.0)
5(18.5)
3(11.1)
4(14.8)
1(3.7)
5(18.5)
3(11.1)
1(3.7)
1(3.7)
4(14.8)
0(0.0)
33(100.0)
1(3.0)
6(18.1)
5(15.2)
2(6.1)
7(21.2)
4(12.1)
1(3.0)
0(0.0)
5(15.2)
2(6.1)
33(100.0)
6(18.2)
5(15.2)
3(9.1)
2(6.1)
10(30.3)
3(9.1)
0(0.0)
0(0.0)
3(9.1)
1(3.0)
43(100.0)
8(18.6)
6(14.0)
3(7.0)
4(9.3)
6(14.0)
6(14.0)
1(2.3)
3(7.0)
5(11.6)
1(2.3)
FIGURE 16-43
Cooperative Study on causes of death by age group. This study
revealed a high rate of attrition among pediatric transplantation
recipients under the age of 5 years. It is unclear whether this high
rate is due to a higher rate of infection. (From Tejani and coworkers [39]; with permission.)
FIGURE 16-44
Data from the 1995 North American Pediatric Renal Transplant Cooperative Study showing a total of 214 deaths. Infection was the leading cause of death, occurring in 74
patients. This graph depicts the survival distribution estimates by donor source. Infants
aged under 2 years at the time of transplantation have a mortality rate of 14%. This rate
is significantly higher (P < 0.001) than in other age groups, with a mortality rate between
4.7% and 8.0%. (From Warady and coworkers [5]; with permission.)
100
95
Patient survival, %
612
Unknown
causes
90
85
80
75
Living donor
Cadaveric donor
70
0
12
24
36
48
Follow-up, mo
60
Numbers at risk at: Baseline 12 24 36 48

Living donor
1800 1393 1033 815 535
Cadaveric donor 1873 1362 1080 774 536
16.20
Recipient age
01 (n = 154)
25 (n = 413)
612 (n = 926)
1317 (n = 964)
Cumulative mortality, %
30
25
20
15
10
FIGURE 16-45
Data from the North American Pediatric Renal Transplant Cooperative Study of patient
mortality by recipient age. A significant difference (P < 0.001) in 1-year mortality rates by
age groups occurred: 13.6% (21 of 154) for 0- to 1-year-old recipients; 8.0% (33 of 413)
for 2- to 5-year-old recipients; 3.6% (33 of 926) for 6- to 12-year-old recipients; and 4.5%
(43 of 964) for 13- to 17-year-old recipients. Mortality also is increased for recipients of
kidneys from young cadaveric donors. A dramatic increase in cumulative mortality is seen,
with increasing concordance between young donor and recipient ages. (From Tejani and
5
0
0
Cumulative mortality, %
30
10
20
30
40

No (n = 2140)
Yes (n = 310)
25
20
FIGURE 16-46
The effect of acute tubular necrosis (ATN) on patient survival. The development of ATN
leads to a significantly higher (P = 0.0001) mortality rate of 13.2% (risk ratio of 3.1) for
the 310 patients reported on in the registry. A 25% mortality rate and 6.4 risk ratio were
noted for the 188 patients who developed graft failure within 30 days after transplantation
(P < 0.001). (From Tejani and coworkers [39]; with permission.)
15
10
5
0
0
10
20
30
40
References
1. Ettenger RB: Renal transplantation. In Renal Disease in Children.
Edited by Barakat AY. New York: Springer-Verlag; 1990:371384.
2. Warady BA, Hebert D, Sullivan EK, et al.: Renal transplantation,
chronic dialysis and chronic renal insufficiency in children and
adolescents: 1995 Annual Report of the North American Pediatric
Renal Transplant Cooperative Study. Pediatr Nephrol 1997,
11:4964.
Am J Kidney Dis 30:S128144.
4. Harmon WE: Treatment of children with chronic renal failure. Kidney
Int 1995, 47:951961.
5. Warady BA, Hebert D, Sullivan EK, et al.: Renal transplantation,
chronic dialysis and chronic renal insufficiency in children and
adolescents: 1995 Annual Report of the North American Pediatric
11:4964.
6. UNOS Bull 1997, 2(10), October.
7. Tejani A, Stablein D, Alexander S, et al.: Analysis of rejection outcomes and implications. Transplantation 1995, 59:502.
8. Stablein DM, Tejani A: Five-year patient and graft survival in North
American children. Kidney Int 1995, 44:516.
9. Tejani A, Sullivan EK: Factors that impact on the outcome of second
renal transplants in children. Transplantation 1996, 62:606611.
10. Harmon WE: Treatment of children with chronic renal failure. Kidney
Int 1995, 47:951961.
11. McEnery P, Stablein DM: Does human lymphocyte antigen matching

improve the outcome in pediatric renal transplants? J Am Soc
Nephrol 1992, 2:S234S237.
12. Fine RN, Tejani A, Sullivan EK: Pre-emptive renal transplantation in
children: report of the North American Pediatric Renal Transplant
Cooperative Study. Clin Transplantation 1994, 8:474478.
13. Red Book: Report of the Committee on Infectious Diseases, edn 24.
Edited by Georges Peter. Elk Grove: American Academy of Pediatrics;
1997:1819.
14. Furth SL, Neu AM, Sullivan EK, et al.: Immunization practices in
children with renal disease: a report of the North American Pediatric
11:443446.
15. Tejani A, Sullivan EK: Higher maintenance cyclosporine dose
decreased the risk of graft failure in North American children: a
report of the North American Pediatric Renal Transplant Study. J Am
Soc Nephrol 1996, 7:550555.
16. McEnery PT, Stablein DM, Arbus G, Tejani A: Renal transplantation
in children: a report of the North American Pediatric Renal
Transplant Cooperative Study. N Engl J Med 1992, 326:17271732.
17. Tzakis AG, Reyes J, Todo S, et al.: Two-year experience with FK-506
in pediatric patients. Transplant Proc 1993, 25:619621.
18. Reding R, Wallemacq PE, Lamy ME, et al. Conversion from
cyclosporine to FK-506 for salvage of immunocompromised pediatric
liver allografts. Transplant 1994, 57:93100.
19. Ellis D. Clinical use of tacrolimus (FK-506) in infants and children
with renal transplants. Pediatr Nephrol 1995, 9:487494.
20. Ettenger R, Cohen A, Nast C, et al.: Mycophenolate mofetil as maintenance immunosuppression in pediatric renal transplantation.
Transplant Proc 1997, 29:340341.
21. Rees L, Rigden SPA, Ward GM: Chronic renal failure and growth.
Arch Dis Child 1989, 64:573577.
22. Tejani A, Fine R, Alexander S, et al.: Factors predictive of sustained growth
in children after renal transplantation: The North American Pediatric Renal
Transplant Cooperative Study. J Pediatr 1993, 122:397402.
23. Harmon WE, Jabs K: Factors affecting growth after renal transplantation. J Am Soc Nephrol 1992, 2:S295S303.
16.21
30. Ingulli E, Tejani A: An analytical review of growth hormone studies in

children after renal transplantation. Pediatr Nephrol 1995,
9:S61S65.
31. Tonshoff B: Efficacy and safety of growth hormone treatment in short
children with renal allografts: 3-year experience. Kidney Int
44:199207.
32. Yadin O, Grimm PC, Ettenger RB: Renal transplantation in children.
Pediatr Ann 1991, 20:662667.
33. Tejani A, Cortes C, Stablein D: Clinical correlates of chronic rejection
in pediatric renal Transplantation: a report of the North American
Pediatric Renal Transplant Cooperative Study. Transplantation 1996,
61:10541058.
Bethesda, MD, The National Institutes of Health, The National
Institute of Diabetes and Digestive and Kidney Diseases, 1995. Am J
Kidney Dis 1995, 26:S1S186.
34. Palleschi J, Novick AC, Braun WE: Vascular complications of renal

transplantation. Urology 1990, 16:61.
25. Najjar MF, Rowland M: Anthropometric reference data and the

prevalence of overweight. Vital Health Stat 1987, 11:1073.
36. Baluarte HJ, Gruskin AB, Ingelfinger JR, et al.: Analysis of hypertension in children post-renal transplantation: a report of the North
American Pediatric Renal Transplant Cooperative Study (NAPTRCS).
Pediatr Nephrol 1994, 8:570573.
26. Turenne MN, Port FK, Strawderman RL, et al.: Growth rates in pediatric dialysis patients and renal transplant recipients. Am J Kidney Dis
1997, 30:193203.
27. Jabs K, Sullivan EK, Avner ED, Harmon WE: Alternate day steroid
dosing improves growth without adversely affecting graft survival or
long-term graft function. Transplantation 1996, 61:3136.
28. Broyer M: Results and side-effects of treating children with growth
hormone after kidney transplantation: a preliminary report. Acta
Paediatr Suppl 1996, 417:7679.
29. Laine J, Krogerus L, Sarna S, et al.: Recombinant human growth hormone treatment: its effect on renal allograft function and histology.
35. Singh A, Stablein D, Tejani A: Risk factors for vascular thrombosis in

pediatric renal transplantation. Transplantation 1997, 63:12631267.
37. Fine RN, Ettenger R: Renal transplantation in children. Kidney

Transplantation: Principles and Practice, edn 4. Edited by Morris PJ.
Philadelphia: WB Saunders Company; 1994:418.
38. Kashton CE, McEnery PT, Tejani A, Stablein DM: Renal allograft survival according to primary diagnosis: a report of the North American
Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1995,
9:679684.
39. Tejani A, Sullivan EK, Alexander S, et al.: Post-transplant deaths and
factors that influence the mortality rate in North American children.
Recurrent Disease in the

Transplanted Kidney
Jeremy B. Levy
any patients receiving renal allografts become identified simply

as recipients of kidney transplantation. All subsequent events
involving changes in renal function are attributed to the
process and natural history of transplantation itself: acute and chronic
rejection, immunosuppressive drug nephrotoxicity, graft vasculature
thrombosis or stenosis, ischemia, infection, and lymphoproliferative
disorders. However, it is important to remember the nature of the
underlying disease that caused the initial renal failure, even if the disease
occurred many years previously. Recurrence of the primary disease
often causes pathologic changes within the allograft; clinical manifestations such as proteinuria and hematuria; and less commonly, renal
failure. Thus, focal segmental glomerulosclerosis (FSGS) frequently
causes recurrent proteinuria after transplantation, which may begin as
early as minutes after the graft is vascularized [1]. All patients with
diabetes develop recurrent basement membrane and mesangial pathology
within their allografts [2], and recurrent oxalate deposition can cause
rapid renal allograft failure in patients with oxalosis [3]. Identifying
patients at particular risk of primary disease recurrence allows
consideration of therapeutic maneuvers that may minimize the incidence
of recurrence.
Living-related transplantation poses additional dilemmas. For many
nephritides good evidence exists for an increased incidence of recurrent
primary disease in related as opposed to cadaveric grafts. Data from
the Eurotransplant Registry suggests a fourfold increased incidence of
recurrence of glomerulonephritis, causing graft loss in grafts from living
related donors (16.7% vs 4%) [4].
Finally, the recurrence of glomerulonephritis after transplantation,
in particular, can cause specific diagnostic problems. It may be caused
by recurrent disease, development of de novo glomerulonephritis in the
transplanted organ, or transplanted glomerulonephritis from a donor
with unrecognized disease. Glomerulonephritis after transplantation
must be distinguished from chronic rejection causing glomerulopathy
and cyclosporine-induced glomerulotoxicity. Each of the following
diseases can present diagnostic dilemmas and cause graft failure:
CHAPTER
17
17.2
recurrence of FSGS, mesangial immunoglobulin A disease,

hemolytic uremic syndrome, mesangiocapillary glomerulonephritis, and antiglomerular basement membrane disease.
Overall, three groups of diseases recur in patients with
transplantations: metabolic disorders, especially primary hyperoxaluria and diabetes; systemic diseases, including systemic
lupus erythematosus, sickle cell disease, systemic sclerosis,
hepatitis C virusassociated nephropathies and systemic
vasculitis; and a variety of glomerulonephritides. For immunemediated systemic diseases the standard transplantation
immunosuppressive regimens often prevent recurrence of primary
DISEASES THAT RECUR AFTER

Metabolic
Systemic
Glomerulonephritis
Diabetes mellitus
Oxalosis
Amyloidosis
Fabrys disease
Systemic lupus
erythematosus
Systemic vasculitis
Sickle cell disease
Hepatitis C virus
associated nephropathy
Systemic sclerosis
MCGN
Antiglomerular basement
membrane disease
RECURRENT DISEASE AFTER
De novo glomerulonephritis
Transplanted glomerulonephritis
Chronic rejection
Acute allograft glomerulopathy
Chronic allograft glomerulopathy
Acute rejection
Allograft ischemia
Cytomegalovirus infection
disease, which also may be true for the glomerulonephritides.

Some evidence exists that in the glomerulonephritides there is a
reduced incidence of recurrence with the use of cyclosporine.
Confirmed recurrence of all the glomerulonephritides causes
graft loss in 4% of adults and 7% of children receiving allografts
[4,5]. Although few data exist on the treatment of most forms
of recurrent nephritis, plasma exchange or immunoadsorption
are proving beneficial at reducing nephrotic range proteinuria
in recurrent FSGS [6,7], and recurrent renal oxalate deposition
often can be abrogated after transplantation in patients with
primary hyperoxaluria [8,9].
FIGURE 17-1
Many diseases can recur in transplanted kidneys, although fewer
cause graft failure. Those disorders that can cause loss of allografts
include oxalosis (primary hyperoxaluria) and some glomerulonephritides, particularly mesangiocapillary glomerulonephritis (MCGN),
focal segmental glomerulosclerosis, and sometimes hemolytic uremic
syndrome. Diabetes recurs almost universally in isolated renal grafts
but rarely causes graft failure. Histologic recurrence of diabetic
vascular pathology and glomerular pathology is much more infrequent
in patients receiving combined pancreas and kidney transplantations
[10,11]. Hepatitis C virus is now recognized as a cause of a number
of problems after transplantation, including an increased risk of
recurrent and de novo glomerulonephritis (MCGN and membranous)
and allograft glomerulopathy [12].
FIGURE 17-2
Acute cellular rejection and cyclosporine toxicity usually can be distinguished easily from
recurrent glomerular disease. Recurrent hemolytic uremic syndrome, however, can cause a
microangiopathy similar to cyclosporine toxicity, with erythrocyte fragments visible both
in blood films and within glomerular capillary loops. The major diagnostic difficulty lies
with chronic rejection, especially in the form of transplantation glomerulopathy, and de
novo or transplanted glomerulonephritis. Chronic transplantation glomerulopathy occurs
in 4% of renal allografts and usually is associated with proteinuria of more than 1 g/d,
beginning a few months after transplantation. Chronic glomerulopathy shares some features
with both recurrent mesangiocapillary glomerulonephritis type I and hemolytic uremic
syndrome: glomerular capillary wall thickening, mesangial expansion, and double contour
patterns of the capillary walls with mesangial cell interposition [13]. Thus, a definitive
diagnosis of recurrent nephritis may require histologic characterization of the underlying
primary renal disease and a graft biopsy before transplantation.
Recurrent Disease in the Transplanted Kidney
17.3
FIGURE 17-3
Biopsy showing rejection (panel A) and membranous changes (panel B) in a woman
8 months after transplantation. The patient initially had idiopathic membranous
nephropathy that progressed to end-stage renal failure over 5 years. She subsequently
received a cadaveric allograft but developed proteinuria and renal dysfunction after
8 months. The biopsy shows recurrent membranous disease, with thickened glomerular
capillary loops (and spikes on a silver stain), and features of acute interstitial rejection,
with a pronounced cellular infiltrate and tubulitis. Additional sections also showed evidence of chronic cyclosporine toxicity. In many patients, transplantation biopsies have
features of several pathologic processes. Recurrent nephritis can be overlooked in a
biopsy showing evidence of chronic rejection, cyclosporine toxicity, or both.
INVESTIGATING RECURRENT DISEASE

Renal biopsy with immunofluorescence and electron microscopy
Cyclosporin A level
Urine microscopy and culture
24-h urine protein
Renal ultrasonography
Antiglomerular basement membrane autoantibody and antineutrophil cytoplasm antibody
Cytomegalovirus serology and viral antigen detection
Hepatitis C virus serology and RNA detection
FIGURE 17-4
Confirming a diagnosis of recurrent disease requires a renal biopsy.
Features that favor recurrence include an active urine sediment
with erythrocytes and erythrocyte casts, heavy proteinuria, and
normal cyclosporine levels. Serologic testing for antiglomerular
basement membrane antibody is important in patients with
Alports or Goodpastures syndrome, and blood film examination
for patients with previous hemolytic uremic syndrome. Immunofluorescence and electron microscopic studies are rarely performed
routinely on transplantation biopsies but can be vital in making a
diagnosis of recurrent nephritis.
17.4
RECURRENT DISEASES AFTER KIDNEY TRANSPLANTATION

Recurrent diseases that commonly cause graft failure
Histologic recurrence only, graft failure uncommon
Histologic recurrence rare
Primary hyperoxaluria type I

Mesangiocapillary GN type I (and less commonly, type II)
Immunoglobulin A disease?
Diabetes mellitus
Immunoglobulin A disease
Membranous GN
Mesangiocapillary GN type II
Antiglomerular basement membrane disease
Systemic vasculitis (antineutrophil cytoplasm antibodyassociated)
Fabrys disease

Systemic vasculitis
Idiopathic rapidly progressive GN
Membranous GN
FIGURE 17-5
The prevalence and incidence of recurrent disease after transplantation is difficult to ascertain. Certainly, system lupus erythematosus
and idiopathic rapidly progressive glomerulonephritis rarely recur
in grafts, whereas in some groups of patients recurrence of focal
segmental glomerulosclerosis is universal [4]. There is much debate
as to the frequency of recurrence of immunoglobulin A disease and
whether there is any association of recurrence with graft dysfunction
[14,15]. Recurrence of an underlying primary renal disease may

cause changes within the allograft and predispose patients to acute
rejection and graft failure, eg, upregulation of human leukocyte
antigens in parenchymal tissue. Proteinuria and dyslipidemia also
can lead to changes in the expression of cell surface proteins critical
for antigen presentation and immune regulation.
HISTOLOGIC AND CLINICAL RECURRENCE OF RENAL

DISEASE AFTER KIDNEY TRANSPLANTATION
Disease
Diabetes mellitus
Primary hyperoxaluria
Mesangiocapillary glomerulonephritis type I
Mesangiocapillary glomerulonephritis type II
Vasculitis
Amyloidosis
Histologic recurrence rate, %

50100
40100
1015 without risk factors
50100 with risk factors
2575
3075
970
3040
357
510
<1
045
116
2033
Clinical recurrence rate, %

10, after 10 years
32100
50
140
145
50100
1020
50
25
Rare
1050
040
2060
FIGURE 17-6
Accurate data for recurrence rates are difficult
to obtain, especially because transplantation
biopsies often are not performed routinely
after transplantation without a specific indication. Thus, some recurrence rates may be
overrepresented in failing grafts, with
asymptomatic recurrence being undetected.
Many recurrent diseases do not cause urinary
abnormalities or symptoms. Diseases that
are slowly progressive also may be underrepresented in studies with only a short follow-up time (eg, immunoglobulin A disease).
17.5

100
Patients with glomerulonephritis
Patients without glomerulonephritis
80
Graft survival, %
Graft survival, %
100
60
40
20
80
60
40
Patients with glomerulonephritis
Patients without glomerulonephritis
20
0
0
10
15
20
25
Grafted before 1983, y
FIGURE 17-7
Actuarial cadaveric survival curves in patients with or without
glomerulonephritis (GN) as the primary disease. A Significantly
worse renal graft survival in patients receiving grafts before 1983
if their underlying disease was GN, rather than any other disease
(P < 0.015; diabetes excluded). B, Since the introduction of
10
Grafted since 1983, y
cyclosporine (in transplantations after 1983), graft survival curves

are the same for patients with or without GN. For patients receiving a living related graft, however, GN still carries an excess risk of
recurrent disease causing graft failure [4]. (Adapted from from
Michielsen [16].)
RECURRENCE OF ORIGINAL GLOMERULONEPHRITIS CAUSING GRAFT FAILURE

Living related donor (LRD) kidney transplantations
01
12
23
34
45
Total
Cadaveric kidney transplantations
All LRD transplantation failures

from recurrent GN, %
LRD graft failures from

recurrent GN, %
All cadaveric transplantation

failures from recurrent GN, %
Cadaveric graft failures

from recurrent GN, %
1.9
0.7
1.5
0
0.8
4.4
25
9
33
0
14
16.7
0.2
0.5
0.3
0.25
0.3
1.3
1.5
8.7
5.8
4.8
6.6
4
FIGURE 17-8
Several studies have reported an increased incidence of recurrent
glomerulonephritis (GN) after renal transplantation in grafts from
living related donors. In one study with histologic data available on
both donors and recipients, GN recurred in 8.7% of 149 cadaveric
grafts compared with 25.8% of 124 living donor grafts [16,17]. The
data shown here are from the Eurotransplant Registry. These data
demonstrate a substantial excess of recurrent GN causing graft failure
in living donor grafts compared with cadaveric grafts from the same
centers over the same time period [4]. Up to one third of all the graft
failures in grafts from living related donors were due to recurrent
disease compared with less than 1 in 10 graft failures in cadaveric
transplantations. No difference in recurrence rates was seen in any
of the first 5 years after transplantation. GNglomerulonephritis.
(Adapted from Kotanko and coworkers [4].)
17.6

40
40
35
Graft loss from recurrence, %
45
Recurrence, %
35
30
25
20
15
P<0.02
10
Nephx
No Nephx
30
25
20
15
10
Time of follow-up, y
CAUSE OF GRAFT LOSS IN RENAL GRAFT

RECIPIENTS WITH DIABETES DURING THE
FIRST AND SECOND DECADES
Deaths with functioning grafts:

Sepsis
Malignancy
Other
Rejection
Recurrent diabetic nephropathy
Technical
Other
10
First decade, %
(No. of patients)
Second decade, %
(No. of patients)
56 (104)
16
14
2
24
31 (62)
0 (0)
8 (14)
5 (9)
76 (19)
40
4
16
16
16(4)
8 (2)
0 (0)
0 (0)
FIGURE 17-10
Recurrence of diabetes in renal allografts is a common histologic
finding but a rare cause of graft loss. The most frequent cause of
death in the second decade after transplantation was cardiovascular
disease, and the most common cause of graft loss was the death of
a patient with a functioning graft. Only 2 of 100 patients surviving
more than 10 years suffered graft loss from recurrent diabetic
nephropathy, occurring at 12.6 and 13.6 years after transplantation
[2]. The incidence of vascular complications and the need for amputations, however, are substantially increased in patients with diabetes
receiving transplantations. In most centers, overall graft survival rates
are lower for recipients with diabetes than for those without diabetes.
(Adapted from Najarian and coworkers [2].)
15
20
Time of follow-up, y
FIGURE 17-9
Bilateral pretransplantation native nephrectomy has been advocated
to reduce the likelihood of recurrence of nephritis in renal transplantations. The data shown here indicate that of 364 transplantations in patients with a diagnosis of primary glomerulonephritis,
an increased recurrence rate exists in those 61 patients with bilateral
pretransplantation nephrectomies compared with the 303 patients
Cause
20
15
Nephx
No Nephx
0
0
P<0.01
10
without nephrectomy (24.6% vs 12.2%; P < 0.02) [18]. Overall,

14% of patients having transplantation developed recurrent
glomerulonephritis (panel A), and 52% of grafts in these patients
failed (panel B). Thus, pretransplantation nephrectomy has no
place in preventing recurrent nephritis. (From Odorico and
coworkers [18].)
Hyaline vasculopathy
almost universal
Glomerular capillary
basement membrane
thickening
Mesangial
Transplant
expansion,
microalbuminuria
18% of patients have

severe
mesangial expansion
(Kimmelsteil-Wilson
nodules)
13
Years
FIGURE 17-11
Diabetic changes in renal allografts transplanted into patients with
diabetes. Diabetic changes (especially glomerular capillary wall
thickening and hyaline vasculopathy) probably occur in all these
recipients [2,10]. Diabetic changes occur slowly, however, and rarely
are severe enough to cause graft dysfunction. The serum creatinine
at 10 years in 95 patients from Minnesota with renal allografts
functioning for more than 10 years was 1.5 0.1 mg/dL (mean
standard error of the mean) and in 10 patients with allograft function
for 15 or more years was 1.6 0.3 mg/dL [2]. Classic nodular
glomerulosclerosis is much rarer. Recurrence of diabetic nephropathy
can be prevented by simultaneous pancreatic and renal transplantation. At 2 years, most patients receiving a combined pancreatic and
kidney graft have no histologic changes on renal biopsy and normal
basement membrane thickness on electron microscopy of glomerular
tissue [10,11]. Intensive insulin treatment with good glycemic control
after transplantation also prevents the development of recurrent
glomerular and arteriolar lesions.
17.7
Alanine: glyoxylate
aminotransferase
(AGT)
Glycine
Glyoxylate
Cofactor: pyridoxine
Lactate dehydrogenase
L--hydroxy acid oxidase
Glycolate oxidase
Glyoxylate
reductase
Oxalate
Glycolate
FIGURE 17-12
Primary hyperoxaluria type I in renal failure. Primary hyperoxaluria
type I is an autosomal recessive inborn error of metabolism resulting
from a deficiency (or occasionally incorrect subcellular localization)
of hepatic peroxisomal alanineglyoxylate aminotransferase [8].
Patients excrete excess oxalate as a result of the increased glyoxylate
pool. In many patients, renal disease is manifested by chronic renal
failure. Once the glomerular filtration rate has decreased below 25
mL/min the combination of oxalate overproduction and reduced
urinary excretion leads to systemic oxalosis, with calcium oxalate
deposition in many tissues. Renal transplantation alone has yielded
poor results in the past, with 1-year graft survival rates of only
26% [3]. Combined hepatorenal transplantation simultaneously
replaces renal function and corrects the underlying metabolic defect.
The 1-year liver graft survival rate is 88%, with patient survival of
80% at 5 years. Of 24 renal grafts from the European experience
of hepatorenal transplantation, 17 were still functioning at 3 months
to 2 years after transplantation [19].
PATIENT MANAGEMENT IN RENAL OR HEPATORENAL

TRANSPLANTATIONS FOR PRIMARY HYPEROXALURIA
Aggressive preoperative dialysis (and possibly continued postoperatively)
Maintenance of high urine output
Low oxalate, low ascorbic acid, diet low in vitamin D
Phosphate supplements
Magnesium glycerophosphate
High-dose pyridoxine (500 mg/d)
Thiazide diuretics
FIGURE 17-13
Histologic slide of a patient who received an isolated renal allograft
for primary hyperoxaluria type I in which oxylate crystals are seen
clearly within the tubules and interstitium. The major hazards for
the renal graft after transplantation include early acute nephrocalcinosis caused by rapid mobilization of the systemic oxalate deposits.
Acute tubular obstruction by calcium oxalate crystals also can
occur. Late nephrocalcinosis leads to progressive loss of renal function
over several years. Rejection episodes are less common in patients
receiving combined liver and kidney grafts than in those receiving
kidney transplantation alone [3,19]. Acute rejection with renal
dysfunction, however, causes additional episodes of acute calcium
oxalate deposition in the kidney. Recurrent oxalosis can be seen as
early as 3 months after transplantation.
FIGURE 17-14
Daily hemodialysis for at least 1 week before transplantation
depletes the systemic oxalate pool to some extent. Some centers
continue aggressive hemodialysis after transplantation, regardless
of the renal function of the transplanted organ. In patients receiving
combined hepatorenal grafts, dietary measures to reduce oxalate
production are not as important as they are in patients receiving
isolated kidney grafts. In these patients, excess production of
oxalate from glyoxylate still occurs. Magnesium and phosphate
supplements are powerful inhibitors of calcium oxalate crystallization
and should be used in all recipients, whereas thiazide diuretics may
reduce urinary calcium excretion. Pyridoxine is a cofactor for alanine
glyoxylate aminotransferase and can increase the activity of the enzyme
in some patients. Pyridoxine has no role in combined hepatorenal
transplantation. For most patients the ideal option is probably a
combined transplantation when their glomerular filtration rate
decreases below 25 mL/min [8,9].
17.8
AMYLOIDOGENIC AND RELATED DISEASES CAUSING RENAL FAILURE

Disease
Nonhereditary
Systemic amyloidosis associated with chronic inflammatory disorders (especially rheumatoid arthritis)
Systemic amyloidosis associated with immune dyscrasia: multiple myeloma, monoclonal gammopathy,
occult immune dyscrasia, lymphoma
Hereditary
Familial Mediterranean fever
Ostertag-type (autosomal dominant, early hypertension, and renal impairment)
Muckle-Wells syndrome (deafness, nephropathy, urticaria, and limb pain)
Hereditary renal amyloidosis
Familial nephropathic systemic amyloidosis
Light chain deposition disease
FIGURE 17-15
The most common cause of amyloidosis leading to renal failure is
rheumatoid arthritis [20]. However, increasing numbers of patients
with myeloma and AL amyloid, or primary amyloidosis, are now
receiving peripheral blood stem cell transplantations or bone marrow allografts. Thus, these patients are surviving long enough to
consider renal transplantation. Over 60 patients with renal failure
resulting from systemic amyloid A (AA) amyloidosis have been
reported to have received renal allografts. Graft survival in these
patients is the same as that of a matched population. Histologic
Fibril protein
Precursor protein
Amyloid A
AL
Serum amyloid A
Monoclonal immunoglobulin
light chain
Amyloid A
Not known
Not known
Fibrinogen
Apolipoprotein A
AL or immunoglobulin light chains
Serum amyloid A
Not known
Not known
Fibrinogen
Apolipoprotein A
Immunoglobulin light chains
recurrence of renal amyloid has been reported in 20% to 33% of

these grafts within 2 years of transplantation [20,21]. Patient survival
is reduced, owing to infections and vascular complications, to 68% at
1 year and 51% at 2 years. Recurrence is characterized by proteinuria
11 months to 3 years after transplantation. Recurrent light chain
deposition disease is found in half of patients receiving allografts, with
graft loss in one third despite plasmapheresis and chemotherapy [4].
Heavy proteinuria is seen at the onset of recurrence. ALprimary
amyloidosis.
FIGURE 17-16
Microradioangiography comparing the
vasculature of the kidney in a patient with
no disease (panel A) and a patient with
homozygous sickle cell disease (panel B)
[22]. Despite the frequency of renal damage
in sickle cell disease, only 4% of patients
progress to end-stage renal disease, and little
experience exists with renal transplantation.
Three patients have been reported with
recurrent sickle cell nephropathy. In one
case, a patient developed renal dysfunction
3.5 years after transplantation; a biopsy
showed glomerular sclerosis, tubular
atrophy, and interstitial fibrosis, without
features of rejection. A second study reported
recurrent sickle cell nephropathy leading to
graft failure in two of eight patients receiving
transplantation [23]. Concentration defects
were observed within 12 months of grafting.
Patients also suffered an increased incidence
of sickle cell crises after renal transplantation,
possibly associated with the increase in
hematocrit.
FEATURES OF RECURRENT
SYSTEMIC LUPUS
ERYTHEMATOSUS
Rash
Arthralgia
Proteinuria (usually nonnephrotic)
Increasing anti-DNA antibody titers
Increasing antinuclear antibody titers
Decreasing complement levels (C3 and C4)
FIGURE 17-17
Nephritis caused by systemic lupus erythematosus (SLE) rarely recurs in transplantations. SLE accounts for approximately 1%
of all patients receiving allografts, and less
than 1% of these will develop recurrent
renal disease. Time to recurrence has been
reported as 1.5 to 9 years after transplantation [24,25]. Cyclosporine therapy does not
prevent recurrence. It is reasonable to
ensure that serologic test results for SLE are
minimally abnormal before transplantation
and certainly that patients have no evidence
of active extrarenal disease. Patients with
lupus anticoagulant and anticardiolipin
antibodies are at risk of thromboembolic
events, including renal graft vein or artery
thrombosis. These patients may require
anticoagulation therapy, or platelet inhibition with aspirin.
17.9
RELAPSE RATE IN ANTINEUTROPHIL CYTOPLASM

ANTIBODYASSOCIATED SYSTEMIC VASCULITIS
Series
Hammersmith Hospital
19741997 [26]
Habitz and coworkers
19801995 [26]
Schmitt and coworkers
19821993 [26]
Patients, n
Relapse rate on dialysis,

relapses/patient/y
Relapse rate after transplantation,

relapses/patient/y
59
0.088
0.018
18
0.24
0.06
18
0.3
0.1
FIGURE 17-18
Recurrence of Wegeners granulomatosis or microscopic polyangiitis has been reported
after transplantation, with overall renal and extrarenal recurrence rates of up to 29% and
renal recurrences alone of up to 16% [27]. Graft loss has been reported in up to 40% of
patients with renal recurrence. In the most recent data from the Hammersmith Hospital,
however, renal recurrences were rare, with only 0.018 relapses per patient per year after
transplantation [26]. These patients have often been on long courses of immunosuppressive therapy before receiving a graft. Extrarenal recurrence of Wegeners granulomatosis
can involve the ureter, causing stenosis and obstructive nephropathy. Serial monitoring of
antineutrophil cytoplasmic antibodies after transplantation is important in all patients
with vasculitis because changes in titer may predict disease relapse [28,29]. (Adapted from
Allen and coworkers [26].)
RENAL COMPLICATIONS OF HEPATITIS C VIRUS

Clinical:
Proteinuria
Nephrotic syndrome
Microscopic hematuria
Histologic and laboratory findings
Mesangiocapillary glomerulonephritis with or without cryoglobulinemia,
hypocomplementemia, rheumatoid factors
Membranous nephropathy: normal complement, no cryoglobulinemia
or rheumatoid factor
Acute and chronic transplantation glomerulopathy
FIGURE 17-19
Recurrence of both mesangiocapillary glomerulonephritis (MCGN)
and, less frequently, membranous nephropathy is well described
after transplantation. Nineteen cases of de novo or recurrent
MCGN after transplantation have been described in patients with
hepatitis C virus (HCV) [12]. Almost all had nephrosis and exhibited
symptoms 2 to 120 months after transplantation. Eight patients
had demonstrable cryoglobulin, nine had hypocomplementemia,
and most had normal liver function test results. Membranous GN
is the most common de novo GN reported in allografts, and it is
possible that HCV infection may be associated with its development
[12]. Twenty patients with recurrent or de novo membranous GN
and HCV viremia have been reported. In one study, 8% of patients
with membranous GN had HCV antibodies and RNA compared
with less than 1% of patients with other forms of GN (excluding
MCGN) [30]. Prognosis in these patients was poor, with persistent
heavy proteinuria and declining renal function.
17.10

FIGURE 17-20
Focal segmental glomerulosclerosis accounts for 7% to 10% of
patients requiring renal replacement therapy. The overall recurrence
rate is approximately 20% to 30% [1,4,31]. These numbers, however,
may be an underestimate because of biopsy sampling errors. Patients
at high risk for recurrence can be identified, particularly children
with rapid evolution of their original disease and mesangial expansion
on biopsy [1,32]. Recurrence manifests with proteinuria (often
1040 g/d), developing hours to weeks after transplantation. In
children the mean time to recurrence is 14 days. Recurrence is not
benign and leads to graft loss in up to half of patients. Patients at
highest risk for recurrence should not receive grafts from living
related donors.
RISK FACTORS FOR RECURRENT FOCAL SEGMENTAL

GLOMERULOSCLEROSIS AFTER TRANSPLANTATION
Risk factor
Recurrence rate, %
Age <5 y
Age < 15 y with progression to end-stage renal disease
within 3 y
First graft lost from focal segmental glomerulosclerosis
Adults without risk factors
50
80100
7585
1015
Graft loss occurs in half of all patients with recurrent focal segmental glomerulosclerosis
and nephrotic syndrome.
A. RECURRENT FOCAL SEGMENTAL GLOMERULOSCLEROSIS

AND ACUTE RENAL FAILURE AFTER TRANSPLANTATION
Patients with recurrence, n
Patients with no recurrence, n
16
10
7
40
Acute renal failure (23)

No acute renal failure (50)
B. ACUTE REJECTION EPISODES AMONG ACUTE RENAL FAILURE CASES

Patients with recurrence
>1 acute rejection episode

No rejection
Acute renal failure
No acute renal failure
Patients with no recurrence,

no acute renal failure
16
0
7
3
11
29
FIGURE 17-21
Patients with recurrent focal segmental
glomerulosclerosis are at substantially
increased risk of developing both acute
renal failure (panel A) after transplantation
and acute rejection episodes (panel B). In
one study, 23 of 26 patients with recurrence
developed one or more episodes of rejection, compared with only 11 of 40 patients
without recurrence [31]. Although the mechanism for the increased rate of acute dysfunction and rejection is unclear, proteinuria and
dyslipidemia may alter the expression of cell
surface immunoregulatory molecules and
major histocompatibility complex antigens.
(Adapted from Kim and coworkers [31].)
17.11
8
6
4
1
2
0
5
10
8
3
2
0
500
600
Urinary protein excretion, g/d
400
8
6
4
2
2
60
155
55
10
110
160
12
210 260
Diagnosis
Features
Recurrent FSGS
Recurrent heavy proteinuria within 3 mo

Original disease caused renal failure in <3 y
Insidious onset of proteinuria
Features of chronic rejection on biopsy, especially vascular sclerosis and glomerulopathy
Previous thrombotic microangiopathy affecting glomeruli
Original disease not FSGS
Chronic rejection excluded
Characteristic immunohistology and electron microscopy, especially in immunoglobulin
A disease
Cyclosporine-related
De novo FSGS
Other glomerulonephritides
FSGSfocal segmental glomerulosclerosis.
10
0
500
520
540
560
580
FIGURE 17-22
Serum creatinine concentrations and urinary protein excretion in four patients (AD) with
recurrent nephrotic syndrome after transplantation treated by protein adsorption. Each
bar indicates one cycle of treatment and the numbers above the bars indicate the sessions
of treatment in that cycle. A number of studies have demonstrated that both plasma
exchange and protein adsorption (using protein A sepharose), can decrease urinary protein
excretion in recurrent focal segmental glomerulosclerosis [6,7,33]. Four examples are
shown here. In this study, protein excretion decreased by 82% but returned to pretreatment
levels within 2 months in seven of eight patients. More intensive treatment regimens have
led to longer remissions [7]. The nature of the circulating factor responsible for protein
leakage is unknown. There are case reports of children with recurrent focal segmental
glomerulosclerosis responding to high-dose intravenous cyclosporine with remission of
nephrotic syndrome. However, cyclosporine does not prevent recurrence when used as
part of the initial immunosuppressive regimen. (Adapted from Dantal and coworkers [6].)
DIFFERENTIAL DIAGNOSIS OF SEGMENTAL GLOMERULAR

SCARS ON TRANSPLANTATION BIOPSY
Rejection
10
10
10
2
5 5
3
FIGURE 17-23
Segmental glomerular scars in a functioning
graft is a common finding. The interpretation of the biopsy requires knowledge of
the previous histology in the native kidneys
and the clinical course after transplantation.
Immunohistology and electron microscopy
can be particularly helpful in this setting.
Recurrent focal segmental glomerulosclerosis
is the most common cause of early massive
proteinuria. Both rejection and cyclosporine
therapy, however, can cause segmental scars
indistinguishable from those of focal segmental glomerulosclerosis. Recurrent or de
novo immunoglobulin A disease in an allograft also can cause segmental glomerular
scarring, but with mesangial hypercellularity,
immunoglobulin A detectable by immunostaining, and paramesangial deposits on
17.12
RECURRENT IMMUNOGLOBULIN A DISEASE

Features
Histologic recurrence, 25%75%
Clinical recurrence, 1%40%
Time to recurrence, 2 mo to 4 y
Clinical presentation: asymptomatic, low-grade proteinuria, microscopic hematuria
Susceptibility: human leukocyte antigen B35, DR4; immunoglobulin A rheumatoid factors
Graft loss, <10%
FIGURE 17-24
Up to 75% of patients with immunoglobulin A (IgA) disease develop
histologic recurrence within their grafts, which usually presents with
microscopic hematuria and proteinuria [4,14,15]. Many patients,
however, only will have recurrence noted on a routine biopsy after
transplantation. Most studies suggest that the risk of graft loss
resulting from recurrent disease is low (<10%) [4]. However, longterm follow-up in some studies has suggested an increasing rate of
graft loss with time, approaching 20% at 46 months [14,15].
Conversely, one study has documented 100% graft survival at 2
years in patients with IgA disease who had IgA antihuman leukocyte
antigen (HLA) antibodies [34]. The mechanism is unclear. The
association of IgA disease and the HLA alleles B35 and DR4 may
explain the increased risk of recurrence in grafts from living related
donors because family members are more likely to share HLA genes.
RECURRENT HENOCH-SCHONLEIN PURPURA

Features
Risk of recurrence, 30%75%
Clinical recurrence, up to 45%
Time to recurrence, immediately to 20 mo
Clinical presentation: often asymptomatic; hematuria, proteinuria, arthralgia,
purpuric rash, melena
Susceptibility: rapid development of renal failure in native kidneys, age >14 y
Graft loss: up to 20%, increased in grafts from living related donors
FIGURE 17-25
Histologic slide of a biopsy from a patient with recurrent immunoglobulin A (IgA) nephropathy. This patient developed proteinuria 9
months after receiving a cadaveric allograft. The biopsy shows features
of recurrent IgA disease with mesangial expansion and a glomerular
tuft adhesion to Bowmans capsule. Immunohistology confirmed
deposition of IgA in the mesangium. At the earliest stages of recurrence, mesangial IgA and complement C3 are detectable by 3
months after transplantation, with electron-dense deposits in the
paramesangium but normal appearance on light microscopy. In
patients with progressive renal dysfunction, crescents often are
found in the glomerulus.
FIGURE 17-26
Most studies have shown that histologic recurrence of HenochSchonlein purpura (HSP) is common but rarely causes graft loss.
Grafts from living related donors have a substantially increased
risk of failure as a result of recurrent HSP. Patients can develop
both renal and extrarenal manifestations of HSP, especially arthralgia. Rapid evolution of the original disease and older age at presentation (>14 y) seem to be risk factors for clinical recurrence.
Cyclosporine does not prevent recurrence. It has been arbitrarily
suggested that transplantation should be avoided for 12 months
after resolution of the purpura; however, individual cases of recurrent disease have been reported despite delays of over 3 years
between resolution of purpura and grafting.
MESANGIOCAPILLARY GLOMERULONEPHRITIS
Feature
Type I
Type II
Histologic recurrence
Clinical recurrence
Time to recurrence
9%70%
30%40%
2 wk to 7 y (median, 1.5 y)
Rarely asymptomatic;
proteinuria, nephrotic
syndrome, microscopic
hematuria
Grafts from living related donor
50%100%
10%20%
1 mo to 7 y (usually <1 y)
Frequently asymptomatic
nonnephrotic proteinuria,
microscopic hematuria
Risk factors
Mononuclear
cell nucleus
Endothelial
cell
Endothelial cell
Capillary
lumen
Interpositioned
mesangial
cell
Podocytes
Subendothelial
deposits
Basement membrane
Cell nucleus
Capillary
lumen
Basement
membrane
Continuous band of
electron-dense material
in basement membrane
Podocyte
foot
processes
Male, rapidly progressive

course of initial disease,
nephrotic syndrome after
transplantation
17.13
FIGURE 17-27
Both mesangiocapillary glomerulonephritis (MCGN) type I (mesangial and subendothelial deposits) and type II (dense deposit disease)
commonly recur after transplantation. Silent recurrence is found
more often in type II disease, whereas recurrence of type I MCGN
frequently causes nephrotic syndrome and graft failure [35]. An
increased risk of recurrence of type I MCGN occurs in grafts from
living related donors. Type II disease recurs more often in male
patients who progressed rapidly to end-stage renal failure before
transplantation. The onset of nephrotic syndrome in type II disease
usually heralds graft failure. No established treatment for recurrent
disease exists, although anecdotally aspirin plus dipyridamole and
cyclophosphamide have been used with some success in recurrent
type I MCGN. Plasma exchange has been reported to improve the
histologic changes and induce a clinical remission in one patient
with recurrence of type II MCGN [36].
FIGURE 17-28
Electron micrographs of mesangiocapillary glomerulonephritis (MCGN) type I (A) and
type II (B). The histologic features of recurrence are the same as for the primary disease.
In type II MCGN the ribbonlike band of electron-dense material within the glomerular
basement membrane has been observed as early as 3 weeks after transplantation. Initially,
the recurrence is focal but subsequently progresses to involve most of the capillary walls.
Failing grafts frequently have segmental glomerular necrosis and extracapillary crescents.
Making the diagnosis is not difficult when electron microscopy has been performed on
the transplantation biopsy. In MCGN type I, electron-dense deposits first appear in the
mesangium and subsequently in a subendothelial position. Mesangial cell interposition
frequently is visible on electron microscopy, and on light microscopy the capillary walls
appear thickened and show a double contour. The differential diagnosis is MCGN caused
by acute or chronic transplantation glomerulopathy. Global changes, immune deposits,
and increased mesangial cells, however, are rare in chronic transplantation glomerulopathy.
Endocapillary proliferation and macrophages within capillary loops are important features
of acute transplantation glomerulopathy, which usually are absent in recurrent MCGN [13].
17.14
FEATURES OF RECURRENT AND DE NOVO MEMBRANOUS NEPHROPATHY AFTER TRANSPLANTATION

Features
De novo membranous
Recurrent membranous
Incidence
Time of onset
Histology
2%5%
Often asymptomatic; proteinuria, nephrotic syndrome develops slowly
4 mo to 6 y (mean 22 mo)
Identical to native membranous nephropathy, often shows features of
chronic rejection
None specific
Increased over controls; may be as high as 50% but most patients also
have chronic rejection
3%57%
Proteinuria, nephrotic syndrome develops rapidly
1 wk to 2 y (mean 10 mo)
Identical to native membranous nephropathy, often shows features of
chronic rejection
Male gender, aggressive clinical course
50%60%, but some studies have shown no increased graft failure rate
compared with other nephritides
Risk factors for graft failure

Incidence of graft failure
FIGURE 17-29
Recurrence of membranous nephropathy in transplantations is variable,
with studies reporting incidences from 3% to 57% [4,37]. The major
differential diagnosis is de novo membranous nephropathy in patients
with a different underlying renal pathology. De novo allograft membranous glomerulonephritis reported in 2% to 5% of transplantations
is often asymptomatic and usually associated with chronic rejection
FIGURE 17-30
Histologic slide of a biopsy showing extensive spike formation
along the glomerular basement membrane. This woman had recurrent
membranous disease 8 months after transplantation. She developed
nephrotic range proteinuria and subsequent renal dysfunction.
Both recurrent and de novo membranous glomerulonephritis are
indistinguishable from idiopathic membranous nephropathy. The
initial lesions are generally stage I or II, although the deposits
subsequently become diffuse and intramembranous.
[38]. In contrast, recurrent disease frequently causes nephrotic syndrome, developing within the first 2 years after transplantation. Data
on the incidence of graft failure attributable to membranous disease
are confusing. Cyclosporine therapy has made no difference in the
incidence of the two entities, and hepatitis C virus infection may be
associated with membranous disease after transplantation.

Histologic slide showing deposition of antiglomerular basement
membrane (GBM) antibody along the GBM, which is seen in over
half of patients with Goodpastures syndrome who receive an allograft
while circulating antibodies are still detectable [39]. In most of these
cases no histologic abnormalities are seen within the glomerulus, however, and patients remain asymptomatic with normal renal function.
Approximately 25% of patients with antibody deposition will develop
features of crescentic and rapidly progressive glomerulonephritis and
subsequently suffer graft loss. Delaying transplantation for at least 6
months after antibodies have become undetectable reduces the
recurrence rate to only 5% to 15%.
Antibody titer, %
100
17.15
DIFFERENTIAL DIAGNOSIS OF LINEAR DEPOSITION

OF IMMUNOGLOBULIN ALONG THE GLOMERULAR
BASEMENT MEMBRANE IN TRANSPLANTATION BIOPSY
Immunosuppression
alone
Recurrent antiglomerular basement membrane disease

Antiglomerular basement membrane disease in patients with Alports syndrome
Chronic transplant glomerulopathy
Diabetes mellitus
Myeloma
Recurrent mesangiocapillary glomerulonephritis type I
(rarely fibrillary nephritis, and normal cadaveric grafts after initial perfusion)
No treatment
50
With plasma
exchange
+
immunosuppression
0
0
9
Time, mo
12
15
FIGURE 17-32
Without treatment, circulating antiglomerular basement membrane autoantibodies become undetectable within 6 to 18 months
of disease onset [40,41]. Treatment of the primary disease with
plasma exchange, cyclophosphamide, and steroids leads to rapid
loss of circulating antibodies. Patients who need transplantation
while circulating antibodies are still detectable should be treated
with plasma exchange before and after transplantation to minimize
circulating antibody levels and with cyclophosphamide therapy for
2 months. A similar approach should be used in patients with clinical recurrence. Patients who have linear immunoglobulin deposition in the absence of focal necrosis, crescents, or renal dysfunction
do not require treatment.
MUTATIONS IN GLOMERULAR BASEMENT

MEMBRANE COLLAGEN GENES
Chromosome Collagen
13
2
1 and 2 chains of type IV

3 and 4 chains of type IV
X
X
5 chain of type IV
6 chain of type IV
Diseases caused by mutations

Autosomal recessive or dominant
Alports syndrome
Classic X-linked Alports syndrome
Diffuse leiomyomatosis
FIGURE 17-33
Linear immunoglobulin G (IgG) is found in 1% to 4% of routine
renal allograft biopsies from patients with neither antiglomerular
basement membrane (GBM) disease nor Alports syndrome. Linear
antibody deposition in anti-GBM disease is diffuse and global and, in
practice, is rarely confused with the nonspecific antibody deposition
seen in other conditions. In chronic transplantation glomerulopathy
the antibody deposition is focal and segmental, and focal necrosis and
cellular crescents are extremely rare. The finding of linear antibody
deposits on a transplantation biopsy should lead to testing for
circulating anti-GBM antibodies. Early graft loss or dysfunction,
along with linear IgG staining, may be the first indication that a
patient with an unidentified cause for end-stage renal disease has
Alports syndrome.
FIGURE 17-34
Mutations have been identified in about half of patients with Alports
syndrome and are found in the genes for the 3, 4, or 5 chains of
type IV collagen, which are the major constituents of the glomerular
basement membrane. After transplantation, approximately 15% of
patients develop linear deposition of immunoglobulin G (IgG)
along the glomerular basement membrane (GBM), and circulating
anti-GBM antibodies specific for the 3 or 5 chains of type IV
collagen [4244]. It is unclear why only some patients develop
antibodies. Clinical disease, however, is rare. Only 20% of patients
with antibody deposition develop urinary abnormalities from 1
month to 2 years after grafting. Those patients who do develop
proteinuria or hematuria usually lose their grafts. In some cases,
treatment with cyclophosphamide did not prevent graft loss.
17.16

FIGURE 17-35
The microangiopathic hemolysis of recurrent hemolytic uremic
syndrome (HUS) is identical to the original disease, with extensive
erythrocyte fragmentation and thrombocytopenia. The incidence
of HUS recurrence is difficult to assess. At one extreme, five of 11
children suffered graft loss because of recurrent disease. However,
most series have reported substantially lower recurrence rates: no
recurrences in 16 adults and children, one of 34 grafts in 28 children,
and two probable recurrences of 24 grafts in 20 children [4,45,46].
Graft loss occurs in 10% to 50% of patients with recurrence. HUS
has been diagnosed 1 day to 15 months after transplantation (usually
in less than 2 months), and the incidence of recurrence is increased in
patients receiving grafts less than 3 months after their initial disease.
Treatment of recurrent disease is plasma exchange for plasma or
cryosupernatant, or plasma infusions, and dose reduction of cyclosporine. Recurrence may be prevented by aspirin and dipyridamole.
FIGURE 17-36
Blood film abnormalities, microangiopathic hemolytic anemia,
thrombocytopenia, and acute renal failure occur in accelerated
hypertension and acute vascular rejection. A renal biopsy usually
distinguishes acute vascular rejection, and malignant hypertension
should be obvious clinically. The microangiopathy of cyclosporine
can be difficult to differentiate from hemolytic uremic syndrome;
however, glomerular pathology usually is less marked and vascular
changes more obvious with cyclosporine toxicity. De novo
hemolytic uremic syndrome also has been reported in patients
treated with tacrolimus (FK-506) [27].
DIFFERENTIAL DIAGNOSIS OF RECURRENT

HEMOLYTIC UREMIC SYNDROME
Thrombotic microangiopathy associated with cyclosporine
Acute vascular rejection
Accelerated phase hypertension
Tacrolimus- (FK-506) associated thrombotic microangiopathy
OTHER CONDITIONS THAT RECUR IN RENAL ALLOGRAFTS

Disease
Recurrence rate
Outcome
Comments
Systemic sclerosis
Fabrys disease
20%
Rare recurrence of
ceramide in the graft
50%
50%
0%
Usually graft failure

Poor
Differentiation from acute and chronic vascular rejection can be difficult

Renal transplantation does not halt the progress of Fabrys disease because the new kidney is
not an adequate source of -galactosidase; patients have frequent systemic complications
Nephrosis reported between 21 and 60 mo
Recurrence associated with extrarenal features including arthralgias and purpura
Cystinosis does not recur; however, the allograft can become infiltrated by macrophages
containing cysteine, with no pathologic or clinical effect
Immunotactoid glomerulopathy
Mixed essential cryoglobulinemia
Cystinosis
Nephrotic syndrome
Poor
Good
FIGURE 17-37
A number of other conditions have been reported to recur in allografts. Very few patients with systemic sclerosis have received
transplantation, and the incidence of acute renal failure caused by
systemic sclerosis has declined with the widespread use of angiotensinconverting enzyme (ACE) inhibitors. About 20% of patients with a
malignant course of scleroderma receiving a transplantation develop
recurrence, which usually causes graft loss. The value of ACE

inhibitors after transplantation is unknown. Two of four patients
with immunotactoid glomerulopathy developed recurrent disease
heralded by massive proteinuria. Transplantation in Fabrys disease
rarely leads to graft-related problems; however, patients die from
systemic complications of ceramide deposition.
MANAGEMENT OF RECURRENT DISEASE AFTER KIDNEY TRANSPLANTATION

Disease
Treatment of recurrence
Plasma exchange, immunoadsorption, steroids,

angiotensin-converting enzyme inhibitors,
nonsteroidal anti-inflammatory drugs
With crescents: plasma exchange, cytotoxics
?Steroids
Aspirin, dipyridamole
?Plasma exchange
?Cytotoxics and steroids
Plasma exchange, cyclophosphamide
Plasma exchange, plasma infusion
Cyclophosphamide and steroids
Glycemic control
Aggressive perioperative dialysis, hydration, low oxalate
diet, low ascorbic acid diet, phosphate supplements,
magnesium glycerophosphate, pyridoxine
Mesangiocapillary glomerulonephritis type II
Antineutrophil cytoplasm antibodyassociated vasculitis
Diabetes
Oxalosis
WHEN TO AVOID USING LIVING RELATED DONORS

IN KIDNEY TRANSPLANTATION
Focal segmental glomerulosclerosis with risk factors for early recurrence
Mesangiocapillary glomerulonephritis type II with risk factors
(familial immunoglobulin A nephropathy and hemolytic uremic syndrome)
17.17
FIGURE 17-38
No controlled data exist on the management
of recurrent disease after transplantation.
For patients with primary hyperoxaluria,
measures to prevent further deposition of
oxalate have proved successful in controlling
recurrent renal oxalosis [9]. In diabetes
mellitus, the pathophysiology of recurrent
nephropathy undoubtedly reflects the same
insults as those causing the initial renal failure,
and good evidence exists that glycemic control
can slow the development of end-organ
damage. Plasma exchange and immunoadsorption are promising therapies for
patients with nephrosis who have recurrent
focal segmental glomerulosclerosis; however,
these therapies do not provide sustained
remission [6,7]. In all these cases, establishing
a diagnosis of recurrent disease is critical in
identifying a possible treatment modality.
FIGURE 17-39
In these diseases, rapid recurrence leading to graft failure is frequent
enough to warrant extreme caution in using living related donors.
Even excluding these conditions, the overall rate of recurrence of
glomerulonephritis is substantially increased in living related donors,
and patients should be made aware of this risk [4]. For familial
diseases, the risk of recurrence is even higher (eg, some families
with immunoglobulin A disease and hemolytic uremic syndrome).
Finally, recurrent glomerulonephritis has been reported in up to
30% of renal isografts, with disease onset between 2 weeks and
16 years after grafting.
References
1. Tejani A, Stablein DH: Recurrence of focal segmental glomerulonephritis
posttransplantation: a special report of the North American Pediatric
Renal Transplant Cooperative Study. J Am Soc Nephrol 1992,
2(suppl):258263.
2. Najarian JS, Kaufman DB, Fryd DS, et al.: Long term survival following
kidney transplantation in 100 type I diabetic patients. Transplantation
1989, 47:106113.
3. Broyer M, Brunner FP, Brynger H, et al.: Kidney transplantation in
primary oxalosis: data from the EDTA registry. Nephrol Dial
Transplant 1990, 5:332336.
4. Kotanko P, Pusey CD, Levy JB: Recurrent glomerulonephritis following
renal transplantation. Transplantation 1997, 63:10451052.
5. Cameron JS: Recurrent primary disease following renal transplantation.
In Advanced Renal Medicine. Edited by Raine AEG. Oxford: Oxford
6. Dantal J, Bigot E, Bogers W, et al.: Effect of plasma protein adsorption
on protein excretion in kidney-transplant recipients with recurrent
nephrotic syndrome. N Engl J Med 1994, 330:714.
7. Artero ML, Sharma R, Savin VJ, et al.: Plasmapheresis reduces proteinuria and serum capacity to injure glomeruli in patients with recurrent
focal glomerulosclerosis. Am J Kidney Dis 1994, 23:574581.
8. Watts RWE: Primary hyperoxaluria type 1. Q J Med 1994, 87:593599.
9. Allen AR, Thompson EM, Williams G, et al.: Selective renal transplantation in primary hyperoxaluria type 1. Am J Kidney Dis 1996,
27:891895.
10. Bilous RW, Mauer SM, Sutherland DE, et al.: The effects of pancreas
transplantation on the glomerular structure of renal allografts in patients
with insulin-dependent diabetes. N Engl J Med 1989, 321:8085.
11. Remuzzi G, Ruggenenti P, Mauer SM: Pancreas and kidney/pancreas
transplants: experimental medicine or real improvement? Lancet
1994, 343:2731.
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Atlas of Diseases of The Kidney

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Atlas of Diseases of The Kidney

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Diseases of Water

Disorders of Water, Electrolytes, and Acid-Base

Normal water intake

Total body water

Variable water excretion

Fixed water excretion

Total insensible losses

Total urine output

Water intake and distribution

Physiology of the Renal Diluting

Diseases of Water Metabolism

Generation of medullary hypertonicity

Collecting system water

Disorders of Water, Electrolytes, and Acid-Base

Determinants of delivery of H2O

Collecting duct impermeability depends on

Diseases of Water Metabolism

Henle. 5) In the thin ascending limb of the loop of Henle, NaCl

Osmolality, mOsm/kg H2O

Disorders of Water, Electrolytes, and Acid-Base

Diseases of Water Metabolism

AQUAPORINS AND THEIR CHARACTERISTICS

Size (amino acids)

Apical membrane and intracellular vesicles

different channels have been cloned and characterized; however,

Disorders of Water, Electrolytes, and Acid-Base

Isotonic volume depletion

Control of Water Balance and

Decreased plasma osmolality

Increased ADH release

Decreased ADH release

Decreased plasma osmolality

Increased plasma osmolality

Decreased ADH release and thirst

Increased ADH release and thirst

anatomically distinct. Between the limits imposed by the osmotic

Diseases of Water Metabolism

Disorder involving urine

Disorder involving urine

Approach to the Hyponatremic Patient

Substances the increase osmolality

Substances that increase osmolality and decrease serum sodium

Disorders of Water, Electrolytes, and Acid-Base

Reabsorption of sodium chloride

ADH release or action

1. Intrarenal factors such as a diminished glomerular filtration rate

Assessment of volume status

Euvolemia (no edema)

Diseases of Water Metabolism

DRUGS ASSOCIATED WITH HYPONATREMIA

DIAGNOSTIC CRITERIA FOR THE SYNDROME OF

CAUSES OF THE SYNDROME OF INAPPROPRIATE

Central Nervous System Disorders

Disorders of Water, Electrolytes, and Acid-Base

SIGNS AND SYMPTOMS OF HYPONATREMIA

Diseases of Water Metabolism

HYPONATREMIC PATIENTS AT RISK FOR

Acute cerebral edema

Postoperative menstruant females

Osmotic demyelination syndrome

SYMPTOMS OF CENTRAL PONTINE MYELINOLYSIS

images, hypointense. These lesions do not enhance with gadolinium.

Disorders of Water, Electrolytes, and Acid-Base