Atlas of Diseases of Kidney

Diseases of Water
Metabolism
Sumit Kumar
Tomas Berl
T
he maintenance of the tonicity of body fluids within a very nar-
row physiologic range is made possible by homeostatic mecha-
nisms 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 prevail-
ing physiologic needs. In the first section of this chapter, the physiol-
ogy 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 dilu-
tion 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 mecha-
nism 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 hyperna-
tremia and management strategies are described.
CHAPTER
1
1.2 Disorders of Water, Electrolytes, and Acid-Base
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
Water intake and distribution

Normal water intake
(1.0–1.5 L/d) Fig. 1-12) and by cultural and social behav-
iors. Water intake is finely balanced by the
need to maintain physiologic serum osmo-
lality between 285 to 290 mOsm/kg. Both
water that is drunk and that is generated
Water of cellular through metabolism are distributed in the
metabolism extracellular and intracellular compart-
(350–500 mL/d) ments that are in constant equilibrium.
Intracellular Extracellular Total body water Total body water equals approximately
compartment compartment 42L
(27 L) (15 L) (60% body weight
60% of total body weight in young men,
in a 70-kg man) 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)
Fixed water excretion Variable water excretion
in the extracellular compartment.
Assuming normal glomerular filtration
rate to be about 125 mL/min, the total
Water excretion
volume of blood filtered by the kidney is

Filtrate/d
about 180 L/24 hr. Only about 1 to 1.5 L
180L is excreted as urine, however, on account
of the complex interplay of the urine con-
Stool Sweat Pulmonary centrating and diluting mechanism and the
0.1 L/d 0.1 L/d 0.3 L/d effect of antidiuretic hormone to different
segments of the nephron, as depicted in the
following figures.
Total insensible losses Total urine output
~0.5 L/d 1.0–1.5 L/d
Diseases of Water Metabolism 1.3
Generation of medullary hypertonicity

Normal function of the thick
ascending limb of loop of Henle
Urea delivery
;;;;;;;;;;;
Normal medullary blood flow
;;;;
;;;; ;;;;;;;;;;;
;;;;;;;;;;;;;;;
;;;;;;;;;;;
;;;;
NaCl
;;;; ;;;;;;;;;;;
;;;;;;;;;;;;;;;
H 2O
GFR
;;;;;;;;;;;
H 2O
;;;;;;;;;;;;;;;
ADH
ADH
;;;; ;;;;;;;;;;;
NaCl
;;;;
;;;; ;;;;;;;;;;;
NaCl H 2O
;;;;
;;;;;;;;;;;
Determinants of delivery of NaCl NaCl
H 2O
NaCl to distal tubule:
;;;;
;;;;;;;;;;;
GFR ADH
NaCl
;;;; ;;;
;;;;;;;;;;;
Proximal tubular fluid and
H 2O
solute (NaCl) reabsorption H 2O
H 2O
;;;; ;;;
;;;;;;;;;;;
NaCl
;;;;
;;;;;;;;;;;
H 2O
;;;
;;;;
;;;; ;;;
;;;
;;; Collecting system water
;;
Water delivery
permeability determined by
;;
NaCl movement Presence of arginine vasopressin
Solute concentration Normal collecting system
FIGURE 1-2
Determinants of the renal concentrating mechanism. Human kidneys have two popula-
tions of nephrons, superficial and juxtamedullary. This anatomic arrangement has impor-
tant 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 person’s needs and
dictated by the plasma osmolality. After two thirds of the filtered load (180 L/d) is isotoni-
cally 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 collect-
ing 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 col-
lecting 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.
FIGURE 1-3
Normal functioning of Determinants of the urinary dilution mech-
Thick ascending limb of loop of Henle anism include 1) delivery of water to the
Cortical diluting segment
;;;;;;;;;;;;
thick ascending limb of the loop of Henle,
distal convoluted tubule, and collecting sys-
;;;;
;;;;;;;;;;;;
;;;;
tem of the nephron; 2) generation of maxi-
;;;;;;;;;;;;
mally hypotonic fluid in the diluting seg-
ments (ie, normal thick ascending limb of
;;;;
;;;;;;;;;;;;
;;;;
the loop of Henle and cortical diluting seg-
;;;;;;;;;;;;
NaCl
;;;;
;;;;;;;;;;;;
H 2O
ment); 3) maintenance of water imperme-
ability of the collecting system as deter-
mined by the absence of antidiuretic
GFR
;;;;
;;;;;;;;;;;;
;;;;
hormone (ADH) or its action and other
;;;;;;;;;;;; Impermeable antidiuretic substances. GFR—glomerular

H 2O
;;;;
;;;;;;;;;;;;
NaCl collecting filtration rate; NaCl—sodium chloride;
duct H2O—water.
;;;;
;;;;;;;;;;;;
;;;;
;;;;;;;;;;;;
;;;;
Determinants of delivery of H2O NaCl H 2O
to distal parts of the nephron
;;;;;;;;;;;;
;;;;
GFR NaCl
;;;;;;;;;;;;
;;;;
Proximal tubular H2O and
NaCl reabsorption H 2O
;;;;;;;;;;;;
;;;;
NaCl
;;;;;;;;;;;;
;;;;
;;;;;;;;;;;;
;;;;
H 2O
;;;;;;;;;;;;
;;;;
;;;;;;;;;;;;
Collecting duct impermeability depends on
Absence of ADH
H 2O
Absence of other antidiuretic substances
FIGURE 1-4
Distal tubule Mechanism of urine concentration:
Urea
overview of the passive model. Several
models of urine concentration have been
2 put forth by investigators. The passive
Cortex H 2O model of urine concentration described by
H 2O
Kokko and Rector [3] is based on perme-
Na+ Na+ ability characteristics of different parts of
K+ K+ 1
2Cl2– 2Cl2– the nephron to solute and water and on the
Urea Outer medullary fact that the active transport is limited to
NaCl
Na+ Na+ collecting duct the thick ascending limb. 1) Through the
K+ K+ Na+, K+, 2 Cl cotransporter, the thick
2Cl2– 2Cl2–
ascending limb actively transports sodium
Urea chloride (NaCl), increasing the interstitial
H 2O
Outer medulla tonicity, resulting in tubular fluid dilution
with no net movement of water and urea
on account of their low permeability. 2)
H 2O Inner medullary The hypotonic fluid under antidiuretic hor-
4 collecting duct mone action undergoes osmotic equilibra-
3 H 2O tion with the interstitium in the late distal
Urea
tubule and cortical and outer medullary
collecting duct, resulting in water removal.
NaCl NaCl Urea concentration in the tubular fluid rises
Urea
5 on account of low urea permeability. 3) At
the inner medullary collecting duct, which
is highly permeable to urea and water, espe-
NaCl
cially in response to antidiuretic hormone,
Inner medulla Loop of Henle Collecting tubule the urea enters the interstitium down its
concentration gradient, preserving intersti-
tial 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 Henle. 5) In the thin ascending limb of the loop of Henle, NaCl
descending thin limb of loop of Henle, which is relatively imperme- moves passively down its concentration gradient into the intersti-
able to NaCl and urea, making the tubular fluid hypertonic with tium, making tubular fluid less concentrated with little or no move-
high NaCl concentration as it arrives at the bend of the loop of ment of water. H2O—water.
FIGURE 1-5
Pathways for urea recycling. Urea plays an important role in the
Cortex generation of medullary interstitial hypertonicity. A recycling mech-
anism operates to minimize urea loss. The urea that is reabsorbed
Urea
into the inner medullary stripe from the terminal inner medullary
Urea
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
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
Urea
through to the thick ascending limb of the loop of Henle, the distal
Outer collecting tubule, and the collecting duct, before it reaches the
stripe Outer inner medullary collecting duct (pathway B). This process is facili-
Inner
Urea medulla tated by the close anatomic relationship that the hairpin loop of
stripe Henle and the vasa recta share [4].
Urea
Collecting
duct
Urea
Urea
Ascending vasa recta Pathway B
Pathway A Urea Inner

medulla
FIGURE 1-6
1500 Changes in the volume and osmolality of
20 mL 0.3 mL tubular fluid along the nephron in diuresis
and antidiuresis. The osmolality of the tubu-
1200 lar fluid undergoes several changes as it pass-
es through different segments of the tubules.
Tubular fluid undergoes marked reduction in
Osmolality, mOsm/kg H2O
900 its volume in the proximal tubule; however,

this occurs iso-osmotically with the glomeru-
lar filtrate. In the loop of Henle, because of
the aforementioned countercurrent mecha-
600 nism, the osmolality of the tubular fluid
rises sharply but falls again to as low as
100 mOsm/kg as it reaches the thick ascend-
300
Maximal ADH ing limb and the distal convoluted tubule.
100 mL 30 mL 2.0 mL Thereafter, in the late distal tubule and the
collecting duct, the osmolality depends on
20 mL no ADH 16 mL the presence or absence of antidiuretic hor-
0 mone (ADH). In the absence of ADH, very
Proximal tubule Loop of Henle Distal tubule Outer and little water is reabsorbed and dilute urine
and cortical inner medullary results. On the other hand, in the presence
collecting tubule collecting ducts of ADH, the collecting duct, and in some
species, the distal convoluted tubule, become
highly permeable to water, causing reabsorp-
tion of water into the interstitium, resulting
in concentrated urine [5].
FIGURE 1-7
Paraventricular neurons Osmoreceptors Pathways of antidiuretic hormone release. Antidiuretic hormone is
Pineal responsible for augmenting the water permeability of the cortical
Baroreceptors Third ventricle and medullary collecting tubules, thus promoting water reabsorp-
VP,NP tion via osmotic equilibration with the isotonic and hypertonic
Supraoptic neuron
interstitium, respecively. The hormone is formed in the supraoptic
Tanycyte
and paraventricular nuclei, under the stimulus of osmoreceptors
SON
and baroreceptors (see Fig. 1-11), transported along their axons
Optic chiasm and secreted at three sites: the posterior pituitary gland, the portal
Superior hypophysial capillaries of the median eminence, and the cerebrospinal fluid of
artery the third ventricle. It is from the posterior pituitary that the antidi-
Portal capillaries uretic hormone is released into the systemic circulation [6].
in zona externa of Mammilary body SON—supraoptic nucleus; VP—vasopressin; NP—neurophysin.
median eminence VP,NP
Posterior pituitary
Long portal vein
Systemic venous system
Anterior pituitary
Short portal vein VP,NP
FIGURE 1-8
Exon 1 Exon 2 Exon 3 Structure of the human arginine vasopressin
(AVP/antidiuretic hormone) gene and the
prohormone. Antidiuretic hormone (ADH)
is a cyclic hexapeptide (mol. wt. 1099) with
Pre-pro-vasopressin AVP Gly Lys Arg Neurophysin II Arg Glycopeptide a tail of three amino acids. The biologically
(164 AA) (Cleavage site) inactive macromolecule, pre-pro-vaso-
pressin is cleaved into the smaller, biologi-
Signal
peptide cally active protein. The protein of vaso-
pressin is translated through a series of sig-
nal transduction pathways and intracellular
Pro-vasopressin AVP Gly Lys Arg Neurophysin II Arg Glycopeptide
cleaving. Vasopressin, along with its bind-
ing protein, neurophysin II, and the glyco-
protein, are secreted in the form of neurose-
cretory granules down the axons and stored
Products of AVP NH2 + Neurophysin II + Glycopeptide in nerve terminals of the posterior lobe of
pro-vasopressin
the pituitary [7]. ADH has a short half-life
of about 15 to 20 minutes and is rapidly
metabolized in the liver and kidneys.
Gly—glycine; Lys—lysine; Arg—arginine.
FIGURE 1-9
Intracellular action of antidiuretic hormone. The multiple actions
AQP-3 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
Recycling vesicle
duct cell. This interaction of vasopressin with the V2 receptor leads
to increased adenylate cyclase activity via the stimulatory G protein
Endocytic (Gs), which catalyzes the formation of cyclic adenosine 3’, 5’-
cAMP retrieval
monophosphate (cAMP) from adenosine triphosphate (ATP). In
ATP AQP-2
turn, cAMP activates a serine threonine kinase, protein kinase A
AQP-2 (PKA). Cytoplasmic vesicles carrying the water channel proteins
migrate through the cell in response to this phosphorylation
PKA H 2O process and fuse with the apical membrane in response to increas-
ing vasopressin binding, thus increasing water permeability of the
Gαs AQP-2 collecting duct cells. These water channels are recyled by endocyto-
sis once the vasopressin is removed. The water channel responsible
Gαs
for the high water permeability of the luminal membrane in
Exocytic
insertion response to vasopressin has recently been cloned and designated as
aquaporin-2 (AQP-2) [8]. The other members of the aquaporin
AVP Recycling vesicle family, AQP-3 and AQP-4 are located on the basolateral mem-
branes and are probably involved in water exit from the cell. The
molecular biology of these channels and of receptors responsible
AQP-4 for vasopressin action have contributed to the understanding of the
syndromes of genetically transmitted and acquired forms of vaso-
Basolateral Luminal
pressin resistance. AVP—arginine vasopressin.
AQUAPORINS AND THEIR CHARACTERISTICS
AQP-1 AQP-2 AQP-3 AQP-4

Size (amino acids) 269 271 285 301
Permeability to small solutes No No Urea glycerol No
Regulation by antidiurectic hormone No Yes No No
Site Proximal tubules; Collecting duct; principal cells Medullary collecting Hypothalamic—supraoptic, paraventricular nuclei;
descending thin limb duct; colon ependymal, granular, and Purkinje cells
Cellular localization Apical and basolateral Apical membrane and intracellu- Basolateral membrane Basolateral membrane of the prinicpal cells
membrane lar vesicles
Mutant phenotype Normal Nephrogenic diabetes insipidus Unknown Unknown
FIGURE 1-10
Aquaporins and their characteristics. An ever growing family of different channels have been cloned and characterized; however,
aquaporin (AQP) channels are being described. So far, about seven only four have been found to have any definite physiologic role.
FIGURE 1-11
Isotonic volume depletion Osmotic and nonosmotic regulation of antidiuretic hormone (ADH) secretion. ADH is
Isovolemic osmotic increase secreted in response to changes in osmolality and in circulating arterial volume. The
50
“osmoreceptor” cells are located in the anterior hypothalamus close to the supraoptic
45 nuclei. Aquaporin-4 (AQP-4), a candidate osmoreceptor, is a member of the water channel
40 family that was recently cloned and characterized and is found in abundance in these neu-
Plasma AVP, pg/mL
35 rons. 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
30
so efficient that the plasma osmolality usually does not vary by more than 1% to 2%
25 despite wide fluctuations in water intake [9]. There are several other nonosmotic stimuli
20 for ADH secretion. In conditions of decreased arterial circulating volume (eg, heart failure,
15 cirrhosis, vomiting), decrease in inhibitory parasympathetic afferents in the carotid sinus
baroreceptors affects ADH secretion. Other nonosmotic stimuli include nausea, which can
10
lead to a 500-fold rise in circulating ADH levels, postoperative pain, and pregnancy. Much
5 higher ADH levels can be achieved with hypovolemia than with hyperosmolarity, although
0 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 mecha-
0 5 10 15 20 nism, that under normal conditions, causes either intake or exclusion of water in an effort
Change, % to restore serum osmolality to normal.
Control of Water Balance and

Serum Sodium Concentration
Increased plasma osmolality Decreased plasma osmolality

or or
decreased arterial circulating volume increased arterial circulating blood volume
Increased thirst Increased ADH release Decreased thirst Decreased ADH release
Increased water Decreased water Decreased water Decreased water

intake excretion intake excretion
Water retention Water excretion
Decreased plasma osmolality Increased plasma osmolality

or and
increased arterial circulating volume decreased arterial circulating volume
Decreased ADH release and thirst Increased ADH release and thirst
A B
FIGURE 1-12
Pathways of water balance (conservation, A, and excretion, B). In anatomically distinct. Between the limits imposed by the osmotic
humans and other terrestrial animals, the thirst mechanism plays thresholds for thirst and ADH release, plasma osmolality may be
an important role in water (H2O) balance. Hypertonicity is the regulated still more precisely by small osmoregulated adjustments
most potent stimulus for thirst: only 2% to 3 % changes in plasma in urine flow and water intake. The exact level at which balance
osmolality produce a strong desire to drink water. This absolute occurs depends on various factors such as insensible losses through
level of osmolality at which the sensation of thirst arises in healthy skin and lungs, and the gains incurred from eating, normal drink-
persons, called the osmotic threshold for thirst, usually averages ing, and fat metabolism. In general, overall intake and output come
about 290 to 295 mOsm/kg H2O (approximately 10 mOsm/kg into balance at a plasma osmolality of 288 mOsm/kg, roughly
H2O above that of antidiuretic hormone [ADH] release). The so- halfway between the thresholds for ADH release and thirst [10].
called thirst center is located close to the osmoreceptors but is
FIGURE 1-13
Plasma osmolality Pathogenesis of dysnatremias. The countercurrent mechanism of
280 to 290 mOsm/kg H2O the kidneys in concert with the hypothalamic osmoreceptors via
antidiuretic hormone (ADH) secretion maintain a very finely tuned
Decrease Increase 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 culmi-
Supression Supression Stimulation Stimulation nates in hypernatremia. Hyponatremia reflects a disturbance in
of thirst of ADH release of thirst of ADH release
homeostatic mechanisms characterized by excess total body H2O
relative to total body sodium, and hypernatremia reflects a defi-
ciency of total body H2O relative to total body sodium [11].
(From Halterman and Berl [12]; with permission.)
Dilute urine Concentrated urine
Disorder involving urine Disorder involving urine

dilution with H2O intake concentration with inadequate
H2O intake
Hyponatremia Hypernatremia
Approach to the Hyponatremic Patient

pseudohyponatremia, since, in most but not all situations, hypona-
EFFECTS OF OSMOTICALLY ACTIVE tremia reflects hypo-osmolality.
SUBSTANCES ON SERUM SODIUM 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
Substances that increase osmol- across cell membranes (eg, urea, methanol, ethanol, and ethylene
Substances the increase osmolality ality and decrease serum sodium glycol) do not cause water movement and cause hypertonicity
without changing serum sodium (translocational hyponatremia) without causing cell dehydration. Typical examples are an uremic
patient with a high blood urea nitrogen value and an ethanol-
Urea Glucose
intoxicated person. On the other hand, in a patient with diabetic
Ethanol Mannitol
ketoacidosis who is insulinopenic the glucose is not permeant
Ethylene glycol Glycine across cell membranes and, by its presence in the extracellular
Isopropyl alcohol Maltose fluid, causes water to move from the cells to extracellular space,
Methanol 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.
FIGURE 1-14 Glycine is used as an irrigant solution during transurethral resec-
Evaluation of a hyponatremic patient: effects of osmotically active tion of the prostate and in endometrial surgery. Pseudohypo-
substances on serum sodium. In the evaluation of a hyponatremic natremia occurs when the solid phase of plasma (usually 6%
patient, a determination should be made about whether hyponatrem- to 8%) is much increased by large increments of either lipids
ia is truly hypo-osmotic and not a consequence of translocational or or proteins (eg, in hypertriglyceridemia or paraproteinemias).
FIGURE 1-15
Pathogenesis of hyponatremia. The
↓ Reabsorption of sodium chloride
in distal convoluted tubule normal components of the renal diluting
Thiazide diuretics mechanism are depicted in Figure 1-3.
Hyponatremia results from disorders of
this diluting capacity of the kidney in the
following situations:
1. Intrarenal factors such as a dimin-
ished glomerular filtration rate
↓ Reabsorption of sodium (GFR), or an increase in proximal
chloride in thick ascending tubule fluid and sodium reabsorp-
limb of loop of Henle
tion, or both, which decrease distal
Loop diuretics
GFR diminished Osmotic diuretics delivery to the diluting segments of
Age Interstitial disease the nephron, as in volume depletion,
Renal disease
congestive heart failure, cirrhosis, or
Congestive heart failure
Cirrhosis nephrotic syndrome.
Nephrotic syndrome 2. A defect in sodium chloride transport
Volume depletion out of the water-impermeable seg-
NaCl ments of the nephrons (ie, in the thick
ascending limb of the loop of Henle).
This may occur in patients with inter-
stitial renal disease and administra-
tion of thiazide or loop diuretics.
↑ ADH release or action 3. Continued secretion of antidiuretic
Drugs hormone (ADH) despite the presence
Syndrome of inappropriate of serum hypo-osmolality mostly
antidiuretic hormone
secretion, etc. stimulated by nonosmotic mecha-
nisms [12].
NaCl—sodium chloride.
Assessment of volume status
Hypovolemia Euvolemia (no edema) Hypervolemia

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

DIURETIC HORMONE SECRETION
Antidiuretic hormone analogues

Deamino-D-arginine vasopressin (DDAVP) Pulmonary
Oxytocin Carcinomas Disorders Central Nervous System Disorders
Drugs that enhance release of antidiuretic hormone Bronchogenic Viral pneumonia Encephalitis (viral or bacterial)
Chlorpropamide Duodenal Bacterial pneumonia Meningitis (viral, bacterial, tuberculous,
Clofibrate Pancreatic Pulmonary abscess fungal)
Carbamazepine-oxycarbazepine Thymoma Tuberculosis Head trauma
Vincristine Gastric Aspergillosis Brain abscess
Nicotine Lymphoma Positive-pressure Brain tumor
Narcotics Ewing’s sarcoma breathing Guillain-Barré syndrome
Antipsychotics Bladder Asthma Acute intermittent porphyria
Antidepressants Carcinoma of the Pneumothorax Subarachnoid hemorrhage or subdural
Ifosfamide ureter Mesothelioma hematoma
Drugs that potentiate renal action of antidiuretic hormone Prostatic Cystic fibrosis Cerebellar and cerebral atrophy
Chlorpropamide Oropharyngeal Cavernous sinus thrombosis
Cyclophosphamide Neonatal hypoxia
Nonsteroidal anti-inflammatory drugs Hydrocephalus
Acetaminophen Shy-Drager syndrome
Drugs that cause hyponatremia by unknown mechanisms Rocky Mountain spotted fever
Haloperidol Delirium tremens
Fluphenazine Cerebrovascular accident (cerebral
Amitriptyline thrombosis or hemorrhage)
Thioradazine Acute psychosis
Fluoxetine Multiple sclerosis
FIGURE 1-17 FIGURE 1-18

Drugs that cause hyponatremia. Drug-induced hyponatremia is Causes of the syndrome of inappropriate antidiuretic hormone
mediated by antidiuretic hormone analogues like deamino-D-argi- secretion (SIADH). Though SIADH is the commonest cause of
nine-vasopressin (DDAVP), or antidiuretic hormone release, or by hyponatremia in hospitalized patients, it is a diagnosis of exclusion.
potentiating the action of antidiuretic hormone. Some drugs cause It is characterized by a defect in osmoregulation of ADH in which
hyponatremia by unknown mechanisms [13]. (From Veis and Berl plasma ADH levels are not appropriately suppressed for the degree
[13]; with permission.) of hypotonicity, leading to urine concentration by a variety of mech-
anisms. Most of these fall into one of three categories (ie, malignan-
cies, pulmonary diseases, central nervous system disorders) [14].
FIGURE 1-19
DIAGNOSTIC CRITERIA FOR THE SYNDROME OF Diagnostic criteria for the syndrome of inappropriate antidiuretic
INAPPROPRIATE ANTIDIURETIC HORMONE hormone secretion (SIADH). Clinically, SIADH is characterized by
SECRETION a decrease in the effective extracellular fluid osmolality, with inap-
propriately concentrated urine. Patients with SIADH are clinically
euvolemic and are consuming normal amounts of sodium and
Essential water (H2O). They have elevated urinary sodium excretion. In the
Decreased extracellular fluid effective osmolality (< 270 mOsm/kg H2O) evaluation of these patients, it is important to exclude adrenal, thy-
Inappropriate urinary concentration (> 100 mOsm/kg H2O) roid, pituitary, and renal disease and diuretic use. Patients with
Clinical euvolemia clinically suspected SIADH can be tested with a water load. Upon
Elevated urinary sodium concentration (U[Na]), with normal salt and H2O intake administration of 20 mL/kg of H2O, patients with SIADH are
Absence of adrenal, thyroid, pituitary, or renal insufficiency or diuretic use unable to excrete 90% of the H2O load and are unable to dilute
Supplemental their urine to an osmolality less than 100 mOsm/kg [15]. (Modified
Abnormal H2O load test (inability to excrete at least 90% of a 20–mL/kg H2O load from Verbalis [15]; with permission.)
in 4 hrs or failure to dilute urinary osmolality to < 100 mOsm/kg)
Plasma antidiuretic hormone level inappropriately elevated relative to plasma osmolal-
ity
No significant correction of plasma sodium with volume expansion, but improvement
after fluid restriction
FIGURE 1-20
SIGNS AND SYMPTOMS OF HYPONATREMIA 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 thera-
Central Nervous System Gastrointestinal System py than the absolute value itself. Most patients with serum sodium
values above 125 mEq/L are asymptomatic. The rapidity with
Mild Anorexia
which hyponatremia develops is critical in the initial evaluation of
Apathy Nausea
such patients. In the range of 125 to 130 mEq/L, the predominant
Headache Vomiting
symptoms are gastrointestinal ones, including nausea and vomiting.
Lethargy
Musculoskeletal System Neuropsychiatric symptoms dominate the picture once the serum
Moderate
Cramps sodium level drops below 125 mEq/L, mostly because of cerebral
Agitation edema secondary to hypotonicity. These include headache, lethargy,
Diminished deep tendon reflexes
Ataxia reversible ataxia, psychosis, seizures, and coma. Severe manifesta-
Confusion tions of cerebral edema include increased intracerebral pressure,
Disorientation tentorial herniation, respiratory depression and death.
Psychosis Hyponatremia-induced cerebral edema occurs principally with
Severe rapid development of hyponatremia, typically in patients managed
Stupor with hypotonic fluids in the postoperative setting or those receiving
Coma diuretics, as discussed previously. The mortality rate can be as
Pseudobulbar palsy great as 50%. Fortunately, this rarely occurs. Nevertheless, neuro-
Tentorial herniation logic symptoms in a hyponatremic patient call for prompt and
Cheyne-Stokes respiration immediate attention and treatment [16,17].
Death
FIGURE 1-21
1 Cerebral adaptation to hyponatremia.
Na+/H2O ↓Na+/↑H2O 3 ↓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 cra-
nium causes increased intracranial pressure,
leading to neurologic symptoms. To prevent
this from happening, mechanisms geared
Normonatremia Acute hyponatremia Chronic hyponatremia toward volume regulation come into opera-
A tion, to prevent cerebral edema from devel-
oping 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,
K+ within 1 to 3 hours, a decrease in cerebral extracellular volume occurs by movement of
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 indi-
vidual osmolytes during adaptation to chronic hyponatremia. Thereafter, if hyponatremia
Inositol persists, other organic osmolytes such as phosphocreatine, myoinositol, and amino acids
Cl– like glutamine, and taurine are lost. The loss of these solutes markedly decreases cerebral
Taurine swelling. Patients who have had a slower onset of hyponatremia (over 72 to 96 hours or
B Other
longer), the risk for osmotic demyelination rises if hyponatremia is corrected too rapidly
[18,19]. Na+—sodium; K+—potassium; Cl-—chloride.
HYPONATREMIC PATIENTS AT RISK FOR SYMPTOMS OF CENTRAL PONTINE MYELINOLYSIS

NEUROLOGIC COMPLICATIONS
Initial symptoms
Complication Persons at Risk Mutism
Dysarthria
Acute cerebral edema Postoperative menstruant females Lethargy and affective changes
Elderly women taking thiazides
Classic symptoms
Children Spastic quadriparesis
Psychiatric polydipsic patients Pseudobulbar palsy
Hypoxemic patients
Lesions in the midbrain, medulla oblongata, and pontine tegmentum
Osmotic demyelination syndrome Alcoholics Pupillary and oculomotor abnormalities
Malnourished patients Altered sensorium
Hypokalemic patients Cranial neuropathies
Extrapontine myelinolysis
Burn victims
Ataxia
Elderly women taking thiazide diuretics Behavioral abnormalities
Parkinsonism
Dystonia
FIGURE 1-22
Hyponatremic patients at risk for neurologic complications. Those
at risk for cerebral edema include postoperative menstruant FIGURE 1-23
women, elderly women taking thiazide diuretics, children, psychi- Symptoms of central pontine myelinolysis. This condition has been
atric patients with polydipsia, and hypoxic patients. In women, described all over the world, in all age groups, and can follow cor-
and, in particular, menstruant ones, the risk for developing neuro- rection of hyponatremia of any cause. The risk for development of
logic complications is 25 times greater than that for nonmenstruant central pontine myelinolysis is related to the severity and chronicity
women or men. The increased risk was independent of the rate of of the hyponatremia. Initial symptoms include mutism and
development, or the magnitude of the hyponatremia [21]. The dysarthria. More than 90% of patients exhibit the classic symptoms
osmotic demyelination syndrome or central pontine myelinolysis of myelinolysis (ie, spastic quadriparesis and pseudobulbar palsy),
seems to occur when there is rapid correction of low osmolality reflecting damage to the corticospinal and corticobulbar tracts in
(hyponatremia) in a brain already chronically adapted (more than the basis pontis. Other symptoms occur on account of extension of
72 to 96 hours). It is rarely seen in patients with a serum sodium the lesion to other parts of the midbrain. This syndrome follows a
value greater than 120 mEq/L or in those who have hyponatremia biphasic course. Initially, a generalized encephalopathy, associated
of less than 48 hours’ duration [20,21]. (Adapted from Lauriat and with a rapid rise in serum sodium, occurs. This is followed by the
Berl [21]; with permission.) 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.)
A B
FIGURE 1-24
A, Imaging of central pontine myelinolysis. Brain imaging is the images, hypointense. These lesions do not enhance with gadolinium.
most useful diagnostic technique for central pontine myelinolysis. They may not be apparent on imaging until 2 weeks into the illness.
Magnetic resonance imaging (MRI) is more sensitive than computed Other diagnostic tests are brainstem auditory evoked potentials,
tomography (CT). On CT, central pontine and extrapontine lesions electroencephalography, and cerebrospinal fluid protein and myelin
appear as symmetric areas of hypodensity (not shown). On T2 basic proteins [22]. B, Gross appearance of the pons in central pon-
images of MRI, the lesions appear as hyperintense and on T1 tine myelinolysis. (From Laureno and Karp [22]; with permission.)
FIGURE 1-25
Severe hyponatremia (<125 mmol/L) Treatment of severe euvolemic hyponatrem-
ia (<125 mmol/L). The evaluation of a
hyponatremic patient involves an assessment
Symptomatic Asymptomatic
of whether the patient is symptomatic, and
if so, the duration of hyponatremia should
Acute Chronic Chronic be ascertained. The therapeutic approach
Duration <48 h Duration >48 h Rarely <48 h to the hyponatremic patient is determined
more by the presence or absence of symp-
toms than by the absolute level of serum
Emergency correction needed Some immediate correction needed No immediate sodium. Acutely hyponatremic patients
Hypertonic saline 1–2 mL/kg/h Hypertonic saline 1–2 mL/kg/h correction needed are at great risk for permanent neurologic
Coadministration of furosemide Coadministration of furosemide
Change to water restriction upon sequelae from cerebral edema if the hypona-
10% increase of sodium or if tremia is not promptly corrected. On the
symptoms resolve other hand, chronic hyponatremia carries
Perform frequent measurement the risk of osmotic demyelination syndrome
of serum and urine electrolytes if corrected too rapidly. The next step
Do not exceed 1.5 mmol/L/hr
or 20 mmol/d involves a determination of whether the
patient has any risk factors for development
of neurologic complications.
The commonest setting for acute, sympto-
matic hyponatremia is hospitalized, postop-
Long-term management
Identification and treatment of
erative patients who are receiving hypotonic
reversible causes fluids. In these patients, the risk of cerebral
Water restriction edema outweighs the risk for osmotic
Demeclocycline, 300–600 mg bid demyelination. In the presence of seizures,
Urea, 15–60 g/d obtundation, and coma, rapid infusion of
V2 receptor antagonists
3% sodium chloride (4 to 6 mL/kg/h) or
even 50 mL of 29.2% sodium chloride has
been used safely. Ongoing careful neurolog-
ic monitoring is imperative [20].
A. GENERAL GUIDELINES FOR THE TREATMENT OF B. TREATMENT OF CHRONIC SYMPTOMATIC

SYMPTOMATIC HYPONATREMIA* HYPONATREMIA
Acute hyponatremia (duration < 48 hrs) Calculate the net water loss needed to raise the serum sodium (SNa) from 110 mEq/L
Increase serum sodium rapidly by approximately 2 mmol/L/h until symptoms resolve to 120 mEq/L in a 50 kg person.
Full correction probably safe but not necessary Example
Chronic hyponatremia (duration > 48 hrs) Current SNa Total body water (TBW) = Desired SNa New TBW
Initial increase in serum sodium by 10% or 10 mmol/L Assume that TBW = 60% of body weight
Perform frequent neurologic evaluations; correction rate may be reduced with Therefore TBW of patient = 50 0.6 = 30 L
improvement in symptoms 110 mEq/L 30 L
New TBW = = 27.5 L
At no time should correction exceed rate of 1.5 mmol/L/h, or increments of 120 mEq/L
15 mmol/d Thus the electrolyte-free water loss needed to raise the SNa to
Measure serum and urine electrolytes every 1–2 h 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
*The sum of urinary cations (UNa + UK) should be less than the concentration of this case, 250 mL/h
infused sodium, to ensure excretion of electrolyte-free water. 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
FIGURE 1-26 water lost in the urine
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 treat-
ment of chronic symptomatic hyponatremia, since cerebral water is exceed 1.0 to 1.5 mEq/L/h, and the total increment in 24 hours
increased by approximately 10%, a prompt increase in serum sodi- should not exceed 15 mmol/d [12]. A specific example as to how
um by 10% or 10 mEq/L is permissible. Thereafter, the patient’s to increase a patient’s serum sodium is illustrated in B.
fluids should be restricted. The total correction rate should not
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
Pharmacologic inhibition of
antidiuretic hormone action
Lithium Inhibits the kidney’s response to 900–1200 mg/d Unrestricted water intake Polyuria, narrow therapeutic
antidiuretic hormone range, neurotoxicity
Demeclocycline Inhibits the kidney’s response to 1200 mg/d initially; then, Effective; unrestricted water Neurotoxicity, polyuria, photo-
antidiurectic hormone 300–900 mg/d intake sensitivity, nephrotoxicity
V2-receptor antagonist Antagonizes vasopressin action Ongoing trials
Increased solute intake
Furosemide Increases free water clearance Titrate to optimal dose; coad- Effective Ototoxicity, K+ and Mg2+ depletion
minister 2–3 g sodium chloride
Urea Osmotic diuresis 30–60 g/d Effective; unrestricted water Polyuria, unpalatable gastro-
intake intestinal symptoms
FIGURE 1-27
Management options for patients with chronic asymptomatic antidiuretic hormone (ADH) secretion, it must be treated as a
hyponatremia. If the patient has chronic hyponatremia and is chronic disorder. As summarized here, the treatment strategies
asymptomatic, treatment need not be intensive or emergent. involve fluid restriction, pharmacologic inhibition of ADH action,
Careful scrutiny of likely causes should be followed by treatment. and increased solute intake. Fluid restriction is frequently success-
If the cause is determined to be the syndrome of inappropriate ful in normalizing serum sodium and preventing symptoms [23].
FIGURE 1-28
MANAGEMENT OF NONEUVOLEMIC Management of noneuvolemic hyponatremia. Hypovolemic
HYPONATREMIA hyponatremia results from the loss of both water and solute, with
relatively greater loss of solute. The nonosmotic release of antidi-
uretic hormone stimulated by decreased arterial circulating blood
Hypovolemic hyponatremia volume causes antidiuresis and perpetuates the hyponatremia.
Volume restoration with isotonic saline Most of these patients are asymptomatic. The keystone of therapy
Identify and correct causes of water and sodium losses
is isotonic saline administration, which corrects the hypovolemia
and removes the stimulus of antidiuretic hormone to retain fluid.
Hypervolemic hyponatremia Hypervolemic hyponatremia occurs when both solute and water
Water restriction are increased, but water more than solute. This occurs with heart
Sodium restriction failure, cirrhosis and nephrotic syndrome. The cornerstones of
Substitiute loop diuretics for thiazide diurectics treatment include fluid restriction, salt restriction, and loop diuret-
Treatment of timulus for sodium and water retention ics [20]. (Adapted from Lauriat and Berl [20]; with permission.)
V2-receptor antagonist
Approach to the Hypernatremic Patient

FIGURE 1-29
↓ ADH release or action Pathogenesis of hypernatremia. The renal
Nephrogenic DI concentrating mechanism is the first line of
Central DI defense against water depletion and hyper-
(see Fig. 1-)
osmolality. When renal concentration is
impaired, thirst becomes a very effective
mechanism for preventing further increases
in serum osmolality. The components of the
↓ Reabsorption of sodium
chloride in thick ascending normal urine concentrating mechanism are
limb of loop of Henle shown in Figure 1-2. Hypernatremia results
Loop diuretics from disturbances in the renal concentrating
GFR diminished Osmotic diuretics
Age mechanism. This occurs in interstitial renal
Interstitial disease disease, with administration of loop and
Renal disease
osmotic diuretics, and with protein malnu-
trition, in which less urea is available to
generate the medullary interstitial tonicity.
Urea Hypernatremia usually occurs only when
NaCl 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
↓ Urea in the medulla
Water diuresis
thirst [24]. GFR—glomerular filtration rate;
Decreased dietary ADH—antidiuretic hormone; DI—diabetes
protein intake insipidus.
Assessment of volume status
Hypovolemia Euvolemia (no edema) Hypervolemia

•Total body water ↓↓ •Total body water ↓ •Total body water ↑
•Total body sodium ↓ •Total body sodium ←→ •Total body sodium ↑↑
UNa>20 UNa<20 UNa variable UNa>20
Renal losses Extrarenal losses Renal losses Extrarenal losses Sodium gains
Osmotic or loop diuretic Excessive sweating Diabetes insipidus Insensible losses Primary
Postobstruction Burns Hypodipsia Respiratory Hyperaldosteronism
Intrinsic renal disease Diarrhea Dermal Cushing's sydrome
Fistulas Hypertonic dialysis
Hypertonic sodium bicarbonate
Sodium chloride tablets
FIGURE 1-30
Diagnostic algorithm for hypernatremia. As for hyponatremia, the ini- and respiratory tract, in febrile or other hypermetabolic states. Very
tial evaluation of the patient with hypernatremia involves assessment of high urine osmolality reflects an intact osmoreceptor–antidiuretic
volume status. Patients with hypovolemic hypernatremia lose both hormone–renal response. Thus, the defense against the development
sodium and water, but relatively more water. On physical examination, of hyperosmolality requires appropriate stimulation of thirst and the
they exhibit signs of hypovolemia. The causes listed reflect principally ability to respond by drinking water. The urine sodium (UNa) value
hypotonic water losses from the kidneys or the gastrointestinal tract. varies with the sodium intake. The renal water losses that lead to
Euvolemic hyponatremia reflects water losses accompanied by inad- euvolemic hypernatremia are a consequence of either a defect in
equate water intake. Since such hypodipsia is uncommon, hyperna- vasopressin production or release (central diabetes insipidus) or
tremia usually supervenes in persons who have no access to water or failure of the collecting duct to respond to the hormone (nephrogenic
who have a neurologic deficit that impairs thirst perception—the very diabetes insipidus) [23]. (Modified from Halterman and Berl [12];
young and the very old. Extrarenal water loss occurs from the skin with permission.)
FIGURE 1-31
Urine volume = CH2O + COsm Physiologic approach to polyuric disorders. Among euvolemic hyper-
natremic patients, those affected by polyuric disorders are an impor-
tant subcategory. Polyuria is arbitrarily defined as urine output of
more than 3 L/d. Urine volume can be conceived of as having two
COsm CH2O
Isotonic or hypertonic urine Hypotonic urine 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
Polyuria due to increased Polyuria due to increased has been added to (positive free water clearance [CH2O]) or subtract-
solute excretion free water clearance ed (negative CH2O) from the isotonic portion of the urine osmolar
Sodium chloride Excessive water intake clearance (Cosm) to create either a hypotonic or hypertonic urine.
Diuretics Psychogenic polydipsia
Consumption of an average American diet requires the kidneys to
Renal sodium wasting Defect in thirst
Excessive salt intake Hyper-reninemia excrete 600 to 800 mOsm of solute each day. The urine volume in
Bicarbonate Potassium depletion which this solute is excreted is determined by fluid intake. If the
Vomiting/metabolic alkalosis Renal vascular disease urine is maximally diluted to 60 mOsm/kg of water, the 600 mOsm
Alkali administration Renal tumors will need 10 L of urine for effective osmotic clearance. If the concen-
Mannitol Renal hypoperfusion
trating mechanism is maximally stimulated to 1200 mOsm/kg of
Diuretics Increased renal water excretion
Bladder lavage Impaired renal water concentrating water, osmotic clearance will occur in a minimum of 500 mL of
Treatment of cerebral edema mechanism urine. This flexibility is affected when drugs or diseases alter the
Decreased ADH secretion renal concentrating mechanism.
Increased ADH degradation Polyuric disorders can be secondary to an increase in solute clear-
Resistance to ADH action
ance, free water clearance, or a combination of both. ADH—antidi-
uretic hormone.
WATER DEPRIVATION TEST CLINICAL FEATURES OF

DIABETES INSIPIDUS
Urine Osmolality with Plasma Arginine Increase in Urine

Water Deprivation Vasopressin (AVP) Osmolality with Abrupt onset
Diagnosis (mOsm/kg H2O) after Dehydration Exogenous AVP Equal frequency in both sexes
Normal > 800 > 2 pg/mL Little or none Rare in infancy, usual in second decade of life
Complete central < 300 Indetectable Substantial Predilection for cold water
diabetes insipidus Polydipsia
Partial central 300–800 < 1.5 pg/mL > 10% of urine osmolality Urine output of 3 to 15 L/d
diabetes insipidus after water deprivation Marked nocturia but no diurnal variation
Nephrogenic < 300–500 > 5 pg/mL Little or none Sleep deprivation leads to fatigue and irritability
diabetes insipidus Severe life-threatening hypernatremia can be associat-
Primary polydipsia > 500 < 5 pg/mL Little or none ed with illness or water deprivation
* 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 FIGURE 1-33
60 minutes. The expected responses are given above. Clinical features of diabetes insipidus.
Other clinical features can distinguish com-
FIGURE 1-32 pulsive water drinkers from patients with
central diabetes insipidus. The latter usually
Water deprivation test. Along with nephrogenic diabetes insipidus and primary polydipsia,
has abrupt onset, whereas compulsive water
patients with central diabetes insipius present with polyuria and polydipsia. Differentiating
drinkers may give a vague history of the
between these entities can be accomplished by measuring vasopressin levels and determin-
onset. Unlike compulsive water drinkers,
ing the response to water deprivation followed by vasopressin administration [25]. (From
patients with central diabetes insipidus have
Lanese and Teitelbaum [26]; with permission.)
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].
FIGURE 1-34
CAUSES OF DIABETES INSIPIDUS 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
Central diabetes insipidus Nephrogenic diabetes insipidus system involvement with infection, tumors, granuloma, or trauma.
The nephrogenic causes can be congenital or acquired [23].
Congenital Congenital
Autosomal-dominant X-linked
Autosomal-recessive Autosomal-recessive
Acquired Acquired
Post-traumatic Renal diseases (medullary cystic disease,
Iatrogenic polycystic disease, analgesic nephropathy,
Tumors (metastatic from breast, sickle cell nephropathy, obstructive uro-
craniopharyngioma, pinealoma) pathy, chronic pyelonephritis, multiple
myeloma, amyloidosis, sarcoidosis)
Cysts
Hypercalcemia
Histiocytosis
Hypokalemia
Granuloma (tuberculosis, sarcoid)
Drugs (lithium compounds, demeclocycline,
Aneurysms
methoxyflurane, amphotericin, foscarnet)
Meningitis
Encephalitis
Guillain-Barré syndrome
Idiopathic
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 autoso-
mal dominant inherited disease associated
SP VP NP NP NP CP with marked loss of cells in the supraoptic
nuclei. Molecular biology techniques have
Exon 1 Exon 2 Exon 3 revealed multiple point mutations in the
vasopressin-neurophysin II gene. This con-
83 dition usually presents early in life [25].
–19..–16 47 A rare autosomal-recessive form of central
79 87 DI has been described that is characterized
50 by DI, diabetes mellitus (DM), optic atro-
14 phy (OA), and deafness (DIDMOAD or
Wolfram’s syndrome). This has been linked
17 to a defect in chromosome-4 and involves
57 abnormalities in mitochondrial DNA [27].
20
SP—signal peptide; VP—vasopressin;
61 NP—neurophysin; GP—glycoprotein.
–3 24 62 67
–1 65
Missense mutation Stop codon Deletion
FIGURE 1-36
TREATMENT OF CENTRAL DIABETES INSIPIDUS 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
Condition Drug Dose useful. It has a short duration of action that allows for careful mon-
itoring and avoiding complications like water intoxication. This
Complete central DI dDAVP 10–20 (g intranasally q 12–24 h drug should be used with caution in patients with underlying coro-
Partial central DI Vasopressin tannate 2–5 U IM q 24–48 h nary artery disease and peripheral vascular disease, as it can cause
Aqueous vasopressin 5–10 U SC q 4–6 h vascular spasm and prolonged vasoconstriction. For the patient
Chlorpropamide 250–500 mg/d with established central DI, desmopressin acetate (dDAVP) is the
Clofibrate 500 mg tid–qid agent of choice. It has a long half-life and does not have significant
Carbamazepine 400–600 mg/d 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].
FIGURE 1-37
T T S A M Extracellular Congenital nephrogenic diabetes insipidus,
P *
A
S L M –NH2
S H
S
P
L L G
P
V 1
X-linked–recessive form. This is a rare dis-
N S P
S
ease of male patients who do not concen-
S trate their urine after administration of
Q R F
E
R
D R antidiuretic hormone. The pedigrees of
T G
P A P A E P W affected families have been linked to a
L P L F
L D D
K D C G
R group of Ulster Scots who emigrated to
R T W A A S G G P E
A P
A
R A L W G E R
T D L Halifax, Nova Scotia in 1761 aboard the
C V V
A L C
D T N
Y * W E ship called “Hopewell.” According to
E Q R R V A G
L L P Q A A Q F T W W A A P F
the Hopewell hypothesis, most North
* L A V V K
A L I Q L V
F S I L A L F V
Y
V
L Q
M L F P Q
I
F V
M V F F
L V L L M
L * American patients with this disease are
L A A A P L
A V A V G M L A C W
A S
L D
C L H
A Y S L L T L P
V L N L descendants of a common ancestor with a
G S V L M
S S
Y S L A F A A
G I V Y
S C
T
A L V N F I G I L
A A W C Q V I
V V N P W
I single gene defect. Recent studies, howev-
A
L L H V M T
V L
V V L
I F M T
L Y A
*
*
A
I
P
L
D P
S
er, disproved this hypothesis [28]. The
R E R R S F C C
R A
R
H R H
I V
V
S S L A
R
gene defect has now been traced to 87 dif-
W L
R N
G H A
W
A T
K
S
S E L R
S G ferent mutations in the gene for the vaso-
R R G I S R
C
H L V S A
T
pressin receptor (AVP-R2) in 106 presum-
A H A V
R
G *
V
A
A P ably unrelated families [29]. (From Bichet,
P P P
M S G G C S E D Q P G L
S et al. [29]; with permission.)
L G E
A P T
Y R H G P S
S G T
E T A
R S
R * S S
P G R L A K 371
G R R R G D T S
S –COOH
Intracellular
FIGURE 1-38
Urinary lumen L A P A Congenital nephrogenic diabetes insipidus (NDI), autosomal-
S 11 V
L A V 9,12 R V recessive form. In the autosomal recessive form of NDI, mutations
D N A T
G A 8 P G have been found in the gene for the antiiuretic hormone (ADH)–
R L
I S
N K sensitive water channel, AQP-2. This form of NDI is exceedingly
M F
D N S D rare as compared with the X-linked form of NDI [30]. Thus far, a
A S
P T
13 C D total of 15 AQP-2 mutations have been described in total of 13
G H
T 6 T T W families [31]. The acquired form of NDI occurs in various kidney
I A V
Q A L P S H
E G
Y
H F
diseases and in association with various drugs, such as lithium
L Q I W
P
W L
V
A
L A
T
V G
L
L I
G and amphotericin B. (From Canfield et al. [31]; with permission.)
N I Q M A A G 4 E V G H L
P
A L S A V
A
F
L A
L
G
V
G F G A G V A
G L L L L
L T
S I
V F F I G T G Q
L
Q G
F
G
L
F A L I S 12 S
L 13 V L A V L L
T L Q V L L
A Y F C A Y
A A I P T N
F L G L A
A
F
P
G V
Y
E L
H R S 7
A N F
F I L T E P
S V D G
V E R R P
A 1 G S A
R A V K
S H H S
F I L
C P Q
A S S L S
2 N G H P E
I L 11 R
P V G R
M S E L
W E L R A L T
V K A
3 V C A V
T V A S
Q L
R K
R
Principal cell V E
R E
G
L
-intracellular E W D T D P E
ACQUIRED NEPHROGENIC DIABETES INSIPIDUS: PATIENT GROUPS AT

CAUSES AND MECHANISMS INCREASED RISK FOR
SEVERE HYPERNATREMIA
Defect in Generation
of Medullary Defect in cAMP Downregulation Elders and infants
Disease State Interstitial Tonicity Generation of AQP-2 Other Hospitalized patients receiving
Chronic renal failure ✔ ✔ ✔ Downregulation of V2 Hypertonic infusions
receptor message Tube feedings
Hypokalemia ✔ ✔ ✔ Osmotic diuretics
Hypercalcemia ✔ ✔ Lactulose
Sickle cell disease ✔ Mechanical ventilation
Protein malnutrition ✔ ✔ Altered mental status
Demeclocycline ✔ Uncontrolled diabetes mellitus
Lithium ✔ ✔ Underlying polyuria
Pregnancy Placental secretion of
vasopressinase
FIGURE 1-40
Patient groups at increased risk for severe
FIGURE 1-39 hypernatremia. Hypernatremia always
Causes and mechanisms of acquired nephrogenic diabetes insidpidus. Acquired nephrogenic reflects a hyperosmolar state. It usually
diabetes insipidus occurs in chronic renal failure, electrolyte imbalances, with certain drugs, occurs in a hospital setting (reported inci-
in sickle cell disease and pregnancy. The exact mechanism involved has been the subject of dence 0.65% to 2.23% of all hospitalized
extensive investigation over the past decade and has now been carefully elucidated for most patients) with very high morbidity and mor-
of the etiologies. tality (estimates of 42% to over 70%) [12].
SIGNS AND SYMPTOMS OF Hypovolemic Euvolemic Hypervolemic

hypernatremia hypernatremia hypernatremia
HYPERNATREMIA
Correction of volume deficit Correction of water deficit Removal of sodium

Central Nervous System Administer isotonic saline until Calculate water deficit Discontinue offending agents
Mild hypovolemia improves Administer 0.45% saline, 5% Administer furosemide
Treat causes of losses (insulin, dextrose or oral water to replace Provide hemodialysis, as
Restlessness relief of urinary tract obstruction, the deficit and ongoing losses needed, for renal failure
Lethargy removal of osmotic diuretics) In central diabetes insipidus with
Altered mental status severe losses, aqueous vasopressin
Irritability (pitressin) 5 U SC q 6 hr
Correction of water deficit Follow serum sodium
Moderate concentration carefully to avoid
Calculate water deficit
Disorientation Administer 0.45% saline, 5% water intoxication
Confusion dextrose or oral water replacing
Severe deficit and ongoing losses
Stupor Long term therapy
Central diabetes insipidus (see
Coma Table 1–12)
Seizures Nephrogenic diabetes insipidus
Death Correct plasma potassium and
calcium concentration
Respiratory System Remove offending drugs
Labored respiration Low-sodium diet
Thiazide diuretics
Gastrointestinal System Amiloride (for lithium-induced
Intense thirst nephrogenic diabetes insipidus)
Nausea
Vomiting
FIGURE 1-42
Musculoskeletal System Management options for patients with hypernatremia. The primary goal in the treatment
Muscle twitching of hypernatremia is restoration of serum tonicity. Hypovolemic hypernatremia in the con-
Spasticity text of low total body sodium and orthostatic blood pressure changes should be managed
Hyperreflexia with isotonic saline until blood pressure normalizes. Thereafter, fluid management general-
ly 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
FIGURE 1-41 dialysis. In euvolemic hypernatremic patients, water losses far exceed solute losses, and the
Signs and symptoms of hypernatremia. mainstay of therapy is 5% dextrose. To correct the hypernatremia, the total body water
Hypernatremia always reflects a hyperosmo- deficit must be estimated. This is based on the serum sodium concentration and on the
lar state; thus, central nervous system symp- assumption that 60% of the body weight is water [24]. (Modified from Halterman and
toms are prominent in affected patients [12]. Berl [12]; with permission.)
FIGURE 1-43
GUIDELINES FOR THE TREATMENT OF Guidelines for the treatment of symptomatic hypernatremia.
SYMPTOMATIC HYPERNATREMIA* Patients with severe symptomatic hypernatremia are at high risk of
dying and should be treated aggressively. An initial step is estimat-
ing the total body free water deficit, based on the weight (in kilo-
Correct at a rate of 2 mmol/L/h grams) and the serum sodium. During correction of the water
Replace half of the calculated water deficit over the first 12–24 hrs deficit, it is important to perform serial neurologic examinations.
Replace the remaining deficit over the next 24–36 hrs
Perform serial neurologic examinations (prescribed rate of correction can be
decreased as symptoms improve)
Measure serum and urine electrolytes every 1–2 hrs
*If UNa + U K is less than the concentration of PNa, then water loss is ongoing and
needs to be replaced.
References
1. Jacobson HR: Functional segmentation of the mammalian nephron. 16. Berl T, Schrier RW: Disorders of water metabolism. In Renal and
Am J Physiol 1981, 241:F203. Electrolyte Disorders, edn. 4. Edited by Schrier RW. Philadelphia:
2. Goldberg M: Water control and the dysnatremias. In The Sea Within Lippincott-Raven, 1997:54.
Us. Edited by Bricker NS. New York: Science and Medicine 17. Berl T, Anderson RJ, McDonald KM, Schreir RW: Clinical Disorders
Publishing Co., 1975:20. of water metabolism. Kidney Int 1976, 10:117.
3. Kokko J, Rector F: Countercurrent multiplication system without 18. Gullans SR, Verbalis JG: Control of brain volume during hyperosmo-
active transport in inner medulla. Kidney Int 1972, 114. lar and hypoosmolar conditions. Annu Rev Med 1993, 44:289.
4. Knepper MA, Roch-Ramel F: Pathways of urea transport in the mam- 19. Zarinetchi F, Berl T: Evaluation and management of severe hypona-
tremia. Adv Intern Med 1996, 41:251.
malian kidney. Kidney Int 1987, 31:629.
20. Lauriat SM, Berl T: The Hyponatremic Patient: Practical focus on
5. Vander A: In Renal Physiology. New York: McGraw Hill, 1980:89.
therapy. J Am Soc Nephrol 1997, 8(11):1599.
6. Zimmerman E, Robertson AG: Hypothalamic neurons secreting vaso- 21. Ayus JC, Wheeler JM, Arieff AI: Postoperative hyponatremic
pressin and neurophysin. Kidney Int 1976, 10(1):12. encephalopathy in menstruant women. Ann Intern Med
7. Bichet DG: Nephrogenic and central diabetes insipidus. In Diseases of 1992,117:891.
the Kidney, edn. 6. Edited by Schrier RW, Gottschalk CW. Boston: 22. Laureno R, Karp BI: Myelinolysis after correction of hyponatremia.
Little, Brown, and Co., 1997:2430 Ann Intern Med 1997, 126:57.
8. Bichet DG : Vasopressin receptors in health and disease. Kidney Int 23. Kumar S, Berl T: Disorders of serum sodium concentration. Lancet
1996, 49:1706. 1998. in press.
9. Dunn FL, Brennan TJ, Nelson AE, Robertson GL: The role of blood 24. Cogan MG: Normal water homeostasis. In Fluid & Electrolytes,
osmolality and volume in regulating vasopressin secretion in the rat. Physiology and Pathophysiology. Edited by Cogan MG. Norwalk:
J Clin Invest 1973, 52:3212. Appleton & Lange, 1991:94.
10. Rose BD: Antidiuretic hormone and water balance. In Clinical 25. Rittig S, Robertson G, Siggaard C, et al.: Identification of 13 new
Physiology of Acid Base and Electrolyte Disorders, edn. 4. New York: mutations in the vasopressin-neurophysin II gene in 17 kindreds with
McGraw Hill, 1994. familial autosomal dominant neurohypophyseal diabetes insipidus.
Am J Hum Genet 1996, 58:107.
11. Cogan MG: Normal water homeostasis. In Fluid & Electrolytes,
26. Lanese D, Teitelbaum I: Hypernatremia. In The Principles and
Physiology and Pathophysiology. Edited by Cogan MG. Norwalk:
Practice of Nephrology, edn. 2. Edited by Jacobson HR, Striker GE,
Appleton & Lange, 1991:98.
Klahr S. St. Louis: Mosby, 1995:895.
12. Halterman R, Berl T: Therapy of dysnatremic disorders. In Therapy in 27. Barrett T, Bundey S: Wolfram (DIDMOAD) syndrome. J Med Genet
Nephrology and Hypertension. Edited by Brady H, Wilcox C. 1997, 29:1237.
Philadelphia: WB Saunders, 1998, in press.
28. Holtzman EJ, Ausiello DA: Nephrogenic Diabetes insipidus: Causes
13. Veis JH, Berl T, Hyponatremia: In The Principles and Practice of revealed. Hosp Pract 1994, Mar 15:89–104.
Nephrology, edn. 2. Edited by Jacobson HR, Striker GE, Klahr S.
29. Bichet D, Oksche A, Rosenthal W: Congential Nephrogenic Diabetes
St.Louis: Mosby, 1995:890. Insipidus. J Am Soc Nephrol 1997, 8:1951.
14. Berl T, Schrier RW: Disorders of water metabolism. In Renal and 30. Lieburg van, Verdjik M, Knoers N, et al.: Patients with autosomal
Electrolyte Disorders, edn 4. Philadelphia: Lippincott-Raven, nephrogenic diabetes insipidus homozygous for mutations in the
1997:52. aquaporin 2 water channel. Am J Hum Genet 1994, 55:648.
15. Verbalis JG: The syndrome of ianappropriate diuretic hormone secre- 31. Canfield MC, Tamarappoo BK, Moses AM, et al.: Identification and
tion and other hypoosmolar disorders. In Diseases of the Kidney, edn. characterization of aquaporin-2 water channel mutations causing
6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown, and nephrogenic diabetes insipidus with partial vasopressin response.
Co., 1997:2393. Hum Mol Genet 1997, 6(11):1865.
Disorders of
Sodium Balance
David H. Ellison
S
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 vol-
ume 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 toler-
ated 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 asso-
ciated 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, hormon-
al 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
CHAPTER
the blood volume decreases sufficiently to return the blood pressure to
2
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
levels. Examples of these disorders include chronic renal failure (see Chapter 1). Disorders of sodium balance are disorders of
and states of mineralocorticoid excess. In this case, the price of ECF volume. This construct has a physiologic basis because
a return to sodium balance is hypertension. Disorders of sodi- water balance and sodium balance can be controlled separately
um balance that result from secondary renal sodium retention, and by distinct hormonal systems. It should be emphasized,
as in congestive heart failure, lead to more profound volume however, that disorders of sodium balance frequently lead to or
expansion owing to hypotension. In mild to moderates cases, are associated with disorders of water balance. This is evident
volume expansion eventually returns the MAP to its set point; from Figure 2-24 in which hyponatremia is noted to be a sign
the price of sodium balance in this case is edema. In more severe of either ECF volume expansion or contraction. Thus, the dis-
cases, volume expansion never returns blood pressure to nor- tinction between disorders of sodium and water balance is use-
mal, and renal sodium retention is unremitting. In still other sit- ful in constructing differential diagnoses; however, the close
uations, such as nephrotic syndrome, volume expansion results interrelationships between factors that control sodium and
from changes in both the renal set point and body volume dis- water balance should be kept in mind.
tribution. In this case, the price of sodium balance may be both The figures herein describe characteristics of sodium home-
edema and hypertension. In each of these cases, renal sodium ostasis in normal persons and also describe several of the regu-
(and chloride) retention results from a discrepancy between the latory systems that are important participants in controlling
existing MAP and the renal set point. renal sodium excretion. Next, mechanisms of sodium transport
The examples listed previously emphasize that disorders of along the nephron are presented, followed by examples of dis-
sodium balance do not necessarily abrogate the ability to orders of sodium balance that illuminate current understanding
achieve sodium balance. When balance is defined as the equa- of their pathophysiology. Recently, rapid progress has been
tion of sodium intake and output, most patients with ECF made in unraveling mechanisms of renal volume homeostasis.
expansion (and edema or hypertension) or ECF volume deple- Most of the hormones that regulate sodium balance have been
tion achieve sodium balance. They do so, however, at the cloned and sequenced. Intracellular signaling mechanisms
expense of expanded or contracted ECF volume. The failure to responsible for their effects have been characterized. The renal
achieve sodium balance at normal ECF volumes characterizes transport proteins that mediate sodium reabsorption also have
these disorders. been cloned and sequenced. The remaining challenges are to
Frequently, distinguishing disorders of sodium balance from integrate this information into models that describe systemic
disorders of water balance is useful. According to this scheme, dis- volume homeostasis and to determine how alterations in one or
orders of water balance are disorders of body osmolality and usu- more of the well-characterized systems lead to volume expan-
ally are manifested by alterations in serum sodium concentration sion or contraction.
Normal Extracellular Fluid Volume Homeostasis

FIGURE 2-1
Adult male
Fluid volumes in typical adult men and
Extravascular Adult female women, given as percentages of body
(15%) weight. In men (A), total body water typi-
ECF volume Extravascular cally is 60% of body weight (Total body
(20%) (11%) ECF volume
Plasma (5%) water = Extracellular fluid [ECF] volume +
(15%)
Blood volume Plasma (4%) Intracellular fluid [ICF] volume). The ECF
(9%) RBC (4%) Blood volume
RBC (3%) volume comprises the plasma volume and
(7%)
the extravascular volume. The ICF volume
ICF volume comprises the water inside erythrocytes
ICF volume
(40%) (35%) (RBCs) and inside other cells. The blood
volume comprises the plasma volume plus
A B 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].
Disorders of Sodium Balance 2.3
FIGURE 2-2
14 10 Effects of changes in dietary sodium (Na) intake on extracellular fluid (ECF) volume. The
Dietary sodium intake, g

9
8 dietary intake of Na was increased from 2 to 5 g, and then returned to 2 g. The relation-
ECF volume, L
13
7 ship between dietary Na intake (dashed line) and ECF volume (solid line) is derived from
6 the model of Walser [1]. In this model the rate of Na excretion is assumed to be propor-
12 5
4 tional to the content of Na in the body (At) above a zero point (A0) at which Na excretion
11 3 ceases. This relation can be expressed as dAt/dt = I - k(At - A0), where I is the dietary Na
2
1 intake and t is time. The ECF volume is approximated as the total body Na content divid-
10 0 ed by the plasma Na concentration. (This assumption is strictly incorrect because approxi-
0 5 10 15 20 25 mately 25% of Na is tightly bound in bone; however, this amount is nearly invariant and
Days 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 Urinary sodium excretion, g/d

0 1 2 3 4 5 6 0 1 2 3 4 5 6
18 100
17 98
96
16
Mean arterial pressure, mmHg
94
15
ECF volume, L
92
14 90
88
13
86
12
∆≈ 18% ∆≈ 1%
84
11
82
10 80
0 1 2 3 4 5 6 0 1 2 3 4 5 6
A Sodium intake, g/d B Sodium intake, g/d
FIGURE 2-3
Relation between dietary sodium (Na), extracellular fluid (ECF) vol- intake when consuming a “no added salt” diet. The light blue bar
ume, and mean arterial pressure (MAP). A, Relation between the indicates that a “low-salt” diet generally contains about 2 g/d of Na.
dietary intake of Na, ECF volume, and urinary Na excretion at Note that increasing the dietary intake of Na from very low to nor-
steady state in a normal person. Note that 1 g of Na equals 43 mmol mal levels leads to an 18% increase in ECF volume. B, Relation
(43 mEq) of Na. At steady state, urinary Na excretion essentially is between the dietary intake of Na and MAP in normal persons. MAP
identical to the dietary intake of Na. As discussed in Figure 2-2, ECF is linearly dependent on Na intake; however, increasing dietary Na
volume increases linearly as the dietary intake of Na increases. At an intake from very low to normal levels increases the MAP by only
ECF volume of under about 12 L, urinary Na excretion ceases. The 1%. Thus, arterial pressure is regulated much more tightly than is
gray bar indicates a normal dietary intake of Na when consuming a ECF volume. (A, Data from Walser [1]; B, Data from Luft and
typical Western diet. The dark blue bar indicates the range of Na coworkers [3].)
in extracellular fluid (ECF) volume result

6 from increases in sodium chloride (NaCl)
UNaV, X normal 5 and fluid intake or decreases in kidney vol-
4 ume output. An increase in ECF volume
+ NaCl and
3 fluid intake increases the blood volume, thereby increas-
2 Net volume
ing the venous return to the heart and car-
intake
1 Nonrenal diac output. Increases in cardiac output
– fluid loss
0 + increase arterial pressure both directly and
0 50 100 150 200 by increasing peripheral vascular resistance
MAP, mm Hg (autoregulation). Increased arterial pressure
+ – Rate of change + is sensed by the kidney, leading to increased
Arterial Kidney volume Extracellular kidney volume output (pressure diuresis
of extracellular
pressure output fluid volume
fluid volume and pressure natriuresis), and thus return-
+ ing the ECF volume to normal. The inset
+ shows this relation between mean arterial
Total peripheral
+ resistance Blood volume pressure (MAP), renal volume, and sodium
+ excretion [4]. The effects of acute increases
+ Autoregulation in arterial pressure on urinary excretion are
+ +
Cardiac output Venous return
Mean circulatory shown by the solid curve. The chronic
filling pressure 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 increas-
FIGURE 2-4 es, urinary output increases, leading to
Schema for the kidney blood volume pressure feedback mechanism adapted from the decreased ECF volume and return to the
work of Guyton and colleagues [6]. Positive relations are indicated by a plus sign; original pressure set point. UNaV—urinary
inverse relations are indicated by a minus sign. The block diagram shows that increases sodium excretion volume.
FIGURE 2-5
Lumen Blood
Sodium (Na) reabsorption along the mammalian nephron. About
Na
DCT 25 moles of Na in 180 L of fluid daily is delivered into the
Cl 5-7% 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
CD
3-5% thick ascending limb indicated in light blue; about 5% to 7%
along the distal convoluted tubule (DCT), indicated in dark gray;
PROX
60% – + and 3% to 5% along the collecting duct (CD) system, indicated in
Na light gray. All Na transporting cells along the nephron express the
Lumen Blood
ouabain-inhibitable sodium-potassium adenosine triphosphatase
Lumen H 2O Blood K (Na-K ATPase) pump at their basolateral (blood) cell surface. (The
Na pump is not shown here for clarity.) Unique pathways are
HCO3
H H+ expressed at the luminal membrane that permit Na to enter cells.
OH Lumen Blood
CO2 + – The most quantitatively important of these luminal Na entry path-
Na
H2CO3 K ways are shown here. These pathways are discussed in more detail
HCO3
CA Cl in Figures 2-15 to 2-19. CA—carbonic anhydrase; Cl—chloride;
H 2O CO2 K
CO2—carbon dioxide; H—hydrogen; H2CO3—carbonic acid;
Na HCO3—bicarbonate; K—potassium; OH—hydroxyl ion.
LOH
25%
Mechanisms of Extracellular
Fluid Volume Control
FIGURE 2-6
↑ Renal tubular sodium reabsoption 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
↑ ERSNA ↑ Angiotensin II ↑ Aldosterone ↑ FF operating only in one direction and not all pathways are shown.
The major antinatriuretic systems are the renin-angiotensin-aldos-
↑ Activation of terone axis and increased efferent renal sympathetic nerve activity
↑ Renin (ERSNA). The most important natriuretic mechanism is pressure
baroreceptors
natriuresis, because the level of renal perfusion pressure (RPP)
determines the magnitude of the response to all other natriuretic
↓ Arterial pressure 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
ECFV contraction
hormone. Within the kidney, kinins and renomedullary
prostaglandins are important modulators of the natriuretic
response of the kidney. AVP—arginine vasopressin; FF—filtration
Normal ECF volume
fraction. (Modified from Gonzalez-Campoy and Knox [7].)
ECFV expansion
↑ ANP ↑ Arterial pressure ↑ Kinins
↑ RIHP ↑ Prostaglandins
↓ Renal tubular sodium reabsoption
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
ACE
juxtaglomerular apparatus of the kidney, as shown in Figures 2-8
and 2-9. Renin cleaves the 10 N-terminal amino acids from
SVR 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 pri-
Angiotensinogen mary amino acid structures of angiotensins I and II are shown in
DRVYIHPFHL DRVYIHPF
single letter codes. Angiotensin II increases systemic vascular resis-
Angiotensin I Angiotensin II tance (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
Aldo decrease urinary Na (and chloride excretion; UNaV).
Renin –
–
UNaV
FIGURE 2-8
The juxtaglomerular (JG) apparatus. This apparatus brings into close apposition the afferent
B (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 appa-
N ratus (cells),” forms at the interface of these components. MD cells express the Na-K-2Cl
JG (sodium-potassium-chloride) cotransporter (NKCC2) at the apical membrane [10,11]. By
N
A 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
IM increase renin secretion when the NaCl concentration in the lumen is low [12]. Cells in the
G MD 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). B—Bowman’s space, G—glomerular capillary; IM—intraglomerular mesangium. (From
G JG E Barajas [13]; with permission.)
FIGURE 2-9
ANP
Schematic view of a (granular) juxtaglomerular cell showing secre-
tion mechanisms of renin [8]. Renin is generated from prorenin.
– Prorenin Renin secretion is inhibited by increases in and stimulated by
β1 decreases in intracellular calcium (Ca) concentrations. Voltage-sen-
Renin Sympathetic sitive Ca channels in the plasma membrane are activated by mem-
Renin AC nerves brane stretch, which correlates with arterial pressure and is
assumed to mediate baroreceptor-sensitive renin secretion. Renin
↑cAMP AT1 All secretion is also stimulated when the concentration of sodium (Na)
+ and chloride (Cl) at the macula densa (MD) decreases [12,14]. The
– – +
NO mediators of this effect are less well characterized; however, some
↑Ca ↑Ca
studies suggest that the effect of Na and Cl in the lumen is more
–
potent than is the baroreceptor mechanism [15]. Many other fac-
PGE2 +
PGI2
tors affect rates of renin release and contribute to the physiologic
Membrane
depolarization regulation of renin. Renal nerves, by way of receptors coupled
+ + to adenylyl cyclase (AC), stimulate renin release by increasing the
Membrane production of cyclic adenosine monophosphate (cAMP), which
stretch reduces Ca release. Angiotensin II (AII) receptors (AT1 receptors)
+
inhibit renin release, as least in vitro. Prostaglandins E2 and I2
MD NaCl (PGE2 and PGI2, respectively) strongly stimulate renin release
Arterial through mechanisms that remain unclear. Atrial natriuretic peptide
pressure (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].
FIGURE 2-10
AME or Licorice
Basolateral Apical Mechanism of aldosterone action in the distal nephron [19]. Aldosterone, the predominant
human mineralocorticoid hormone, enters distal nephron cells through the plasma mem-
Cortisone brane and interacts with its receptor (the mineralocorticoid receptor [MR], or Type I
receptor). Interaction between aldosterone and this receptor initiates induction of new
11β HSD
proteins that, by way of mechanisms that remain unclear, increase the number of sodium
Cortisol Cortisol GR channels (ENaC) and sodium-potassium adenosine triphosphatase (Na-K ATPase) pumps
at the cell surface. This increases transepithelial Na (and potassium) transport. Cortisol,
↑ ENaC the predominant human glucocorticoid hormone, also enters cells through the plasma
Cortisone ↑ Na/K ATPase membrane and interacts with its receptor (the glucocorticoid receptor [GR]). Cortisol,
11β HSD however, also interacts with mineralocorticoid receptors; the affinity of cortisol and aldos-
Cortisol terone for mineralocorticoid receptors is approximately equal. In distal nephron cells, this
MR interaction also stimulates electrogenic Na transport [20]. Cortisol normally circulates at
concentrations 100 to 1000 times higher than the circulating concentration of aldosterone.
Aldo Aldo In aldosterone-responsive tissues, such as the distal nephron, expression of the enzyme
MR 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 inhi-
Distal nephron cell bition of the enzyme by ingestion of licorice, leads to hypertension owing to chronic stim-
ulation of distal Na transport by endogenous glucocorticoids [21].
FIGURE 2-11
↑ Preload Control of systemic hemodynamics by the atrial natriuretic peptide
(ANP) system. Increases in atrial stretch (PRELOAD) increase ANP
SLRRSSCFGGRLDRIGAQSGLGCNSFRY
+ secretion by cardiac atria. The primary amino acid sequence of
ANP is shown in single letter code with its disulfide bond indicated
Plasma ANP by the lines. The amino acids highlighted in blue are conserved
+ – between ANP, brain natriuretic peptide, and C-type natriuretic pep-
+ – –
tide. ANP has diverse functions that include but are not limited to
Vagal afferent Capillary Renal NaCl Renin Arteriolar the following: stimulating vagal afferent activity, increasing capillary
activity permeability reabsoption secretion contraction permeability, inhibiting renal sodium (Na) and water reabsorption,
+ inhibiting renin release, and inhibiting arteriolar contraction. These
– + +
+
effects reduce sympathetic nervous activity, reduce angiotensin II
+ Angiotensin II
+ + generation, reduce aldosterone secretion, reduce total peripheral
Sympathetic Aldosterone + resistance, and shift fluid out of the vasculature into the intersti-
efferent Fluid shift – tium. The net effect of these actions is to decrease cardiac output,
activity into vascular volume, and peripheral resistance, thereby returning pre-
+ interstitium Vascular load toward baseline. Many effects of ANP (indicated by solid
volume Peripheral
vascular arrows) are diminished in patients with edematous disorders (there
Cardiac – + resistance is an apparent resistance to ANP). Effects indicated by dashed
output arrows may not be diminished in edematous disorders; these effects
↓ Preload 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
Blood
Na retention [22]. (Modified from Brenner and coworkers [23].)
pressure
20 Afferent Efferent
Wild type
18 Cerebral cortex
Knockout Carotid
16 sinus Hypothalamus
ANP infusion
UNAV, mmol/min/g body wt
14 IX Medulla
12 X
Carotid X
10 bodies
8
6
Thoracic
4
2
0
15 30 45 60 75 90 105 120 135 150 165 180
Time, min Blood vessel
Lumbar
Adrenal
FIGURE 2-12
Mechanism of atrial natriuretic peptide (ANP) action on the kid-
ney. Animals with disruption of the particulate form of guanylyl Kidney
cyclase (GC) manifest increased mean arterial pressure that is inde- Other somatic
(eg, muscle, splanchnic
pendent of dietary intake of sodium chloride. To test whether ANP
viscera, joint receptors)
mediates its renal effects by way of the action of GC, ANP was
Sacral
Spinal
infused into wild-type and GC-A–deficient mice. In wild-type ani- cord
mals, ANP led to prompt natriuresis. In GC-A–deficient mice, no
effect was observed. UNaV—urinary sodium excretion volume. Splanchnic
(Modified from Kishimoto [24].) 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.)
FIGURE 2-14
Normal effective Low effective Cellular mechanisms of increased solute
arterial volume arterial volume
and water reabsorption by the proximal
GFR =Filtration fraction ↓GFR =↑Filtration fraction tubule in patients with “effective” arterial
RPF ↓↓RPF volume depletion. A, Normal effective arte-
rial volume in normal persons. B, Low
Filtration Filtration effective arterial volume in patients with
both decreased glomerular filtration rates
A E A E
(GFR) and renal plasma flow (RPF). In con-
trast 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
onc onc than does the GFR. The increased filtration
Reabsorption Reabsorption fraction concentrates the plasma protein
(indicated by the dots) in the peritubular
capillaries leading to increased plasma
Pt Pi Pt Pi
oncotic pressure (onc). Increased plasma
oncotic pressure reduces the amount of
Backleak ↓ Backleak backleak from the peritubular capillaries.
A B Simultaneously, the increase in filtration
fraction reduces volume delivery to the
FIGURE 2-14 (continued)

peritubular capillary, decreasing its hydrostatic pressure, and there- reduced, owing to diminished GFR, the hydrostatic gradient from
by reducing the renal interstitial hydrostatic pressure (Pi). Even tubule to interstitium is increased, favoring increased volume reab-
though the proximal tubule hydrostatic pressure (Pt) may be sorption. A—afferent arteriole; E—efferent arteriole.
Mechanisms of Sodium and Chloride

Transport along the Nephron
FIGURE 2-15
Lumen Cellular mechanisms and regulation of sodium chloride (NaCl) and
volume reabsorption along the proximal tubule. The sodium-potas-
α Renal sium adenosine triphosphate (Na-K ATPase) pump (shown as
Na+ +
nerves white circle with light blue outline) at the basolateral cell mem-
See figure 2-13 brane keeps the intracellular Na concentration low; the K concen-
H+ + tration high; and the cell membrane voltage oriented with the cell
AT1 All interior negative, relative to the exterior. Many pathways partici-
– + See figure 2-7 pate in Na entry across the luminal membrane. Only the sodium-
hydrogen (Na-H) exchanger is shown because its regulation in
DA1 Dopamine states of volume excess and depletion has been characterized exten-
sively. Activity of the Na-H exchanger is increased by stimulation
– ↑FF
H 2O of renal nerves, acting by way of receptors and by increased lev-
~ See figure 2-14 els of circulating angiotensin II (AII), as shown in Figures 2-7 and
3Na+ 2K+ 2-13 [25–28]. Increased levels of dopamine (DA1) act to inhibit
activity of the Na-H exchanger [29,30]. Dopamine also acts to
+ ↓Pi inhibit activity of the Na-K ATPase pump at the basolateral cell
Na+ + ↑onc
membrane [30]. As described in Figure 2-14, increases in the filtra-
Cl- tion fraction (FF) lead to increases in oncotic pressure (onc) in per-
Interstitum itubular 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 paracel-
lular pathway.
FIGURE 2-16
Lumen Cellular mechanisms and regulation of sodium (Na) and chloride
(Cl) transport by thick ascending limb (TAL) cells. Na, Cl, and
cAMP ? potassium (K) enter cells by way of the bumetanide-sensitive Na-K-
Na +
2Cl cotransporter (NKCC2) at the apical membrane. K recycles back
V2 AVP through apical membrane K channels (ROMK) to permit continued
2Cl – operation of the transporter. In this nephron segment, the asymmet-
K –
ric operations of the luminal K channel and the basolateral chloride
– PR PGE2 channel generate a transepithelial voltage, oriented with the lumen
K positive. This voltage drives paracellular Na absorption. Although
Cl
20-HETE arginine vasopressin (AVP) is known to stimulate Na reabsorption by
20-COOH-AA TAL cells in some species, data from studies in human subjects sug-
c-P450 gest AVP has minimal or no effect [31,32]. The effect of AVP is
Arachidonic ~ mediated by way of production of cyclic adenosine monophosphate
acid 3Na+ 2K+ (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
Na least in part by inhibiting the Na-K-2Cl cotransporter [33–35]. PGE2
also inhibits vasopressin-stimulated Na transport, in part by activat-
ing Gi and inhibiting adenylyl cyclase [36]. Increases in medullary
Interstitum
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
A 0.16 mol NaCl H 2O upregulation of NKCC2 in the group treated with saline [37].
kD
Gi—inhibitory G protein; PR—prostaglandin receptor; V2— AVP
199-
receptors. (Modified from Ecelbarger [37].)
120-
87-
48-
FIGURE 2-17
Lumen Mechanisms and regulation of sodium (Na) and chloride (Cl)
transport by the distal nephron. As in other nephron segments,
Aldo receptor + Aldo intracellular Na concentration is maintained low by the action of
+
Na See figure Y the Na-K ATPase (sodium-potassium adenosine triphosphatase)
pump at the basolateral cell membrane. Na enters distal convolut-
+ ed tubule (DCT) cells across the luminal membrane coupled direct-
Cl α ly 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) [38–40]. Transepithelial
+ ~ Na transport in this segment is also stimulated by sympathetic
3Na+ 2K+
nerves acting by way of receptors [41,42]. The DCT is imperme-
able to water.
AT1 All
See figure 2-7
DCT
– + Interstitum
Lumen Interstitum ↑GFR

– +
Na Na
Aldo receptor + Aldo Na Na cGMP
Na + Na Na – AR ANP
+ Na GC
~
+ 3Na+ 2K+
K PGE2 –
cAMP
R Lumen
α PGE2 ~
+
Gi 3Na+ 2K+
AC
H 2O
Gs + V2 AVP
ATP H 2O
V2 AVP
CCT –
MCT
+
FIGURE 2-18
Principal cortical collecting tubule (CCT) cells. In these cells, sodi- FIGURE 2-19
um (Na) enters across the luminal membrane through Na channels Cellular mechanism of the medullary collecting tubule (MCT).
(ENaC). The movement of cationic Na from lumen to cell depolar- Sodium (Na) and water are reabsorbed along the MCT. Atrial natri-
izes the luminal membrane, generating a transepithelial electrical uretic peptide (ANP) is the best-characterized hormone that affects
gradient oriented with the lumen negative with respect to intersti- Na absorption along this segment [22]. Data on the effects of argi-
tium. This electrical gradient permits cationic potassium (K) to dif- nine vasopressin (AVP) and aldosterone are not as consistent
fuse preferentially from cell to lumen through K channels [46,49]. Prostaglandin E2 (PGE2) inhibits Na transport by inner
(ROMK). Na transport is stimulated when aldosterone interacts medullary collecting duct cells and may be an important intracellu-
with its intracellular receptor [43]. This effect involves both lar mediator for the actions of endothelin and interleukin-1 [50,51].
increases in the number of Na channels at the luminal membrane ANP inhibits medullary Na transport by interacting with a G-pro-
and increases in the number of Na-K ATPase (Sodium-potassium tein–coupled receptor that generates cyclic guanosine monophos-
adenosine triphosphatase) pumps at the basolateral cell membrane. phate (cGMP). This second messenger inhibits a luminal Na channel
Arginine vasopressin (AVP) stimulates both Na absorption (by that is distinct from the Na channel expressed by the principal cells
interacting with V2 receptors and, perhaps, V1 receptors) and of the cortical collecting tubule, as shown in Figure 2-18 [52,53].
water transport (by interacting with V2 receptors) [44–46]. V2 Under normal circumstances, ANP also increases the glomerular fil-
receptor stimulation leads to insertion of water channels (aquapor- tration rate (GFR) and inhibits Na transport by way of the effects
in 2) into the luminal membrane [47]. V2 receptor stimulation is on the renin-angiotensin-aldosterone axis, as shown in Figures 2-7
modified by PGE2 and 2 agonists that interact with a receptor to 2-10. These effects increase Na delivery to the MCT. The combi-
that stimulates Gi [48]. AC—adenylyl cyclase; ATP—adenosine nation of increased distal Na delivery and inhibited distal reabsorp-
triphosphate; cAMP—cyclic adenosine monophosphate; CCT—cor- tion leads to natriuresis. In patients with congestive heart failure,
tical collecting tubule; Gi—inhibitory G protein; Gs—stimulatory distal Na delivery remains depressed despite high levels of circulat-
G protein; R—Ri receptor. ing ANP. Thus, inhibition of apical Na entry does not lead to natri-
uresis, despite high levels of MCT cGMP. AR—ANP receptor;
GC—guanylyl cyclase; K—potassium; V2—receptors.
Causes, Signs, and Symptoms of Extracellular

Fluid Volume Expansion and Contraction
CAUSES OF VOLUME EXPANSION CAUSES OF VOLUME DEPLETION
Primary renal sodium retention (with hypertension but without edema) Extrarenal losses (urine sodium concentration low)
Hyperaldosteronism (Conn’s syndrome) Gastrointestinal salt losses
Cushing’s syndrome Vomiting
Inherited hypertension (Liddle’s syndrome, glucocorticoid remediable hyperaldo- Diarrhea
steronism, pseudohypoaldosteronism Type II, others) Nasogastric or small bowel aspiration
Renal failure Intestinal fistulae or ostomies
Nephrotic syndrome (mixed disorder) Gastrointestinal bleeding
Secondary renal sodium retention Skin and respiratory tract losses
Hypoproteinemia Burns
Nephrotic syndrome Heat exposure
Protein-losing enteropathy Adrenal insufficiency
Cirrhosis with ascites Extensive dermatologic lesions
Cystic fibrosis
Low cardiac output
Pulmonary bronchorrhea
Hemodynamically significant pericardial effusion
Drainage of large pleural effusion
Constrictive pericarditis
Valvular heart disease with congestive heart failure Renal losses (urine sodium concentration normal or elevated)
Severe pulmonary disease Extrinsic
Cardiomyopathies Solute diuresis (glucose, bicarbonate, urea, mannitol, dextran, contrast dye)
Peripheral vasodilation Diuretic agents
Pregnancy Adrenal insufficiency
Gram-negative sepsis Selective aldosterone deficiency
Anaphylaxis Intrinsic
Arteriovenous fistula Diuretic phase of oliguric acute renal failure
Trauma Postobstructive diuresis
Cirrhosis Nonoliguric acute renal failure
Idiopathic edema (?) Salt-wasting nephropathy
Drugs: minoxidil, diazoxide, calcium channel blockers (?) Medullary cystic disease
Increased capillary permeability Tubulointerstitial disease
Idiopathic edema (?) Nephrocalcinosis
Burns
Allergic reactions, including certain forms of angioedema
Adult respiratory distress syndrome
Interleukin-2 therapy
Malignant ascites FIGURE 2-21
Sequestration of fluid (“3rd spacing,” urine sodium concentration low) In volume depletion, total body sodium is decreased.
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 pres-
sure may not increase sufficiently to increase urinary Na excretion
until edema develops.
CLINICAL SIGNS OF VOLUME CLINICAL SIGNS OF VOLUME LABORATORY SIGNS OF VOLUME

EXPANSION DEPLETION DEPLETION OR EXPANSION
Edema Orthostatic decrease in blood pressure and increase Hypernatremia

Pulmonary crackles in pulse rate Hyponatremia
Ascites Decreased pulse volume Acid-base disturbances
Jugular venous distention Decreased venous pressure Abnormal plasma potassium
Hepatojugular reflux Loss of axillary sweating Decrease in glomerular filtration rate
Hypertension Decreased skin turgor Elevated blood urea nitrogen–creatinine ratio
Dry mucous membranes Low functional excretion of sodium (FENa)
FIGURE 2-22
Clinical signs of volume expansion. FIGURE 2-23 FIGURE 2-24
Clinical signs of volume depletion. 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 metabol-
ic alkalosis, and hypokalemia are common
in both conditions. The similarity of the lab-
oratory 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
from a reduction in mean arterial pressure
Myocardial ↓ Extracellular (MAP). Some disorders decrease cardiac
dysfunction fluid volume output, such as congestive heart failure
owing to myocardial dysfunction; others
– – High output decrease systemic vascular resistance, such
AV fistula Cirrhosis Pregnancy
failure 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
Cardiac output × Systemic vascular resistance = Mean arterial pressure
result. As shown in Figures 2-3 and 2-4,
small changes in MAP lead to large changes
+ in urinary Na excretion. Although edema-
tous disorders usually are characterized as
Sodium excretion resulting from contraction of the effective
(pressure natriuresis) arterial volume, the MAP, as a determinant
of renal perfusion pressure, may be the cru-
cial variable (Figs. 2-26 and 2-28 provide
FIGURE 2-25 supportive data). The mechanisms of edema
Summary of mechanisms of sodium (Na) retention in volume contraction and in depletion in nephrotic syndrome are more complex
of the “effective” arterial volume. In secondary Na retention, Na retention results primarily and are discussed in Figures 2-36 to 2-39.
Mechanisms of Extracellular Fluid Volume

Expansion in Congestive Heart Failure
130 130
MI J Lab Clin Med 1978
125 125
AVF Am J Physiol 1977
120 120

115 115
110 110
105 105
100 100
95 95
90 90
Control Small MI Large MI Control Balance Na Ret. Ascites
A AVF B Cirrhosis
FIGURE 2-26
Role of renal perfusion pressure in sodium (Na) retention. A, Results which experimental cirrhosis was induced in dogs by sporadic feeding
from studies in rats that had undergone myocardial infarction (MI) or with dimethylnitrosamine. Three cirrhotic stages were identified based
placement of an arteriovenous fistula (AVF) [54]. Rats with small and on the pattern of Na retention. In the first, dietary Na intake was bal-
large MIs were identified. Both small and large MIs induced signifi- anced by Na excretion. In the second, renal Na retention began, but
cant Na retention when challenged with Na loads. Renal Na retention still without evidence of ascites or edema. In the last, ascites were
occurred in the setting of mild hypotension. AVF also induced signifi- detected. Because Na was retained before the appearance of ascites,
cant Na retention, which was associated with a decrease in mean arte- “primary” renal Na retention was inferred. An alternative interpreta-
rial pressure (MAP) [55,56]. Figure 2-3 has shown that Na excretion tion of these data suggests that the modest decrease in MAP is respon-
decreases greatly for each mm Hg decrease in MAP. B, Results of two sible for Na retention in this model. Note that in both heart failure
groups of experiments performed by Levy and Allotey [57,58] in and cirrhosis, Na retention correlates with a decline in MAP.
FIGURE 2-27
600 10 Mechanism of sodium (Na) retention in high-output cardiac failure.
UNaV
UNaV, mmol/d or plasma ANP, pg/mL or MAP, mmHg;
ANP Effects of high-output heart failure induced in dogs by arteriovenous

MAP (AV) fistula [59]. After induction of an AV fistula (day 0), plasma
500
PRA 8 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
PRA, ng ANG I mL-1•h-1
400
line) declined modestly. After day 5, the plasma atrial natriuretic
6 peptide concentration (ANP; dashed line) increased because of vol-
300 ume expansion, returning urinary Na excretion to baseline levels.
Thus, Na retention, mediated in part by the renin-angiotensin-aldos-
4 terone system, led to volume expansion. The volume expansion sup-
200 pressed 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
2 maintaining Na excretion in compensated congestive heart failure.
100
This effect of ANP has been confirmed directly in experiments using
anti-ANP antibodies [60]. AI—angiotensin I.
0 0
-5 0 5 10 15 20 25 30 35 40
Days
FIGURE 2-28
400
ANP Mechanism of renal resistance to atrial natriuretic peptide (ANP) in experimental low-out-
UNaV, µmol/min
300 ANP & SAR put heart failure. Low-output heart failure was induced in dogs by thoracic inferior vena
ANP & AII caval constriction (TIVCC), which also led to a significant decrease in renal perfusion
200 ANP & AII & SAR pressure (RPP) (from 127 to 120 mm Hg). ANP infusion into dogs with TIVCC did not
AII & SAR increase urinary sodium (Na) excretion (UNaV, ANP group). In contrast, when the RPP
100 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
0
saralasin (SAR) was infused to block renal AII receptors. SAR did not significantly affect
Baseline TIVCC Infusion
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].)
FIGURE 2-29
30
Mechanism of extracellular fluid (ECF) vol-
Intersititial volume, L
30
Blood volume, L
+ ume expansion in congestive heart failure.
Fluid intake 20
20 A primary decrease in cardiac output (indi-
Net volume
intake cated by dark blue arrow) leads to a
Nonrenal 10 10 decrease in arterial pressure, which decreas-
fluid loss –
+ es pressure natriuresis and volume excre-
0 0 tion. These decreases expand the ECF vol-
0 10 20 30 ume. The inset graph shows that the ratio
ECF volume, L of interstitial volume (solid line) to plasma
+ – Rate of change + volume (dotted line) increases as the ECF
Arterial Kidney volume Extracellular
of extracellular
pressure output fluid volume volume expands because the interstitial
fluid volume
+
compliance increases [62]. Thus, although
expansion of the ECF volume increases
Total peripheral blood volume and venous return, thereby
+ resistance Blood volume
+ restoring cardiac output toward normal,
+ Autoregulation this occurs at the expense of a dispropor-
+ +
Mean circulatory tionate expansion of interstitial volume,
filling pressure often manifested as edema.
Mechanisms of Extracellular Fluid

Volume Expansion in Cirrhosis
FIGURE 2-30
Underfill theory Vasodilation theory Overflow theory Three theories of ascites formation in hepatic cirrhosis. Hepatic
venous outflow obstruction leads to portal hypertension.
Hepatic venous SVR – Hepatic venous According to the underfill theory, transudation from the liver leads
outflow obstruction outflow obstruction 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 clini-
cal or experimental cirrhosis. Furthermore, this theory predicts that
ascites would develop before renal Na retention, when the reverse
Transudation Transudation generally occurs. According to the overflow theory, increased por-
tal 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 hypertension–induced signals for renal Na
retention remains unclear. The vasodilation theory suggests that
Renin portal hypertension leads to vasodilation and relative arterial
↓ Blood volume ↑ ECF volume 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
FIGURE 2-31
Vasodilators Vasoconstrictors
Alterations in cardiovascular hemodynamics in hepatic cirrhosis. Hepatic dysfunction and
Nitric oxide portal hypertension increase the production and impair the metabolism of several vasoac-
Glucagon
CGRP tive substances. The overall balance of vasoconstriction and vasodilation shifts in favor of
ANP SNS dilation. Vasodilation may also shift blood away from the central circulation toward the
VIP RAAS periphery and away from the kidneys. Some of the vasoactive substances postulated to
Substance P Vasopressin
ET-1 participate in the hemodynamic disturbances of cirrhosis include those shown here.
Prostaglandin E2 ANP—atrial natrivretic peptide; ET-1—endothelin-1; CGRP—calcitonin gene related
Encephalins
TNF peptide; RAAS—renin/angiotensin/aldosterone system; TNF—tumor necrosis factor;
Andrenomedullin VIP— vasoactive intestinal peptide. (Data from Møller and Henriksen [64].)
FIGURE 2-32
C.O.=5.22 L/min C.O.=6.41 L/min
Effects of cirrhosis on central and noncentral blood volumes. The central blood volume is
3.64 L 4.34 L 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 non-
1.31 L central blood volumes. The higher cardiac output (CO) results from peripheral vasodila-
1.81 L
tion. Perfusion of the kidney is reduced significantly in patients with cirrhosis. (Data from
Central blood Hillarp and coworkers [65].)
Central blood volume
volume
Noncentral Noncentral
A blood volume B blood volume
Control subjects, n=16 Cirrhotic patients, n=60

FIGURE 2-33
15 15
Control Contribution of nitric oxide to vasodilation and sodium (Na)
Cirrhosis retention in cirrhosis. Compared with control rats, rats having cir-
Cirrhosis & L-name rhosis induced by carbon tetrachloride and phenobarbital exhibited
PRA, ng/min/h or AVP, pg/mL
increased plasma renin activity (PRA) and plasma arginine vaso-

10 10 pressin (AVP) concentrations. At steady state, the urinary Na excre-
UNaV, mmol/d
tion (UNaV) was similar in both groups. After treatment with L-
NAME for 7 days, plasma renin activity decreased to normal lev-
els, AVP concentrations decreased toward normal levels, and
urinary Na excretion increased by threefold. These changes were
5 5 associated with a normalization of mean arterial pressure and car-
diac output. (Data compiled from Niederberger and coworkers
[66,67] and Martin and Schrier [68].)
0 0
PRA AVP UNaV
FIGURE 2-34
30
Mechanisms of sodium (Na) retention in
(with low albumin)
30
Blood volume, L
cirrhosis. A primary decrease in systemic

+ 20
Fluid intake 20 vascular resistance (indicated by dark blue
Net volume arrow), induced by mediators shown in
intake 10 10 Figure 2-31, leads to a decrease in arterial
Nonrenal
fluid loss – pressure. The reduction in systemic vascular
+ 0 0 resistance, however, is not uniform and
0 10 20 30 favors movement of blood from the central
ECF volume, L (“effective”) circulation into the peripheral
+ – Rate of change + circulation, as shown in Figure 2-32.
pressure output
of extracellular
fluid volume
Hypoalbuminemia shifts the interstitial to
fluid volume blood volume ratio upward (compare the
+
interstitial volume with normal [dashed
Total peripheral Central Peripheral
line], and low [solid line], protein levels in
+ resistance blood volume blood volume the inset graph). Because cardiac output
increases and venous return must equal car-
+ +
diac output, dramatic expansion of the
+
Mean circulatory extracellular fluid (ECF) volume occurs.
filling pressure
Mechanisms of Extracellular Fluid Volume

Expansion in Nephrotic Syndrome
FIGURE 2-35
14 Changes in plasma protein concentration affect the net oncotic pressure difference across
12 capillaries (c - i) in humans. Note that moderate reductions in plasma protein concen-
tration have little effect on differences in transcapillary oncotic pressure. Only when plas-
C - i, mmHg
10 ma protein concentration decreases below 5 g/dL do changes become significant. (Data

from Fadnes and coworkers [69].)
8
4
2
0 2 4 6 8
Plasma protein concentration, g/dL
300 20 35 30
PRA
250 30 ANP
25
UNaV, mmol/24 hrs ( )
15
Albumin, g/L ( )
200 25
PRA, ng/L × sec
ANP, fmol/mL
20
150 10 20
15
15
100
5 10
10
50
5 5
0 0
-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 0 0
Days 20 mEq 300 mEq AGN NS
Controls
FIGURE 2-36
Time course of recovery from minimal change nephrotic syndrome FIGURE 2-37
in five children. Note that urinary Na excretion (squares) increases Plasma renin activity (PRA) and atrial natriuretic peptide (ANP)
before serum albumin concentration increases. The data suggest concentration in the nephrotic syndrome. Shown are PRA and
that the natriuresis reflects a change in intrinsic renal Na retention. ANP concentration (standard error) in normal persons ingesting
The data also emphasize that factors other than hypoalbuminemia diets high (300 mEq/d) and low (20 mEq/d) in sodium (Na) and in
must contribute to the Na retention that occurs in nephrosis. patients with acute glomerulonephritis (AGN), predominantly post-
UNaV—urinary Na excretion volume. (Data from Oliver and streptococcal, or nephrotic syndrome (NS). Note that PRA is sup-
Owings [70].) pressed in patients with AGN to levels below those in normal per-
sons 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 pathogen-
esis of Na retention in NS as well. (Data from Rodrígeuez-Iturbe
and coworkers [71].)
FIGURE 2-38
100 100
Control Sites of sodium (Na) reabsorption along the nephron in control
PAN and nephrotic rats (induced by puromycin aminonucleoside
80 80 [PAN]). The glomerular filtration rates (GFR) in normal and
nephrotic rats are shown by the hatched bars. Note the modest
Fractional absorption, %
reduction in GFR in the nephrotic group, a finding that is common

GFR, % of control
60 60 in human nephrosis. Fractional reabsorption rates along the proxi-

mal tubule, the loop of Henle, and the superficial distal tubule are
indicated. The fractional reabsorption along the collecting duct
40 40 (CD) is estimated from the difference between the end distal and
urine deliveries. The data suggest that the predominant site of
20 20 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
0 0 nephrons. Asterisk—data inferred from the difference between dis-
GFR Proximal Loop Distal CD (*) tal and urine samples. (Data from Ichikawa and coworkers [72].)
FIGURE 2-39
30
Mechanisms of extracellular fluid (ECF) vol-
30
Blood volume, L
ume expansion in nephrotic syndrome.
+ 20
Fluid intake 20 Nephrotic syndrome is characterized by
Net volume hypoalbuminemia, which shifts the relation
intake 10 10 between blood and interstitial volume
Nonrenal
fluid loss – upward (dashed to solid lines in inset). As
+ 0 0 discussed in Figure 2-35, these effects of
0 10 20 30 hypoalbuminemia are evident when serum
ECF volume, L albumin concentrations decrease by more
+ – Rate of change + than half. In addition, however, hypoalbu-
pressure output
of extracellular
fluid volume
minemia may induce vasodilation and arteri-
fluid volume al hypotension that lead to sodium (Na)
+ retention, independent of transudation of
Total peripheral fluid into the interstitium [73,74]. Unlike
+ resistance Blood volume other states of hypoproteinemia and vasodi-
+ lation, however, nephrotic syndrome usually
+ is associated with normotension or hyperten-
+
Mean circulatory sion. Coupled with the observation made in
filling pressure Figure 2-36 that natriuresis may take place
before increases in serum albumin concentra-
tion 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 2-
37, 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
35 Relation between glomerular filtration rate (GFR) and fractional sodium (Na) excretion
30 (FENa). The normal FENa is less than 1%. Adaptations in chronic renal failure maintain
25
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.
FENA, %
20
15
10
5
0
0 20 40 60 80 100 120
GFR, mL/min
FIGURE 2-41
18 15 Effects of dietary sodium (Na) intake on extracellular fluid (ECF)
Normal
14 volume in chronic renal failure (CRF) [75]. Compared with normal
Mild CRF
17 persons, patients with CRF have expanded ECF volume at normal
Severe CRF 13
12 Na intake. Furthermore, the time necessary to return to neutral
16 balance on shifting from one to another level of Na intake is
11 increased. Thus, whereas urinary Na excretion equals dietary
Dietary sodium intake, g

10 intake of Na within 3 to 5 days in normal persons, this process
15
ECF volume, L
9 may take up to 2 weeks in patients with CRF. This time delay

8 means that not only are these patients susceptible to volume over-
14
load, but also to volume depletion. This phenomenon can be mod-
7
eled simply by reducing the time constant (k) given in the equation
13 6 in Figure 2-2, and leaving the set point (A0) unchanged. The curves
5 here represent time constants of 0.79 ±0.05 day-1 (normal), 0.5
12 day-1 (mild CRF), and 0.25 day-1 (severe CRF).
4
11 3
2
10 1
0 5 10 15 20 25
Days
References
1. Walser M: Phenomenological analysis of renal regulation of sodium 12. Briggs JP: Whys and the wherefores of juxtaglomerular apparatus
and potassium balance. Kidney Int 1985, 27:837–841. functions.Kidney Int 1996, 49:1724–1726.
2. Simpson FO: Sodium intake, body sodium, and sodium excretion. 13. Barajas L: Architecture of the juxtaglomerular apparatus. In
Lancet 1990, 2:25–29. Hypertension: Pathophysiology, Diagnosis and Treatment. Edited by
3. Luft FC, Weinberger MH, Grim CE: Sodium sensitivity and resistance Laragh JH, Brenner BM. New York: Raven Press; 1990:XX–XX.
in normotensive humans. Am J Med 1982, 72:726–736. 14. Skott O, Briggs JP: Direct demonstration of macula densa mediated
4. Guyton AC: Blood pressure control: special role of the kidneys and renin secretion. Science 1987, 237:1618–1620.
body fluids. Science 1991, 252:1813–1816. 15. Hall JE, Guyton AC: Changes in renal hemodynamics and renin
release caused by increased plasma oncotic pressure. Am J Physiol
5. Lassiter WE: Regulation of sodium chloride distribution within the
1976, 231:1550.
extracellular space. In The Regulation of Sodium and Chloride
Balance. Edited by Seldin DW, Giebisch G. New York: Raven Press; 16. Bachmann S, Bosse HM, Mundel P: Topography of nitric oxide syn-
1990:23–58. thesis by localizing constitutive NO synthetases in mammalian kidney.
Am J Physiol 1995, 268:F885–F898.
6. Hall JE, Jackson TE: The basic kidney-blood volume-pressure regula-
tory system: the pressure diuresis and natriuresis phenomena. In 17. Johnson RA, Freeman RH: Renin release in rats during blockade of
Arterial Pressure and Hypertension. Edited by Guyton AC. nitric oxide synthesis. Am J Physiol 1994, 266:R1723–R1729.
Philadelphia: WB Saunders Co, 1998:87–99. 18. Schricker K, Hegyi I, Hamann M, et al.: Tonic stimulation of renin
7. Gonzalez-Campoy JM, Knox FG: Integrated responses of the kidney gene expression by nitric oxide is counteracted by tonic inhibition
to alterations in extracellular fluid volume. In The Kidney: Physiology through angiotensin II. Proc Natl Acad Sci USA 1995, 92:8006–8010.
and Pathophysiology, edn 2. Edited by Seldin DW, Giebisch G. New 19. Funder JW: Mineralocorticoids, glucocorticoids, receptors and
York: Raven Press; 1992:2041–2097. response elements. Science 1993, 259:1132–1133.
8. Hall JE, Brands MW: The renin-angiotensin-aldosterone systems. In 20. Náray-Fejes-Tóth A, Fejes-Tóth G: Glucocorticoid receptors mediate
The Kidney: Physiology and Pathophysiology, edn 2. Edited by Seldin mineralocorticoid-like effects in cultured collecting duct cells. Am J
DW, Giebisch G. New York: Raven Press; 1992:1455–1504. Physiol Renal Fluid Electrolyte Physiol 1990, 259:F672–F678.
9. Laragh JH, Sealey JE: The intergrated regulation of electrolyte balance 21. Mune T, Rogerson FM, Nikkila H, et al.: Human hypertension caused
and blood pressure by the renin system. In The Regulation of Sodium by mutations in the kidney isozyme of 11*beta*-hydroxysteroid dehy-
and Chloride Balance. Edited by Seldin DW, Giebisch G. New York: drogenase. Nature Genet 1995, 10:394–399.
Raven Press, 1990:133–193. 22. Hollander W, Judson WE: The relationship of cardiovascular and
10. Obermüller N, Kunchaparty S, Ellison DH, Bachmann S: Expression renal hemodynamic function to sodium excretion in patients with
of the Na-K-2Cl cotransporter by macula densa and thick ascending severe heart disease but without edema. J Clin Invest 1956,
limb cells of rat and rabbit nephron. J Clin Invest 1996, 98:635–640. 35:970–979.
11. Lapointe J-Y, Bell PD, Cardinal J: Direct evidence for apical Na+:2Cl- 23. Brenner BM, Ballermann BJ, Gunning ME, Zeidel ML: Diverse bio-
:K+ cotransport in macula densa cells. Am J Physiol 1990, logical actions of atrial natriuretic peptide. Physiol Rev 1990,
258:F1466–F1469. 70:665–700.
24. Kishimoto I, Dubois SK, Garbers DL: The heart communicates with 46. Kudo LH, Van Baak AA, Rocha AS: Effects of vasopressin on sodium
the kidney exclusively through the guanylyl cyclase-A receptor: Acute transport across inner medullary collecting duct. Am J Physiol 1990,
handling of sodium and water in response to volume expansion. Proc 258:F1438–F1447.
Natl Acad Sci USA 1996, 93:6215–6219. 47. Nielsen S, Chou C-L, Marples D, et al.: Vasopressin increases water
25. Korner PI: Integrative neural cardiovascular control. Physiol Rev permeability of kidney collecting duct by inducing translocation of
1971, 51:312–367. aquaporin: CD water channels to plasma membrane. Proc Natl Acad
26. Cogan MG: Neurogenic regulation of proximal bicarbonate and chlo- Sci USA 1995, 92:1013–1017.
ride reabsorption. Am J Physiol 1986, 250:F22–F26. 48. Schafer JA: Salt and water homeostasis: Is it just a matter of good
27. Geibel J, Giebisch G, Boron WF: Angiotensin II stimulates both Na+- bookkeeping? J Am Soc Nephrol 1994, 4:1933–1950.
H+ exchange and Na+/HCO-3 cotransport in the rabbit proximal 49. Husted RF, Laplace JR, Stokes JB: Enhancement of electrogenic Na+
tubule. Proc Natl Acad Sci USA 1990, 87:7917–7920. transport across rat inner medullary collecting duct cells in culture.
28. Block RD, Zikos D, Fisher KA, et al.: Peterson DR: Activation of J Clin Invest 1990, 86:498–506.
proximal tubular Na+-H+ exchanger by angiotensin II. Am J Physiol
50. Zeidel ML, Jabs K, Kikeri D, Silva P: Kinins inhibit conductive Na+
1992, 263:F135–F143.
uptake by rabbit inner medullary collecting duct cells. Am J Physiol
29. Bertorello A, Aperia A: Regulation of Na+-K+-ATPase activity in kid- Renal Fluid Electrolyte Physiol 1990, 258:F1584–F1591.
ney proximal tubules: involvement of GTP binding proteins. Am J
Physiol 1989, 256:F57–F62. 51. Zeidel ML: Hormonal regulation of inner medullary collecting duct
sodium transport. Am J Physiol Renal Fluid Electrolyte Physiol 1993,
30. Aperia AC: Regulation of sodium transport. Curr Opinion Nephrol 265:F159–F173.
Hypertens 1995, 4:416–420.
52. Light DB, Ausiello DA, Stanton BA: Guanine nucleotide-binding pro-
31. Bouby N, Bankir L, Trinh-Trang-Tan MM, et al.: Selective ADH- tein, i 3, directly activates a cation channel in rat renal inner
induced hypertrophy of the medullary thick ascending limb in medullary collecting duct cells. J Clin Invest 1989, 84:352–356.
Brattleboro rats. Kidney Int 1985, 28:456–466.
53. Light DB, Schwiebert EM, Karlson KH, Stanton BA: Atrial natriuretic
32. Chabardès D, Gagnan-Brunette M, Imbert-Tébol M: Adenylate
peptide inhibits a cation channel in renal inner medullary collecting
cyclase responsiveness to hormones in various portions of the human
duct cells. Science 1989, 243:383–385.
nephron. J Clin Invest 1980, 65:439–448.
33. Stokes JB: Effects of prostaglandin E2 on chloride transport across the 54. Hostetter TH, Pfeffer JM, Pfeffer MA, et al.: Cardiorenal hemody-
rabbit thick ascending limb of Henle. J Clin Invest 1979, 64:495–502. namics and sodium excretion in rats with myocardial dysfunction. Am
J Physiol 1983, 245:H98–H103.
34. Escalante B, Erlij D, Falck JR, McGiff JC: Effect of cytochrome P450
arachidonate metabolites on ion transport in rabbit kidney loop of 55. Villarreal D, Freeman RH, Brands MW: DOCA administration and
Henle. Science 1991, 251:799–802. atrial natriuretic factor in dogs with chronic heart failure. Am J
Physiol 1989, 257:H739–H745.
35. Amlal H, Legoff C, Vernimmen C, et al.: Na(+)-K+(NH4+)-2Cl-
cotransport in medullary thick ascending limb: control by PKA, PKC, 56. Villarreal D, Freeman RH, Davis JO, et al.: Atrial natriuretic factor
and 20-HETE. Am J Physiol 1996, 271:C455–C463. secretion in dogs with experimental high-output heart failure. Am J
Physiol 1987, 252:H692–H696.
36. Culpepper RM, Adreoli TE: Interactions among prostaglandin E2,
antidiuretic hormone and cyclic adenosine monophosphate in modu- 57. Levy M, Allotey JBK: Temporal relationsips between urinary salt
lating Cl- absorption in single mouse medullary thick ascending limbs retention and altered systemic hemodynamics in dogs with experimen-
of Henle. J Clin Invest 1983, 71:1588–1601. tal cirrhosis. J Lab Clin Med 1978, 92:560–569.
37. Ecelbarger CA, Terris J, Hoyer JR, et al.: Localization and regulation 58. Levy M: Sodium retention and ascites formation in dogs with experi-
of the rat renal Na+-K+-2Cl-, cotransporter, BSC-1. Am J Physiol mental portal cirrhosis. Am J Physiol 1977, 233:F572–F585.
Renal Fluid Electrolyte Physiol 1996, 271:F619–F628.
59. Villarreal D, Freeman RH, Johnson RA: Neurohumoral modulators
38. Chen Z, Vaughn DA, Blakeley P, Fanestil DD: Adrenocortical steroids and sodium balance in experimental heart failure. Am J Physiol Heart
increase renal thiazide diuretic receptor density and response. J Am Circ Physiol 1993, 264:H1187–H1193.
Soc Nephrol 1994, 5:1361–1368.
60. Awazu M, Ichikawa I: Alterations in renal function in experimental
39. Velázquez H, Bartiss A, Bernstein PL, Ellison DH: Adrenal steroids congestive heart failure. Sem Nephrology 1994, 14:401–411.
stimulate thiazide-sensitive NaCl transport by the rat renal distal
tubule. Am J Physiol 1996, 39:F211–F219. 61. Redfield MM, Edwards BS, Heublein DM, Burnett JC Jr: Restoration
of renal response to atrial natriuretic factor in experimental low-out-
40. Wang T, Giebisch G: Effects of angiotensin II on electrolyte transport put heart failure. Am J Physiol 1989, 257:R917–R923.
in the early and late distal tubule in rat kidney. Am J Physiol Renal
Fluid Electrolyte Physiol 1996, 271:F143–F149. 62. Manning RD Jr, Coleman TG, Samar RE: Autoregulation, cardiac
output, total peripheral resistance and the “quantitative cascade” of
41. Wang T, Chan YL: Neural control of distal tubular bicarbonate and
the kidney-blood volume system for pressure control. In Arterial
fluid transport. Am J Physiol 1989, 257:F72–F76.
Pressure and Hypertension. Edited by Guyton AC. Philadelphia: WB
42. Bencsáth P, Szénási G, Takács L: Water and electrolyte transport in Saunders Co; 1980:139–155.
Henle’s loop and distal tubule after renal sympathectomy in the rat.
Am J Physiol 1985, 249:F308–F314. 63. Albillos A, Colombato LA, Groszmann RJ: Vasodilation and sodium
retention in prehepatic portal hypertension. Gastroenterology 1992,
43. Rossier BC, Palmer LG: Mechanisms of aldosterone action on sodium 102:931–935.
and potassium transport. In The Kidney: Physiology and
Pathophysiology, edn 2. Edited by Seldin DW, Giebisch G. New York: 64. Møller S, Henriksen JH: Circulatory abnormalities in cirrhosis with
Raven Press, 1992:1373–1409. focus on neurohumoral aspects. Sem Nephrol 1997, 17:505–519.
44. Breyer MD, Ando Y: Hormonal signalling and regulation of salt and 65. Hillarp A, Zöller B, Dahlbäck M: Activated protein C resistance as a
water transport in the collecting duct. Ann Rev Physiol 1994, basis for venous thrombosis. Am J Med 1996, 101:534–540.
56:711–739. 66. Niederberger M, Martin P-Y, Ginès P, et al.: Normalization of nitric
45. Schafer JA, Hawk CT: Regulation of Na+ channels in the cortical collect- oxide production corrects arterial vasodilation and hyperdynamic cir-
ing duct by AVP and mineralocorticoids. Int Kidney 1992, 41:255–268. culation in cirrhotic rats. Gastroenterology 1995, 109:1624–1630.
67. Niederberger M, Ginès P, Tsai P, et al.: Increased aortic cyclic guano- 71. Rodrígeuez-Iturbe B, Colic D, Parra G, Gutkowska J: Atrial natriuret-
sine monophosphate concentration in experimental cirrhosis in rats: ic factor in the acute nephritic and nephrotic syndromes. Kidney Int
evidence for a role of nitric oxide in the pathogenesis of arterial 1990, 38:512–517.
vasodilation in cirrhosis. Hepatology 1995, 21:1625–1631. 72. Ichikawa I, Rennke HG, Hoyer JR, et al.: Role for intrarenal mecha-
68. Martin P-Y, Schrier RW: Pathogenesis of water and sodium retention nisms in the impaired salt excretion of experimental nephrotic syn-
in cirrhosis. Kidney Int 1997, 51(suppl 59):S-43–S-49. drome. J Clin Invest 1983, 71:91–103.
69. Fadnes HO, Pape JF, Sundsfjord JA: A study on oedema mechanism 73. Manning RD Jr: Effects of hypoproteinemia on renal hemodynamics,
in nephrotic syndrome. Scand J Clin Lab Invest 1986, 46:533–538. arterial pressure, and fluid volume. Am J Physiol 1997, 252:F91–F98.
70. Oliver WJ, Owings CL: Sodium excretion in the nephrotic syn- 74. Manning RD Jr, Guyton AC: Effects of hypoproteinemia on fluid vol-
drome: relation to serum albumin concentration, glomerular filtra- umes and arterial pressure. Am J Physiol 1983, 245:H284–H293.
tion rate, and aldosterone secretion rate. Am J Dis Child 1967, 75. Mitch WE, Wilcox CS: Disorders of body fluids, sodium and potassi-
113:352–362. um in chronic renal failure. Am J Med 1982, 72:536–550.
Disorders of Potassium
Metabolism
Fredrick V. Osorio
Stuart L. Linas
P
otassium, the most abundant cation in the human body, regu-
lates 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 extracel-
lular, 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 trans-
cellular 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 distribu-
tion. 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 algo-
rithms for hypokalemia and hyperkalemia are offered.
Recently, the molecular defects responsible for a variety of diseases
associated with disordered potassium metabolism have been discov- CHAPTER
ered [3–8]. Hypokalemia and Liddle’s syndrome [3] and hyper-
kalemia and pseudohypoaldosteronism type I [4] result from muta-
3
tions at different sites on the epithelial sodium channel in the distal
tubules. The hypokalemia of Bartter’s syndrome can be accounted for
by two separate ion transporter defects in the thick ascending limb of
Henle’s loop [5]. Gitelman’s syndrome, a clinical variant of Bartter’s
syndrome, is caused by a mutation in an ion cotransporter in a apparent mineralocorticoid excess [7] and glucocorticoid-
completely different segment of the renal tubule [6]. The genet- remediable aldosteronism [8] have recently been elucidated
ic mutations responsible for hypokalemia in the syndrome of and are illustrated below.
Overview of Potassium Physiology

FIGURE 3-1
PHYSIOLOGY OF POTASSIUM BALANCE: External balance and distribution of potassium. The usual Western
DISTRIBUTION OF POTASSIUM 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
ECF 350 mEq (10%) ICF 3150 mEq (90%)
body potassium is located in the intracellular fluid (ICF), the
Plasma 15 mEq (0.4%) Muscle 2650 mEq (76%) majority in muscle. Although the extracellular fluid (ECF) contains
Interstitial fluid 35 mEq (1%) Liver 250 mEq (7%) about 10% of total body potassium, less than 1% is located in the
Bone 300 mEq (8.6%) Erythrocytes 250 mEq (7%) plasma [9]. Thus, disorders of potassium metabolism can be classi-
[K+] = 3.5–5.0 mEq/L [K+] = 140–150 mEq/L fied as those that are due 1) to altered intake, 2) to altered elimina-
Urine 90–95 mEq/d Urine 90–95 mEq/d tion, or 3) to deranged transcellular potassium shifts.
Stool 5–10mEq/d Stool 5–10mEq/d
Sweat < 5 mEq/d Sweat < 5 mEq/d
FIGURE 3-2
FACTORS CAUSING TRANSCELLULAR Factors that cause transcellular potassium shifts.
POTASSIUM SHIFTS
Factor Plasma K+
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 ↑
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 hyperpo-
larization 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 adren-
ergic receptor (2R). The generation of cyclic adenosine monophos-
phate (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 catecholamine-
stimulated 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 Henle’s loop (see below). The major site of active potassi-
um 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 repre-
sents the difference between potassium secreted and potassium
reabsorbed [11]. During states of total body potassium depletion,
potassium reabsorption is enhanced. Reabsorbed potassium initial-
ly 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.

Cellular mechanisms of renal potassium transport: proximal tubule Cellular mechanisms of renal potassium transport: cortical collect-
and thick ascending limb. A, Proximal tubule potassium reabsorp- ing tubule. A, Principal cells of the cortical collecting duct: apical
tion is closely coupled to proximal sodium and water transport. sodium channels play a key role in potassium secretion by increas-
Potassium is reabsorbed through both paracellular and cellular ing the intracellular sodium available to Na+-K+-ATPase pumps and
pathways. Proximal apical potassium channels are normally by creating a favorable electrical potential for potassium secretion.
almost completely closed. The lumen of the proximal tubule is neg- Basolateral Na+-K+-ATPase creates a favorable concentration gradi-
ative in the early proximal tubule and positive in late proximal ent for passive diffusion of potassium from cell to lumen through
tubule segments. Potassium transport is not specifically regulated in potassium-selective channels. B, Intercalated cells. Under conditions
this portion of the nephron, but net potassium reabsorption is of potassium depletion, the cortical collecting duct becomes a site
closely coupled to sodium and water reabsorption. B, In the thick for net potassium reabsorption. The H+-K+-ATPase pump is regu-
ascending limb of Henle’s loop, potassium reabsorption proceeds lated by potassium intake. Decreases in total body potassium
by electroneutral Na+-K+-2Cl- cotransport in the thick ascending increase pump activity, resulting in enhanced potassium reabsorp-
limb, the low intracellular sodium and chloride concentrations pro- tion. This pump may be partly responsible for the maintenance of
viding the driving force for transport. In addition, the positive metabolic alkalosis in conditions of potassium depletion [11].
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 com-
peting for the Cl- site on this carrier.
Hypokalemia: Diagnostic Approach

that, during some conditions (eg, ketoaci-
dosis), transcellular shifts and potassium
depletion exist simultaneously. Spurious
hypokalemia results when blood speci-
mens 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 hypo-
kalemia, as their in vivo serum potassium
values are normal. Theophylline poison-
ing prevents cAMP breakdown (see Fig.
3-3). Barium poisoning from the inges-
tion 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 administra-
tion of insulin. Hypokalemic periodic
paralysis can be inherited as an autoso-
mal-dominant disease or acquired by
FIGURE 3-7 patients with thyrotoxicosis, especially
Overview of diagnostic approach to hypokalemia: hypokalemia without total body Chinese males. Therapy of megaloblastic
potassium depletion. Hypokalemia can result from transcellular shifts of potassium into anemia is associated with potassium
cells without total body potassium depletion or from decreases in total body potassium. uptake by newly formed cells, which is
Perhaps the most dramatic examples occur in catecholamine excess states, as after adminis- occasionally of sufficient magnitude to
tration of 2adreneric receptor (2AR) agonists or during “stress.” It is important to note cause hypokalemia [13].
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 associ-
ated with metabolic acidosis, alkalosis, or
no acid-base disturbance. Stool has a rela-
tively 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,
FIGURE 3-8 like that associated ith anorexia or a “tea
Diagnostic approach to hypokalemia: hypokalemia with total body potassium depletion sec- and toast” diet, can lead to hypokalemia,
ondary to extrarenal losses. In the absence of redistribution, measurement of urinary potassium owing to delayed renal conservation of
is helpful in determining whether hypokalemia is due to renal or to extrarenal potassium loss- potassium; however, progressive potassium
es. The normal kidney responds to several (3 to 5) days of potassium depletion with appropri- depletion does not occur unless intake is
ate renal potassium conservation. In the absence of severe polyuria, a “spot” urinary potassium well below 15 mEq of potassium per day.
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 ill-
defined. 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 colon’s capacity for
net potassium secretion. The osmotic diure-
sis associated with diabetic ketoacidosis
FIGURE 3-9 results in potassium depletion, although
Diagnostic approach to hypokalemia: hypokalemia due to renal losses with normal acid- patients may initially present with a normal
base status or metabolic acidosis. Hypokalemia is occasionally observed during the diuret- serum potassium value, owing to altered
ic recovery phase of acute tubular necrosis (ATN) or after relief of acute obstructive transcellular potassium distribution.
FIGURE 3-10
Hypokalemia and magnesium depletion. Hypokalemia and mag-
nesium depletion can occur concurrently in a variety of clinical
settings, including diuretic therapy, ketoacidosis, aminoglycoside
therapy, and prolonged osmotic diuresis (as with poorly con-
trolled 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 pre-
sentation. Attempts at oral and intravenous potassium replace-
ment of up to 80 mEq/day were unsuccessful in correcting the
hypokalemia. Once serum magnesium was corrected, however,
serum potassium quickly normalized [14].
FIGURE 3-11
Diagnostic approach to hypokalemia:
hypokalemia due to renal losses with meta-
bolic alkalosis. The urine chloride value is
helpful in distinguishing the causes of
hypokalemia. Diuretics are a common
cause of hypokalemia; however, after dis-
continuing 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-deple-
tion alkalosis and hypokalemia.
results in salt wasting and elevated renin

and aldosterone levels. The hyperaldostero-
nism 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 recy-
cling and diminish Na+-K+-2Cl- cotrans-
porter activity. Recently, mutations in the
gene that encodes for the Na+-K+-2Cl-
cotransporter and the ATP-sensitive potassi-
um channel have been described in kindreds
with Bartter’s syndrome. Because loop
diuretics interfere with the Na+-K+-2Cl-
cotransporter, surrepititious diuretic abusers
have a clinical presentation that is virtually
indistinguishable from that of Bartter’s
syndrome. B, Gitelman’s syndrome, which
typically presents later in life and is associ-
ated with hypomagnesemia and hypocalci-
FIGURE 3-12 uria, is due to a defect in the gene encoding
Mechanisms of hypokalemia in Bartter’s syndrome and Gitelman’s syndrome. A, A defec- for the thiazide-sensitive Na+-Cl- cotrans-
tive Na+-K+-2Cl- cotransporter in the thick ascending limb (TAL) of Henle’s loop can porter. The mild volume depletion results in
account for virtually all features of Bartter’s syndrome. Since approximately 30% of fil- more avid sodium and calcium reabsorption
tered sodium is reabsorbed by this segment of the nephron, defective sodium reabsorption by the proximal nephrons.
FIGURE 3-13
Diagnostic approach to hypokalemia: hypokalemia due to renal losses with hypertension and metabolic alkalosis.
FIGURE 3-14
CHARACTERISTICS OF HYPOKALEMIA WITH Distinguishing characteristics of
HYPERTENSION AND METABOLIC ALKALOSIS hypokalemia associated with hypertension
and metabolic alkalosis.
Response to
Aldosterone Renin Dexamethasone
Primary aldosteronism ↑ ↓ —
11 -hydroxysteroid ↓ ↓ +
dehydrogenase deficiency
Glucocorticoid remediable ↑ ↓ +
aldosteronism
Liddle’s syndrome ↓→ ↓ —
FIGURE 3-15
Mechanism of hypokalemia in Liddle’s syndrome. The amiloride-
sensitive 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 extracel-
lular loop, and intracellular amino and carboxyl terminals.
Truncation mutations of either the or subunit carboxyl termi-
nal result in greatly increased sodium conductance, which creates
a favorable electrochemical gradient for potassium secretion.
Although patients with Liddle’s syndrome are not universally
hypokalemic, they may exhibit severe potassium wasting with
thiazide diuretics. The hypokalemia, hypertension, and metabolic
alkalosis that typify Liddle’s syndrome can be corrected with
amiloride or triamterene or restriction of sodium.
FIGURE 3-16
Mechanism of hypokalemia in the syndrome of apparent mineralo-
corticoid excess (AME). Cortisol and aldosterone have equal affini-
ty 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 hypermineralo-
corticoid state results in increased transcription of subunits of the
sodium channel and the Na+-K+-ATPase pump. The favorable elec-
trochemical gradient then favors potassium secretion [7,15].
produced in the zona glomerulosa and corti-

sol, 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 pro-
duced 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 seg-
ment). 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
FIGURE 3-17 zona fasciculata gives rise to characteristic ele-
Genetics of glucocorticoid-remediable aldosteronism (GRA): schematic representation of vations in 18-oxidation products of cortisol
unequal crossover in GRA. The genes for aldosterone synthase (Aldo S) and 11 -hydroxylase (18-hydroxycortisol and 18-oxocortisol),
(11 -OHase) are normally expressed in separate zones of the adrenal cortex. Aldosterone is which are diagnostic for GRA [8].
Hypokalemia: Clinical Manifestations
CLINICAL MANIFESTATIONS OF HYPOKALEMIA
Cardiovascular Renal/electrolyte
Abnormal electrocardiogram Functional alterations
Predisposition for digitalis toxicity Decreased glomerular filtration rate
Atrial ventricular arrhythmias Decreased renal blood flow
Hypertension Renal concentrating defect
Neuromuscular Increased renal ammonia production
Smooth muscle Chloride wasting
Constipation/ileus Metabolic alkalosis
Bladder dysfunction Hypercalciuria
Skeletal muscle Phosphaturia
Weakness/cramps Structural alterations
Tetany Dilation and vacuolization of
Paralysis proximal tubules
Myalgias/rhabdomyolysis Medullary cyst formation
Interstitial nephritis
Endocrine/metabolic
Decreased insulin secretion
Carbohydrate intolerance
Increased renin FIGURE 3-19
Decreased aldosterone Electrocardiographic changes associated with hypokalemia. A, The
Altered prostaglandin synthesis U wave may be a normal finding and is not specific for hypokalemia.
Growth retardation 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
FIGURE 3-18 hypokalemia. C, Sagging of the ST segment, flattening of the T wave,
and a prominent U wave are seen with progressive hypokalemia.
Clinical manifestations of 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].
FIGURE 3-20
Renal lesions associated with hypokalemia. The predominant pathologic finding accompa-
nying 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 infiltra-
tion, interstitial scarring, and tubule atrophy have been described. Increased renal ammo-
nia 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 dis-
tribution, 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 intoxica-
tion). Hypokalemic periodic paralysis and hypokalemia associated
with myocardial infarction (secondary to endogenous -adrenergic
agonist release) are best managed by potassium supplementation [19].
FIGURE 3-22
Treatment of hypokalemia.
Hyperkalemia: Diagnostic Approach

either leukocytes or platelets results in leak-
age 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 con-
centrations 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. Hyper-
chloremic 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 con-
trol promote movement of water and potas-
sium out of cells. Depolarizing muscle relax-
ants such as succinylcholine increase perme-
ability of muscle cells and should be avoided
by hyperkalemic patients. The mechanism
of hyperkalemia with -adrenergic blockade
FIGURE 3-23 is illustrated in Figure 3-3. Digitalis impairs
Approach to hyperkalemia: hyperkalemia without total body potassium excess. Spurious function of the Na+-K+-ATPase pumps and
hyperkalemia is suggested by the absence of electrocardiographic (ECG) findings in patients blocks entry of potassium into cells. Acute
with elevated serum potassium. The most common cause of spurious hyperkalemia is fluoride intoxication can be treated with
hemolysis, which may be apparent on visual inspection of serum. For patients with extreme cation-exchange resins or dialysis, as
leukocytosis or thrombocytosis, potassium levels should be measured in plasma samples attempts at shifting potassium back into
that have been promptly separated from the cellular components since extreme elevations in cells may not be successful.
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 potassi-
um loads. Hidden sources of endogenous and
exogenous potassium—and drugs that pre-
dispose to hyperkalemia—are listed.
FIGURE 3-25
Approach to hyperkalemia: hyporeninemic
hypoaldosteronism. Hyporeninemic hypoal-
dosteronism 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 hypoaldostero-
nism. Although the transtubular potassium
gradient should be low in both disorders,
exogenous mineralocorticoid would normal-
ize transtubular potassium gradient in
hyporeninemic hypoaldosteronism.
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 potassi-
um concentrations, and the anion composition of the fluid in the
lumen. Use of the TTKG assumes that negligible amounts of potassi-
um 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, indepen-
dent of urine flow rate. The urine must at least be iso-osmolal with
respect to serum if the TTKG is to be meaningful [20].
FIGURE 3-27
CAUSES FOR HYPERKALEMIA WITH AN Clinical application of the transtubular potassium gradient (TTKG).
INAPPROPRIATELY LOW TTKG THAT IS UNRESPONSIVE The TTKG in normal persons varies much but is genarally within
TO MINERALOCORTICOID CHALLENGE 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 hyperaldostero-
Potassium-sparing diuretics Increased distal nephron potassium nism. The expected TTKG during hyperkalemia is greater than 10.
Amiloride reabsorption An inappropriately low TTKG in a hyperkalemic patient suggests
Triamterene Pseudohypoaldosteronism type II hypoaldosteronism or a renal tubule defect. Administration of the
Urinary tract obstruction mineralocorticoid 9 -fludrocortisone (0.05 mg) should cause TTKG
Spironolactone
to rise above 7 in cases of hypoaldosteronism. Circumstances are
Tubular resistance to aldosterone
listed in which the TTKG would not increase after mineralocorticoid
challenge, because of tubular resistance to aldosterone [21].
Sickle cell disease
Urinary tract obstruction
Pseudohypoaldosteronism type I
Drugs
Trimethoprim
Pentamidine
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 mani-
fest 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 glucocor-
ticoid and mineralocorticoid deficiencies are
seen in Addison’s disease and in defects of
aldosterone biosynthesis.
FIGURE 3-29
Approach to hyperkalemia: pseudohypoaldosteronism. The mecha-
nism 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 reab-
sorption is enhanced in the intercalated cells of the medullary col-
lecting duct (see Fig. 3-4). The transtubule potassium gradient
(TTKG) in both situations is inappropriately low and fails to nor-
malize in response to mineralocorticoid replacement.
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, hyper-
kalemia, and metabolic acidosis. Kidney and adrenal function are
normal, and patients do not respond to exogenous mineralocorti-
coids. 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 cyto-
plasmic amino terminal or extracellular loop of either subunit dis-
rupt the integrity of the sodium channel and result in loss of chan-
nel 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 hydro-
gen ion secretion, hyperkalemia and metabolic acidosis ensue.
Interestingly, when mutations are introduced into the cytoplasmic
carboxyl terminal, sodium channel activity is increased and Liddle’s
syndrome is observed [4].
Hyperkalemia: Clinical Manifestations

FIGURE 3-31
CLINICAL MANIFESTATIONS OF HYPERKALEMIA Clinical manifestations of hyperkalemia.
Cardiac Renal electrolyte

Abnormal electrocardiogram Decreased renal NH4+ production
Atrial/ventricular arrhythmias Natriuresis
Pacemaker dysfunction Endocrine
Neuromuscular Increased aldosterone secretion
Paresthesias Increased insulin secretion
Weakness
Paralysis
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 sinu-
soidal 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.
References
1. MacNight ADC: Epithelial transport of potassium. Kidney Int 1977, 4. Chang SS, Grunder S, Hanukoglu A, et al.: Mutations in subunits of
11:391–397. the epithelial sodium channel cause salt wasting with hyperkalemic
2. Bia MJ, DeFronzo RA: Extrarenal potassium homeostasis. Am J acidosis, pseudohypoaldosteronism type I. Nature Genetics 1996,
Physiol 1981, 240:F257–262. 12:248–253.
3. Hansson JH, Nelson-Williams C, Suzuki H, et al.: Hypertension caused 5. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogene-
by a truncated epithelial sodium channel gamma subunit: Genetic het- ity of Bartter’s syndrome revealed by mutations in the K+ channel,
erogeneity of Liddle’s syndrome. Nature Genetics 1995, 11:76–82. ROMK. Nature Genetics 1996, 14:152–156.
6. Pollack MR, Delaney VB, Graham RM, Hebert SC. Gitelman’s syn- 14. Whang R, Flink EB, Dyckner T, et al.: Magnesium depletion as a
drome (Bartter’s variant) maps to the thiazide-sensitive co-transporter cause of refractory potassium repletion. Arch Int Med 1985,
gene locus on chromosome 16q13 in a large kindred. J Am Soc 145:1686–1689.
Nephrol 1996, 7:2244–2248.
15. Funder JW: Corticosteroid receptors and renal 11 -hydroxysteroid
7. Sterwart PM, Krozowski ZS, Gupta A, et al.: Hypertension in the syn- dehydrogenase activity. Semin Nephrol 1990, 10:311–319.
drome of apparent mineralocorticoid excess due to a mutation of the 11
16. Marriott HJL: Miscellaneous conditions: Hypokalemia. In Practical
(-hydroxysteroid dehydrogenase type 2 gene. Lancet 1996, 347:88–91.
Electrocardiography, edn 8. Baltimore: Williams and Wilkins; 1988.
8. Pascoe L, Curnow KM, Slutsker L, et al.: Glucocorticoid suppressable
hyperaldosteronism results from hybrid genes created by unequal 17. Riemanschneider TH, Bohle A: Morphologic aspects of low-potassi-
crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci USA um and low-sodium nephropathy. Clin Nephrol 1983, 19:271–279.
1992, 89:8237–8331. 18. Tolins JP, Hostetter MK, Hostetter TH: Hypokalemic nephropathy in
9. Welt LG, Blyth WB. Potassium in clinical medicine. In A Primer on the rat: Role of ammonia in chronic tubular injury. J Clin Invest
Potassium Metabolism. Chicago: Searle & Co.; 1973. 1987, 79:1447–1458.
10. DeFronzo RA: Regulation of extrarenal potassium homeostasis by 19. Sterns RH, Cox M, Fieg PU, et al.: Internal potassium balance and
insulin and catecholamines. In Current Topics in Membranes and the control of the plasma potassium concentration. Medicine 1981,
Transport, vol. 28. Edited by Giebisch G. San Diego: Academic Press; 60:339–344.
1987:299–329. 20. Kamel KS, Quaggin S, Scheich A, Halperin ML: Disorders of potassi-
11. Giebisch G, Wang W: Potassium transport: from clearance to channels um homeostasis: an approach based on pathophysiology. Am J Kidney
and pumps. Kidney Int 1996, 49:1642–1631. Dis 1994, 24:597–613.
12. Jamison RL: Potassium recycling. Kidney Int 1987, 31:695–703. 21. Ethier JH, Kamel SK, Magner PO, et al.: The transtubular potassium
13. Nora NA, Berns AS: Hypokalemic, hypophosphatemic thyrotoxic concentration gradient in patients with hypokalemia and hyper-
periodic paralysis. Am J Kidney Dis 1989, 13:247–251. kalemia. Am J Kidney Dis 1990, 15:309–315.
Divalent Cation
Metabolism: Magnesium
James T. McCarthy
Rajiv Kumar
M
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 cofac-
tor 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 magne-
sium balance. In turn, magnesium balance affects numerous intracellular
and systemic processes [1–12].
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 abnormali- CHAPTER
ty of the thick ascending limb of the loop of Henle that prevents excre-
tion of calcium. This abnormality may also extend to Mg. In familial
4
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].
Magnesium Distribution
FIGURE 4-1
TOTAL BODY MAGNESIUM (MG) DISTRIBUTION Total distribution of magnesium (Mg) in
the body. Mg (molecular weight, 24.305 D)
is predominantly distributed in bone, mus-
Location Percent of Total Mg Content, mmol* Mg Content, mg* cle, and soft tissue. Total body Mg content
is about 24 g (1 mol) per 70 kg. Mg in
Bone 53 530 12720 bone is adsorbed to the surface of hydroxy-
Muscle 27 270 6480 apatite crystals, and only about one third is
Soft tissue 19.2 192 4608 readily available as an exchangeable pool.
Erythrocyte 0.5 5 120 Only about 1% of the total body Mg is in
Serum 0.3 3 72 the serum and interstitial fluid
Total 1000 24000 [1,2,8,9,11,12].
*data typical for a 70 kg adult
FIGURE 4-2
Intracellular magnesium (Mg)
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.
Proteins, enzymes, Total cellular Mg concentration can vary from 5 to 20 mmol,
citrate, Endoplasmic depending on the type of tissue studied, with the highest Mg con-
ATP, ADP reticulum centrations being found in skeletal and cardiac muscle cells. Our
– understanding of the concentration and distribution of intracellular
Membrane
– Mg has been facilitated by the development of electron microprobe
proteins
– analysis techniques and fluorescent dyes using microfluorescence
spectrometry. Intracellular Mg is predominantly complexed to
organic molecules (eg, adenosine triphosphatase [ATPase], cell and
Mg2+ nuclear membrane-associated proteins, DNA and RNA, enzymes,
DNA proteins, and citrates) or sequestered within subcellular organelles
(mitochondria and endoplasmic reticulum). A heterogeneous distri-
bution of Mg occurs within cells, with the highest concentrations
Ca • Mg • Mg2+ being found in the perinuclear areas, which is the predominant site
ATPase RNA 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 concentra-
Mitochondria tions of total intracellular or extracellular Mg [1,3,11]. ADP—
adenosine diphosphate; ATP—adenosine triphosphate; Ca+—ion-
ized calcium.
Divalent Cation Metabolism: Magnesium 4.3
Intracellular Magnesium Metabolism

glycerol (DAG). DAG activates Mg influx
Extracellular [Mg2+] = 0.7-1.2mmol by way of protein kinase C (pK C) activity.
Mg2+ Mitochondria may accumulate Mg by the
ß-Adrenergic receptor Na+ (Ca2+?)
Plasma membrane exchange of a cytosolic Mg2+-ATP for a
? mitochondrial matrix Pi molecule. This
+? exchange mechanism is Ca2+-activated and
+? Mg2+?
Mg2+ bidirectional, depending on the concentra-
Adenylyl cyclase cAMP E.R. or
+ tions of Mg2+-ATP and Pi in the cytosol
ATP+Mg2+
S.R. [Mg2+] = 0.5mmol and mitochondria. Inositol 1,4,5-trisphos-
2+ Ca2+
Cellular
Mg Mitochondrion
Ca2+ phate (IP3) may also increase the release of
Nucleus Pi + Mg2+? Mg from endoplasmic reticulum or sar-
ADP ATP•Mg +
coplasmic reticulum (ER or SR, respective-
? Ca2+ ly), which also has a positive effect on this
Mg2+ Mg2+-ATP-Pi exchanger. Other potential
Mg2+?
+? pK C D.G. + IP3 mechanisms affecting cytosolic Mg include
? a hypothetical Ca2+-Mg2+ exchanger locat-
Plasma membrane
Muscarinic receptor or ed in the ER and transport proteins that
Na+ (Ca2+?)
vasopressin receptor can allow the accumulation of Mg within
Extracellular the nucleus or ER. A balance must exist
between passive entry of Mg into the cell
and an active efflux mechanism because
FIGURE 4-3 the concentration gradient favors the
Regulation of intracellular magnesium (Mg2+) in the mammalian cell. Shown is an exam- movement of extracellular Mg (0.7–1.2
ple of Mg2+ movement between intracellular and extracellular spaces and within intracel- mmol) into the cell (free Mg, 0.5 mmol).
lular compartments. The stimulation of adenylate cyclase activity (eg, through stimulation This Mg extrusion process may be energy-
of -adrenergic receptors) increases cyclic adenosine monophosphate (cAMP). The requiring or may be coupled to the move-
increase in cAMP induces extrusion of Mg from mitochondria by way of mitochondrial ment of other cations. The cellular move-
adenine nucleotide translocase, which exchanges 1 Mg2+-adenosine triphosphate (ATP) ment of Mg generally is not involved in the
for adenosine diphosphate (ADP). This slight increase in cytosolic Mg2+ can then be transepithelial transport of Mg, which is
extruded through the plasma membrane by way of a Mg-cation exchange mechanism, primarily passive and occurs between cells
which may be activated by either cAMP or Mg. Activation of other cell receptors (eg, [1–3,7]. (From Romani and coworkers [3];
muscarinic receptor or vasopressin receptor) may alter cAMP levels or produce diacyl- with permission.)
Mg2+
Extracellular
Outer membrane
2+ N
Mg2+ Mg Periplasm
Mg2+
Mg2+ 1 2 3 4 5 6 7 8 9 10 12 3
CorA Periplasm Periplasm
MgtB ATP MgtA Cytoplasm Cytoplasm

N C
ATP C
Mg2+ ADP
Cytosol Mg2+ ADP
Mg2+
MgtA and MgtB CorA
A 37 kDa? B
FIGURE 4-4
A, Transport systems of magnesium (Mg). Specific membrane- against their chemical gradient. Low levels of extracellular Mg
associated Mg transport proteins only have been described in bac- are capable of increasing transcription of these transport proteins,
teria such as Salmonella. Although similar transport proteins are which increases transport of Mg into Salmonella. The CorA sys-
believed to be present in mammalian cells based on nucleotide tem has three membrane-spanning segments. This system mediates
sequence analysis, they have not yet been demonstrated. Both Mg influx; however, at extremely high extracellular Mg concen-
MgtA and MgtB (molecular weight, 91 and 101 kDa, respective- trations, this protein can also mediate Mg efflux. Another cell
ly) are members of the adenosine triphosphatase (ATPase) family membrane Mg transport protein exists in erythrocytes (RBCs).
of transport proteins. B, Both of these transport proteins have six This RBC Na+-Mg2+ antiporter (not shown here) facilitates the
C-terminal and four N-terminal membrane-spanning segments, outward movement of Mg from erythrocytes in the presence of
with both the N- and C-terminals within the cytoplasm. Both extracellular Na+ and intracellular adenosine triphosphate (ATP)
proteins transport Mg with its electrochemical gradient, in con- [4,5]. ADP—adenosine diphosphate; C—carbon; N—nitrogen.
trast to other known ATPase proteins that usually transport ions (From Smith and Maguire [4]).
Gastrointestinal Absorption of Magnesium

FIGURE 4-5
Gastrointestinal absorption of dietary intake of magnesium (Mg).
The normal adult dietary intake of Mg is 300 to 360 mg/d (12.5–15
mmol/d). A Mg intake of about 3.6 mg/kg/d is necessary to maintain
Gastrointestinal
absorption of
Mg balance. Foods high in Mg content include green leafy vegetables
dietary magnesium (Mg) (rich in Mg-containing chlorophyll), legumes, nuts, seafoods, and
meats. Hard water contains about 30 mg/L of Mg. Dietary intake is
Mg absorption % of intake the only source by which the body can replete Mg stores. Net intesti-
Site mmol/day mg/day absorption nal Mg absorption is affected by the fractional Mg absorption within
a specific segment of intestine, the length of that intestinal segment,
Stomach 0 0 0
Duodenum 0.63 15 5 and transit time of the food bolus. Approximately 40% to 50% of
Jejunum 1.25 30 10 dietary Mg is absorbed. Both the duodenum and jejunum have a
Proximal 1.88 45 15 high fractional absorption of Mg. These segments of intestine are rel-
Ileum atively short, however, and the transit time is rapid. Therefore, their
Distal 1.25 30 10 relative contribution to total Mg absorption is less than that of the
Ileum
ileum. In the intact animal, most of the Mg absorption occurs in the
Colon 0.63 15 5
ileum and colon. 1,25-dihydroxy-vitamin D3 may mildly increase the
Total* 5.6 135 45 intestinal absorption of Mg; however, this effect may be an indirect
*Normal dietary Mg intake = 300 mg (12.5 mmol) per day 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 con-
tain 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 [2,6,8–13].
10
7
9 Physiological
Mg-intake,
Magnesium absorbed M Mg , mmol

6
8 6 mmol/d
Mg transported, µEq/h
7 5
6
3 4
5
4 3
3 13
3 2
22
2
3 1
1
12
0 0
0 3 6 9 12 15 18 21 24 0 10 20 30 40
A [Mg] in bicarbonate saline, mEq/L B Oral magnesium dose m, mmol
FIGURE 4-6
Intestinal magnesium (Mg) absorption. In rats, the intestinal Mg
10 absorption is related to the luminal Mg concentration in a curvilin-
ear fashion (A). This same phenomenon has been observed in
Net Mg absorption, mEq/10 hrs
humans (B and C). The hyperbolic curve (dotted line in B and C)

8
seen at low doses and concentrations may reflect a saturable tran-
scellular process; whereas the linear function (dashed line in B and
6 C) at higher Mg intake may be a concentration-dependent passive
intercellular Mg absorption. Alternatively, an intercellular process
4 that can vary its permeability to Mg, depending on the luminal Mg
concentration, could explain these findings (see Fig. 4-7) [13–15]. (A,
From Kayne and Lee [13]; B, from Roth and Wermer [14]; C, from
2
Fine and coworkers [15]; with permission.)
0
0 20 40 60 80
C Mg intake, mEq/meal
FIGURE 4-7
Mechanism of
intestinal magnesium absorption 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 transcel-
Nucleus lular 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
Lumen
Mg2+ 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 partici-
A pation of an energy-dependent mechanism for extrusion of Mg from intestinal cells. If such
Mg2+ a system exists, it is believed it would consist of two stages. 1) Mg would enter the apical
Mg2+
B 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 move-
Mg2+
K+ ment of Mg has been demonstrated to occur by both gradient-driven and solvent-drag
Na+ mechanisms. This intercellular path may be the only means by which Mg moves across the
ATPase 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 mem-
brane-associated proteins (eg, sodium-potassium adenosine triphosphate [Na-K ATPase])
near the tight junction and affect its permeability (see Fig. 4-6) [13–15].
Renal Handling of Magnesium

FIGURE 4-8
Afferent Efferent The glomerular filtration of magnesium (Mg). Total serum Mg
arteriole arteriole 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 ultrafil-
terable Mg is the total of the ionized and complexed fractions.
Normal total serum Mg is approximately 1.7 to 2.1 mg/dL (about
0.70–0.90 mmol/L) [1,2,7–9,11,12].
Glomerular
capillary
Bowman's
Mg2+-protein space
Mg2+ionized Mg2+complexed
Mg2+-ultrafilterable
% of total
Mg2+ serum Mg2+
Ionized Mg 60%
Protein-bound Mg 33% Proximal
Complexed Mg 7% tubule
*Normal total serum Mg =
1.7–2.1 mg/dL (0.70–0.9 mmol/L)
tion of Mg and about 20% of the filtered Mg has been reab-

Juxtamedullary Superficial cortical sorbed. Mg reabsorption occurs passively through paracellular
nephron nephron
pathways. Hydrated Mg has a very large radius that decreases its
5–10% intercellular permeability in the PCT when compared with sodi-
0–5%
um. The smaller hydrated radius of sodium is 50% to 60% reab-
Filtered Filtered sorbed in the PCT. No clear evidence exists of transcellular reab-
Mg2+ Mg2+
(100%) sorption or secretion of Mg within the mammalian PCT. In the
(100%)
20% pars recta of the proximal straight tubule (PST), Mg reabsorption
can continue to occur by way of passive forces in the concentrat-
65% ing kidney. In states of normal hydration, however, very little Mg
65% 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 deple-
20% tion. 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 jux-
Excreted tamedullary and superficial cortical nephrons. A small amount of
(5%) Mg is absorbed in the distal convoluted tubule. Mg transport in
the connecting tubule has not been well quantified. Little reab-
sorption occurs and no evidence exists of Mg secretion within the
FIGURE 4-9 collecting duct. Normally, 95% of the filtered Mg is reabsorbed
The renal handling of magnesium (Mg2+). Mg is filtered at the by the nephron. In states of Mg depletion the fractional excretion
glomerulus, with the ultrafilterable fraction of plasma Mg entering of Mg can decrease to less than 1%; whereas Mg excretion can
the proximal convoluted tubule (PCT). At the end of the PCT, the increase in states of above-normal Mg intake, provided no evi-
Mg concentration is approximately 1.7 times the initial concentra- dence of renal failure exists [1,2,6–9,11,12].
FIGURE 4-10
Mg absorption in cTAL
Magnesium (Mg) reabsorption in the cortical thick ascending limb (cTAL) of the loop of
–78mV Henle. Most Mg reabsorption within the nephron occurs in the cTAL owing primarily to
+8mV 0mV
voltage-dependent Mg flux through the intercellular tight junction. Transcellular Mg
movement occurs only in response to cellular metabolic needs. The sequence of events nec-
essary to generate the lumen-positive electrochemical gradient that drives Mg reabsorption
is as follows: 1) A basolateral sodium-potassium-adenosine triphosphatase (Na+-K+-
6 ATPase) decreases intracellular sodium, generating an inside-negative electrical potential
2Na+ difference; 2) Intracellular K is extruded by an electroneutral K-Cl (chloride) cotrans-
1Cl–
porter; 3) Cl is extruded by way of conductive pathways in the basolateral membrane; 4)
4 1 The apical-luminal Na-2Cl-K (furosemide-sensitive) cotransport mechanism is driven by
3Na+ 3Na+
6Cl– 2K+ the inside-negative potential difference and decrease in intracellular Na; 5) Potassium is
3K+ 2 2K+ recycled back into the lumen by way of an apical K conductive channel; 6) Passage of
2Cl– approximately 2 Na molecules for every Cl molecule is allowed by the paracellular path-
3
3K+ 4Cl– way (intercellular tight junction), which is cation permselective; 7) Mg reabsorption occurs
5
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
Mg
~1.0mmol
A
Mg Mg 0.5mmol
~1.0mmol
FIGURE 4-11
JMg, pmol.min–1.mm–1
Voltage-dependent net magnesium (Mg) flux in the cortical thick
ascending limb (cTAL). Within the isolated mouse cTAL, Mg flux
0.8
(JMg) occurs in response to voltage-dependent mechanisms. With
a relative lumen-positive transepithelial potential difference (Vt),
0.6
Mg reabsorption increases (positive JMg). Mg reabsorption equals
0.4 zero when no voltage-dependent difference exists, and Mg is
capable of moving into the tubular lumen (negative JMg) when a
(7)
0.2 lumen-negative voltage difference exists [1,16]. (From di Stefano
and coworkers [16]).
Vt, mV
–18 –15 –12 –9 –6 –3 3 6 9 12 15 18
–0.2 (15)
–0.4
(8) –0.6
–0.8
FIGURE 4-12
JMg2+ Effect of hormones on magnesium (Mg)
AVP GLU HCT PTH ISO INS transport in the cortical thick ascending
1.0 limb (cTAL). In the presence of arginine
Net fluxes, pmol • min–1• mm–1
* *
* vasopressin (AVP), glucagon (GLU), human
0.8 calcitonin (HCT), parathyroid hormone
* (PTH), 1,4,5-isoproteronol (ISO), and
0.6
* * insulin (INS), increases occur in Mg reab-
0.4 sorption from isolated segments of mouse
cTALs. These hormones have no effect on
0.2 medullary TAL segments. As already has
C C C C C C C C C C C C been shown in Figure 4-3, these hormones
0
affect intracellular “second messengers”
and cellular Mg movement. These hor-
mone-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].
Asterisk—significant change from preceding
period; JMg—Mg flux; C—control, absence
of hormone. (Adapted from de Rouffignac
and Quamme [1].)
Magnesium Depletion
FIGURE 4-13
CAUSES OF MAGNESIUM (Mg) DEPLETION 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 [1,2,8–13].
Poor Mg intake Other
Starvation Lactation
Anorexia Extensive burns
Protein calorie malnutrition Exchange transfusions
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
FIGURE 4-14
Renal magnesium (Mg) wasting
Renal magnesium (Mg) wasting. Mg is normally reabsorbed in the
Thiazides(?)
proximal tubule (PT), cortical thick ascending limb (cTAL), and dis-
Tubular defects tal convoluted tubule (DCT) (see Fig. 4-9). Volume expansion and
Volume Bartter's syndrome osmotic diuretics inhibit PT reabsorption of Mg. Several renal dis-
expansion Gitelman's syndrome eases and electrolyte disturbances (asterisks) inhibit Mg reabsorption
• Osmotic diuresis Renal tubular acidosis in both the PT and cTAL owing to damage to the epithelial cells and
Glucose Medullary calcinosis the intercellular tight junctions, plus disruption of the electrochemi-
Mannitol Drugs/toxins cal forces that normally favor Mg reabsorption. Many drugs and
Urea Cis-platinum
• Diuretic phase toxins directly damage the cTAL. Thiazides have little direct effect
Amphotericin B
acute renal failure* Cyclosporine
on Mg reabsorption; however, the secondary hyperaldosteronism
• Post obstructive diuresis* Pentamidine and hypercalcemia effect Mg reabsorption in CD and/or cTAL.
• Hypercalcemia* ? Aminoglycosides* Aminoglycosides accumulate in the PT, which affects sodium reab-
• Phosphate depletion* Foscarnet (?ATN) sorption, also leading to an increase in aldosterone. Aldosterone leads
• Chronic renal disease* Ticarcillin/carbenicillin
• ? Aminoglycosides* to volume expansion, decreasing Mg reabsorption. Parathyroid
? Digoxin
• Renal transplant* hormone has the direct effect of increasing Mg reabsorption in
• Interstitial nephritis* Electrolyte imbalances cTAL; however, hypercalcemia offsets this tendency. Thyroid hor-
Hypercalcemia*
Phosphate depletion*
mone increases Mg loss. Diabetes mellitus increases Mg loss by way
Metabolic acidosis of both hyperglycemic osmotic diuresis and insulin abnormalities
Starvation (deficiency and resistance), which decrease Mg reabsorption in the
Ketoacidosis proximal convoluted tubule and cTAL, respectively. Cisplatin causes a
Alcoholism Gitelman-like syndrome, which often can be permanent [1,2,8–12].
Hormonal changes
Hyperaldosteronism
Primary
hyperparathyroidism
Hyperthyroidism
Uncontrolled diabetes
mellitus
FIGURE 4-15
SIGNS AND SYMPTOMS OF HYPOMAGNESEMIA Signs and symptoms of hypomagnesemia. Symptoms of hypomag-
nesemia 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, neu-
Cardiovascular Muscular
romuscular symptoms predominate and are similar to those seen in
Electrocardiographic results Cramps
hypocalcemia and hypokalemia. Electrocardiographic changes of
Prolonged P-R and Q-T intervals, Weakness
hypomagnesemia include an increased P-R interval, increased Q-T
U waves Carpopedal spasm
duration, and development of U waves. Mg deficiency increases the
Angina pectoris Chvostek’s sign mortality of patients with acute myocardial infarction and conges-
?Congestive heart failure Trousseau’s sign tive heart failure. Mg depletion hastens atherogenesis by increasing
Atrial and ventricular arrhythmias Fasciculations total cholesterol and triglyceride levels and by decreasing high-den-
?Hypertension Tremulous sity lipoprotein cholesterol levels. Hypomagnesemia also increases
Digoxin toxicity Hyperactive reflexes hypertensive tendencies and impairs insulin release, which favor
Atherogenesis Myoclonus atherogenesis. Low levels of Mg impair parathyroid hormone
Neuromuscular Dysphagia (PTH) release, block PTH action on bone, and decrease the activity
Central nervous system Skeletal of renal 1--hydroxylase, which converts 25-hydroxy-vitamin D3
Seizures Osteoporosis into 1,25-dihydroxy-vitamin D3, all of which contribute to
Obtundation Osteomalacia hypocalcemia. Mg is an integral cofactor in cellular sodium-potas-
Depression sium-adenosine triphosphatase activity, and a deficiency of Mg
Psychosis impairs the intracellular transport of K and contributes to renal
Coma wasting of K, causing hypokalemia [6,8–12].
Ataxia
Nystagmus
Choreiform and athetoid movements
Magnesium deficiency Total serum Mg

(On normal diet of
250–350 mg/d of Mg)
Insulin Altered synthesis Enhanced AII
resistance of eicosanoids action Normal Low
(1.7–2.1 mg/dL) (<1.7 mg/dL)
(↓PGI2 , : ↑TXA2 , and 12-HETE)

24 hour urine Mg 24 hour urine Mg
↑Platelet
↑Aldosterone Normal Low Low High
aggregation
(> 24 mg/24 hrs) (< 24 mg/24 hrs) (< 24 mg/24 hrs) (> 24 mg/24 hrs)
Increased vasomotor tone ↑Na+ reabsorption No Mg Mg deficiency

deficiency present
Hypertension Check for

nonrenal causes
Tolerance Mg test Mg deficiency
(see Figure 4–18) present
FIGURE 4-16 Renal Mg wasting
Mechanism whereby magnesium (Mg) deficiency could lead Normal Mg
to hypertension. Mg deficiency does the following: increases Mg retention retention
angiotensin II (AII) action, decreases levels of vasodilatory
prostaglandins (PGs), increases levels of vasoconstrictive PGs
and growth factors, increases vascular smooth muscle cytosolic No Mg Mg deficiency
deficiency present
calcium, impairs insulin release, produces insulin resistance, and
Normal Check for
alters lipid profile. All of these results of Mg deficiency favor the nonrenal causes
development of hypertension and atherosclerosis [10,11].
Na+—ionized sodium; 12-HETE—hydroxy-eicosatetraenoic [acid];
TXA2—thromboxane A2. (From Nadler and coworkers [17].) 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
[2,6,8–15,18]. (Adapted from Al-Ghamdi and coworkers [11].)
FIGURE 4-18
MAGNESIUM (Mg) TOLERANCE TEST FOR PATIENTS The magnesium (Mg) tolerance test, in various forms [2,6,8–12,18],
WITH NORMAL SERUM MAGNESIUM 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
Time Action
effort to replenish Mg stores. (From Ryzen and coworkers [18].)
0 (baseline) Urine (spot or timed) for molar Mg:Cr ratio
0–4 h IV infusion of 2.4 mg (0.1 mmol) of Mg/kg lean body
wt in 50 mL of 50% dextrose
0–24 h Collect urine (staring with Mg infusion) for Mg and Cr
End Calculate % Mg retained (%M)
(24-h urine Mg) ([Preinfusion urine Mg:Cr] [24-h urine Cr])

%M=1 100
Total Mg infused
Mg retained, % Mg deficiency
>50 Definite
20–50 Probable
<20 None
Cr—creatinine; IV—intravenous; Mg—magnesium.

MAGNESIUM SALTS USED IN MAGNESIUM REPLACEMENT THERAPY
Magnesium salt Chemical formula Mg content, mg/g Examples* Mg content Diarrhea

Gluconate Cl2H22MgO14 58 Magonate® 27-mg tablet ±
54 mg/5 mL
Chloride MgCl2 . (H2O)6 120 Mag-L-100 100-mg capsule +
Lactate C6H10MgO6 120 MagTab SR* 84-mg caplet +
Citrate C12H10Mg3O14 53 Multiple 47–56 mg/5 mL ++
Hydroxide Mg(OH)2 410 Maalox®, Mylanta®, Gelusil® 83 mg/ 5 mL and 63-mg tablet ++
Riopan® 96 mg/5 mL
Oxide MgO 600 Mag-Ox 400® 241-mg tablet ++
Uro-Mag® 84.5-mg tablet
Beelith® 362-mg tablet
Sulfate MgSO4 . (H2O)7 100 IV 10%—9.9 mg/mL ++
IV 50%—49.3 mg/mL
Oral epsom salt 97 mg/g ++
Milk of Magnesia Phillips’ Milk of Magnesia® 168 mg/ 5 mL ++
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.
FIGURE 4-20
GUIDELINES FOR MAGNESIUM (Mg) REPLACEMENT Acute Mg replacement for life-threatening events such as seizures or
potentially lethal cardiac arrhythmias has been described [8–12,19].
Acute increases in the level of serum Mg can cause nausea, vomit-
Life-threatening event, eg, seizures and cardiac arrhythmia ing, cutaneous flushing, muscular weakness, and hyporeflexia. As
Mg levels increase above 6 mg/dL (2.5 mmol/L), electrocardio-
I. 2–4 g MgSO4 IV or IM stat II. IV drip over first 24 h graphic changes are followed, in sequence, by hyporeflexia, respira-
(2–4 vials [2 mL each] of 50% MgSO4) to provide no more tory paralysis, and cardiac arrest. Mg should be administered with
Provides 200–400 mg of Mg (8.3–16.7 mmol Mg) than 1200 mg (50
mmol) Mg/24 h
caution in patients with renal failure. In the event of an emergency
Closely monitor: the acute Mg load should be followed by an intravenous (IV) infu-
Deep tendon reflexes sion, providing no more than 1200 mg (50 mmol) of Mg on the
Heart rate first day. This treatment can be followed by another 2 to 5 days of
Blood pressure Mg repletion in the same dosage, which is used in less urgent situa-
Respiratory rate tions. Continuous IV infusion of Mg is preferred to both intramus-
Serum Mg (<2.5 mmol/L [6.0 mg/dL]) cular (which is painful) and oral (which causes diarrhea) adminis-
Serum K tration. A continuous infusion avoids the higher urinary fractional
excretion of Mg seen with intermittent administration of Mg.
Subacute and chronic Mg replacement Patients with mild Mg deficiency may be treated with oral Mg salts
I. 400–600 mg (16.7–25 mmol Mg daily for 2–5 d)
rather than parenteral Mg and may be equally efficacious [8].
Administration of Mg sulfate may cause kaliuresis owing to excre-
IV: continuous infusion
tion of the nonreabsorbable sulfate anion; Mg oxide administration
IM: painful
has been reported to cause significant acidosis and hyperkalemia
Oral: use divided doses to minimize diarrhea
[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.
References
1. de Rouffignac C, Quamme G: Renal magnesium handling and its 12. Nadler JL, Rude RK: Disorders of magnesium metabolism.
hormonal control. Physiol Rev 1994, 74:305–322. Endocrinol Metab Clin North Am 1995, 24:623–641.
2. Quamme GA: Magnesium homeostasis and renal magnesium han- 13. Kayne LH, Lee DBN: Intestinal magnesium absorption. Miner
dling. Miner Electrolyte Metab 1993, 19:218–225. Electrolyte Metab 1993, 19:210–217.
3. Romani A, Marfella C, Scarpa A: Cell magnesium transport and 14. Roth P, Werner E: Intestinal absorption of magnesium in man. Int J
homeostasis: role of intracellular compartments. Miner Electrolyte Appl Radiat Isotopes 1979, 30:523–526.
Metab 1993, 19:282–289.
15. Fine KD, Santa Ana CA, Porter JL, Fordtran JS: Intestinal absorption
4. Smith DL, Maguire ME: Molecular aspects of Mg2+ transport systems.
of magnesium from food and supplements. J Clin Invest 1991,
Miner Electrolyte Metab 1993, 19:266–276.
88:396–402.
5. Roof SK, Maguire ME: Magnesium transport systems: genetics and
protein structure (a review). J Am Coll Nutr 1994, 13:424–428. 16. di Stefano A, Roinel N, de Rouffignac C, Wittner M: Transepithelial
Ca+ and Mg+ transport in the cortical thick ascending limb of Henle’s
6. Sutton RAL, Domrongkitchaiporn S: Abnormal renal magnesium han-
loop of the mouse is a voltage-dependent process. Renal Physiol
dling. Miner Electrolyte Metab 1993, 19:232–240.
Biochem 1993, 16:157–166.
7. de Rouffignac C, Mandon B, Wittner M, di Stefano A: Hormonal con-
trol of magnesium handling. Miner Electrolyte Metab 1993, 19:226–231. 17. Nadler JL, Buchanan T, Natarajan R, et al.: Magnesium deficiency
produces insulin resistance and increased thromboxane synthesis.
8. Whang R, Hampton EM, Whang DD: Magnesium homeostasis and
Hypertension 1993, 21:1024–1029.
clinical disorders of magnesium deficiency. Ann Pharmacother 1994,
28:220–226. 18. Ryzen E, Elbaum N, Singer FR, Rude RK: Parenteral magnesium tol-
9. McLean RM: Magnesium and its therapeutic uses: a review. Am J Med erance testing in the evaluation of magnesium deficiency. Magnesium
1994, 96:63–76. 1985, 4:137–147.
10. Abbott LG, Rude RK: Clinical manifestations of magnesium deficien- 19. Oster JR, Epstein M: Management of magnesium depletion. Am J
cy. Miner Electrolyte Metab 1993, 19:314–322. Nephrol 1988, 8:349–354.
11. Al-Ghamdi SMG, Cameron EC, Sutton RAL: Magnesium deficiency: 20. Physicians’ Desk Reference (PDR). Montvale, NJ: Medical Economics
pathophysiologic and clinical overview. Am J Kid Dis 1994, 24:737–752. Company; 1996.
Divalent Cation
Metabolism: Calcium
James T. McCarthy
Rajiv Kumar
C
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 addi-
tion 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 D–parathyroid hormone (PTH) system [1–7].
CHAPTER
5
Calcium Distribution
FIGURE 5-1
TOTAL DISTRIBUTION OF CALCIUM IN THE BODY 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 Content* Ca is incorporated into the hydroxyapatite crystals of bone, and
about 1% of bone Ca is available as an exchangeable pool. Only
Location Concentration mmol mg 1% of the total body calcium exists outside of the skeleton.
Bone 99% ~31.4 103 ~1255 103
Extracellular fluid 2.4 mmol 35 ~1400
Intracellular fluid 0.1 mol <1 <40
Total ~31.5 103 ~1260 103
*data for a 70 kg person
Intracellular Calcium Metabolism

adaptable coordination sphere that facilitates its binding to
[Ca2+]o≈1-3mM
the irregular geometry of proteins, a binding that is readily
Ca2+o +8-0mV reversible. Low intracellular Ca concentrations can function as
-50mV either a first or second messenger. The extremely low concentra-
tions of intracellular Ca are necessary to avoid Ca-phosphate
Ca2+-binding proteins;
microprecipitation and make Ca an extremely sensitive cellular
VOC phosphate, citrate, etc. complexes
messenger. Less than 1% of the total intracellular Ca exists in
ROC the free ionized form, with a concentration of approximately
SOC Ca2+i
0.1 µmol/L. Technical methods available to investigate intracel-
lular free Ca concentration include Ca-selective microelectrodes,
[Ca2+]i<10-3mM Mitochondria
bioluminescent indicators, metallochromic dyes, Ca-sensitive
fluorescent indicators, electron-probe radiographic microanaly-
sis, and fluorine-19 nuclear magnetic resonance imaging.
Intracellular Ca is predominantly sequestered within the endo-
Nucleus plasmic 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,
Sarcoplasmic or and Ca can be complexed to phosphate, citrate, and other
~ anions. Intracellular Ca is closely regulated by balancing Ca
2+
endoplasmic
SRCa Ca s reticulum entry by way of voltage-operated channels (VOC), receptor-
ATPase operated channels (ROC), and store-operated channels (SOC),
InsP3 receptor with active Ca efflux by way of plasma membrane–associated
Ca2+ Ca-adenosine triphosphatase (ATPase) and a Na-Ca exchanger.
Intracellular Ca also is closely regulated by balancing Ca move-
Na+
Plasma ment into the SR (SR Ca-ATPase) and efflux from the SR by an
membrane ~ 3Na+: Ca2+exchanger inositol 1,4,5-trisphosphate (InsP3) receptor [1–7].
ATPase The highest concentration of intracellular Ca is found in the
brush border of epithelial cells, where there is also the highest
Ca2+ Ca2+
concentration of Ca-binding proteins such as actin-myosin and
calbindin. Intracellular Ca messages are closely modulated by
FIGURE 5-2 the phospholipase C-InsP3 pathway and also the phospholipase
General scheme of the distribution and movement of intracellu- A2–arachidonic acid pathway, along with intracellular Ca, which
lar calcium (Ca). In contrast to magnesium, Ca has a particularly itself modulates the InsP3 receptor.
Divalent Cation Metabolism: Calcium 5.3
Vitamin D and Parathyroid Hormone Actions

FIGURE 5-3
Metabolism of vitamin D. The compound 7-
dehydrocholesterol, through the effects of heat
7-dehydrocholesterol (37°C) and (UV) light (wavelength 280–305
nm), is converted into vitamin D3 in the skin.
HO Skin
Vitamin D3 is then transported on vitamin D
UV light binding proteins (VDBP) to the liver. In the
liver, vitamin D3 is converted to 25-hydroxy-
vitamin D3 by the hepatic microsomal and
mitochondrial cytochrome P450–containing
vitamin D3 25-hydroxylase enzyme. The 25-
Vitamin D3 hydroxy-vitamin D3 is transported on VDBP
to the proximal tubular cells of the kidney,
where it is converted to 1,25-dihydroxy-vita-
Liver 25-hydroxylase min D3 by a 1--hydroxylase enzyme, which
HO also is a cytochrome P450–containing enzyme.
The genetic information for this enzyme is
OH encoded on the 12q14 chromosome.
Alternatively, 25-hydroxy-vitamin D3 can be
+ – 25-hydroxy- + converted to 24R,25-dihydroxy-vitamin D3, a
PTH Hypercalcemia vitamin D3 1, 25(OH)2D3 relatively inactive vitamin D metabolite. 1,25-
PTHrP Hyperphosphatemia Hypercalcemia dihydroxy-vitamin D3 can then be transported
Hypophosphatemia 1, 25(OH)2D3 Hyperphosphatemia by VDBP to its most important target tissues
Hypocalcemia Acidosis
24R, 25(OH)2D3
HO in the distal tubular cells of the kidney, intesti-
Kidney, intestine,
IGF-1 other tissue nal epithelial cells, parathyroid cells, and bone
Kidney 1-alpha- 24-hydroxylase OH cells. VDBP is a 58 kD -globulin that is a
hydroxylase
member of the albumin and -fetoprotein gene
family. The DNA sequence that encodes for
OH OH this protein is on chromosome 4q11-13. 1,25-
dihydroxy-vitamin D3 is eventually metabo-
1, 25-hydroxy- 24, 25-hydroxy- lized to hydroxylated and conjugated polar
vitamin D3 vitamin D3 metabolites in the enterohepatic circulation.
Occasionally, 1,25-dihydroxy-vitamin D3 also
may be produced in extrarenal sites, such as
HO OH HO monocyte-derived cells, and may have an
Various tissue enzymes antiproliferative effect in certain lymphocytes
Hydroxylated and conjugated polar metabolites and keratinocytes [1,7–9]. (Adapted from
Kumar [1].)
FIGURE 5-4
Oral calcium intake Soft tissue and Calcium (Ca) flux between body compartments. Ca balance is a
~1000 mg/d intracellular complex process involving bone, intestinal absorption of dietary
calcium
Ca, and renal excretion of Ca. The parathyroid glands, by their
production of parathyroid hormone, and the liver, through its par-
Intestine
ticipation in vitamin D metabolism, also are integral organs in the
400 mg Extracellular 500 mg maintenance of Ca balance. (From Kumar [1]; with permission.)
fluid and
200 mg plasma 500 mg
10,000 mg 9800 mg
Feces Bone
800 mg
Kidney
Urine
200 mg
??? 1,25(OH)2D3 FIGURE 5-5

Effects of 1,25-dihydroxy-vitamin D3 (calcitriol) on bone. In
addition to the effects on parathyroid cells, the kidney, and intesti-
Osteoblast
T-lymphocyte Monoblast
nal epithelium, calcitriol has direct effects on bone metabolism.
precusor
Calcitriol can promote osteoclast differentiation and activity from
monocyte precursor cells. Calcitriol also promotes osteoblast dif-
ferentiation into mature cells. (From Holick [8]; with permission.)
Osteoblast Osteoclast
Cytokines
Osteocalcin
Osteopontin
Alkaline
Phosphatase
Bone
DNA binding Hinge region Calcitiriol binding 12q12-14 chromosome, near the gene
for the 1--hydroxylase enzyme. The
gly→asp
30 VDR is found in the intestinal epithelium,
his→gln parathyroid cells, kidney cells, osteoblasts,
32 arg→gln and thyroid cells. VDR also can be detect-
70 ed in keratinocytes, monocyte precursor
arg→gln
42 cys→trp tyr→stop cells, muscle cells, and numerous other
arg→gln 187 292 tissues. The allele variations for the vita-
77 min D receptor. Two allele variations
NH2 COOH exist for the vitamin D receptor (VDR):
18 424 the b allele and the B allele. In general,
42 44 149 271
lys→glu phe→ile gln→stop arg→leu normal persons with the b allele seem to
have a higher bone mineral density [9].
ZN Among patients on dialysis, those with
Mutant amino acid the b allele may have higher levels of
circulating parathyroid hormone (PTH)
FIGURE 5-6 [7,9,10,11]. COOH—carboxy terminal;
The vitamin D receptor (VDR). Within its target tissues, calcitriol binds to the VDR. NH2—amino terminal. (From Root [7];
The VDR is a 424 amino acid polypeptide. Its genomic information is encoded on the with permission.)
FIGURE 5-7
VDBP 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
VDR-D3 complex D–binding protein (VDBP). The free form of 1,25(OH)2D3 enters the tar-
get cell and interacts with the vitamin D receptor (VDR) at the nucleus.
This complex is phosphorylated and combined with the nuclear accessory
1,25 (OH)2D3 factor (RAF). This forms a heterodimer, which then interacts with the vit-
VDRE amin D responsive element (VDRE). The VDRE then either promotes or
VDR
RAF
inhibits the transcription of messenger RNA (mRNA) for proteins regu-
Pi lated by 1,25(OH)2D3, such as Ca-binding proteins, the 25-hydroxy-vita-
Regulation
min D3 24-hydroxylase enzyme, and parathyroid hormone. Pi—inorganic
mRNA
phosphate. (Adapted from Holick [8].)
transcription
Nucleus
CaBP
24-OHase
PTH
Osteocalcin
Osteopontin
Alkaline phosphatase
FIGURE 5-8
Parathyroid cell
Metabolism of parathyroid hormone (PTH).
The PTH gene is located on chromosome
Cell membrane 11p15. PTH messenger RNA (mRNA) is
Ca2+ Sensing transcribed from the DNA fragment and
receptor then translated into a 115 amino acid–
DNA containing molecule of prepro-PTH. In the
Ca2+
G-protein VDRE rough endoplasmic reticulum, this under-
VDR
goes hydrolysis to a 90 amino acid–contain-
ing molecule, pro-PTH, which undergoes
Nucleus further hydrolysis to the 84 amino
OH acid–containing PTH molecule. PTH is then
PTH mRNA stored within secretory granules in the cyto-
plasm for release. PTH is metabolized by
hepatic Kupffer cells and renal tubular cells.
Transcription of the PTH gene is inhibited
PTH mRNA by 1,25-dihydroxy-vitamin D3, calcitonin,
HO OH
Degradation and hypercalcemia. PTH gene transcription
1,25 (OH)2D3 is increased by hypocalcemia, glucocorti-
or Calcitriol PTH PTH proPTH preproPTH
coids, and estrogen. Hypercalcemia also can
Secretory
Rough endoplasmic
increase the intracellular degradation of
granules PTH. PTH release is increased by hypocal-
reticulum
Golgi apparatus
cemia, -adrenergic agonists, dopamine,
and prostaglandin E2. Hypomagnesemia
blocks the secretion of PTH [7,12]. VDR—
vitamin D receptor; VDRE—vitamin D
responsive element. (Adapted from Tanaka
FIGURE 5-9
1 34 84
PTH (mw 9600) N C Parathyroid-hormone–related protein
(PTHrP). PTHrP was initially described as
1 141
PTH-like peptide N C the causative circulating factor in the
(mw 16,000) humoral hypercalcemia of malignancy, par-
ticularly in breast cancer, squamous cell
cancers of the lung, renal cell cancer, and
-2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 other tumors. It is now clear that PTHrP
can be expressed not only in cancer but
PTH LYS ARG SER VAL SER GLU ILE GLN LEU MET HIS ASN LEU GLY LYS
also in many normal tissues. It may play an
PTH-like peptide LYS ARG ALA VAL SER GLU HIS GLN LEU LEU HIS ASP LYS GLY LYS important role in the regulation of smooth
muscle tone, transepithelial Ca transport
(eg, in the mammary gland), and the differ-
entiation of tissue and organ development
[7,13]. Note the high degree of homology
between PTHrP and PTH at the amino end
of the polypeptides. MW—molecular
weight; N—amino terminal; C—carboxy
terminal. (From Root [7]; with permission.)
SP
50
NH2
100
*
X X X
200
HS
X
250
300
X Inactivating
Arg186Gln
400
350
Asp216Glu
Tyr219Glu
450
Glu298Lys
Ser608Stop
Ser658Tyr
550
500
Gly670Arg
Pro749Arg
Arg796Trp
Val818Ile
600
S Stop
* Activating
Glu128Ala
S
X
614 671 684 746 771 829 829
Cell
membrane
636 651 701 726 793 808 863
P
P X
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 increases CaSR-Ca binding, which activates the G-protein. The G-
triphosphate (GTP) or G-protein–coupled polypeptide receptor. protein then activates the phospholipase C--1–phosphatidylinosi-
The human CaSR has approximately 1084 amino acid residues. tol-4,5-biphosphate pathway to increase intracellular Ca, which
The CaSR mediates the effects of Ca on parathyroid and renal tis- then decreases translation of parathyroid hormone (PTH), decreas-
sues. CaSR also can be found in thyroidal C cells, brain cells, and es PTH secretion, and increases PTH degradation. The CaSR also
in the gastrointestinal tract. The CaSR allows Ca to act as a first is an integral part of Ca homeostasis within the kidney. The gene
messenger on target tissues and then act by way of other second- for CaSR is located on human chromosome 3q13 [3,4,7,14–16].
messenger systems (eg, phospholipase enzymes and cyclic adeno- PKC—protein kinase C; HS—hydrophobic segment; NH2—amino
sine monophosphate). Within parathyroid cells, hypercalcemia terminal. (From Hebert and Brown [4]; with permission.)
Gastrointestinal Absorption of Calcium

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 (20–30 mmol/d). Foods high in Ca content include milk,
Gastrointestinal
absorption of
dairy products, meat, fish with bones, oysters, and many leafy
dietary calcium (Ca) green vegetables (eg, spinach and collard greens). Although serum
Ca levels can be maintained in the normal range by bone resorp-
Net Ca absorption % of intake tion, dietary intake is the only source by which the body can
Site mmol/d mg/d absorbed replenish stores of Ca in bone. Ca is absorbed almost exclusively
within the duodenum, jejunum, and ileum. Each of these intesti-
Stomach 0 0 0
nal segments has a high absorptive capacity for Ca, with their
Duodenum 0.75 30 3 relative Ca absorption being dependent on the length of each
Jejunum 1.0 40 4 respective intestinal segment and the transit time of the food
Ileum 3.25 130 13 bolus. Approximately 400 mg of the usual 1000 mg dietary Ca
intake is absorbed by the intestine, and Ca loss by way of intesti-
Colon 0 0 0
nal secretions is approximately 200 mg/d. Therefore, a net
absorption of Ca is approximately 200 mg/d (20%). Biliary and
Total* 5 200 20 pancreatic secretions are extremely rich in Ca. 1,25-dihydroxy-
*Normal dietary Ca intake =1000 mg (25 mmol) per day vitamin D3 is an extremely important regulatory hormone for
intestinal absorption of Ca [1,2,17,18].
FIGURE 5-12
Lumen
Proposed pathways for calcium (Ca) absorption across the intestinal
Ca2+ Ca2+ Ca2+ Ca2+ epithelium. Two routes exist for the absorption of Ca across the
1 2 3 4 intestinal epithelium: the paracellular pathway and the transcellular
Microvilli 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 absorp-
Actin tive route may be indirectly influenced by 1,25-dihydroxy-vitamin D3
Myosin-I (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,
Calmodulin
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
Ca2+ channel or Ca transporter into the apical section of the microvillae.
Ca2+ Calbindin-Ca2+
complex Because the intestinal concentration of Ca usually is 10-3 mol and the
Free intracellular Ca concentration is 10-6 mol, a large concentration gra-
Ca2+ Calbindin- dient favors the passive movement of Ca. Ca is rapidly and reversibly
Micro- diffusion synthesis
vesicular bound to the calmodulin-actin-myosin I complex. Ca may then move
transport to the basolateral area of the cell by way of microvesicular transport,
Calcitriol or ionized Ca may diffuse to this area of the cell. (2) As the calmod-
ulin complex becomes saturated with Ca, the concentration gradient
Ca2+ Nucleus for the movement of Ca into the microvillae is not as favorable,
which slows Ca absorption. (3) Under the influence of calcitriol,
Exocytosis Ca2+
Na 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
Na/Ca Ca2+-ATPase Ca concentration again favors the movement of Ca into the microvil-
exchange
Ca2+ Ca2+ lae. As the calbindin-Ca complex dissociates, the free intracellular Ca
Lamina propria is actively extruded from the cell by either the Ca-adenosine triphos-
phatase (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].
Renal Handling of Calcium

FIGURE 5-13
Afferent Efferent Glomerular filtration of calcium (Ca). Total serum Ca consists of
arteriole arteriole 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 2.2–2.5 mmol/L).
Ca can be bound to albumin and globulins. For each 1.0 gm/dL
Glomerular decrease in serum albumin, total serum Ca decreases by 0.8 mg/dL;
capillary for each 1.0 gm/dL decrease in serum globulin fraction, total serum
Bowman's Ca decreases by 0.12 mg/dL. Ionized Ca is also affected by pH. For
Ca2+-Protein space every 0.1 change in pH, ionized Ca changes by 0.12 mg/dL.
Ca2+ Ca2+ Alkalosis decreases the ionized Ca [1,6,7].
ionized complexed
Ca2+-ultrafilterable
Proximal
tubule
FIGURE 5-14
Parathyroid hormone Ca2+ ATPase, VDR,
CaBP-D, Na+/Ca2+ exchanger
Renal handling of calcium (Ca). Ca is filtered at the glomerulus,
and 1,25(OH)2D3
colocalized here with the ultrafilterable fraction (UFCa) of plasma Ca entering the
Calcitonin
proximal tubule (PT). Within the proximal convoluted tubule
Thiazides
(PCT) and the proximal straight tubule (PST), isosmotic reabsorp-
CNT tion 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
DCT reabsorbed. Passive paracellular pathways account for about 80%
of Ca reabsorption in this segment of the nephron, with the
PCT remaining 20% dependent on active transcellular Ca movement.
Cortex CTAL 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
Medulla MAL and calcitonin (CT) stimulates Ca reabsorption here. However, the
cortical segments (cTAL) reabsorb about 20% of the initially fil-
tered load of Ca. Under normal conditions, most of the Ca reab-
Papilla sorption in the cTAL is passive and paracellular, owing to the
favorable electrochemical gradient. Active transcellular Ca trans-
port 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 trans-
port occurs. The DCT is the primary site in the nephron at which
Ca reabsorption is regulated by PTH and 1,25(OH)2D3. Active
100 PT DT Urine transcellular Ca transport must account for Ca reabsorption in the
100 DCT, because the transepithelial voltage becomes negative, which
Ca remaining in tubular fluid, %
would not favor passive movement of Ca out of the tubular lumen.

80 About 10% of the filtered Ca is reabsorbed in the DCT, with
another 3% to 10% of filtered Ca reabsorbed in the connecting
60 tubule (CNT) by way of mechanisms similar to those in the DCT
40
[1,2,6, 7,18]. ATPase—adenosine triphosphatase; CaBP-D—Ca-
(40) binding protein D; DT—distal tubule; VDR—vitamin D receptor.
20 (Adapted from Kumar [1].)
(20) (2)
(10)
0
FIGURE 5-15
Cortical thick ascending limb
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
5
Ca2+, Mg2+ receptor (CaSR) of cells in the cTAL. (2) Activation of the G-pro-
–
tein increases intracellular free ionized Ca (Ca2+) by way of the
Na +
inositol 1,4,5-trisphosphate (IP3) pathway, which increases the
2Cl– G-protein Ca2+ activity of the P450 enzyme system. The G-protein also increases
+ ↑Ca2+ IP3 activity of phospholipase A2 (PLAA), which increases the concen-
K 2 1
– PK-C tration of arachidonic acid (AA). (3) The P450 enzyme system
PLA2
Urinary 3 CaSR increases production of 20-hydroxy-eicosatetraenoic acid (20-
AA
space P-450 HETE) from AA. (4) 20-HETE inhibits hormone-stimulated pro-
system duction of cyclic adenosine monophosphate (cAMP), blocks sodi-
4
– 20-HETE um reabsorption by the sodium-potassium-chloride (Na-K-2Cl)
– ATP Hormone
recptor cotransporter, and inhibits movement of K out of K-channels. (5)
K+ cAMP These changes alter the electrochemical forces that would normally
5 favor the paracellular movement of Ca (and Mg) such that Ca (and
Ca2+, Mg2+ – Mg) is not passively reabsorbed. Both the lack of movement of Na
+ Hormone into the renal interstitium and inhibition of hormonal (eg, vaso-
pressin) effects impair the ability of the nephron to generate maxi-
mally concentrated urine [3,4,14]. ATP—adenosine triphosphate;
PK-C—protein kinase C.
FIGURE 5-16
DHP sensitive Thiazide sensitive
channel channel Ca2+ Postulated mechanism of the Ca transport pathway shared by PTH
Ca2+ and 1,25(OH)2D3. Cyclic adenosine monophosphate (cAMP) gener-
Tubular lumen
ated by PTH stimulation leads to increased influx of Ca into the
apical dihydropyridine-sensitive Ca channel. There also is increased
+ Distal activity of the basolateral Na-Ca exchanger and, perhaps, of the
Ca2+ Ca2+
convoluted plasma membrane–associated Ca-adenosine triphosphatase
tubule cell (PMCA), which can rapidly extrude the increased intracellular free
Ca (Ca2+). Calcitriol (1,25(OH)2D3), by way of the vitamin D
CaBP28 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
CaBP9 channels by decreasing the concentration of unbound free Ca2+ and
Ca2+ Nucleus facilitates Ca movement to the basolateral membrane. CaBP9 stimu-
cAMP VDR
+ ?+
+ lates PMCA activity, which increases extrusion of Ca by the cell.
ATP Similar hormonally induced mechanisms of Ca transport are
Na+
PTH believed to exist throughout the cortical thick ascending limb, the
~ PMCA DCT, and the connecting tubule (CNT) [6]. ATP—adenosine
Calcitriol
triphosphate; Na+—ionized sodium.
Ca2+ Ca2+
Disturbances of Serum Calcium

FIGURE 5-17
Hypocalcemia Physiologic response to hypocalcemia.
Parathyroid glands 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,
Kidney which increases the synthesis of 1,25-dihy-
droxy-vitamin D3 (1,25(OH)2D3). PTH
+ +
increases bone resorption by osteoclasts.
PTH and 1,25(OH)2D3 stimulate Ca reab-
PTH↑ PTH
Gastrointestinal sorption in the distal convoluted tubule
tract + Parathyroid cell (DCT). 1,25(OH)2D3 increases the fractional
DCT Nucleus
PT
absorption of dietary Ca by the gastrointesti-
nal (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 Causes of hypocalcemia (decrease in ionized plasma calcium).
Lack of parathyroid hormone (PTH) Increased calcium complexation

After thyroidectomy or parathyroidectomy “Bone hunger” after parathyroidectomy
Hereditary (congenital) hypoparathyroidism Rhabdomyolysis
Pseudohypoparathyroidism (lack of Acute pancreatitis
effective PTH) Tumor lysis syndrome
Hypomagnesemia (blocks PTH secretion) (hyperphosphatemia)
Malignancy (increased
Lack of Vitamin D
osteoblastic activity)
Dietary deficiency or
malabsorption (osteomalacia)
Inadequate sunlight
Defective metabolism
Anticonvulsant therapy
Liver disease
Renal disease
Vitamin D–resistant rickets
FIGURE 5-19
Hypercalcemia Thyroid and Physiologic response to hypercalcemia.
parathyroid glands Hypercalcemia directly inhibits both
+ parathyroid hormone (PTH) release
and synthesis. The decrease in PTH and
hypercalcemia decrease the activity of the
C-cells 1--hydroxylase enzyme located in the
– ↑CT
Kidney 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
PTH↑ PTH
Gastrointestinal thyroid gland to increase synthesis of calci-
tract – – tonin (CT). Bone resorption by osteoclasts
Parathyroid cell
PT
DCT Nucleus 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
– Bone decrease in 1,25(OH)2D3 decreases gas-
–
trointestinal (GI) tract absorption of dietary
1,25(OH)2D3↓ Ca. All of these effects tend to return serum
Ca to normal levels [1].
↓Intestinal Ca2+ absorption ↑Renal Ca2+ excretion ↓Bone resorption
Normocalcemia
FIGURE 5-20
CAUSES OF HYPERCALCEMIA Causes of hypercalcemia (increase in
ionized plasma calcium).
Excess parathyroid hormone (PTH) production Increased intestinal absorption of calcium

Primary hyperparathyroidism Vitamin D intoxication
“Tertiary” hyperparathyroidism* Milk-alkali syndrome*
Excess 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) Decreased renal excretion of calcium
Vitamin D intoxication Familial hypocalciuric hypercalcemia
Sarcoidosis and granulomatous diseases Thiazides
Severe hypophosphatemia
Impaired bone formation and incorporation of
Neoplastic production of 1,25(OH)2D3 (lymphoma)
calcium
Increased bone resorption Aluminum intoxication*
Metastatic (osteolytic) tumors (eg, breast, colon, prostate) Adynamic (“low-turnover”) bone disease*
Humoral hypercalcemia Corticosteroids
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.

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

Saline and loop diuretics Increase renal excretion of calcium
Corticosteroids Block 1,25-dihydroxy-vitamin D3
synthesis and bone resorption
Ketoconazole Blocks P450 system, decreases
1, 25-dihydroxy-vitamin D3
Oral or intravenous phosphate Complexes calcium
Calcitonin Inhibits bone resorption
Mithramycin Inhibits bone resorption
Bisphosphonates Inhibit bone resorption
*Always identify and treat the primary cause of hypercalcemia.
Secondary Hyperparathyroidism
FIGURE 5-22
Renal failure 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
↓Number of nephrons 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--hydroxy-
PT –
lase enzyme in the remaining PT cells, further contributing to the
decrease in levels of 1,25(OH)2D3. 1,25(OH)2D3 deficiency decreas-
es intestinal absorption of calcium (Ca), leading to hypocalcemia,
which is augmented by the direct effect of hyperphosphatemia.
Hypocalcemia and hyperphosphatemia stimulate PTH release and
↓H+ excretion synthesis and can recruit inactive parathyroid cells into activity and
↓P excretion PTH production. Hypocalcemia also may decrease intracellular
degradation of PTH. The lack of 1,25(OH)2D3, which would ordi-
1,25(OH)2D3↓ Hyperphosphatemia narily feed back to inhibit the transcription of prepro-PTH and
exert an antiproliferative effect on parathyroid cells, allows the
↓Ca
absorption Gastrointestinal increased PTH production to continue. In CRF there may be
tract decreased expression of the Ca-sensing receptor (CaSR) in parathy-
roid 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 VDR-
1,25(OH)2D3 complex is less effective at suppressing PTH produc-
tion and cell proliferation. The deficiency of 1,25(OH)2D3 may also
decrease VDR synthesis, making parathyroid cells less sensitive to
Hypocalcemia
↓Activity
1,25(OH)2D3. Although the PTH receptor in bone cells is downreg-
↓Activity ulated 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, cardiovascu-
VDR CaSR lar system, nervous system, and integument) by way of alterations
of intracellular Ca. Current therapeutic methods used to decrease
Increased PTH release in CRF include correction of hyperphosphatemia,
transcription
↓Degradation maintenance of normal to high-normal levels of plasma Ca, admin-
of PTH istration of 1,25(OH)2D3 orally or intravenously, and administra-
Release PTH tion of a Ca-ion sensing receptor (CaSR) agonist [14–16,19–22].
↑PTH
↑Proliferation
ProPTH
Pre-proPTH Nucleus
Hyperparathyroidism
Parathyroid cell
Calcium and Vitamin D Preparations

FIGURE 5-23
CALCIUM CONTENT OF ORAL Calcium (Ca) content of oral Ca preparations.
CALCIUM PREPARATIONS
Calcium (Ca) salt Tablet size, mg Elemental Ca, mg, %

Carbonate 1250 500 (40)
Acetate 667 169 (25)
Citrate 950 200 (21)
Lactate 325 42 (13)
Gluconate 500 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 Calcifediol Calcitriol

(Vitamin D2) (25-hydroxy-vitamin D3) Dihydrotachysterol (1,25-dihydroxy-vitamin D3)
Commercial name Calciferol Calderol® (Organon, Inc, DHT Intensol® (Roxane Rocaltrol® (Roche Laboratories,
West Orange, NJ) Laboratories, Columbus, OH) Nutley, NJ)
Calcijex® (Abbott Laboratories,
Abbott Park, NJ)
Oral preparations 50,000 IU tablets 20- and 50-µg capsules 0.125-, 0.2-, 0.4-mg tablets 0.25- and 0.50-µg capsules
Usual daily dose

Hypoparathyroidism 50,000–500,000 IU 20–200 µg 0.2–1.0 mg 0.25–5.0 µg
Renal failure Not used 20–40 µg* 0.2-0.4 mg* 0.25–0.50 µg
Time until increase in 4–8 wk 2–4 wk 1–2 wk 4–7 d
serum calcium†
Time for reversal of 17–60 d 7–30 d 3–14 d 2–10 d
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.
References
1. Kumar R: Calcium metabolism. In The Principles and Practice of 13. Philbrick WM, Wysolmerski JJ, Galbraith S, et al.: Defining the roles
Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: of parathyroid hormone-related protein in normal physiology. Physiol
Mosby-Year Book; 1995, 964–971. Rev 1996, 76:127–173.
2. Johnson JA, Kumar R: Renal and intestinal calcium transport: roles of 14. Goodman WG, Belin TR, Salusky IB: In vivo> assessments of
vitamin D and vitamin D-dependent calcium binding proteins. Semin calcium-regulated parathyroid hormone release in secondary
Nephrol 1994, 14:119–128. hyperparathyroidism [editorial review]. Kidney Int 1996,
3. Hebert SC, Brown EM, Harris HW: Role of the Ca2+-sensing receptor 50:1834–1844.
in divalent mineral ion homeostasis. J Exp Biol 1997, 200:295–302.
15. Chattopadhyay N, Mithal A, Brown EM: The calcium-sensing
4. Hebert SC, Brown EM: The scent of an ion: calcium-sensing and its roles receptor: a window into the physiology and pathophysiology of
in health and disease. Curr Opinion Nephrol Hypertens 1996, 5:45–53.
mineral ion metabolism. Endocrine Rev 1996, 17:289–307.
5. Berridge MJ: Elementary and global aspects of calcium signalling.
16. Nemeth EF, Steffey ME, Fox J: The parathyroid calcium receptor:
J Exp Biol 1997, 200:315–319.
a novel therapeutic target for treating hyperparathyroidism. Pediatr
6. Friedman PA, Gesek FA: Cellular calcium transport in renal epithelia: Nephrol 1996, 10:275–279.
measurement, mechanisms, and regulation. Physiol Rev 1995,
75:429–471. 17. Wasserman RH, Fullmer CS: Vitamin D and intestinal calcium transport:
7. Root AW: Recent advances in the genetics of disorders of calcium facts, speculations and hypotheses. J Nutr 1995, 125:1971S–1979S.
homeostasis. Adv Pediatr 1996, 43:77–125. 18. Johnson JA, Kumar R: Vitamin D and renal calcium transport. Curr
8. Holick MF: Defects in the synthesis and metabolism of vitamin D. Opinion Nephrol Hypertens 1994, 3:424–429.
Exp Clin Endocrinol 1995, 103:219–227. 19. McCarthy JT, Kumar R: Renal osteodystrophy. In The Principles and
9. Kumar R: Calcium transport in epithelial cells of the intestine and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S.
kidney. J Cell Biochem 1995, 57:392–398. St. Louis: Mosby-Year Book; 1995, 1032–1045.
10. White CP, Morrison NA, Gardiner EM, Eisman JA: Vitamin D recep- 20. Felsenfeld AJ: Considerations for the treatment of secondary hyper-
tor alleles and bone physiology. J Cell Biochem 1994, 56:307–314. parathyroidism in renal failure. J Am Soc Nephrol 1997, 8:993–1004.
11. Fernandez E, Fibla J, Betriu A, et al.: Association between vitamin D 21. Parfitt AM. The hyperparathyroidism of chronic renal failure: a
receptor gene polymorphism and relative hypoparathyroidism in disorder of growth. Kidney Int 1997, 52:3–9.
patients with chronic renal failure. J Am Soc Nephrol 1997,
8:1546–1552. 22. Salusky IB, Goodman WG: Parathyroid gland function in secondary
hyperparathyroidism. Pediatr Nephrol 1996, 10:359–363.
12. Tanaka Y, Funahashi J, Imai T, et al.: Parathyroid function and bone
metabolic markers in primary and secondary hyperparathyroidism. 23. Physicians’ Desk Reference (PDR). Montvale NJ: Medical Economics
Sem Surg Oncol 1997, 13:125–133. Company; 1996.
Disorders of
Acid-Base Balance
Horacio J. Adrogué
Nicolaos E. Madias
M
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 man-
agement 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 iso-
hydric principle in the living organism, which specifies that all the
other buffer systems are in equilibrium with the carbonic acid-bicar-
bonate buffer pair. Thus, as indicated by the Henderson equation,
-
[H+] = 24 PaCO2/[HCO3] (the equilibrium relationship of the car-
bonic 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 deter-
minants, PaCO2 and the plasma bicarbonate concentration. Those
acid-base disorders initiated by a change in PaCO2 are referred to as CHAPTER
respiratory disorders; those initiated by a change in plasma bicarbon-
ate concentration are known as metabolic disorders. There are four
6
cardinal acid-base disturbances: respiratory acidosis, respiratory alka-
losis, metabolic acidosis, and metabolic alkalosis. Each can be
encountered alone, as a simple disorder, or can be a part of a mixed-
disorder, defined as the simultaneous presence of two or more simple
acid-base disturbances. Mixed acid-base disorders are frequent- illustrated: the underlying pathophysiology, secondary
ly observed in hospitalized patients, especially in the critically ill. adjustments in acid-base equilibrium in response to the initi-
The clinical aspects of the four cardinal acid-base ating disturbance, clinical manifestations, causes, and thera-
disorders are depicted. For each disorder the following are peutic principles.
Respiratory Acidosis
FIGURE 6-1
Arterial blood [H+], nEq/L Quantitative aspects of adaptation to respiratory acidosis.
150 125 100 80 70 60 50 40 30 20 Respiratory acidosis, or primary hypercapnia, is the acid-base dis-
turbance initiated by an increase in arterial carbon dioxide tension
PaCO2 120 100 90 80 70 60 50
mm Hg (PaCO2) and entails acidification of body fluids. Hypercapnia elic-
40 its adaptive increments in plasma bicarbonate concentration that
50 should be viewed as an integral part of respiratory acidosis. An
immediate increment in plasma bicarbonate occurs in response to
Chron acidosis
Arterial plasma [HCO–3], mEq/L
hypercapnia. This acute adaptation is complete within 5 to 10 min-

40
ic resp
30 utes from the onset of hypercapnia and originates exclusively from

acidic titration of the nonbicarbonate buffers of the body (hemo-
iratory
globin, intracellular proteins and phosphates, and to a lesser extent

30 Acute respira plasma proteins). When hypercapnia is sustained, renal adjust-
tory 20
acidosis ments markedly amplify the secondary increase in plasma bicar-
Normal
bonate, further ameliorating the resulting acidemia. This chronic
20
adaptation requires 3 to 5 days for completion and reflects genera-
10 tion of new bicarbonate by the kidneys as a result of upregulation
of renal acidification [2]. Average increases in plasma bicarbonate
10
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
6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7
have been used for construction of 95% confidence intervals for
graded degrees of acute or chronic respiratory acidosis represented
Arterial blood pH
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
Steady-state relationships in respiratory acidosis: acid-base parameters [3]. Note that for the same level of PaCO2,
average increase per mm Hg rise in PaCO2
the degree of acidemia is considerably lower in chronic respiratory
[HCO–3] mEq/L [H+] nEq/L acidosis than it is in acute respiratory acidosis. Assuming a steady
Acute adaptation 0.1 0.75 state is present, values falling within the areas in color are consis-
Chronic adaptation 0.3 0.3 tent with but not diagnostic of the corresponding simple disorders.
Acid-base values falling outside the areas in color denote the pres-
ence of a mixed acid-base disturbance [4].
Disorders of Acid-Base Balance 6.3
acid production, leading to generation of new bicarbonate ions

Eucapnia -
Stable Hypercapnia (HCO3) for the body fluids. Conservation of these new bicarbonate
Net acid excretion
ions is ensured by the gradual augmentation in the rate of renal bicar-

bonate 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 bicar-
bonate 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
Chloride excretion
net acid excretion is accompanied by a transient increase in chloride

excretion. Thus, the resultant ammonium chloride (NH4Cl) loss gen-
erates 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
Bicarbonate reabsorption
hypercapnia are under active investigation. Available evidence sup-

ports 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+-
0 1 2 3 4 5 ATPase–containing subapical vesicles to the luminal membrane of
Days
proximal tubule cells as well as type A intercalated cells of the cortical
and medullary collecting ducts. New H+-ATPase pumps thereby are
FIGURE 6-2 recruited to the luminal membrane for augmented acidification [6,7].
Renal acidification response to chronic hypercapnia. Sustained hyper- Furthermore, chronic hypercapnia increases the steady-state abun-
-
capnia entails a persistent increase in the secretory rate of the renal dance of mRNA coding for the basolateral Cl—HCO3 exchanger
tubule for hydrogen ions (H+) and a persistent decrease in the reab- (band 3 protein) of type A intercalated cells in rat renal cortex and
sorption rate of chloride ions (Cl-). Consequently, net acid excretion medulla, likely indicating increased band 3 protein levels and there-
(largely in the form of ammonium) transiently exceeds endogenous fore augmented basolateral anion exchanger activity [8].
its development include the magnitude and

SIGNS AND SYMPTOMS OF RESPIRATORY ACIDOSIS time course of the hypercapnia, severity of
the acidemia, and degree of attendant
hypoxemia. Progressive narcosis and coma
may occur in patients receiving uncon-
Central Nervous System Respiratory System Cardiovascular System trolled oxygen therapy in whom levels of
Mild to moderate hypercapnia Breathlessness Mild to moderate hypercapnia arterial carbon dioxide tension (PaCO2)
Cerebral vasodilation Central and peripheral cyanosis Warm and flushed skin may reach or exceed 100 mm Hg. The
Increased intracranial pressure (especially when breathing Bounding pulse hemodynamic consequences of carbon
Headache room air) Well maintained cardiac dioxide retention reflect several mecha-
Confusion Pulmonary hypertension output and blood pressure nisms, including direct impairment of
Combativeness Diaphoresis
myocardial contractility, systemic vasodila-
Hallucinations Severe hypercapnia
Cor pulmonale
tion caused by direct relaxation of vascular
Transient psychosis
Myoclonic jerks Decreased cardiac output smooth muscle, sympathetic stimulation,
Flapping tremor Systemic hypotension and acidosis-induced blunting of receptor
Severe hypercapnia Cardiac arrhythmias responsiveness to catecholamines. The net
Manifestations of pseudotumor cerebri Prerenal azotemia effect is dilation of systemic vessels, includ-
Stupor Peripheral edema ing the cerebral circulation; whereas vaso-
Coma constriction might develop in the pul-
Constricted pupils monary and renal circulations. Salt and
Depressed tendon reflexes water retention commonly occur in chronic
Extensor plantar response hypercapnia, especially in the presence of
Seizures
cor pulmonale. Mechanisms at play include
Papilledema
hypercapnia-induced stimulation of the
renin-angiotensin-aldosterone axis and the
sympathetic nervous system, elevated levels
of cortisol and antidiuretic hormone, and
FIGURE 6-3 increased renal vascular resistance. Of
Signs and symptoms of respiratory acidosis. The effects of respiratory acidosis on the central course, coexisting heart failure amplifies
nervous system are collectively known as hypercapnic encephalopathy. Factors responsible for most of these mechanisms [1,2].
Pump Load
Cerebrum Ventilatory requirement

Voluntary control (CO2 production, O2 consumption)
Controller Brain stem

Automatic control
Spinal cord
Airway resistance
Phrenic and
intercostal nerves
Effectors Lung elastic recoil
Muscles
of respiration ∆V
∆V
Ppl Chest wall elastic recoil
Pabd 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 res-
piratory 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 con-
traction 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 suffi-
cient to counterbalance the opposing effect of the combined loads, including the airway flow resis-
tance, 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).
DETERMINANTS AND CAUSES OF CARBON DIOXIDE RETENTION
Respiratory Pump Load

Depressed Central Drive Abnormal Neuromuscular Transmission Increased Ventilatory Demand Lung Stiffness
Acute Acute High carbohydrate diet Acute
General anesthesia High spinal cord injury Sorbent-regenerative hemodialysis Severe bilateral pneumonia
Sedative overdose Guillain-Barré syndrome Pulmonary thromboembolism or bronchopneumonia
Head trauma Status epilepticus Fat, air pulmonary embolism Acute respiratory
Cerebrovascular accident Botulism Sepsis distress syndrome
Central sleep apnea Tetanus Hypovolemia Severe pulmonary edema
Cerebral edema Crisis in myasthenia gravis Atelectasis
Augmented Airway Flow Resistance
Brain tumor Hypokalemic myopathy Chronic
Acute
Encephalitis Familial periodic paralysis Severe chronic pneumonitis
Upper airway obstruction
Brainstem lesion Drugs or toxic agents eg, curare, Diffuse infiltrative disease eg,
Coma-induced hypopharyngeal obstruction alveolar proteinosis
Chronic succinylcholine, aminoglycosides,
Aspiration of foreign body or vomitus Interstitial fibrosis
Sedative overdose organophosphorus
Laryngospasm
Methadone or heroin addiction Chronic Chest Wall Stiffness
Angioedema
Sleep disordered breathing Poliomyelitis Acute
Obstructive sleep apnea
Brain tumor Multiple sclerosis Rib fractures with flail chest
Inadequate laryngeal intubation
Bulbar poliomyelitis Muscular dystrophy Pneumothorax
Laryngeal obstruction after intubation
Hypothyroidism Amyotrophic lateral sclerosis Hemothorax
Lower airway obstruction
Diaphragmatic paralysis Abdominal distention
Generalized bronchospasm
Myopathic disease eg, polymyositis Ascites
Airway edema and secretions
Muscle Dysfunction Peritoneal dialysis
Severe episode of spasmodic asthma
Acute Chronic
Bronchiolitis of infants and adults
Fatigue Kyphoscoliosis, spinal arthritis
Chronic
Hyperkalemia Obesity
Upper airway obstruction
Hypokalemia Fibrothorax
Tonsillar and peritonsillar hypertrophy
Hypoperfusion state Hydrothorax
Paralysis of vocal cords
Hypoxemia Chest wall tumor
Tumor of the cords or larynx
Malnutrition Airway stenosis after prolonged intubation
Chronic Thymoma, aortic aneurysm
Myopathic disease eg, polymyositis Lower airway obstruction
Airway scarring
Chronic obstructive lung disease eg, bronchitis,
bronchiolitis, bronchiectasis, emphysema
FIGURE 6-5
Determinants and causes of carbon dioxide retention. When the res- muscle dysfunction. A higher load can be caused by increased venti-
piratory pump is unable to balance the opposing load, respiratory latory demand, augmented airway flow resistance, and stiffness of
acidosis develops. Decreases in respiratory pump strength, increases the lungs or chest wall. In most cases, causes of the various determi-
in load, or a combination of the two, can result in carbon dioxide nants of carbon dioxide retention, and thus respiratory acidosis, are
retention. Respiratory pump failure can occur because of depressed categorized into acute and chronic subgroups, taking into consider-
central drive, abnormal neuromuscular transmission, or respiratory ation their usual mode of onset and duration [2].
FIGURE 6-6
Spontaneous Mechanical ventilation
breathing Posthypercapnic metabolic alkalosis. Development of posthypercap-
nic metabolic alkalosis is shown after abrupt normalization of the
arterial carbon dioxide tension (PaCO2) by way of mechanical ven-
80
tilation in a 70-year-old man with respiratory decompensation who
PaCO2, mm Hg
has chronic obstructive pulmonary disease and chronic hypercapnia.

-
The acute decrease in plasma bicarbonate concentration ([HCO3])
60
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 bicarbon-
40
ate is excreted by the kidneys over the next 2 to 3 days, and acid-
base equilibrium is normalized. In contrast, a low-chloride diet sus-
tains the hyperbicarbonatemia and perpetuates the posthypercapnic
40
metabolic alkalosis. Abrupt correction of severe hypercapnia by
way of mechanical ventilation generally is not recommended.
[HCO–3], mEq/L
Low-Cl– diet
–
Rather, gradual return toward the patient’s baseline PaCO2 level
30 Cl - rich diet should be pursued [1,2]. [H+]—hydrogen ion concentration.
20 Cl–- rich diet
7.60
[H+], nEq/L
7.50 30
pH
7.40 40
7.30 50
7.20 60
0 2 4 6 8
Days
FIGURE 6-7
No Remove dentures, foreign bodies, or food particles; Heimlich maneuver Acute respiratory acidosis management.
Airway patency
secured? (subdiaphragmatic abdominal thrust); tracheal intubation; tracheotomy Securing airway patency and delivering an
oxygen-rich mixture are critical initial steps
ent
Yes
ay pat in management. Subsequent measures must
w • Administer O2 via nasal mask or prongs to maintain
Air PaO2 > 60 mm Hg. be directed at identifying and correcting the
Oxygen-rich mixture • Correct reversible causes of pulmonary dysfunction underlying cause, whenever possible [1,9].
delivered with antibiotics, bronchodilators, and PaCO2—arterial carbon dioxide tension.
corticosteroids as needed.
• Monitor patient with arterial blood gases initially at
Alert, blood pH > 7.10, intervals of 20 to 30 minutes and less frequently
or PaCO2 <60 mm Hg thereafter.
Mental status and
blood gases evaluated • 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

Obtunded, blood pH < 7.10, ventilation.
or PaCO2 > 60 mm Hg • 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 6-8
Severe Chronic respiratory acidosis management.
hypercapnic Therapeutic measures are guided by the
encephalopathy No Yes presence or absence of severe hypercapnic
PaO2 > 60 mm Hg Observation, routine care.
or hemodynamic on room air encephalopathy or hemodynamic instability.
instability An aggressive approach that favors the
• Administer O2 via nasal cannula or Venti mask early use of ventilator assistance is most
No • Correct reversible causes of pulmonary appropriate for patients with acute respira-
dysfuntion with antibiotics, bronchodilators,
and corticosteroids as needed.
tory acidosis. In contrast, a more conserva-
tive approach is advisable in patients with
Mental status deteriorates

Hemodynamic instability
chronic hypercapnia because of the great
CO2 retention worsens

PaO2 < 55 mm Hg
Yes difficulty often encountered in weaning
PaO2 ≥ 55 mm Hg, patient stable
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 aci-
• Consider intubation and use of • Consider use of noninvasive nasal mask ventilation dosis only rarely can be resolved [1,9].
standard ventilator support. (NMV) or intubation and standard ventilator support.
• Correct reversible causes of
pulmonary dysfunction with
antibiotics, bronchodilators,
and corticosteroids as needed. • Continue same measures.
Respiratory Alkalosis
FIGURE 6-9
Arterial blood [H+], nEq/L Adaptation to respiratory alkalosis. Respiratory alkalosis, or
150 125 100 80 70 60 50 40 30 20 primary hypocapnia, is the acid-base disturbance initiated by a
decrease in arterial carbon dioxide tension (PaCO2) and entails
PaCO2 120 100 90 80 70 60 50
mm Hg
alkalinization of body fluids. Hypocapnia elicits adaptive decre-
40 ments in plasma bicarbonate concentration that should be viewed
50 as an integral part of respiratory alkalosis. An immediate decre-
ment in plasma bicarbonate occurs in response to hypocapnia. This
acute adaptation is complete within 5 to 10 minutes from the onset

40 30 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,
30 notably lactic acid. When hypocapnia is sustained, renal adjust-
20 ments cause an additional decrease in plasma bicarbonate, further
Normal
Acut
e resp ameliorating the resulting alkalemia. This chronic adaptation
Ch
alkalo iratory
ro alk
20 sis requires 2 to 3 days for completion and reflects retention of hydro-

nic al
res osis
gen ions by the kidneys as a result of downregulation of renal acid-

pir
10
ato
ification [2,10]. Shown are the average decreases in plasma bicar-

ry
10 bonate and hydrogen ion concentrations per mm Hg decrease in

PaCO2after completion of the acute or chronic adaptation to respi-
ratory alkalosis. Empiric observations on these adaptations have
been used for constructing 95% confidence intervals for graded
6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7
degrees of acute or chronic respiratory alkalosis, which are repre-
Arterial blood pH sented by the areas in color in the acid-base template. The black
ellipse near the center of the figure indicates the normal range for
Steady-state relationships in respiratory alkalosis: the acid-base parameters. Note that for the same level of PaCO2,
average decrease per mm Hg fall in PaCO2 the degree of alkalemia is considerably lower in chronic than it is
[HCO–3] mEq/L [H+] nEq/L in acute respiratory alkalosis. Assuming that a steady state is pre-
Acute adaptation 0.2 0.75 sent, values falling within the areas in color are consistent with but
not diagnostic of the corresponding simple disorders. Acid-base
Chronic adaptation 0.4 0.4
values falling outside the areas in color denote the presence of a
mixed acid-base disturbance [4].
FIGURE 6-10
Eucapnia Stable Hypocapnia Renal acidification response to chronic hypocapnia. A, Sustained
Net acid excretion
hypocapnia entails a persistent decrease in the renal tubular secretory

rate of hydrogen ions and a persistent increase in the chloride reab-
sorption 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
Sodium excretion
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 bicar-
Bicarbonate reabsorption
bonate 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 extra-
cellular fluid loss is responsible for the hyperchloremia that typically
0 1 2 3
accompanies chronic respiratory alkalosis. Hyperchloremia is sus-
Days
tained by the persistently enhanced chloride reabsorption rate. If
Km Vmax
dietary sodium is restricted, acid retention is achieved in the compa-
ny of increased potassium excretion. The specific cellular mecha-
NS P<0.01 nisms mediating the renal acidification response to chronic hypocap-
10 1000 nia are under investigation. Available evidence indicates a parallel
decrease in the rates of the luminal sodium ion–hydrogen ion
nmol/mg protein × min
(Na+-H+) exchanger and the basolateral sodium ion–3 bicarbonate

-
ion (Na+-3HCO3) cotransporter in the proximal tubule. This parallel
mmol/L
decrease reflects a decrease in the maximum velocity (Vmax) of each

transporter but no change in the substrate concentration at half-
5 500 maximal 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 mem-
brane of the proximal tubule cells as well as type A intercalated cells
of the cortical and medullary collecting ducts. It remains unknown
Control Chronic Control Chronic whether chronic hypocapnia alters the quantity of the H+-ATPase
hypocapnia hypocapnia pumps as well as the kinetics or quantity of other acidification trans-
(9% O2) (9% O2) porters in the renal cortex or medulla [6]. NS—not significant. (B,
From Hilden and coworkers [11]; with permission.)
FIGURE 6-11
SIGNS AND SYMPTOMS OF RESPIRATORY ALKALOSIS Signs and symptoms of respiratory alkalo-
sis. The manifestations of primary hypocap-
nia frequently occur in the acute phase, but
Central Nervous System Cardiovascular System Neuromuscular System seldom are evident in chronic respiratory
alkalosis. Several mechanisms mediate these
Cerebral vasoconstriction Chest oppression Numbness and paresthesias clinical manifestations, including cerebral
Reduction in intracranial pressure Angina pectoris of the extremities hypoperfusion, alkalemia, hypocalcemia,
Light-headedness Ischemic electrocardiographic changes Circumoral numbness hypokalemia, and decreased release of oxy-
Confusion Normal or decreased blood pressure Laryngeal spasm gen to the tissues by hemoglobin. The car-
Increased deep tendon reflexes Cardiac arrhythmias Manifestations of tetany diovascular effects of respiratory alkalosis
Generalized seizures Peripheral vasoconstriction Muscle cramps are more prominent in patients undergoing
Carpopedal spasm mechanical ventilation and those with
Trousseau’s sign ischemic heart disease [2].
Chvostek’s sign
CAUSES OF RESPIRATORY ALKALOSIS
Central Nervous
Hypoxemia or Tissue Hypoxia System Stimulation Drugs or Hormones Stimulation of Chest Receptors Miscellaneous
Decreased inspired oxygen tension Voluntary Nikethamide, ethamivan Pneumonia Pregnancy
High altitude Pain Doxapram Asthma Gram-positive septicemia
Bacterial or viral pneumonia Anxiety syndrome- Xanthines Pneumothorax Gram-negative septicemia
Aspiration of food, foreign object, hyperventilation syndrome Salicylates Hemothorax Hepatic failure
or vomitus Psychosis Catecholamines Flail chest Mechanical hyperventilation
Laryngospasm Fever Angiotensin II Acute respiratory distress syndrome Heat exposure
Drowning Subarachnoid hemorrhage Vasopressor agents Cardiogenic and noncardiogenic Recovery from metabolic acidosis
Cyanotic heart disease Cerebrovascular accident Progesterone pulmonary edema
Severe anemia Meningoencephalitis Medroxyprogesterone Pulmonary embolism
Left shift deviation of Tumor Dinitrophenol Pulmonary fibrosis
oxyhemoglobin curve Trauma Nicotine
Hypotension
Severe circulatory failure
Pulmonary edema
FIGURE 6-12
Respiratory alkalosis is the most frequent acid-base disorder to permit full chronic adaptation to occur. Consequently, no
encountered because it occurs in normal pregnancy and high- attempt has been made to separate these conditions into acute
altitude residence. Pathologic causes of respiratory alkalosis and chronic categories. Some of the major causes of respiratory
include various hypoxemic conditions, pulmonary disorders, cen- alkalosis are benign, whereas others are life-threatening. Primary
tral nervous system diseases, pharmacologic or hormonal stimu- hypocapnia is particularly common among the critically ill,
lation of ventilation, hepatic failure, sepsis, the anxiety-hyper- occurring either as the simple disorder or as a component of
ventilation syndrome, and other entities. Most of these causes mixed disturbances. Its presence constitutes an ominous prog-
are associated with the abrupt occurrence of hypocapnia; howev- nostic sign, with mortality increasing in direct proportion to the
er, in many instances, the process might be sufficiently prolonged severity of the hypocapnia [2].
FIGURE 6-13
Respiratory alkalosis Respiratory alkalosis management. Because chronic respiratory alka-
losis poses a low risk to health and produces few or no symptoms,
measures for treating the acid-base disorder itself are not required. In
Acute Chronic contrast, severe alkalemia caused by acute primary hypocapnia
requires corrective measures that depend on whether serious clinical
No manifestations are present. Such measures can be directed at reducing
Manage underlying disorder. -
Blood pH ≥ 7.55 plasma bicarbonate concentration ([HCO3]), increasing the arterial
No specific measures indicated.
carbon dioxide tension (PaCO2), or both. Even if the baseline plasma
Yes bicarbonate is moderately decreased, reducing it further can be partic-
ularly rewarding in this setting. In addition, this maneuver combines
Hemodynamic instability, No • Consider having patient rebreathe effectiveness with relatively little risk [1,2].
altered mental status, into a closed system.
or cardiac arrhythmias • Manage underlying disorder.
Yes
Consider measures to correct blood pH ≤ 7.50 by:

• Reducing [HCO–3]:
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.
FIGURE 6-14
Lungs Pseudorespiratory alkalosis. This entity
develops in patients with profound depres-
sion of cardiac function and pulmonary
perfusion but relative preservation of alveo-
Normal lar 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 deliv-
pH 7.40
LV RV
pH 7.38 ered to the lungs for excretion, thereby
PCO2 40 PCO2 46 increasing the venous carbon dioxide ten-
– –
[HCO3 ] 24 [HCO3 ] 26 sion (PCO2). In contrast, the increased ven-
PO2 95 PO2 40
FiO2 0.21 tilation-to-perfusion ratio causes a larger
Peripheral tissues than normal removal of carbon dioxide per
unit of blood traversing the pulmonary cir-
culation, thereby giving rise to arterial
hypocapnia [12,13]. Note a progressive
Arterial Venous widening of the arteriovenous difference in
compartment compartment
pH and PCO2 in the two settings of cardiac
dysfunction. The hypobicarbonatemia in
the setting of cardiac arrest represents a
Circulatory Failure
complicating element of lactic acidosis.
Despite the presence of arterial hypocapnia,
pseudorespiratory alkalosis represents a
special case of respiratory acidosis, as
pH 7.42 pH 7.29 absolute carbon dioxide excretion is
PCO2 35 LV RV PCO2 60 decreased and body carbon dioxide balance
– –
[HCO3 ] 22 [HCO3 ] 28
is positive. Furthermore, the extreme oxy-
PO2 80 PO2 30
FiO2 0.35 gen deprivation prevailing in the tissues
might be completely disguised by the rea-
sonably preserved arterial oxygen values.
Appropriate monitoring of acid-base com-
position 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
Cardiac Arrest must be directed at optimizing systemic
hemodynamics [1,13].
pH 7.37 pH 7.00
PCO2 27 LV RV PCO2 75
[HCO3– ] 15 [HCO–3 ] 18
PO2 116 PO2 17
FiO2 1.00
Metabolic Acidosis
FIGURE 6-15
Arterial blood [H+], nEq/L
Ninety-five percent confidence intervals for metabolic acidosis.
150 125 100 80 70 60 50 40 30 20 Metabolic acidosis is the acid-base disturbance initiated by a
-
PaCO2 120 100 90 80 70 60 50 decrease in plasma bicarbonate concentration ([HCO3]). The resul-
mm Hg tant acidemia stimulates alveolar ventilation and leads to the sec-
40 ondary hypocapnia characteristic of the disorder. Extensive obser-
50
vations in humans encompassing a wide range of stable metabolic
acidosis indicate a roughly linear relationship between the steady-
state decrease in plasma bicarbonate concentration and the associ-

40 30 ated 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
30
20
in plasma bicarbonate concentration. Such empiric observations
Normal have been used for construction of 95% confidence intervals for
20
graded degrees of metabolic acidosis, represented by the area in
sis c
ido oli
color in the acid-base template. The black ellipse near the center of
ac tab
e
M
10 the figure indicates the normal range for the acid-base parameters
10 [3]. Assuming a steady state is present, values falling within the
area in color are consistent with but not diagnostic of simple meta-
bolic acidosis. Acid-base values falling outside the area in color
denote the presence of a mixed acid-base disturbance [4]. [H+]—
6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 hydrogen ion concentration.
Arterial blood pH
FIGURE 6-16
SIGNS AND SYMPTOMS OF METABOLIC ACIDOSIS Signs and symptoms of metabolic acidosis.
Among the various clinical manifestations,
particularly pernicious are the effects of
Respiratory Central severe acidemia (blood pH < 7.20) on the car-
System Cardiovascular System Metabolism Nervous System Skeleton diovascular system. Reductions in cardiac
output, arterial blood pressure, and hepatic
Hyperventilation Impairment of cardiac Increased Impaired metabolism Osteomalacia and renal blood flow can occur and life-
Respiratory distress contractility, arteriolar metabolic demands Inhibition of cell Fractures threatening arrhythmias can develop. Chronic
and dyspnea dilation, venoconstriction, Insulin resistance volume regulation
and centralization of
acidemia, as it occurs in untreated renal tubu-
Decreased strength Inhibition of Progressive obtundation lar acidosis and uremic acidosis, can cause
of respiratory blood volume anaerobic glycolysis Coma calcium dissolution from the bone mineral
muscles and Reductions in cardiac Reduction in adenosine
promotion of output, arterial blood and consequent skeletal abnormalities.
triphosphate synthesis
muscle fatigue pressure, and hepatic
Hyperkalemia
and renal blood flow
Increased
Sensitization to reentrant
protein degradation
arrhythmias and reduction
in threshold for ventricular
fibrillation
Increased sympathetic
discharge but attenuation of
cardiovascular responsiveness
to catecholamines
Normal Metabolic acidosis

FIGURE 6-17
Normal anion gap High anion gap Causes of metabolic acidosis tabulated according to the prevailing
(hyperchloremic) (normochloremic) pattern of plasma electrolyte composition. Assessment of the plas-
A– 10 –
A 10 ma unmeasured anion concentration (anion gap) is a very useful
HCO3– HCO3– 4 A– 30
first step in approaching the differential diagnosis of unexplained
24 HCO3– 4
metabolic acidosis. The plasma anion gap is calculated as the dif-
ference between the sodium concentration and the sum of chloride
Na+ Cl– Na+ Cl– Na+ Cl–
140 106 140 126 140 106
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)
Causes Causes mEq/L, where SD is the standard deviation. However, recent intro-
Renal acidification defects Endogenous acid load
Proximal renal tubular acidosis Ketoacidosis duction of ion-specific electrodes has shifted the normal anion gap
Classic distal tubular acidosis Diabetes mellitus to the range of about 6 ± 3 mEq/L. In one pattern of metabolic aci-
Hyperkalemic distal tubular acidosis Alcoholism dosis, the decrease in bicarbonate concentration is offset by an
Early renal failure Starvation increase in the concentration of chloride, with the plasma anion
Gastrointestinal loss of bicarbonate Uremia
gap remaining normal. In the other pattern, the decrease in bicar-
Diarrhea Lactic acidosis
Small bowel losses Exogenous toxins bonate is balanced by an increase in the concentration of unmea-
Ureteral diversions Osmolar gap present sured anions (ie, anions not measured routinely), with the plasma
Anion exchange resins Methanol chloride concentration remaining normal.
Ingestion of CaCl2 Ethylene glycol
Acid infusion Osmolar gap absent
HCl Salicylates
Arginine HCl Paraldehyde
Lysine HCl
Lactic acidosis
duce lactate during the course of glycolysis, those listed contribute
Glucose substantial quantities of lactate to the extracellular fluid under nor-
mal aerobic conditions. In turn, lactate is extracted by the liver and
Gluconeogenesis 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
Cori between glucose and lactate is known as the Cori cycle. The basal
cycle 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
Muscle Brain Skin RBC Liver Kidney cortex ranging from 1 to 2 mEq/L. Hydrogen ions (H+) released during lac-
tate generation are quantitatively consumed during the use of lactate
Anaerobic glycolysis
H+ + Lactate such that acid-base balance remains undisturbed. Accumulation of
lactate in the circulation, and consequent lactic acidosis, is generated
Overproduction Lactic acidosis Underutilization whenever the rate of production of lactate is higher than the rate of
utilization. The pathogenesis of this imbalance reflects overproduc-
tion of lactate, underutilization, or both. Most cases of persistent lac-
tic acidosis actually involve both overproduction and underutiliza-
FIGURE 6-18 tion of lactate. During hypoxia, almost all tissues can release lactate
Lactate-producing and lactate-consuming tissues under basal condi- into the circulation; indeed, even the liver can be converted from the
tions and pathogenesis of lactic acidosis. Although all tissues pro- premier consumer of lactate to a net producer [1,14].
reduces the availability of adenosine triphosphate (ATP) and NAD+

Glucose (oxidized nicotinamide adenine dinucleotide) within the cytosol. In
PFK turn, these changes cause cytosolic accumulation of pyruvate as a
+ low ATP consequence of both increased production and decreased utiliza-
ADP
Glycolysis
tion. Increased production of pyruvate occurs because the reduced
NAD+
cytosolic supply of ATP stimulates the activity of 6-phosphofruc-
tokinase (PFK), thereby accelerating glycolysis. Decreased utiliza-
tion of pyruvate reflects the fact that both pathways of its con-
NADH
sumption depend on mitochondrial oxidative reactions: oxidative
Pyruvate LDH decarboxylation to acetyl coenzyme A (acetyl-CoA), a reaction cat-
Lactate
Gluconeogenesis + alyzed by pyruvate dehydrogenase (PDH), requires a continuous
high NADH
NAD+ Cytosol supply of NAD+; and carboxylation of pyruvate to oxaloacetate, a
Mitochondrial membrane reaction catalyzed by pyruvate carboxylase (PC), requires ATP. The
increased [NADH]/[NAD+] ratio (NADH refers to the reduced
Mitochondria
form of the dinucleotide) shifts the equilibrium of the lactate dehy-
PD – high NADH+ drogenase (LDH) reaction (that catalyzes the interconversion of
low ATP – H NAD
PC
ADP NAD+ pyruvate and lactate) to the right. In turn, this change coupled with
Acetyl-CoA
NADH the accumulation of pyruvate in the cytosol results in increased
Oxaloacetate TCA – accumulation of lactate. Despite the prevailing mitochondrial dys-
cycle function, 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
FIGURE 6-19 3-phosphate, a key step in glycolysis. Thus, lactate accumulation
Hypoxia-induced lactic acidosis. Accumulation of lactate during can be viewed as the toll paid by the organism to maintain energy
hypoxia, by far the most common clinical setting of the disorder, production during anaerobiosis (hypoxia) [14]. ADP—adenosine
originates from impaired mitochondrial oxidative function that diphosphate; TCA cycle—tricarboxylic acid cycle.
FIGURE 6-20
CAUSES OF LACTIC ACIDOSIS Conventionally, two broad types of lactic
acidosis are recognized. In type A, clinical
evidence exists of impaired tissue oxygena-
Type A: tion. In type B, no such evidence is apparent.
Impaired Tissue Oxygenation Type B: Preserved Tissue Oxygenation Occasionally, the distinction between the
two types may be less than obvious. Thus,
Shock Diseases and conditions Drugs and toxins inadequate tissue oxygenation can at times
Severe hypoxemia Diabetes mellitus Epinephrine, defy clinical detection, and tissue hypoxia
Generalized convulsions Hypoglycemia norepinephrine, can be a part of the pathogenesis of certain
Vigorous exercise Renal failure vasoconstrictor agents
causes of type B lactic acidosis. Most cases
Salicylates
Exertional heat stroke Hepatic failure of lactic acidosis are caused by tissue hypox-
Hypothermic shivering Severe infections Ethanol ia arising from circulatory failure [14,15].
Massive pulmonary emboli Alkaloses Methanol
Severe heart failure Malignancies (lymphoma, Ethylene glycol
Profound anemia leukemia, sarcoma) Biguanides
Mesenteric ischemia Thiamine deficiency Acetaminophen
Carbon monoxide poisoning Acquired Zidovudine
Cyanide poisoning immunodeficiency syndrome Fructose, sorbitol,
Pheochromocytoma and xylitol
Iron deficiency Streptozotocin
D-Lactic acidosis Isoniazid
Nitroprusside
Congenital enzymatic defects
Papaverine
Nalidixic acid
FIGURE 6-21
• Antibiotics (sepsis) Lactic acidosis management. Management
• Dialysis (toxins) of lactic acidosis should focus primarily on
• Discontinuation of incriminated securing adequate tissue oxygenation and on
drugs
No • Insulin (diabetes) aggressively identifying and treating the
Inadequate tissue Cause-specific measures underlying cause or predisposing condition.
oxygenation? • Glucose (hypoglycemia, alcoholism)
• Operative intervention (trauma, Monitoring of the patient’s hemodynamics,
tissue ischemia) oxygenation, and acid-base status should be
Yes
No • Thiamine (thiamine deficiency) used to guide therapy. In the presence of
• Low carbohydrate diet and
Oxygen-rich mixture antibiotics (D-lactic acidosis) severe or worsening metabolic acidemia,
and ventilator support, Circulatory failure? these measures should be supplemented by
if needed judicious administration of sodium bicar-
Yes
bonate, given as an infusion rather than a
bolus. Alkali administration should be
regarded as a temporizing maneuver adjunc-
• Volume repletion tive to cause-specific measures. Given the
• Preload and afterload
No • Continue therapy ominous prognosis of lactic acidosis, clini-
reducing agents Severe/Worsening
• Myocardial stimulants • Manage predisposing cians should strive to prevent its develop-
metabolic acidemia?
(dobutamine, dopamine) conditions ment by maintaining adequate fluid balance,
• Avoid vasoconstrictors optimizing cardiorespiratory function, man-
Yes aging infection, and using drugs that predis-
pose to the disorder cautiously. Preventing
Alkali administration to the development of lactic acidosis is all the
maintain blood pH ≥ 7.20
more important in patients at special risk
for developing it, such as those with dia-
betes mellitus or advanced cardiac, respira-
tory, renal, or hepatic disease [1,14–16].
Diabetic ketoacidosis and nonketotic hyperglycemia

FIGURE 6-22
A
Increased hepatic Role of insulin deficiency and the counter-
glucose production regulatory hormones, and their respective
Glucagon sites of action, in the pathogenesis of hyper-
Increased hepatic Cortisol glycemia and ketosis in diabetic ketoacido-
ketogenesis Counterregulation
Epinephrine sis (DKA).A, Metabolic processes affected
Insulin Growth hormone
deficiency Norepinephrine by insulin deficiency, on the one hand, and
Increased lipolysis excess of glucagon, cortisol, epinephrine,
in adipocytes
norepinephrine, and growth hormone, on
the other. B, The roles of the adipose tissue,
B Decreased glucose
utilization in skeletal
liver, skeletal muscle, and kidney in the
Triglycerides muscle pathogenesis of hyperglycemia and ketone-
Increased mia. Impairment of glucose oxidation in
lipolysis
most tissues and excessive hepatic produc-
tion of glucose are the main determinants
Increased ketogenesis Decreased ketone uptake
of hyperglycemia. Excessive counterregula-
Ketonemia tion and the prevailing hypertonicity, meta-
(metabolic acidosis) bolic acidosis, and electrolyte imbalance
superimpose a state of insulin resistance.
Increased gluconeogenesis Prerenal azotemia caused by volume deple-
Increased glycogenolysis Decreased glucose excretion
Decreased glucose uptake
tion can contribute significantly to severe
Hyperglycemia hyperglycemia. Increased hepatic produc-
(hyperosmolality) tion of ketones and their reduced utilization
by peripheral tissues account for the
ketonemia typically observed in DKA.
Increased protein breakdown Decreased glucose uptake
Decreased amino acid uptake

FIGURE 6-23
Insulin deficiency/resistance
Clinical features of diabetic ketoacidosis (DKA) and nonketotic
Severe Mild
hyperglycemia (NKH). DKA and NKH are the most important
acute metabolic complications of patients with uncontrolled dia-
betes mellitus. These disorders share the same overall pathogene-
Pure DKA Pure NKH sis that includes insulin deficiency and resistance and excessive
Mixed forms
profound DKA + NKH profound counterregulation; however, the importance of each of these
ketosis hyperglycemia endocrine abnormalities differs significantly in DKA and NKH.
As depicted here, pure NKH is characterized by profound hyper-
glycemia, the result of mild insulin deficiency and severe coun-
Mild Severe terregulation (eg, high glucagon levels). In contrast, pure DKA is
Excessive counterregulation characterized by profound ketosis that largely is due to severe
insulin deficiency, with counterregulation being generally of less-
Feature Pure DKA Mixed forms Pure NKH er importance. These pure forms define a continuum that
includes mixed forms incorporating clinical and biochemical fea-
Incidence 5–10 times higher 5–10 times lower
Mortality 5–10% 10–60%
tures of both DKA and NKH. Dyspnea and Kussmaul’s respira-
Onset Rapid (<2 days) Slow (> 5 days) tion result from the metabolic acidosis of DKA, which is general-
Age of patient Usually < 40 years Usually > 40 years ly absent in NKH. Sodium and water deficits and secondary
Type I diabetes Common Rare renal dysfunction are more severe in NKH than in DKA. These
Type II diabetes Rare Common deficits also play a pathogenetic role in the profound hypertonic-
First indication of diabetes Often Often ity characteristic of NKH. The severe hyperglycemia of NKH,
Volume depletion Mild/moderate Severe
often coupled with hypernatremia, increases serum osmolality,
Renal failure (most com- Mild, inconstant Always present
monly of prerenal nature)
thereby causing the characteristic functional abnormalities of the
Severe neurologic Rare Frequent central nervous system. Depression of the sensorium, somno-
abnormalities (coma in 25–50%) lence, obtundation, and coma, are prominent manifestations of
Subsequent therapy with Always Not always NKH. The degree of obtundation correlates with the severity of
insulin serum hypertonicity [17].
Glucose < 800 mg/dL > 800 mg/dL
Ketone bodies ≥ 2 + in 1:1 dilution < 2+ in 1:1 dilution
Effective osmolality < 340 mOsm/kg > 340 mOsm/kg
pH Decreased Normal
[HCO–3] Decreased Normal
[Na+] Normal or low Normal or high
[K+] Variable Variable
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. Shock absent: Normal saline (0.9% NaCl) Potassium chloride should be Half-normal saline (0.45% NaCl) plus
2. Add 100 U of regular insulin to 1 L of normal saline (0.1 at 7 mL/kg/h for 4 h, and half this added to the third liter of IV 1–2 ampules (44-88 mEq) NaHCO3
U/mL), and follow with continuous IV drip of 0.1 U/kg rate thereafter infusion and subsequently per liter when blood pH < 7.0 or
actual body weight per h until correction of ketosis. Shock present: Normal saline and plasma if urinary output is at least total CO2 < 5 mmol/L; in hyper-
3. Give double rate of infusion if the blood glucose level expanders (ie,albumin, low molecular 30–60 mL/h and plasma [K+] chloremic acidosis, add NaHCO3
does not decrease in a 2-h interval (expected decrease weight dextran) at maximal possible rate < 5 mEq/L. when pH < 7.20; discontinue
is 40–80 mg/dL/h or 10% of the initial value.) Start a glucose-containing solution Add K+ to the initial 2 L of IV NaHCO3 in IV infusion when total
(eg, 5% dextrose in water) when blood fluids if initial plasma [K+] CO2>8–10 mmol/L.
4. Give SQ dose (10–30 U) of regular insulin when ketosis
is corrected and the blood glucose level decreases to glucose level decreases to 250 mg/dL. < 4 mEq/L and adequate
300 mg/dL, and continue with SQ insulin injection diuresis is secured.
every 4 h on a sliding scale (ie, 5 U if below 150, 10 U if
150–200, 15 U if 200–250, and 20 U if 250–300 mg/dL).
CO2—carbon dioxide; IV—intravenous; K+—potassium ion; NaCl—sodium chloride; NaHCO3—sodium bicarbonate; SQ—subcutaneous.
FIGURE 6-24
Diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) NKH, in which ketoacidosis is generally absent. Because the fluid
management. Administration of insulin is the cornerstone of manage- deficit is generally severe in patients with NKH, many of whom have
ment for both DKA and NKH. Replacement of the prevailing water, preexisting heart disease and are relatively old, safe fluid replacement
sodium, and potassium deficits is also required. Alkali are adminis- may require monitoring of central venous pressure, pulmonary capil-
tered only under certain circumstances in DKA and virtually never in lary wedge pressure, or both [1,17,18].
Renal tubular acidosis

FIGURE 6-25
FEATURES OF THE RENAL TUBULAR ACIDOSIS (RTA) SYNDROMES Renal tubular acidosis (RTA) defines a
group of disorders in which tubular hydro-
gen ion secretion is impaired out of propor-
Feature Proximal RTA Classic Distal RTA Hyperkalemic Distal RTA tion to any reduction in the glomerular fil-
tration rate. These disorders are character-
Plasma bicarbonate 14–18 mEq/L Variable, may be 15–20 mEq/L ized by normal anion gap (hyperchloremic)
ion concentration < 10 mEq/L metabolic acidosis. The defects responsible
Plasma chloride Increased Increased Increased for impaired acidification give rise to three
ion concentration
distinct syndromes known as proximal RTA
Plasma potassium Mildly decreased Mildly to Mildly to severely increased
(type 2), classic distal RTA (type 1), and
ion concentration severely decreased
hyperkalemic distal RTA (type 4).
Plasma anion gap Normal Normal Normal
Glomerular filtration rate Normal or Normal or Normal to
slightly decreased slightly decreased moderately decreased
Urine pH during acidosis ≤5.5 >6.0 ≤5.5
Urine pH after acid loading ≤5.5 >6.0 ≤5.5
U-B PCO2 in alkaline urine Normal Decreased Decreased
Fractional excretion of >15% <5% <5%
- -
HCO3 at normal [HCO3]p
-
Tm HCO3 Decreased Normal Normal
Nephrolithiasis Absent Present Absent
Nephrocalcinosis Absent Present Absent
Osteomalacia Present Present Absent
Fanconi’s syndrome* Usually present Absent Absent
Alkali therapy High dose Low dose Low dose
-
Tm HCO3—maximum reabsorption of bicarbonate; U-B PCO2—difference 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.
Lumen Proximal tubule cell Blood

B. CAUSES OF PROXIMAL RENAL
TUBULAR ACIDOSIS
CA
CO2
–
CO2 + OH HCO–3 3HCO–3 Selective defect (isolated bicarbonate wasting) Dysproteinemic states
CA
H2CO3 1Na+ Primary (no obvious associated disease) Multiple myeloma
H 2O
Genetically transmitted Monoclonal gammopathy
HCO–3 + H+ H+ Transient (infants) Drug- or toxin-induced
+ Due to altered carbonic anhydrase activity Outdated tetracycline
Na Na+ 3Na +
Acetazolamide 3-Methylchromone
Na+ Sulfanilamide Streptozotocin
2K+
Glucose Mafenide acetate Lead
Amino acids Genetically transmitted Mercury
Phosphate Idiopathic Arginine
Osteopetrosis with carbonic Valproic acid
Indicates possible cellular mechanisms responsible anhydrase II deficiency
for Type 2 proximal RTA Gentamicin
A York-Yendt syndrome
Ifosfamide
Generalized defect (associated with multiple
dysfunctions of the proximal tubule) Tubulointerstitial diseases
FIGURE 6-26 Renal transplantation
Primary (no obvious associated disease)
A and B, Potential defects and causes of proximal renal tubular Sjögren’s syndrome
acidosis (RTA) (type 2). Excluding the case of carbonic anhydrase Sporadic
Genetically transmitted Medullary cystic disease
inhibitors, the nature of the acidification defect responsible for
bicarbonate (HCO3) wastage remains unknown. It might represent Genetically transmitted systemic disease Other renal diseases
defects in the luminal sodium ion– hydrogen ion (Na+-H+) Tyrosinemia Nephrotic syndrome
- Wilson’s disease Amyloidosis
exchanger, basolateral Na+-3HCO3 cotransporter, or carbonic
anhydrase activity. Most patients with proximal RTA have addi- Lowe syndrome Miscellaneous
tional defects in proximal tubule function (Fanconi’s syndrome); Hereditary fructose intolerance (during Paroxysmal
this generalized proximal tubule dysfunction might reflect a defect administration of fructose) nocturnal hemoglobinuria
in the basolateral Na+-K+ adenosine triphosphatase. K+—potassium Cystinosis Hyperparathyroidism
ion; CA—carbonic anhydrase. Causes of proximal renal tubular Pyruvate carboxylate deficiency
acidosis (RTA) (type 2). An idiopathic form and cystinosis are the Metachromatic leukodystrophy
most common causes of proximal RTA in children. In adults, mul- Methylmalonic acidemia
tiple myeloma and carbonic anhydrase inhibitors (eg, acetazo- Conditions associated with chronic hypocalcemia
lamide) are the major causes. Ifosfamide is an increasingly and secondary hyperparathyroidism
common cause of the disorder in both age groups. Vitamin D deficiency or resistance
Vitamin D dependence
B. CAUSES OF CLASSIC DISTAL RENAL

TUBULAR ACIDOSIS
Lumen α Intercalated cell (CCT & MCT) Blood

Primary (no obvious associated disease) Disorders associated
Sporadic with nephrocalcinosis
Genetically transmitted Primary or familial hyperparathyroidism
CO2 HCO–3
Vitamin D intoxication
H + CA Autoimmune disorders
Cl– Milk-alkali syndrome
Hypergammaglobulinemia
OH– Hyperthyroidism
Hyperglobulinemic purpura
Idiopathic hypercalciuria
H+ H2 O Cryoglobulinemia
Genetically transmitted
Familial
K+ Cl– Sporadic
Sjögren’s syndrome
Hereditary fructose intolerance
Thyroiditis
(after chronic fructose ingestion)
Cl– Pulmonary fibrosis
Medullary sponge kidney
Chronic active hepatitis
Fabry’s disease
Primary biliary cirrhosis
Wilson’s disease
Indicates possible cellular mechanisms responsible Systemic lupus erythematosus
A for Type 1 distal RTA Vasculitis Drug- or toxin-induced
Amphotericin B
Genetically transmitted systemic disease
Toluene
FIGURE 6-27 Ehlers-Danlos syndrome
Analgesics
A and B, Potential defects and causes of classic distal renal tubular Hereditary elliptocytosis
Lithium
acidosis (RTA) (type 1). Potential cellular defects underlying classic Sickle cell anemia
Cyclamate
distal RTA include a faulty luminal hydrogen ion–adenosine triphos- Marfan syndrome
Balkan nephropathy
phatase (H+ pump failure or secretory defect), an abnormality in the Carbonic anhydrase I deficiency
basolateral bicarbonate ion–chloride ion exchanger, inadequacy of or alteration Tubulointerstitial diseases
carbonic anhydrase activity, or an increase in the luminal membrane Osteopetrosis with carbonic Chronic pyelonephritis
permeability for hydrogen ions (backleak of protons or permeability anhydrase II deficiency Obstructive uropathy
defect). Most of the causes of classic distal RTA likely reflect a secre- Medullary cystic disease Renal transplantation
tory defect, whereas amphotericin B is the only established cause of a Neuroaxonal dystrophy Leprosy
permeability defect. The hereditary form is the most common cause Hyperoxaluria
of this disorder in children. Major causes in adults include autoim-
mune disorders (eg, Sjögren’s syndrome) and hypercalciuria [19].
CA—carbonic anhydrase.
B. CAUSES OF HYPERKALEMIC
Lumen Principal cell Blood DISTAL RENAL TUBULAR ACIDOSIS
Na+
3Na+ Deficiency of aldosterone Resistance to aldosterone action

– Associated with glucocorticoid deficiency Pseudohypoaldosteronism type I
Potential 2K+ Addison’s disease (with salt wasting)
difference Bilateral adrenalectomy Childhood forms with
Enzymatic defects obstructive uropathy
21-Hydroxylase deficiency Adult forms with
Aldosterone renal insufficiency
K+ 3--ol-Dehydrogenase deficiency
receptor Desmolase deficiency Spironolactone
Acquired immunodeficiency syndrome Pseudohypoaldosteronism type II
Cl– Isolated aldosterone deficiency
(without salt wasting)
Combined aldosterone deficiency
α Intercalated cell Genetically transmitted
and resistance
Aldosterone Corticosterone methyl
Deficient renin secretion
oxidase deficiency
receptor Cyclosporine nephrotoxicity
Transient (infants)
CO2 HCO–3 Uncertain renin status
Sporadic
Voltage-mediated defects
CA Heparin
H+ Cl– Obstructive uropathy
Deficient renin secretion
OH– Diabetic nephropathy
Sickle cell anemia
Lithium
Tubulointerstitial renal disease
H+ H2 O Triamterene
Nonsteroidal antiinflammatory drugs
K+ Amiloride
Cl– -adrenergic blockers
Trimethoprim, pentamidine
Acquired immunodeficiency syndrome
Renal transplantation
Cl–
Angiotensin I-converting enzyme inhibition
Endogenous
Captopril and related drugs
Indicates possible cellular mechanisms in aldosterone deficiency Angiotensin AT, receptor blockers
Indicates defects related to aldosterone resistance
A
FIGURE 6-28
A and B, Potential defects and causes of hyperkalemic distal renal hyporeninemia, impaired conversion of angiotensin I to angiotensin
tubular acidosis (RTA) (type 4). This syndrome represents the most II, or abnormal aldosterone synthesis. Aldosterone resistance can
common type of RTA encountered in adults. The characteristic reflect the following: blockade of the mineralocorticoid receptor;
hyperchloremic metabolic acidosis in the company of hyperkalemia destruction of the target cells in the collecting tubule (tubulointer-
emerges as a consequence of generalized dysfunction of the collect- stitial nephropathies); interference with the sodium channel of the
ing tubule, including diminished sodium reabsorption and impaired principal cell, thereby decreasing the lumen-negative potential dif-
hydrogen ion and potassium secretion. The resultant hyperkalemia ference and thus the secretion of potassium and hydrogen ions
causes impaired ammonium excretion that is an important contri- (voltage-mediated defect); inhibition of the basolateral sodium ion,
bution to the generation of the metabolic acidosis. The causes of potassium ion–adenosine triphosphatase; and enhanced chloride
this syndrome are broadly classified into disorders resulting in ion permeability in the collecting tubule, with consequent shunting
aldosterone deficiency and those that impose resistance to the of the transepithelial potential difference. Some disorders cause
action of aldosterone. Aldosterone deficiency can arise from combined aldosterone deficiency and resistance [20].
FIGURE 6-29
Management of acute metabolic acidosis Treatment of acute metabolic acidosis. Whenever possible, cause-
specific 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 bicarbon-
Alkali therapy for severe ate. The goal of alkali therapy is to return the blood pH to a safer
Cause-specific measures level of about 7.20. Anticipated benefits and potential risks of
acidemia (blood pH<7.20)
alkali therapy are depicted here [1].
Benefits Risks
• Prevents or reverses acidemia- • Hypernatremia/
related hemodynamic compromise. hyperosmolality
• Reinstates cardiovascular • Volume overload
responsiveness to catecholamines. • "Overshoot" alkalosis
• "Buys time," thus allowing cause- • Hypokalemia
specific measures and endogenous • Decreased plasma ionized
reparatory processes to take effect. calcium concentration
• Provides a measure of safety against • Stimulation of organic
additional acidifying stresses. acid production
• Hypercapnia
Metabolic Alkalosis
Arterial blood [H+], nEq/L
FIGURE 6-30
Ninety-five percent confidence intervals for metabolic alkalosis.
150 125 100 80 70 60 50 40 30 20
Metabolic alkalosis is the acid-base disturbance initiated by an
-
PaCO2 120 100 90 80 70 60 50 increase in plasma bicarbonate concentration ([HCO3]). The
mm Hg resultant alkalemia dampens alveolar ventilation and leads to the
40
50 secondary hypercapnia characteristic of the disorder. Available
observations in humans suggest a roughly linear relationship
between the steady-state increase in bicarbonate concentration
40 and the associated increment in the arterial carbon dioxide ten-

30
sion (PaCO2). Although data are limited, the slope of the steady-
-
state PaCO2 versus [HCO3] relationship has been estimated as
30 about a 0.7 mm Hg per mEq/L increase in plasma bicarbonate
20 concentration. The value of this slope is virtually identical to
Normal that in dogs that has been derived from rigorously controlled
20 observations [21]. Empiric observations in humans have been
used for construction of 95% confidence intervals for graded
10
degrees of metabolic alkalosis represented by the area in color in
10 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
6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 metabolic alkalosis. Acid-base values falling outside the area in
Arterial blood pH color denote the presence of a mixed acid-base disturbance [4].
[H+]—hydrogen ion concentration.
FIGURE 6-31
Milk alkali syndrome
Excess alkali Pathogenesis of metabolic alkalosis. Two
Alkali gain Calcium supplements
Enteral crucial questions must be answered when
Absorbable alkali
evaluating the pathogenesis of a case of
Nonabsorbable alkali plus K+
exchange resins metabolic alkalosis. 1) What is the source
of the excess alkali? Answering this ques-
Ringer's solution
Source? Bicarbonate
tion addresses the primary event responsible
Parenteral Blood products for generating the hyperbicarbonatemia. 2)
Nutrition What factors perpetuate the hyperbicarbon-
Dialysis atemia? Answering this question addresses
the pathophysiologic events that maintain
Vomiting the metabolic alkalosis.
Gastric
H+ loss Suction
Villous adenoma
Intestinal
Congenital chloridorrhea
Chloruretic diuretics
Renal Inherited transport defects
Mineralocorticoid excess
Posthypercapnia
H+ shift
K+ depletion
Reduced GFR
Mode of perpetuation?
Increased
renal acidification Cl– responsive defect
Cl– resistant defect
FIGURE 6-32
Baseline Vomiting Maintenance Correction Changes in plasma anionic pattern and body electrolyte balance
Low NaCl and KCl intake High NaCl and KCl intake
45 during development, maintenance, and correction of metabolic
alkalosis induced by vomiting. Loss of hydrochloric acid from the
40
stomach as a result of vomiting (or gastric drainage) generates the
[HCO3– ],
mEq/L
35 hypochloremic hyperbicarbonatemia characteristic of this disorder.

During the generation phase, renal sodium and potassium excre-
30
tion increases, yielding the deficits depicted here. Renal potassium
25 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 concen-
105 -
tration ([HCO3]) stabilizes at an elevated level, and renal excretion
of electrolytes matches intake. Addition of sodium chloride (NaCl)
mEq/L
[Cl– ],
100
and potassium chloride (KCl) in the correction phase repairs the
95 electrolyte deficits incurred and normalizes the plasma bicarbonate
and chloride concentration ([Cl-]) levels [22,23].
0
–200
Cl–
–400
Cumulative balance, mEq
0
Na+
–100
–200
K+
–400
–2 0 2 4 6 8 10 12 14 16 18
Days
Baseline Vomiting Maintenance Correction Baseline Diuresis Maintenance Correction

Low NaCl and KCl intake High NaCl and KCl intake Low NaCl intake
8.0 Low KCl intake High KCl intake
Urine pH
7.0 40
[HCO3– ],
mEq/L
6.0 35
5.0 30
25
Urine HCO–3 excretion,
75
105
50
mEq/d
mEq/L
[Cl– ],
100
25
95
0
125
excretion, mEq/d
Urine net acid
100 100
75 75
Urine net acid excretion,
50 50
mEq/d
25
0 0
–200
Cl–
–25
–50 –400
Cumulative balance, mEq
–2 0 2 4 6 8 10 12 14 16 18 0
Na+
Days –100
FIGURE 6-33 0
K+
Changes in urine acid-base composition during development, main- –100

tenance, and correction of vomiting-induced metabolic alkalosis.
During acid removal from the stomach as well as early in the phase –2 0 2 4 6 8 10 12
after vomiting (maintenance), an alkaline urine is excreted as acid
Days
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). FIGURE 6-34
This acid-base profile moderates the steady-state level of the result-
Changes in plasma anionic pattern, net acid excretion, and body
ing alkalosis. In the steady state (late maintenance phase), as all fil-
electrolyte balance during development, maintenance, and correc-
tered bicarbonate is reclaimed the pH of urine becomes acidic, and
tion of diuretic-induced metabolic alkalosis. Administration of a
the net acid excretion returns to baseline. Provision of sodium
loop diuretic, such as furosemide, increases urine net acid excretion
chloride (NaCl) and potassium chloride (KCl) in the correction
(largely in the form of ammonium) as well as the renal losses of
phase alkalinizes the urine and suppresses the net acid excretion, as
chloride (Cl-), sodium (Na+), and potassium (K+). The resulting
bicarbonaturia in the company of exogenous cations (sodium and
- hyperbicarbonatemia reflects both loss of excess ammonium chlo-
potassium) supervenes [22,23]. HCO3—bicarbonate ion.
ride 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 diure-
sis (maintenance), and as long as the low-chloride diet is continued,
a new steady state is attained in which the plasma bicarbonate con-
-
centration ([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.
Maintenance of Cl–-responsive metabolic alkalosis
Basic mechanisms ↓GFR ↑HCO3– reabsorption
Mediating factors Cl– depletion ECF volume depletion K+ depletion Hypercapnia

HCO–3
Na+
3HCO–3
Cl–
P-cell +
+ K
Na+ K
Na
K
+
↑Na+ reabsorption and consequent ↑H+ and K+ secretion
Na+
Cl–
H+, NH+4
Na+
–
↓GFR K+ Cl
α-cell
HCO3
NH4
+ H+ Cl ↑H+ secretion ↑H+ secretion coupled to K+ reabsorption
↑HCO3 reabsorption
–
K+ + H+
H K+
+ +
NH4 , K Na+ Cl–
Na+ HCO–3 ß-cell
2Cl– + H+
K Cl– Cl
NH4+ Cl HCO3– secretion
↑NH4+ synthesis and HCO3
luminal entry
NH3 NH3
H 2O NH3
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. each of these factors is a vexing task. Notwithstanding, here
Increased renal bicarbonate reabsorption frequently coupled depicted is our current understanding of the participation of
with a reduced glomerular filtration rate are the basic mecha- each of these factors in the nephronal processes that maintain
nisms that maintain chloride-responsive metabolic alkalosis. chloride-responsive metabolic alkalosis [22–24]. In addition to
These mechanisms have been ascribed to three mediating fac- these factors, the secondary hypercapnia of metabolic alkalosis
tors: chloride depletion itself, extracellular fluid (ECF) volume contributes importantly to the maintenance of the prevailing
depletion, and potassium depletion. Assigning particular roles to hyperbicarbonatemia [25].
Maintenance of Cl–-resistant metabolic alkalosis
Basic mechanism ↑HCO3– reabsorption
Mediating factors Mineralocorticoid excess K+ depletion

HCO–3
Na+
3HCO–3
Cl–
P-cell +
K
Na+ Na
K ↑Na+ reabsorption and consequent ↑H+ and K+ secretion
Na+
Cl–
H+, NH+4
Na+
K+ Cl
α-cell
HCO–3
NH+4 H +
Cl– ↑H+ secretion coupled to K+ reabsorption ↑H+ secretion
↑HCO3 reabsorption
–
K+ + H+
H K+
+
NH+4, K Na+ Cl–
Na+ HCO–3 ß-cell
2Cl– H+
+
K Cl– Cl–
NH+4 –Cl
–
↑NH4+ synthesis and HCO 3
luminal entry
NH3 NH3
H 2O NH3
NH3
↑NH4+entry in medulla and secretion
in medullary collecting duct
NH+4
FIGURE 6-36
Maintenance of chloride-resistant metabolic alkalosis. Increased ened bicarbonate reabsorption and include mineralocorticoid
renal bicarbonate reabsorption is the sole basic mechanism that excess and potassium depletion. The participation of these factors
maintains chloride-resistant metabolic alkalosis. As its name in the nephronal processes that maintain chloride-resistant meta-
implies, factors independent of chloride intake mediate the height- bolic alkalosis is depicted [22–24, 26].
FIGURE 6-37
Virtually absent
(< 10 mEq/L)
Urinary composition in the diagnostic evaluation of metabolic alka-
Urinary [Cl–] • Vomiting, gastric suction losis. Assessing the urinary composition can be an important aid in
• Postdiuretic phase of loop the diagnostic evaluation of metabolic alkalosis. Measurement of uri-
and distal agents
• Posthypercapnic state nary chloride ion concentration ([Cl-]) can help distinguish between
Abundant chloride-responsive and chloride-resistant metabolic alkalosis. The
• Villous adenoma of the colon
(> 20 mEq/L)
• Congenital chloridorrhea virtual absence of chloride (urine [Cl-] < 10 mEq/L) indicates signifi-
• Post alkali loading cant chloride depletion. Note, however, that this test loses its diag-
nostic significance if performed within several hours of administra-
Urinary [K+]
tion of chloruretic diuretics, because these agents promote urinary
chloride excretion. Measurement of urinary potassium ion concen-
Low (< 20 mEq/L) • Laxative abuse tration ([K+]) provides further diagnostic differentiation. With the
• Other causes of profound K+ depletion
exception of the diuretic phase of chloruretic agents, abundance of
Abundant both urinary chloride and potassium signifies a state of mineralocor-
(> 30 mEq/L) • Diuretic phase of loop and distal agents ticoid excess [22].
• Bartter's and Gitelman's syndromes
• Primary aldosteronism
• Cushing's syndrome
• Exogenous mineralocorticoid agents
• Secondary aldosteronism
malignant hypertension
renovascular hypertension
primary reninism
• Liddle's syndrome
SIGNS AND SYMPTOMS OF METABOLIC ALKALOSIS
Central Renal (Associated

Nervous System Cardiovascular System Respiratory System Neuromuscular System Metabolic Effects Potassium Depletion)
Headache Supraventricular and Hypoventilation with Chvostek’s sign Increased organic acid and Polyuria
Lethargy ventricular arrhythmias attendant hypercapnia Trousseau’s sign ammonia production Polydipsia
Stupor Potentiation of and hypoxemia Weakness (severity Hypokalemia Urinary concentration defect
Delirium digitalis toxicity depends on degree of Hypocalcemia Cortical and medullary
Tetany Positive inotropic potassium depletion) Hypomagnesemia renal cysts
ventricular effect Hypophosphatemia
Seizures
Potentiation of hepatic
encephalopathy
FIGURE 6-38
Signs and symptoms of metabolic alkalosis. Mild to moderate these clinical manifestations. The arrhythmogenic potential of alka-
metabolic alkalosis usually is accompanied by few if any symp- lemia is more pronounced in patients with underlying heart disease
toms, unless potassium depletion is substantial. In contrast, severe and is heightened by the almost constant presence of hypokalemia,
-
metabolic alkalosis ([HCO3] > 40 mEq/L) is usually a symptomatic especially in those patients taking digitalis. Even mild alkalemia
disorder. Alkalemia, hypokalemia, hypoxemia, hypercapnia, and can frustrate efforts to wean patients from mechanical ventilation
decreased plasma ionized calcium concentration all contribute to [23,24].
of hypercalcemia after primary hyper-

parathyroidism and malignancy. Another
Ingestion of Ingestion of
large amounts large amounts of common presentation of the syndrome origi-
of calcium absorbable alkali nates from the current use of calcium car-
bonate in preference to aluminum as a phos-
phate binder in patients with chronic renal
Augmented body Increased urine calcium Urine Augmented body insufficiency. The critical element in the
content of calcium excretion (early phase) alkalinization bicarbonate stores pathogenesis of the syndrome is the devel-
opment of hypercalcemia that, in turn,
results in renal dysfunction. Generation and
maintenance of metabolic alkalosis reflect
Nephrocalcinosis the combined effects of the large bicarbon-
ate load, renal insufficiency, and hypercal-
Reduced renal cemia. Metabolic alkalosis contributes to
Renal Renal Metabolic
Hypercalcemia
vasoconstriction insufficiency bicarbonate alkalosis the maintenance of hypercalcemia by
excretion increasing tubular calcium reabsorption.
Superimposition of an element of volume
Decreased urine Increased renal contraction caused by vomiting, diuretics, or
calcium excretion reabsorption of calcium hypercalcemia-induced natriuresis can wors-
en each one of the three main components
of the syndrome. Discontinuation of calcium
Increased renal H+ secretion
carbonate coupled with a diet high in sodi-
um chloride or the use of normal saline and
furosemide therapy (depending on the sever-
FIGURE 6-39 ity of the syndrome) results in rapid resolu-
Pathophysiology of the milk-alkali syndrome. The milk-alkali syndrome comprises the triad tion of hypercalcemia and metabolic alkalo-
of hypercalcemia, renal insufficiency, and metabolic alkalosis and is caused by the ingestion sis. Although renal function also improves,
of large amounts of calcium and absorbable alkali. Although large amounts of milk and in a considerable fraction of patients with
absorbable alkali were the culprits in the classic form of the syndrome, its modern version the chronic form of the syndrome serum
is usually the result of large doses of calcium carbonate alone. Because of recent emphasis creatinine fails to return to baseline as a
on prevention and treatment of osteoporosis with calcium carbonate and the availability of result of irreversible structural changes in
this preparation over the counter, milk-alkali syndrome is currently the third leading cause the kidneys [27].
and hypercalciuria and nephrocalcinosis

Clinical syndrome Affected gene Affected chromosome Localization of tubular defect are present. In contrast, Gitelman’s syn-
drome is a milder disease presenting later
Bartter's syndrome TAL in life. Patients often are asymptomatic,
or they might have intermittent muscle
Type 1 NKCC2 15q15-q21
spasms, cramps, or tetany. Urinary con-
centrating ability is maintained; hypocal-
TAL
ciuria, renal magnesium wasting, and
CCD
hypomagnesemia are almost constant fea-
Type 2 ROMK 11q24 tures. On the basis of certain of these clin-
ical features, it had been hypothesized
Gitelman's syndrome that the primary tubular defects in
DCT
Bartter’s and Gitelman’s syndromes reflect
TSC 16q13 impairment in sodium reabsorption in the
thick ascending limb (TAL) of the loop of
Henle and the distal tubule, respectively.
Tubular Peritubular Tubular Peritubular Tubular Peritubular This hypothesis has been validated by
lumen Cell space lumen Cell space lumen Cell space recent genetic studies [28-31]. As illustrat-
2K+ 2K+ Na+ ed here, Bartter’s syndrome now has been
Na+ ATPase ATPase Cl–
3Na +
Na +
3Na+ shown to be caused by loss-of-function
K+,NH+4 + 3Na +
Cl– K ATPase + mutations in the loop diuretic–sensitive

Cl– Cl– K+ 2K sodium-potassium-2chloride cotransporter
Loop diuretics
K + Thiazides K +
(NKCC2) of the TAL (type 1 Bartter’s
K+
H+ 3HCO–3 Cl– syndrome) [28] or the apical potassium
Na+ 3Na+ channel ROMK of the TAL (where it recy-
Ca2+
Ca 2+ cles reabsorbed potassium into the lumen
for continued operation of the NKCC2
Ca2+
Mg2+ cotransporter) and the cortical collecting
Thick ascending limb (TAL) Distal convoluted tuble (DCT) Cortical collecting duct (CCD) duct (where it mediates secretion of potas-
sium by the principal cell) (type 2
Bartter’s syndrome) [29,30]. On the other
FIGURE 6-40 hand, Gitelman’s syndrome is caused by
Clinical features and molecular basis of tubular defects of Bartter’s and Gitelman’s syn- mutations in the thiazide-sensitive Na-Cl
dromes. These rare disorders are characterized by chloride-resistant metabolic alkalosis, cotransporter (TSC) of the distal tubule
renal potassium wasting and hypokalemia, hyperreninemia and hyperplasia of the jux- [31]. Note that the distal tubule is the
taglomerular apparatus, hyperaldosteronism, and normotension. Regarding differentiat- major site of active calcium reabsorption.
ing features, Bartter’s syndrome presents early in life, frequently in association with Stimulation of calcium reabsorption at
growth and mental retardation. In this syndrome, urinary concentrating ability is usual- this site is responsible for the hypocalci-
ly decreased, polyuria and polydipsia are present, the serum magnesium level is normal, uric effect of thiazide diuretics.
FIGURE 6-41
Management of Metabolic alkalosis management. Effective
For alkali gain
metabolic alkalosis Discontinue administrationof management of metabolic alkalosis requires
bicarbonate or its precursors. sound understanding of the underlying
via gastric route pathophysiology. Therapeutic efforts should
Administer antiemetics;
discontinue gastric suction; focus on eliminating or moderating the
For H+ loss administer H2 blockers or processes that generate the alkali excess and
Eliminate source H+-K+ ATPase inhibitors. on interrupting the mechanisms that perpet-
of excess alkali via renal route
Discontinue or decrease loop uate the hyperbicarbonatemia. Rarely, when
and distal diuretics; substitute the pace of correction of metabolic alkalo-
with amiloride, triamterene, or
spironolactone; discontinue
sis must be accelerated, acetazolamide or an
or limit drugs with mineralo- infusion of hydrochloric acid can be used.
For H+ shift corticoid activity. Treatment of severe metabolic alkalosis can
Potassium repletion be particularly challenging in patients with
For decreased GFR advanced cardiac or renal dysfunction. In
ECF volume repletion; such patients, hemodialysis or continuous
renal replacement therapy hemofiltration might be required [1].
For Cl– responsive
Interrupt perpetuating acidification defect
Administer NaCl and KCl
mechanisms
For Cl– resistant

acidification defect
Adrenalectomy or other surgery,
potassiuim repletion, administration
of amiloride, triamterene, or
spironolactone.
References
1. Adrogué HJ, Madias NE: Management of life-threatening acid-base 12. Adrogué HJ, Rashad MN, Gorin AB, et al.: Arteriovenous acid-base
disorders. N Engl J Med, 1998, 338:26–34, 107–111. disparity in circulatory failure: studies on mechanism. Am J Physiol
2. Madias NE, Adrogué HJ: Acid-base disturbances in pulmonary medi- 1989, 257:F1087–F1093.
cine. In Fluid, Electrolyte, and Acid-Base Disorders. Edited by Arieff 13. Adrogué HJ, Rashad MN, Gorin AB, et al.: Assessing acid-base status
Al, DeFronzo RA. New York: Churchill Livingstone; 1995:223–253. in circulatory failure: differences between arterial and central venous
3. Madias NE, Adrogué HJ, Horowitz GL, et al.: A redefinition of nor- blood. N Engl J Med 1989, 320:1312–1316.
mal acid-base equilibrium in man: carbon dioxide tension as a key 14. Madias NE: Lactic acidosis. Kidney Int 1986, 29:752–774.
determinant of plasma bicarbonate concentration. Kidney Int 1979, 15. Kraut JA, Madias NE: Lactic acidosis. In Textbook of Nephrology.
16:612–618. Edited by Massry SG, Glassock RJ. Baltimore: Williams and Wilkins;
4. Adrogué HJ, Madias NE: Mixed acid-base disorders. In The 1995:449–457.
Principles and Practice of Nephrology. Edited by Jacobson HR, 16. Hindman BJ: Sodium bicarbonate in the treatment of subtypes of
Striker GE, Klahr S. St. Louis: Mosby-Year Book; 1995:953–962. acute lactic acidosis: physiologic considerations. Anesthesiology 1990,
5. Krapf R: Mechanisms of adaptation to chronic respiratory acidosis in 72:1064–1076.
the rabbit proximal tubule. J Clin Invest 1989, 83:890–896. 17. AdroguÈ HJ: Diabetic ketoacidosis and hyperosmolar nonketotic syn-
6. Al-Awqati Q: The cellular renal response to respiratory acid-base dis- drome. In Therapy of Renal Diseases and Related Disorders. Edited
orders. Kidney Int 1985, 28:845–855. by Suki WN, Massry SG. Boston: Kluwer Academic Publishers;
7. Bastani B: Immunocytochemical localization of the vacuolar H+- 1997:233–251.
ATPase pump in the kidney. Histol Histopathol 1997, 12:769–779. 18. Adrogué HJ, Barrero J, Eknoyan G: Salutary effects of modest fluid
8. Teixeira da Silva JC Jr, Perrone RD, Johns CA, Madias NE: Rat kid- replacement in the treatment of adults with diabetic ketoacidosis.
ney band 3 mRNA modulation in chronic respiratory acidosis. Am J JAMA 1989, 262:2108–2113.
Physiol 1991, 260:F204–F209. 19. Bastani B, Gluck SL: New insights into the pathogenesis of distal
9. Respiratory pump failure: primary hypercapnia (respiratory acidosis). renal tubular acidosis. Miner Electrolyte Metab 1996, 22:396–409.
In Respiratory Failure. Edited by Adrogué HJ, Tobin MJ. Cambridge, 20. DuBose TD Jr: Hyperkalemic hyperchloremic metabolic acidosis:
MA: Blackwell Science; 1997:125–134. pathophysiologic insights. Kidney Int 1997, 51:591–602.
10. Krapf R, Beeler I, Hertner D, Hulter HN: Chronic respiratory alkalo- 21. Madias NE, Bossert WH, Adrogué HJ: Ventilatory response to chron-
sis: the effect of sustained hyperventilation on renal regulation of acidic metabolic acidosis and alkalosis in the dog. J Appl Physiol 1984,
base equilibrium. N Engl J Med 1991, 324:1394–1401. 56:1640–1646.
11. Hilden SA, Johns CA, Madias NE: Adaptation of rabbit renal cortical 22. Gennari FJ: Metabolic alkalosis. In The Principles and Practice of
Na+-H+-exchange activity in chronic hypocapnia. Am J Physiol 1989, Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St Louis:
257:F615–F622. Mosby-Year Book; 1995:932–942.
23. Sabatini S, Kurtzman NA: Metabolic alkalosis: biochemical mecha- 28. Simon DB, Karet FE, Hamdan JM, et al.: Bartter’s syndrome,
nisms, pathophysiology, and treatment. In Therapy of Renal Diseases hypokalaemic alkalosis with hypercalciuria, is caused by mutations in
and Related Disorders Edited by Suki WN, Massry SG. Boston: the Na-K-2Cl cotransporter NKCC2. Nat Genet 1996, 13:183–188.
Kluwer Academic Publishers; 1997:189–210. 29. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogene-
24. Galla JH, Luke RG: Metabolic alkalosis. In Textbook of Nephrology. ity of Bartter’s syndrome revealed by mutations in the K+ channel,
Edited by Massry SG, Glassock RJ. Baltimore: Williams & Wilkins; ROMK. Nat Genet 1996, 14:152–156.
1995:469–477. 30. International Collaborative Study Group for Bartter-like Syndromes.
25. Madias NE, Adrogué HJ, Cohen JJ: Maladaptive renal response to Mutations in the gene encoding the inwardly-rectifying renal potassi-
secondary hypercapnia in chronic metabolic alkalosis. Am J Physiol um channel, ROMK, cause the antenatal variant of Bartter syndrome:
1980, 238:F283–289. evidence for genetic heterogeneity. Hum Mol Genet 1997, 6:17–26.
26. Harrington JT, Hulter HN, Cohen JJ, Madias NE: Mineralocorticoid- 31. Simon DB, Nelson-Williams C, et al.: Gitelman’s variant of Bartter’s
stimulated renal acidification in the dog: the critical role of dietary syndrome, inherited hypokalaemic alkalosis, is caused by mutations
sodium. Kidney Int 1986, 30:43–48. in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 1996,
27. Beall DP, Scofield RH: Milk-alkali syndrome associated with calcium 12:24–30.
carbonate consumption. Medicine 1995, 74:89–96.
Disorders of
Phosphate Balance
Moshe Levi
Mordecai Popovtzer
T
he physiologic concentration of serum phosphorus (phosphate) in
normal adults ranges from 2.5 to 4.5 mg/dL (0.80–1.44 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 concen-
tration 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 skele-
ton. 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 hemo-
globin. 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 CHAPTER
hypophosphatemia or hyperphosphatemia [3–7].
The kidney plays a major role in the regulation of phosphorus
7
homeostasis. Most of the inorganic phosphorus in serum is ultrafil-
terable at the level of the glomerulus. At physiologic levels of serum
phosphorus and during a normal dietary phosphorus intake, approx-
imately 6 to 7 g/d of phosphorous is filtered by the kidney. Of that
amount, 80% to 90% is reabsorbed by the renal tubules and (type I and type II Na-Pi cotransport proteins). Most of the
the rest is excreted in the urine. Most of the filtered phospho- hormonal and metabolic factors that regulate renal tubular
rus is reabsorbed in the proximal tubule by way of a sodium phosphate reabsorption, including alterations in dietary phos-
gradient-dependent process (Na-Pi cotransport) located on the phate content and parathyroid hormone, have been shown to
apical brush border membrane [8–10]. Recently two distinct modulate the proximal tubular apical membrane expression of
Na-Pi cotransport proteins have been cloned from the kidney the type II Na-Pi cotransport protein [11–16].
FIGURE 7-1
Summary of phosphate metabolism for
a normal adult in neutral phosphate bal-
ance. Approximately 1400 mg of phosphate
is ingested daily, of which 490 mg is excret-
ed in the stool and 910 mg in the urine.
Bone
The kidney, gastrointestinal (GI) tract, and
bone are the major organs involved in
phosphorus homeostasis.
GI intake
1400 mg/d Digestive juice
phosphorus
Formation Resorption
210 mg/d 210 mg/d
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 ECF or serum Major determinants of extracellular fluid or serum inorganic phos-
inorganic phosphate (Pi) concentration phate (Pi) concentration include dietary Pi intake, intestinal Pi
absorption, urinary Pi excretion and shift into the cells.
Dietary intake
Intestinal
absorption Serum Pi Cells
Urinary excretion
Disorders of Phosphate Balance 7.3
Renal Tubular Phosphate Reabsorption

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

High phosphate diet Low phosphate diet
HPO42– Na+ Parathyroid hormone and parathyroid- Growth hormone
Parathyroid hormone HPO42– hormone–related protein
dietary Pi content Insulin
3Na + A– Glucocorticoids Thyroid hormone
Chronic metabolic acidosis 1,25-dihydroxy-vitamin D3
Acute respiratory acidosis Chronic metabolic alkalosis
Aging High calcium diet
Calcitonin High potassium diet
Atrial natriuretic peptide Stanniocalcin
FIGURE 7-5 Fasting
Celluar model of proximal tubular phosphate reabsorption. Major Hypokalemia
physiologic determinants of renal tubular phosphate reabsorption are Hypercalcemia
alterations in parathyroid hormone activity and alterations in dietary Diuretics
phosphate content. The regulation of renal tubular phosphate reab- Phosphatonin
sorption occurs by way of alterations in apical membrane sodium-
phosphate (Na-Pi) cotransport 3Na+-HPO24 activity [11–14].
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
A B 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 net-
work because pretreatment with colchicine
prevents the upregulation of Na-Pi cotrans-
port activity and Na-Pi protein expression
(C, D). In this immunofluorescence micro-
graph, 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
C D membrane results in yellow color [14].

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 immunofluores-
cence 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.
A B
490 600
Cholesterol,
nmol/mg
ng/mg
GlcCer,
440
A 390
1600
0
A PDMP Control DEX
pmol/5s/mg
Na-Pi,
1100 1600
pmol/5s/mg
Na-Pi,
600
Low Pi diet Control High Pi diet
B and/or young and/or aged
FIGURE 7-9
0
Renal cholesterol content modulates renal tubular phosphate reab- B PDMP Control DEX
sorption. 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 con- FIGURE 7-10
tent (A) and Na-Pi cotransport activity (B). Studies in isolated BBM Renal glycosphingolipid content modulates renal tubular phosphate
vesicles and recent studies in opossum kidney cells grown in culture reabsorption. In rats treated with dexamethasone (DEX) and in rats
indicate that direct alterations in cholesterol content per se modu- fed a potassium-deficient diet, an inverse correlation exists between
late Na-Pi cotransport activity [15]. CON—controls. 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].
Hypophosphatemia/Hyperphosphatemia
FIGURE 7-11
MAJOR CAUSES OF HYPOPHOSPHATEMIA Major causes of hypophosphatemia. (From
Angus [1]; with permission.)
Internal redistribution Decreased intestinal absorption Increased urinary excretion

Increased insulin, particularly Inadequate intake Primary and secondary
during refeeding Antacids containing aluminum hyperparathyroidism
Acute respiratory alkalosis or magnesium Vitamin D deficiency or resistance
Hungry bone syndrome Steatorrhea and chronic diarrhea Fanconi’s syndrome
Miscellaneous: osmotic diuresis,
proximally acting diuretics, acute
volume expansion
CAUSES OF MODERATE HYPOPHOSPHATEMIA
Pseudohypophosphatemia Hormonal effects Cellular uptake syndromes Increased excretion into urine
Mannitol Insulin Recovery from hypothermia Hyperparathyroidism
Bilirubin Glucagon Burkitt’s lymphoma Renal tubule defects
Acute leukemia Epinephrine Histiocytic lymphoma Fanconi’s syndrome
Decreased dietary intake Androgens Acute myelomonocytic leukemia X-linked hypophosphatemic rickets
Decreased intestinal absorption Cortisol Acute myelogenous leukemia Hereditary hypophosphatemic rickets
Vitamin D deficiency Anovulatory hormones Chronic myelogenous leukemia with hypercalciuria
Malabsorption Nutrient effects in blast crisis Polyostotic fibrous dysphasia
Steatorrhea Glucose Treatment of pernicious anemia Panostotic fibrous dysphasia
Secretory diarrhea Fructose Erythropoietin therapy Neurofibromatosis
Vomiting Glycerol Erythrodermic psoriasis Kidney transplantation
PO34-binding antacids Lactate Hungry bone syndrome Oncogenic osteomalacia
Amino acids After parathyroidectomy Recovery from hemolytic-uremic
Shift from serum into cells
Xylitol Acute leukemia syndrome
Respiratory alkalosis
Aldosteronism
Sepsis
Licorice ingestion
Heat stroke
Volume expansion
Neuroleptic malignant syndrome
Inappropriate secretion of antidiuretic
Hepatic coma
hormone
Salicylate poisoning
Mineralocorticoid administration
Gout
Corticosteroid therapy
Panic attacks
Diuretics
Psychiatric depression
Aminophylline therapy
FIGURE 7-12
Causes of moderate hypophosphatemia. (From Popovtzer, et al. [6];
with permission.)
CAUSES OF SEVERE HYPOPHOSPHATEMIA CAUSES OF HYPOPHOSPHATEMIA IN PATIENTS

WITH NONKETOTIC HYPERGLYCEMIA OR
DIABETIC KETOACIDOSIS
Acute renal failure: excessive P binders Reye’s syndrome
Chronic alcoholism and alcohol After major surgery
withdrawal Periodic paralysis Decreased net Acute movement of
Dietary deficiency and PO34-binding Acute malaria intestinal phosphate Increased urinary extracellular phos-
antacids Drug therapy absorption phosphate excretion phate into the cells
Hyperalimentation Ifosfamide Decreased phosphate Glucosuria-induced Insulin therapy
Neuroleptic malignant syndrome Cisplatin intake osmotic diuresis
Recovery from diabetic ketoacidosis Acetaminophen intoxication Acidosis
Recovery from exhaustive exercise Cytokine infusions
Kidney transplantation Tumor necrosis factor
Respiratory alkalosis Interleukin-2
Severe thermal burns FIGURE 7-14
Therapeutic hypothermia
Causes of hypophosphatemia in patients with nonketotic hyper-
glycemia or diabetic ketoacidosis.
FIGURE 7-13
Causes of severe hypophosphatemia. (From Popovtzer, et al. [6];
with permission.)
CAUSES OF HYPOPHOSPHATEMIA CAUSES OF HYPOPHOSPHATEMIA IN PATIENTS

IN PATIENTS WITH ALCOHOLISM WITH RENAL TRANSPLANTATION
Decreased net Acute movement of Increased urinary phosphate excretion

intestinal phosphate Increased urinary extracellular phos- Persistent hyperparathyroidism (hyperplasia or adenoma)
absorption phosphate excretion phate into the cells
Proximal tubular defect (possibly induced by glucocorticoids, cyclosporine, or both)
Poor dietary intake of Alcohol-induced Insulin release induced by
phosphate and vitamin D reversible proximal intravenous solutions
Use of phosphate binders tubular defect containing dextrose
to treat recurring gastritis Secondary hyperparathy- Acute respiratory alkalosis FIGURE 7-16
Chronic diarrhea roidism induced by caused by alcohol
vitamin D deficiency withdrawal, sepsis, Causes of hypophosphatemia in patients with renal transplantation.
or hepatic cirrhosis
Refeeding of the patient
who is malnourished
FIGURE 7-15
Causes of hypophosphatemia in patients with alcoholism.
FIGURE 7-17
MAJOR CONSEQUENCES OF HYPOPHOSPHATEMIA 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
SIGNS AND SYMPTOMS OF HYPOPHOSPHATEMIA
Central Skeletal and

nervous system Cardiac Pulmonary smooth muscle Hematologic Metabolic
dysfunction dysfunction dysfunction dysfunction dysfunction Bone disease Renal effects effects
Metabolic Impaired Weakness of the Proximal myopathy Erythrocytes Increased bone Decreased Low parathyroid
encephalopathy myocardial diaphragm Dysphagia and ileus Increased resorption glomerular hormone levels
owing to tissue contractility Respiratory failure Rhabdomyolysis erythrocyte Rickets and osteo- filtration rate Increased 1,25-dihy-
ischemia Congestive heart rigidity malacia caused by Decreased tubular droxy-vitamin D3
Irritability failure Hemolysis decreased bone transport levels
Paresthesias Leukocytes mineralization maximum for Increased creatinine
Confusion bicarbonate phosphokinase
Impaired
Delirium phagocytosis Decreased renal levels
gluconeogenesis Increased aldolase
Coma Decreased
granulocyte Decreased titratable levels
chemotaxis acid excretion
Platelets Hypercalciuria
Defective clot Hypermagnesuria
retraction
Thrombocytopenia
FIGURE 7-18
Signs and symptoms of hypophosphatemia. (Adapted from Hruska
and Slatopolsky [2] and Hruska and Gupta [7].)
FIGURE 7-19
Pseudofractures (Looser’s transformation zones) at the margins of
the scapula in a patient with oncogenic osteomalacia. Similar to the
genetic X-linked hypophosphatemic rickets, a circulating phospha-
turic factor is believed to be released by the tumor, causing phos-
phate 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 pathogno-
monic 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 Kossa’s 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.
FIGURE 7-21(see Color Plate)

Microscopic appearance of bone section from a patient with vita-
min 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 hypophos-

phatemia (plasma phosphate
concentration < 1 mg/dL) Phosphate depletion Hypophosphatemic rickets
10 mg/kg/d, intravenously, until the 2–4 g/d (64 to 128 mmol/d), orally, 1–4 g/d (32 to 128 mmol/d), orally,
plasma phosphate concentration in 3 to 4 divided doses in 3 to 4 divided doses
reaches 2 mg/dL
FIGURE 7-23
PHOSPHATE PREPARATIONS FOR ORAL USE Phosphate preparations for oral use.
Preparation Phosphate, mg Sodium, mEq Potassium, mEq

K-Phos Neutral®, tablet 250 13 1.1
(Beach Pharmaceuticals, Conestee, SC)
Neutra-Phos®, capsule or 75-mL solution 250 7.1 7.1
(Baker Norton Pharmaceuticals, Miami, FL)
Neutra-Phos K®, capsule or 75-mL solution 250 0 14.2
(Baker Norton Pharmaceuticals, Miami, FL)
FIGURE 7-24
PHOSPHATE PREPARATIONS FOR INTRAVENOUS USE Phosphate preparations for intravenous use.
(From Popovtzer, et al. [6]; with permission.)
Phosphate, Sodium, Potassium,

Phosphate preparation Composition, mg/mL mmol/mL mEq/mL mEq/mL
Potassium 236 mg K2HPO4 3.0 0 4.4
224 mg KH2PO4
Sodium 142 mg Na2HPO4 3.0 4.0 0
276 mg NaH2HPO4.H2O
Neutral sodium 10.0 mg Na2HPO 0.09 0.2 0
2.7 mg NaH2PO4.H2O
Neutral sodium, potassium 11.5 mg Na2HPO4 1.10 0.2 0.02
2.6 mg KH2PO4
3 mmol/mL of phosphate corresponds to 93 mg of phosphorus.

CAUSES OF HYPERPHOSPHATEMIA
Pseudohyperphosphatemia Increased endogenous loads Reduced urinary excretion Miscellaneous

Multiple myeloma Tumor lysis syndrome Renal failure Fluoride poisoning
Extreme hypertriglyceridemia Rhabdomyolysis Hypoparathyroidism -Blocker therapy
In vitro hemolysis Bowel infarction Hereditary Verapamil
Increased exogenous phosphorus Malignant hyperthermia Acquired Hemorrhagic shock
Heat stroke Pseudohypoparathyroidism Sleep deprivation
load or absorption
Acid-base disorders Vitamin D intoxication
Phosphorus-rich cow’s milk in premature
Organic acidosis Growth hormone
neonates
Lactic acidosis Insulin-like growth factor-1
Vitamin D intoxication
Ketoacidosis Glucocorticoid withdrawal
PO34-containing enemas
Respiratory acidosis Mg2+ deficiency
Intravenous phosphorus supplements
Chronic respiratory alkalosis Tumoral calcinosis
White phosphorus burns
Diphosphonate therapy
Acute phosphorus poisoning
Hyopophosphatasia
FIGURE 7-25
Causes of hyperphosphatemia. (From Knochel and Agarwal [5];
with permission.)
CLINICAL MANIFESTATIONS OF TREATMENT OF HYPERPHOSPHATEMIA

HYPERPHOSPHATEMIA
Acute hyperphosphatemia in Chronic hyperphosphatemia in

Consequences of secondary patients with adequate renal patients with end-stage renal
changes in calcium, parathyroid function disease
hormone, vitamin D metabolism Consequences of ectopic Saline diuresis that causes phosphaturia Dietary phosphate restriction
and hypocalcemia: calcification:
Phosphate binders to decrease gastroin-
Neuromuscular irritability Periarticular and soft tissue calcification testinal phosphate reabsorption
Tetany Vascular calcification
Hypotension Ocular calcification
Increased QT interval Conduction abnormalities
Pruritus FIGURE 7-27
Treatment of hyperphosphatemia.
FIGURE 7-26
Clinical manifestations of hyperphosphatemia.
A B
FIGURE 7-28
Periarticular calcium phosphate deposits in a patient with end- resolution of calcific masses after dietary phosphate restriction and
stage renal disease who has severe hyperphosphatemia and a high oral phosphate binders. Left shoulder joint before (A) and after (B)
level of the product of calcium and phosphorus. Note the partial treatment. (From Pinggera and Popovtzer [17]; with permission.)
A B
FIGURE 7-29
Resolution of soft tissue calcifications. The palms of the hands of patient has a high level of the product of calcium and phosphorus.
the patient in Figure 7-28 with end-stage renal disease are shown (From Pinggera and Popovtzer [17]; with permission.)
before (A) and after (B) treatment of hyperphosphatemia. The
A B
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 FIGURE 7-32 (see Color Plate)

Roentgenographic appearance of femoral arterial vascular calcifica- Microscopic appearance of a cross section of a calcified artery in a
tion in a patient on dialysis who has severe hyperphosphatemia. The patient with end-stage renal disease undergoing chronic dialysis. The
patient has a high level of the product of calcium and phosphorus. patient has severe hyperphosphatemia and a high level of the prod-
uct 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 patient’s brothers.

Massive periarticular calcium phosphate deposit in the plantar Complications of the use of aluminum-based phosphate binders to
joints in the same patient in Figure 7-33 who has genetic tumoral control hyperphosphatemia. Appearance of bone section from a
calcinosis. patient with end-stage renal disease who was treated with oral alu-
minum 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.
FIGURE 7-36 (see Color Plate) FIGURE 7-37 (see Color Plate)
The same bone section as in Figure 7-35 but under polarizing lens- The same bone section as in Figure 7-35 with positive aluminum
es, illustrating the partially woven appearance of osteoid typical of stain of the trabecular surface. These findings are consistent with
chronic renal failure. 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.
References
1. Agus ZS: Phosphate metabolism. In UpToDate, Inc.. Edited by Burton 10. Suki WN, Rouse D: Renal Transport of calcium, magnesium, and
D. Rose, 1998. phosphate. In The Kidney, edn 5. Edited by Brenner BM.
2. Hruska KA, Slatopolsky E: Disorders of phosphorus, calcium, and Philadelphia: WB Saunders; 1996.
magnesium metabolism. In Diseases of the Kidney, edn 6. Edited by 11. Levi M, Kempson, SA, Lõtscher M, et al.: Molecular regulation of
Schrier RW, Gottschalk CW. Boston: Little and Brown; 1997. renal phosphate transport. J Membrane Biol 1996, 154:1–9.
3. Levi M, Knochel JP: The management of disorders of phosphate 12. Levi M, Lõtscher M, Sorribas V, et al.: Cellular mechanisms of acute
metabolism. In Therapy of Renal Diseases and Related Disorders. and chronic adaptation of rat renal phosphate transporter to alter-
Edited by Massry SG, Suki WN. Boston, Martinus Nijhoff; 1990. ations in dietary phosphate. Am J Physiol 1994, 267:F900–F908.
4. Levi M, Cronin RE, Knochel JP: Disorders of phosphate and magne- 13. Kempson SA, Lõtscher M, Kaissling B, et al.: Effect of parathyroid
sium metabolism. In Disorders of Bone and Mineral Metabolism. hormone on phosphate transporter mRNA and protein in rat renal
Edited by Coe FL, Favus MJ. New York: Raven Press; 1992. proximal tubules. Am J Physiol 1995, 268:F784–F791.
5. Knochel JP, Agarwal R: Hypophosphatemia and hyperphosphatemia. 14. Lõtscher M, Biber J, Murer H, et al.: Role of microtubules in the
In The Kidney, edn 5. Edited by Brenner BM. Philadelphia: WB rapid upregulation of rat renal proximal tubular Na-Pi cotransport
Saunders; 1996. following dietary P restriction. J Clin Invest 1997, 99:1302–1312.
6. Popovtzer M, Knochel JP, Kumar R: Disorders of calcium, phosphorus, 15. Levi M, Baird B, Wilson P: Cholesterol modulates rat renal brush border
vitamin D, and parathyroid hormone activity. In Renal Electrolyte membrane phosphate transport. J Clin Invest 1990, 85:231–237.
Disorders, edn 5. Edited by Schrier RW. Philadelphia: Lippincott- 16. Levi M, Shayman J, Abe A, et al.: Dexamethasone modulates rat renal
Raven; 1997. brush border membrane phosphate transporter mRNA and protein
7. Hruska K, Gupta A: Disorders of phosphate homeostasis. In abundance and glycosphingolipid composition. J Clin Invest 1995,
Metabolic Bone Disease, edn 3. Edited by Avioli LV, SM Krane. 96:207–216.
New York: Academic Press; 1998. 17. Pinggera WF, Popovtzer MM: Uremic osteodystrophy: the therapeutic
8. Murer H, Biber J: Renal tubular phosphate transport: cellular mecha- consequences of effective control of serum phosphorus. JAMA 1972,
nisms. In The Kidney: Physiology and Pathophysiology, edn 2. Edited 222:1640–1642.
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.
Acute Renal Failure:
Causes and Prognosis
Fernando Liaño
Julio Pascual
T
here are many causes—more than fifty are given within this
present chapter—that can trigger pathophysiological mecha-
nisms leading to acute renal failure (ARF). This syndrome is
characterized by a sudden decrease in kidney function, with a conse-
quence of loss of the hemostatic equilibrium of the internal medium.
The primary marker is an increase in the concentration of the nitroge-
nous 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 sur-
viving 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 today’s 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 CHAPTER
of ARF is of great utility for both the patients and their families, the
medical specialists (for analysis of therapeutical maneuvers and
8
options), and for society in general (demonstrating the monetary costs
of treatment). This chapter also contains a brief review of the prog-
nostic tools available for application to ARF.
8.2 Acute Renal Failure
Causes of Acute Renal Failure
Sudden causes Induce Called CAUSES OF PARENCHYMATOUS

affecting
A ACUTE RENAL FAILURE
c
u
Renal Prerenal t
perfusion e
Acute tubular necrosis
r
e Hemodynamic: cardiovascular surgery,* sepsis,* prerenal causes*
n Toxic: antimicrobials,* iodide contrast agents,* anesthesics, immunosuppressive or
GFR a
Parenchymal Parenchymatous l antineoplastic agents,* Chinese herbs, Opiaceous, Extasis, mercurials, organic
structures solvents, venoms, heavy metals, mannitol, radiation
f
a Intratubular deposits: acute uric acid nephropathy, myeloma, severe hypercalcemia,
i
l primary oxalosis, sulfadiazine, fluoride anesthesics
Urine u Organic pigments (endogenous nephrotoxins):
Obstructive r
output e Myoglobin rhabdomyolisis: muscle trauma; infections; dermatopolymyositis;
metabolic alterations; hyperosmolar coma; diabetic ketoacidosis; severe
hypokalemia; hyper- or hyponatremia; hypophosphatemia; severe hypothy-
FIGURE 8-1 roidism; malignant hyperthermia; toxins such as ethylene glycol, carbon
monoxide, mercurial chloride, stings; drugs such as fibrates, statins, opioids
Characteristics of acute renal failure. Acute renal failure is a
and amphetamines; hereditary diseases such as muscular dystrophy,
syndrome characterized by a sudden decrease of the glomerular metabolopathies, McArdle disease and carnitine deficit
filtration rate (GFR) and consequently an increase in blood Hemoglobinuria: malaria; mechanical destruction of erythrocytes with extracorporeal
nitrogen products (blood urea nitrogen and creatinine). It is circulation or metallic prosthesis, transfusion reactions, or other hemolysis;
associated with oliguria in about two thirds of cases. Depending heat stroke; burns; glucose-6-phosphate dehydrogenase; nocturnal paroxystic
on the localization or the nature of the renal insult, ARF is classi- hemoglobinuria; chemicals such as aniline, quinine, glycerol, benzene, phenol,
fied as prerenal, parenchymatous, or obstructive (postrenal). hydralazine; insect venoms
Acute tubulointerstitial nephritis (see Fig. 8-4)
Vascular occlusion
Principal vessels: bilateral (unilateral in solitary functioning kidney) renal artery
CAUSES OF PRERENAL ACUTE RENAL FAILURE thrombosis or embolism, bilateral renal vein thrombosis
Small vessels: atheroembolic disease, thrombotic microangiopathy, hemolytic-uremic
syndrome or thrombotic thrombocytopenic purpura, postpartum acute renal
Decreased effective extracellular volume failure, antiphospholipid syndrome, disseminated intravascular coagulation,
scleroderma, malignant arterial hypertension, radiation nephritis, vasculitis
Renal losses: hemorrhage, vomiting, diarrhea, burns, diuretics
Redistribution: hepatopathy, nephrotic syndrome, intestinal obstruction, pancreatitis, Acute glomerulonephritis
peritonitis, malnutrition Postinfectious: streptococcal or other pathogen associated with visceral abscess,
Decreased cardiac output: cardiogenic shock, valvulopathy, myocarditis, myocardial endocarditis, or shunt
infarction, arrhythmia, congestive heart failure, pulmonary emboli, cardiac tamponade Henoch-Schonlein purpura
Peripheral vasodilation: hypotension, sepsis, hypoxemia, anaphylactic shock, treatment Essential mixed cryoglobulinemia
with interleukin L2 or interferons, ovarian hyperstimulation syndrome Systemic lupus erythematosus
Renal vasoconstriction: prostaglandin synthesis inhibition, -adrenergics, sepsis, hepa- ImmunoglobulinA nephropathy
torenal syndrome, hypercalcemia Mesangiocapillary
Efferent arteriole vasodilation: converting-enzyme inhibitors 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
FIGURE 8-2 coagulation
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. FIGURE 8-3
Causes of parenchymal acute renal failure (ARF). When the sud-
den 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 parenchy-
matous ARF. Multiple causes have been described, some of them
constituting the most frequent ones are marked with an asterisk.
Acute Renal Failure: Causes and Prognosis 8.3
MOST FREQUENT CAUSES OF ACUTE CAUSES OF OBSTRUCTIVE ACUTE RENAL FAILURE

TUBULOINTERSTITIAL NEPHRITIS
Congenital anomalies Retroperitoneal fibrosis Infections

Antimicrobials Immunological Ureterocele Idiopathic Schistosomiasis
Penicillin Systemic lupus erythematosus Bladder diverticula Associated with Tuberculosis
Ampicillin Rejection Posterior urethral valves aortic aneurysm Candidiasis
Rifampicin Infections (at present quite rare) Neurogenic bladder Trauma Aspergillosis
Sulfonamides Neoplasia Acquired uropathies Iatrogenic Actinomycosis
Analgesics, anti-inflammatories Myeloma Benign prostatic hypertrophy Drug-induced Other
Fenoprofen Lymphoma Urolithiasis Gynecologic non-neoplastic Accidental urethral
Ibuprofen Acute leukemia Papillary necrosis Pregnancy-related catheter occlusion
Naproxen Idiopathic Iatrogenic ureteral ligation Uterine prolapse
Amidopyrine Isolated Malignant diseases Endometriosis
Glafenine Associated with uveitis Prostate Acute uric acid nephropathy
Other drugs Bladder Drugs
Cimetidine Urethra -Aminocaproic acid
Allopurinol Cervix Sulfonamides
Colon
Breast (metastasis)
FIGURE 8-4
Most common causes of tubulointerstitial nephritis. During the last
years, acute tubulointerstitial nephritis is increasing in importance as FIGURE 8-5
a cause of acute renal failure. For decades infections were the most Causes of obstructive acute renal failure. Obstruction at any level of
important cause. At present, antimicrobials and other drugs are the the urinary tract frequently leads to acute renal failure. These are the
most common causes. most frequent causes.
FIGURE 8-6
Arterial disease Other parenchymal This figure shows a comparison of the percent-
2.5% 4.5% ages of the different types of acute renal failure
ATN ATN ATIN (ARF) in a western European country in
43.1% Other parenchymal 45% 1.6% 1977–1980 and 1991: A, distribution in a typi-
6.4% Arterial disease cal Madrid hospital; B, the Madrid ARF Study
Obstructive Obstructive 1%
[1]. There are two main differences: 1) the
3.4% 10%
Prerenal Prerenal
appearance of a new group in 1991, “acute
40.6% 21% on chronic ARF,” in which only mild forms
Acute-on-chronic (serum creatinine concentrations between 1.5
13% and 3.0 mg/dL) were considered, for method-
n = 202 n = 748 ological reasons; 2) the decrease in prerenal
A 1977–1980 B 1991 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
FINDINGS OF THE MADRID STUDY 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).
Condition Incidence (per million persons per year) 95% CI
Acute tubular necrosis 88 79–97
Prerenal acute renal failure 46 40–52
Acute on chronic renal failure 29 24–34
Obstructive acute renal failure 23 19–27
Glomerulonephritis (primary or secondary) 6.3 4.8–8.3
Acute tubulointerstitial nephritis 3.5 1.7–5.3
Vasculitis 3.5 1.7–5.3
Other vascular acute renal failure 2.1 0.8–3.4
Total 209 195–223
FIGURE 8-8
The most frequent causes of acute renal
Sclerodermal crisis 1
failure (ARF) in patients with preexisting
Tumoral obstruction 1
ATN Secondary glomerulonephritis 1 chronic renal failure are acute tubular
43% Vasculitis 1 necrosis (ATN) and prerenal failure. The
Other Malignant hypertension 2.1 distribution of causes of ARF in these
15% patients is similar to that observed in
Myeloma 2.1
patients without previous kidney diseases.
Prerenal Acute tubulointerstitial nephritis 2.1 (Data from Liaño et al. [1])
Not recorded
27% 15%
Atheroembolic disease 4.2
FIGURE 8-9
Discovering the cause of acute renal
Bun/SCr
increase
failure (ARF). This is a great challenge
for clinicians. This algorithm could help
Normal or big kidneys to determine the cause of the increase in
Small kidneys (excluding amiloidosis and blood urea nitrogen (BUN) or serum
polycystic kidney disease
creatinine (SCr) in a given patient.
and/or and/or
↑ SCr < 0.5 mg/dL/d ↑ SCr > 0.5 mg/dL/d
Previous and/or and/or Previous

SCr increased SCr normal
CRF ARF
+
Echography Urinary tract
dilatation
↑ SCr < 0.5 mg/dL/d
Normal Repeat
echograph
after 24 h
Flare of previous Acute-on-chronic
disease renal failure
Normal
No Prerenal Yes Obstructive

factors? ARF
Parenchymatous Data indicating Improvement
glomerular or Yes glomerular No
with specific
systemic ARF or systemic treatment?
disease?
Great or
Vascular Yes
Yes small vessel No
ARF disease? Prerenal
Acute ARF
tubulointerstitial Data indicating
nephritis Yes interstitial No
disease?
Tumor lysis Acute
Sulfonamides Crystals or tubular
Yes tubular No
Amyloidosis necrosis
deposits? No
Other
FIGURE 8-10
BIOPSY RESULTS IN THE MADRID STUDY 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
Disease Patients, n cause is acute tubular necrosis (ATN). Patients with well-established
clinical and laboratory features of ATN receive no benefit from renal
Primary GN 12
Extracapillary 6 biopsy. This histologic tool should be reserved for parenchymatous
Acute proliferative 3 ARF cases when there is no improvement of renal function after 3
Endocapillary and extracapillary 2 weeks’ evolution of ARF. By that time, most cases of ATN have
Focal sclerosing 1 resolved, so other causes could be influencing the poor evolution.
Secondary GN 6 Biopsy is mandatory when a potentially treatable cause is suspected,
Antiglomerular basement membrane 3 such as vasculitis, systemic disease, or glomerulonephritis (GN) in
Acute postinfectious 2 adults. Some types of parenchymatous non-ATN ARF might have
Diffuse proliferative (systemic lupus erythematosus) 1*
histologic confirmation; however kidney biopsy is not strictly neces-
Vasculitis 10
Necrotizing 5* sary in cases with an adequate clinical diagnosis such as myeloma,
Wegener’s granulomatosis 3 uric acid nephropathy, or some types of acute tubulointerstitial
Not specified 2 nephritis . Other parenchymatous forms of ARF can be accurately
Acute tubular necrosis 4* diagnosed without a kidney biopsy. This is true of acute post-strepto-
Acute tubulointerstitial nephritis 4 coccal GN and of hemolytic-uremic syndrome in children. Kidney
Atheroembolic disease 2 biopsy was performed in only one of every 16 ARF cases in the
Kidney myeloma 2* Madrid ARF Study [1]. All patients with primary GN, 90% with
Cortical necrosis 1 vasculitis and 50% with secondary GN were diagnosed by biopsy at
Malignant hypertension 1 the time of ARF. As many as 15 patients were diagnosed as having
ImmunoglobulinA GN + ATN 1 acute tubulointerstitial nephritis, but only four (27%) were biopsied.
Hemolytic-uremic syndrome 1 Only four of 337 patients with ATN (1.2%) underwent biopsy.
Not recorded 2 (Data from Liaño et al. [1].)
* One patient with acute-on-chronic renal failure.
Predisposing Factors for Acute Renal Failure

Other
figure shows the
Renal insult
Very Obstructive main causes of
elderly Elderly Young Prerenal ARF, dividing a
Advanced age Acute tubular population diag-
11% 12% 17% necrosis
nosed with ARF
Proteinuria
11% 7% into the very elder-
20%
ly (at least 80
Volume 21% years), elderly (65
depletion 29%
to 79), and young
30%
(younger than 65).
Myeloma Essentially, acute
tubular necrosis
56% (ATN) is less
Diuretic use 48%
39% frequent (P=0.004)
and obstructive
Diabetes ARF more frequent
mellitus (n=103) (n=256) (n=389) (P<0.001) in the
Previous cardiac very old than in
or renal insufficiency FIGURE 8-12 the youngest
Causes of acute renal failure (ARF) rela- patients. Prerenal
tive to age. Although the cause of ARF is diseases appear
Higher probability usually multifactorial, one can define the with similar
for ARF cause of each case as the most likely con- frequency in the
tributor to impairment of renal function. three age groups.
FIGURE 8-11 One interesting approach is to distribute (Data from Pascual
the causes of ARF according to age. This et al. [3].)
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.
Epidemiology of Acute Renal Failure

FIGURE 8-13
EPIDEMIOLOGY OF ACUTE RENAL FAILURE Prospective studies. Prospective epidemiologic
studies of acute renal failure (ARF) in large
populations have not often been published .
Study Period Study Population Incidence The first study reported by Eliahou and
Investigator, Year Country (City) (Study Length) (millions) (pmp/y) colleagues [4] was developed in Israel in the
Eliahou et al., 1973 [4] Israel 1965–1966 (2 yrs) 2.2 52
1960s and included only Jewish patients.
Abraham et al., 1989 [5] Kuwait 1984–1986 (2 yrs) 0.4 95
This summary of available data suggests a
McGregor et al., 1992 [6] United Kingdom 1986–1988 (2 yrs) 0.94 185
progressive increase in ARF incidence that at
(Glasgow) present seems to have stabilized around 200
Sanchez et al., 1992 [7] Spain (Cuenca) 1988–1989 (2 yrs) 0.21 254 cases per million population per year
Feest et al., 1993 [8] United Kingdom 1986–1987 (2 yrs) 0.44 175 (pmp/y). No data about ARF incidence are
(Bristol and Devon) available from undeveloped countries.
Madrid ARF Study Spain (Madrid) 1991–1992 (9 mo) 4.23 209
Group, 1996 [1]
FIGURE 8-14
EPIDEMIOLOGY OF ACUTE RENAL FAILURE: Number of patients needing dialysis for acute renal failure (ARF),
NEED OF DIALYSIS 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 dialy-
Investigator, Year Country Cases (pmp/y) sis facilities for ARF management. In 1973 Israeli figures showed a
lower rate of dialysis than other countries at the same time. The
Lunding et al., 1964 [9] Scandinavia 28
very limited access to dialysis in developing countries supports this
Eliahou et al., 1973 [4] Israel 17*
hypothesis. At present, the need for dialysis in a given area depends
Lachhein et al., 1978 [10] West Germany 30
on the level of health care offered there. In two different countries
Wing et al., 1983 [11] European Dialysis and 29
Transplant Association (eg, the United Kingdom and Spain) the need for dialysis for ARF
Wing et al., 1983 [11] Spain 59 was very much lower when only secondary care facilities were avail-
Abraham et al., 1989 [5] Kuwait 31 able. At this level of health care, both countries had the same rate
Sanchez et al., 1992 [7] Spain 21† of dialysis. The Spanish data of the EDTA-ERA Registry in 1982
McGregor et al., 1992 [6] United Kingdom 31 gave a rate of dialysis for ARF of 59 pmp/y. This rate was similar to
Gerrard et al., 1992 [12] United Kingdom 71 that found in the Madrid ARF Study 10 years later. These data sug-
Feest et al., 1993 [8] United Kingdom 22† gest that, when a certain economical level is achieved, the need of
Madrid ARF Study Group [1] Spain 57 ARF patients for dialysis tends to stabilize.
* Very restrictive criteria.

† Only secondary care facilities.
FIGURE 8-15
HISTORICAL PATTERNS OF ACUTE RENAL FAILURE Historical perspective of acute renal failure
(ARF) patterns in France, India, and South
Africa. In the 1960s and 1970s, obstetrical
Proportion of Cases, % causes were a great problem in both France
and India and overall incidences of ARF were
India France India South Africa similar. Surgical cases were almost negligible in
France 1973 1965–1974 1981–1986 1981–1986 1986–1988 India at that time, probably because of the rel-
Surgical 46 11 30 30 8 ative unavailability of hospital facilities. During
Medical 30 67 70 61 77 the 1980s surgical and medical causes were
Obstetric 24 22 2 9 15 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.
FIGURE 8-15 (Continued)

Changes in classification criteria—inclusion of a larger percentage level of a country determines the spectrum of ARF causes observed;
of medical cases than a decade before—could be an alternative 2) when a developing country improves its economic situation, the
explanation. In addition, obstetric cases had almost disappeared in spectrum moves toward that observed in developed countries; and
France in the 1980s, but they were still an important cause of ARF 3) great differences can be detected in ARF causes among develop-
in India. In a South African study that excluded the white popula- ing countries, depending on their individual economic power. (Data
tion the distribution of ARF causes was almost identical to that from Kleinknecht [13]; Chugh et al. [14]; Seedat et al. [15].)
observed in India 20 years earlier. In conclusion, 1) the economic
25
Percentage of total ARF cases
HD HD UF
20 68% 60% 1%
15 PD
Diarrhea Hemolysis
Obstetric 5%
CRRT PD CRRT
10 1% 31% 33%
5 EDTA (1982) Madrid study (1992)
A 2221 patients B 270 patients

0
1965–1974 1975–1980 1981–1986
Years
FIGURE 8-17
Evolution of dialysis techniques for acute renal failure (ARF) in Spain.
FIGURE 8-16 A, The percentages of different modalities of dialysis performed in
Changing trends in the causes of acute renal failure (ARF) in the Spain in the early 1980s. B, The same information obtained a decade.
Third-World countries. Trends can be identified from the analysis of At this latter time, 90% of conventional hemodialysis (HD) was per-
medical and obstetric causes by the Chandigarh Study [14]. Chugh formed using bicarbonate as a buffer. These rates are those
and colleagues showed how obstetric (septic abortion) and hemolytic of a developed country. In developing countries, dialysis should be
(mainly herbicide toxicity) causes tended to decrease as economic performed according to the available facilities and each individual
power and availability of hospitalization improved with time. These doctor’s experience in the different techniques. PD—peritoneal dial-
causes of ARF, however, did not completely disappear. By contrast, ysis; CRRT—continuous renal replacement technique;
diarrheal causes of ARF, such as cholera and other gastrointestinal dis- UF—isolated ultrafiltration. (A, Data from the EDTA-ERA Registry
eases, remained constant. In conclusion, gastrointestinal causes of ARF [11]; B data from the Madrid ARF Study [1].)
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.
Hospital-Related Epidemiologic Data

FIGURE 8-18
P<0.001 Serum creatinine (SCr) at hospital admission has diagnostic and
60 prognostic implications for acute renal failure (ARF). A, Of the
50 patients included in an ARF epidemiologic study 39% had a
40 normal SCr concentration (less than 1.5 mg/dL) at hospital
admission. It is worth noting that only 22% of the patients had
30
%
clearly established ARF (SCr greater than 3 mg/dL) when admit-

20 ted (no acute-on-chronic case was included). Mortality was
10 significantly higher in patients with normal SCr at admission.
0 (Continued on next page)
A SCr<1.5 mg/dL Mortality SCr>3.0 mg/dL Mortality

B, With the same two groups, acute tubular necrosis (ATN)
ARF Community-acquired Hospital-acquired predominated among the hospital-induced ARF group, whereas
(SCr at admission>3 mg/dL) (SCr at admission<1.5 mg/dL) the obstructive form was the main cause of community-acquired
ARF. In conclusion, the hospital could be considered an ARF
ATN 41.8 58.2 generator, particularly of the most severe forms. Nonetheless,
Prerenal 47.5 52.5
these iatrogenic ARF cases are usually “innocent,” and are an
Obstructive 77.3 22.7
unavoidable consequence of diagnostic and therapeutic maneuvers.
Total 49.7 50.3 (Data from Liaño et al. [1].)
80
70
Medical dept.
60
Mortality, %
34%
50
Trauma
2% 40
ICUs
27% Nephrology 30
13% 20
*
10
Surgical dept. 0
23% Gynecology All cases ICUs Medical Surgical Nephrol
1%
A B *P<0.001 respect to all cases
FIGURE 8-19
Acute renal failure: initial hospital location and mortality. A, two reasons: 1) polytrauma patients are now treated in the ICU
Initial departmental location of ARF patients in a hospital in a and 2) early and effective treatments applied today to trauma
Western country. The majority of the cases initially were seen in patients at the accident scene, and quick transfer to hospital, have
medical, surgical, and intensive care units (ICUs). The cases decreased this cause of ARF. B, Mortality was greater for patients
initially treated in nephrology departments were community initially treated in the ICU and lower in the nephrology setting
acquired, whereas the ARF patients in the other settings generally than rates observed in other departments. These figures were
acquired ARF in those settings. Obstetric-gynecologic ARF cases obtained from 748 ARF patients admitted to 13 different adult
have almost disappeared. ARF of traumatic origin is also rare, for hospitals. (Data from Liaño et al. [1].)
FIGURE 8-20
EPIDEMIOLOGIC VARIABLES 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
Acute Renal Failure in Hospitalized Patients thousand. When the real occurrence was measured in large popula-
Investigator, Year (per 1000 admissions) tions over longer intervals, the incidence of hospital-acquired ARF
decreased to 1.5 per thousand admissions. (Data from
Hou et al., 1983* 49.0 [1,5,16,17,18].)
Shusterman et al., 1987* 19.0
Lauzurica et al., 1989*
First period 16.0
Second period 6.5
Abraham et al., 1989 1.3
Madrid Study, 1992 1.5
* Case-control studies.
Prognosis
HISTORICAL PERSPECTIVE OF MEDICAL PROGNOSIS APPLIED IN ACUTE RENAL FAILURE
Criteria Derivation Applications Advantages Drawbacks

Classical Doctor’s experience Individual prognosis Easy Doctor’s inexperience
Unmeasurable
Traditional Univariate statistical analysis Risk stratification Easy Only one determinant of prognosis is considered
Present Multivariate statistical analysis Risk stratification Measurable Complexity (variable, depending on model)
Computing facilities Individual prognosis? Theoretically, “all” factors influencing outcome
are considered
Future Multivariate analysis Risk stratification Measurable Ideally, none
Computing facilities Individual prognosis “All” factors considered
Patient’s quality of life evaluation
Functional prediction
FIGURE 8-21
Estimating prognosis. The criteria for estimating prognosis in development of multivariable analysis. Theoretically, few of these
acute renal failure can be classified into four periods. The methods can give an individual prognosis [19]. They have not
Classical or heuristic way is similar to that used since the been used for triage. The next step will need a great deal of
Hippocratic aphorisms. The Traditional one based on simple work to design and implement adequate tools to stratify risks
statistical procedures, is not useful for individual prognosis. The and individual prognosis. In addition, the estimate of residual
Present form is more or less complex, depending on what method renal function and survivors’ quality of life, mainly for older
is used, and it is possible, thanks to computing facilities and the people, are future challenges.
Renal insult 100

Cumulative trend
Mean
80
Mortality, %
60
ARF Outcome
40
20 16 20
11 11 11 131110 9
13
10 8 Number
7 8 9 6 55 478 6
6 5 57 5 5 5 64 of
10 2 3 3 1 34 2 3 2
publi-
0 cations
Prognosis 1951 55 60 65 70 75 80 85 1990
Year
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
FIGURE 8-22 patients reported in 258 published papers. As can be appreciated,
Ideally, prognosis should be established as the problem, the episode mortality rate increases slowly but constantly during this follow-up,
of acute renal failure (ARF), starts. Correct prognostic estimation despite theoretically better availability of therapeutic armamentarium
gives the real outcome for a patient or group of patients as precisely (mainly antibiotics and vasoactive drugs), deeper knowledge of dialy-
as possible. In this ideal scenario, this fact is illustrated by giving sis techniques, and wider access to intensive care facilities. This
the same surface area for the concepts of outcome and prognosis. 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 treat-
ed now are usually older, sicker, and more likely to be treated more
aggressively. (From Kierdorf et al. [20]; with permission.)
Prognostic
systems used
in ARF
ICU Specific
methods ARF
methods
Apache
system SAPS MPM OSF Liano
APACHE II APACHE III SAPS I SAPS II MPM I MPM II OSF MODS SOFA Rasmussen
Lohr
Schaefer
Brivet
FIGURE 8-24
Ways of estimating prognosis in acute renal failure (ARF). This can be Sepsis-Related Organ Failure Assessment Score (SOFA) [29] are those
done using either general intensive care unit (ICU) score systems or that seem most suitable for this purpose. APACHE II used to be most
methods developed specifically for ARF patients. ICU systems include used. Other systems (white boxes) have been used in ARF.
Acute Physiological and Chronic Health Evaluation (APACHE) On the other hand, at least 17 specific ARF prognostic methods
[21,22], Simplified Physiologic Score (SAPS)[23,24], Mortality have been developed [20,30]. The figure shows only those that
Prediction Model (MPM) [25,26], and Organ System Failure scores have been used after their publication [31], plus one recently pub-
(OSF) [27]. Multiple Organ Dysfunction Score (MODS) [28] and lished system which is not yet in general use [2].
prognostic methods usually employed in

100 100 the ICU setting. The best curve comes
from the APACHE III method, which has
an area under the ROC curve of 0.74 ±
80 80 0.04 (SE). B, Four ROC curves
corresponding to prognostic methods
Sensitivity, %
60 60 specifically developed for ARF patients

are depicted. The best curve in this panel
40
APACHE II
40
comes from the Liaño method for ARF
APACHE III prognosis. Its area under the curve is
SAPS
SAPS-R
Rasmussen 0.78 ± 0.03 (SE). APACHE—Acute
20 20 Liaño
SAPS-E Physiology and Chronic Health
Lohr
SS
Schaefer Evaluation, (II second version [21]; III
MPM
third version [22]); SAPS—Simplified
0 0
0 20 40 60 80 100 0 20 40 60 80 100 Acute Physiology Score [23]; SAPS-R—
A 1- Specificity, % B 1- Specificity, % SAPS-reduced [33]; SAPS-E—SAPS-
Extended [32]; SS—Sickness Score [33];
MPM—Mortality Prediction Model [25];
FIGURE 8-25 ROC curve—Receiving Operating
Comparison of prognostic methods for acute renal failure (ARF) by ROC curve analy- Characteristic curve; SE—Standard
sis [31]. A method is better when its ROC-curve moves to the upper left square deter- Error. (From Douma [31];
mined by the sensitivity and the reciprocal of the specificity. A, ROC curves of seven with permission.)
100
ACUTE RENAL FAILURE: VARIABLES
Cumulative frequencies of resolved cases, %

STUDIED WITH UNIVARIATE ANALYSIS 8 patients to
Nonsurvivors chronic
80 hemodialysis
Age Hypotension
60 Survivors
Jaundice Catabolism
Sepsis Hemolysis
Burns Hepatic disease 40
Trauma Kind of surgery
NSAIDs Hyperkalemia 20
BUN increments Need for dialysis
Coma Assisted respiration
Oliguria Site of war injuries 0
1 5 10 15 20 25 30 35 40 45 50 55 60
Obstetric origin Disseminated intravascular coagulopathy
Days of ARF evolution
Malignancies Pancreatitis
Cardiovascular disease Antibiotics
X-ray contrast agents Timing of treatment FIGURE 8-27
Acidosis 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.
FIGURE 8-26 Similarly, 60% of survivors had recovered renal function at that time.
Individual factors that have been associated with acute renal failure After 30 days, 90% of the patients had had a final resolution of the
(ARF) outcome. Most of these innumerable variables have been ARF episode, one way or the other. Patients who finally lost renal
related to an adverse outcome, whereas few (nephrotoxicity as a function and needed to be included in a chronic periodic dialysis
cause of ARF and early treatment) have been associated with more program usually had severe forms of glomerulonephritis, vasculitis,
favorable prognosis. For a deep review of variables studied with or systemic disease. (From Liaño et al. [1]; with permission.)
univariate statistical analysis [34, 35]. NSAID—nonsteroidal anti-
inflammatory drugs; BUN—blood urea nitrogen.
Persistent hypotension Assisted repiration

80 100 100
80
80 69
80
Mortality, %
Mortality, %
60
ARF patients, %
60 60
P<0.001 P<0.001
40 40 40
33 32
20 20
20
0 0
0 Yes No Yes No
ss
pir ted
ma
on
n
on
ice
Jaundice Oliguria
ria
iou al
sne
sio
nsc rm
ati
ati
Co
100 100
igu
nd
res ssis
ten
Sed
co No
Jau
Ol
A
po
80 80
Hy
Mortality, %
Mortality, %
67
60 P<0.001 60 52
40 P<0.02
FIGURE 8-28 40 40 36
Precipitating condition of acute renal failure (ARF). The initial 20 20

clinical condition observed in ARF patients is shown. Oliguria:
urine output of less than 400 mL per day; hypotension: systolic 0 0
blood pressure lower than 100 mm Hg for at least 10 hours per Yes No Yes No
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 FIGURE 8-29
outcome (see Fig. 8-29). (Data from Liaño et al. [1].) Mortality associated with the presence or absence of oliguria, per-
sistent 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 Liaño et al. [1].)
FIGURE 8-30
100 92 Consciousness level and mortality. Coma patients had a Glasgow
coma score of 5 or lower. Sedation refers to the use of this kind of
80 77 treatment, primarily in patients with assisted respiration. Both situ-
ations are associated with significantly higher mortality (P<0.001)
Mortality rate, %
60 than that observed in either patients with a normal consciousness

45
level or the total population. (Data from Liaño et al. [1].)
40
30
20
0
Normal Sedation Coma All cases
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
2
Original patient: 1) previous health condition; 2) initial disease—usually,
disease 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
1 3 organ dysfunction syndrome (MODS) frequently appears and
Previous health Kind and severity consequently outcome is associated with a higher fatality rate
condition of kidney insult (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).
Depending on 2 and 3
S No
SIR SIR
S
ARF in a MODS Isolated

complex ARF
Death
Depending on:
*2,3, & 1
Recovery Recovery
*No. of failing organs
*Recovery process
FIGURE 8-32
INDIVIDUAL SEVERITY INDEX 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
ISI=0.032 (age-decade) 0.086 (male) 0.109 (nephrotoxic) 0.109 (oliguria) have been defined in preceding figures. The numbers preceding
0.116 (hypotension) 0.122 (jaundice) 0.150 (coma) 0.154 (consciousness) these keys denote the contribution of each one to the prognosis
0.182 (assisted respiration) 0.210 and are the factor for multiplying the clinical variables; 0.210 is
Case example the equation constant. Each clinical variable takes a value of 1 or
A 55-year-old man was seen because of oliguria following pancreatic surgery. At 0, depending, respectively, on its presence or absence (with the
that moment he was hypotensive and connected to a respirator, and jaundice exception of the age, which takes the value of the patient’s decade).
was evident. He was diagnosed with acute tubular necrosis. His ISI was calculated The parameters are recorded when the nephrologist sees the patient
as follows: the first time. Calculation is easy: only a card with the equation
ISI=0.032(6) 0.086 0.109 0.116 0.122 0.182 0.210 = 0.845 values, a pen, and paper are necessary. A real example is given.
FIGURE 8-33
ATN Acute GN Outcome of acute renal failure (ARF). Long-term outcome of ARF
66 No recovery 11
11 has been studied only in some series of intrinsic or parenchymatous
24 No recovery
31
31
ARF. The figure shows the different long-term prognoses for intrin-
Partial recovery 32
32 47
sic ARF of various causes. Left, The percentages of recovery rate of
35 renal function 1 year after the acute episode of renal failure. Right,
Partial recovery The situation of renal function 5 years after the ARF episode.
24
63
63 57 Acute tubulointerstitial nephritis (TIN) carries the better prognosis:
Total recovery 57
the vast majority of patients had recovered renal function after 1
41 Total recovery 29 and 5 years. Two thirds of the patients with acute tubule necrosis
(ATN) recovered normal renal function, 31% showed partial
1 yr 5 yr 1 yr 5 yr recovery, and 6% experienced no functional recovery. Some
Acute TIN patients with ATN lost renal function over the years. Patients with
HUS/ACN ARF due to glomerular lesions have a poorer prognosis; 24% at 1
No recovery 8 year and 47% at 5 years show terminal renal failure. The poorest
25 Partial recovery evolution is observed with severe forms of acute cortical necrosis
25
or hemolytic-uremic syndrome. GN—glomerulonephritis; HUS—
63 No recovery hemolytic-uremic syndrome; ACN—acute cortical necrosis.
91 (Data from Bonomini et al. [37].)
75 Total recovery
67
27
Partial recovery 9
1 yr 5 yr 1 yr 5 yr
FIGURE 8-34
Age as a prognostic factor in acute renal failure (ARF). There is a
Dead Dead Dead tendency to treat elders with ARF less aggressively because of the
174 113 50 presumed worse outcomes; however, prognosis may be similar to
that found in the younger population. In the multicenter prospec-
Alive Alive Alive tive longitudinal study in Madrid, relative risk for mortality in
225 143 53 patients older than 80 years was not significantly different (1.09 as
compared with 1 for the group younger than 65 years). Age proba-
< 65 yr 65–79 yr > 80 yr bly is not a poor prognostic sign, and outcome seems to be within
(n = 399) (n = 256) (n = 103) acceptable limits for elderly patients with ARF. Dialysis should not
be withheld from patients purely because of their age.
VARIABLES ASSOCIATED WITH PROGNOSIS: PROGNOSIS IN ACUTE RENAL FAILURE

MULTIVARIATE ANALYSIS (16 STUDIES)
1960–1969 P 1980–1989
Assisted respiration 11
No. 119 124
Hypotension or inotropic support 10
Mortality (%) 51 NS 63
Age 8
Mean age (y) 50.9 < 0.0001 63
Cardiac failure/complications 6
Median APACHE II score 32 < 0.0001 35
Jaundice 6
Range (22–45) (25–49)
Diuresis volume 5
Coma 5
Male sex 4
Sepsis 3 FIGURE 8-36
Chronic disease 3
Prognosis in acute renal failure (ARF). This figure shows the utility
Neoplastic disease 2 of a prognostic system for evaluating the severity of ARF over
Other organ failures 2 time, using the experience of Turney [38]. He compared the age,
Serum creatinine 2 mortality, and APACHE II score of ARF patients treated at one
Other conditions 12 hospital between 1960 and 1969 and 1980 and 1989. In the latter
Summary period there were significant increases in both the severity of the
Clinical variables 20 illness as measured by APACHE II and age. Although there was a
Laboratory variables 6
tendency to a higher mortality rate in the second period, this
tendency was not great enough to be statistically significant.
FIGURE 8-35
Outcome of acute renal failure (ARF). A great number of variables
have been associated with outcome in ARF by multivariate analy-
sis. 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 Nonsurvivors Survivors
60
50 Admission in ICU 24 22
42
Mortality, %
40 Before dialysis 22 22
30 24 h after dialysis 25 22
48 h after dialysis 24 22
20
10
22 ± 6 Apache II score 22 ± 6
0
A Dialysis patients Nondialysis patients B
FIGURE 8-37
APACHE score. The APACHE II score is not a good method for median APACHE II score was similar in both the surviving or
estimating prognosis in acute renal failure (ARF) patients. A, nonsurviving ARF patients treated in an intensive care unit.
Data from Verde and coworkers show how mortality was higher Recently Brivet and associates have found that APACHE II score
in their ICU patients with ARF needing dialysis than in those influences ARF prognosis when included as a factor in a more
without need of dialysis, despite the fact that the APACHE II complex logistic equation [2]. Although not useful for prognostic
score before dialysis was equal in both groups [39]. B, Similar estimations, APACHE II score has been used in ARF for risk
data were observed by Schaefer’s group [40], who found that the stratification.
FIGURE 8-38
Analysis of the severity and mortality in acute renal failure (ARF)
Mortality, %
P<0.001 Severity index patients needing dialysis. This figure is an example of the uses of a
80 0.8 severity index for analyzing the effect of treatment on the outcome
P<0.001
66 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
Severity index
60 0.57 0.6
to the sophism that dialysis is not a good treatment; however, it is
%
0.35 also clear that the severity index score for ARF was higher in
40 33 0.4
patients who needed dialysis. Severity index is the mean of the
individual severity index of each of the patients in each group [36].
20 0.2 (Data from Liaño et al. [1].)
0 0
Dialysis No dialysis
FIGURE 8-39
200 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,
Number of cases
150
more than one cause could be present in a given patient. In fact,
100
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
50
patients. The main cause of death was the original disease, which
was present in 55% of nonsurviving patients. Infection and shock
0 were the next most common causes of death, usually concurrent in
septic patients. It is worth noting that, if we exclude from the
a se
eas ry
ion
l
e
k
r
C
US
ing na
he
eas
oc
dis ato
DI
ise
ec t
ed sti
ICT
Ot
mortality analysis patients who died as a result of the original

e
Sh
dis
r
ble inte
al d
spi
Inf
ac
disease, the corrected mortality due to the ARF episode itself

Re
igin
o
rdi
str
and its complications, drops to 27%. GI—gastrointestinal;

Ca
Or
Ga
DIC—disseminated intravascular coagulation.
References
1. Liaño F, Pascual J the Madrid ARF Study Group: Epidemiology of 9. Lunding M, Steiness I, Thaysen JH: Acute renal failure due to tubular
acute renal failure: A prospective, multicenter, community-based necrosis. Immediate prognosis and complications. Acta Med Scand
study. Kidney Int 1996, 50:811–818. 1964, 176:103–119.
2. Brivet FG, Kleinknecht DJ, Loirat P, et al.: Acute renal failure in inten- 10. Lachhein L, Kielstein R, Sauer K, et al.: Evaluation of 433 cases of
sive care units—causes, outcome and prognostic factors of hospital acute renal failure. Proc EDTA 1978, 14:628–629.
mortality: A prospective, multicenter study. Crit Care Med 1995, 11. Wing AJ, Broyer M, Brunner FP, et al.: Combined report on regular
24:192–197. dialysis and transplantation in Europe XIII-1982. Proc EDTA 1983,
3. Pascual J, Liaño F, the Madrid ARF Study Group: Causes and prog- 20:5–78.
nosis of acute renal failure in the very old. J Am Geriatr Soc 1998, 12. Gerrard JM, Catto GRD, Jones MC: Acute renal failure: An iceberg
46:1–5. revisited (Abstract). Nephrol Dial Transplant 1992, 7:458.
4. Eliahou HE, Modan B, Leslau V, et al.: Acute renal failure in the com- 13. Kleinknecht D: Epidemiology of acute renal failure in France today.
munity: An epidemiological study. Acute Renal Failure Conference, In Acute Renal Failure in the Intensive Therapy Unit. Edited by Bihari
Proceedings. New York 1973. D, Neild G. London:Springer-Verlag; 1990:13–21.
5. Abraham G, Gupta RK, Senthilselvan A, et al.: Cause and prognosis 14. Chugh S, Sakhuja V, Malhotra HS, Pereira BJG: Changing trends in
of acute renal failure in Kuwait: A 2-year prospective study. J Trop acute renal failure in Third-World countries—Chandigarh study.
Med Hyg 1989, 92:325–329. Q J Med 1989, 272:1117–1123.
6. McGregor E, Brown I, Campbell H, et al.: Acute renal failure. A 15. Seedat YK, Nathoo BC: Acute renal failure in blacks and Indians in
prospective study on incidence and outcome (Abstract). XXIX South Africa—Comparison after 10 years. Nephron 1993,
Congress of EDTA-ERA, Paris, 1992, p 54.
64:198–201.
7. Sanchez Rodrìguez L, MartÌn Escobar E, Lozano L, et al.: Aspectos
16. Hou SH, Bushinsky DA, Wish JB, et al.: Hospital-acquired renal
epidemiolûgicos del fracaso renal agudo en el ·rea sanitaria de
insufficiency: A prospective study. Am J Med 1983, 74:243–248.
Cuenca. Nefrologìa 1992, 12(Suppl 4):87–91.
8. Feest TG, Round A, Hamad S: Incidence of severe acute renal failure 17. Shusterman N, Strom BL, Murray TG, et al.: Risk factors and out-
in adults: Results of a community based study. Br Med J 1993, come of hospital-acquired acute renal failure. Am J Med 1987,
306:481–483. 83:65–71.
18. Lauzurica R, Caralps A: Insuficiencia renal aguda producida en el 29. Vincent JL, Moreno R, Takala J, et al.: The SOFA (sepsis-related
hospital: Estudio prospectivo y prevenciûn de la misma. Med ClÌn organ failure assessment) score to describe organ dysfunction/failure.
(Barc) 1989, 92:331–334. Intensive Care Med 1996, 22:707–710.
19. Liaño F, Solez K, Kleinknecht D: Scoring the patient with ARF. In 30. Liaño F, Pascual J: Acute renal failure, critical illness and the artificial
Critical Care Nephrology. Edited by Ronco C, Bellomo R. kidney: Can we predict outcome? Blood Purif 1997, 15:346–353.
Dordrecht:Kluwer Academic; 1998; Section 23.1: 1535–1545. 31. Douma CE, Redekop WK, Van der Meulen JHP, et al.: Predicting
20. Kierdorf H, Sieberth HG: Continuous treatment modalities in acute mortality in intensive care patients with acute renal failure treated
renal failure. Nephrol Dial Transplant 1995; 10:2001–2008. with dialysis. J Am Soc Nephrol 1997, 8:111–117.
21. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: A 32. Viviand X, Gouvernet J, Granthil C, Francois G: Simplification of the
severity of disease classification system. Crit Care Med 1985, SAPS by selecting independent variables. Intensive Care Med 1991,
13:818–829. 17:164–168.
22. Knaus WA, Wagner DP, Draper EA, et al.: The APACHE III prognostic 33. Bion JF, Aitchison TC, Edlin SA, Ledingham IM: Sickness scoring and
system: Risk prediction of hospital mortality for critically ill hospitalized response to treatment as predictors of outcome from critical illness.
adults. Chest 1991, 100:1619–1636. Intensive Care Med 1988, 14:167–172.
23. Le Gall JR, Loirat P, Alperovitch A, et al.: A simplified acute physiology 34. Chew SL, Lins RL, Daelemans R, De Broe ME: Outcome in acute
renal failure. Nephrol Dial Transplant 1993, 8:101–107.
score for ICU patients. Crit Care Med 1984, 12:975–977.
35. Liaño F: Severity of acute renal failure: The need of measurement.
24. Le Gall, Lemeshow S, Saulnier F: A new Simplified Acute Phisiology
Nephrol Dial Transplant 1994, 9(Suppl. 4):229–238.
Score (SAPS II) based on a European/North American multicenter
study. JAMA 1993, 270:2957–2963. 36. Liaño F, Gallego A, Pascual J, et al.: Prognosis of acute tubular necro-
sis: An extended prospectively contrasted study. Nephron 1993,
25. Lemeshow S, Teres D, Pastides H, et al.: A method for predicting 63:21–23.
survival and mortality of ICU patients using objectively derived
weights. Crit Care Med 1985, 13:519–525. 37. Bonomini V, Stefoni S, Vangelista A: Long-term patient and renal
prognosis in acute renal failure. Nephron 1984, 36:169–172.
26. Lemeshow S, Teres D, Klar J, et al.: Mortality probability models
38. Turney JH: Why is mortality persistently high in acute renal failure?
(MPM II) based on an international cohort of intensive care unit
Lancet 1990, 335:971.
patients. JAMA 1993, 270:2478–2486.
39. Verde E, Ruiz F, Vozmediano MC, et al.: Valor predictivo del
27. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: Prognosis in
APACHE II en el fracaso renal agudo de las unidades de cuidados
acute organ-system failure. Ann Surg 1985, 202:685–693.
intensivos (Abstract). Nefrologìa 1996, 16(Suppl. 19):32.
28. Marshall JC, Cook DJ, Christou NV, et al.: Multiple organ dysfunction 40. Schaefer JH, Jochimsen F, Keller F, et al.: Outcome prediction of acute
score: A reliable descriptor of a complex clinical outcome. Crit Care renal failure in medical intensive care. Intensive Care Med 1991,
Med 1995, 23:1638–1652. 17:19–24.
Renal Histopathology, Urine
Cytology, and Cytopathology
of Acute Renal Failure
Lorraine C. Racusen
Cynthia C. Nast
C
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 membranoprolif-
erative 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 anti–glomerular
basement membrane disease; and, in the absence of immune
complexes, the pauci-immune processes, which include the small
vessel vasculitides, including Wegener’s 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 CHAPTER
failure. The urine sediment in these diseases often contains red blood
cells and red cell casts.
9
Vascular diseases (involving veins, arteries, or arterioles and capillar-
ies) can lead to hypoperfusion and acute renal failure. Venous thrombo-
sis, most often due to trauma or a nephrotic state, and arterial throm-
bosis due to trauma or vasculitis, cause parenchymal ischemia and
infarction. Small vessel vasculitides involve small arteries, arteri- process or associated with immune glomerular injury. Tubulitis
oles, and glomerular capillaries, causing injury and necrosis in the is seen when the inflammatory reaction extends into the tubu-
glomerular tuft, which may result in crescent formation. lar epithelium. Epithelial cell injury is often produced by such
Thrombotic microangiopathies result from endothelial injury inflammatory processes. The urine sediment reveals white
damage in small arteries and arterioles, producing thrombosis, blood cells and white cell casts, which may include numerous
obstruction to blood flow, and glomerular hypoperfusion. Urine polymorphonuclear leukocytes or eosinophils.
sediment in these diseases often shows hematuria or cellular casts, The most common cause of acute renal failure is injury to
reflecting ischemia. tubule epithelium. Primary tubule cell injury typically results
Interstitial inflammatory processes lead to acute renal failure from ischemia, toxic injury, or both. Cell injury results in dis-
via compression of peritubular capillaries or injury to tubules. ruption of the epithelium and its normal reabsorptive func-
Causes of acute interstitial nephritis include infection, and tions, and may lead to obstruction of tubule lumens. Cell exfo-
immune-mediated reactions. With infection, polymorphonu- liation often occurs, and intact cells and cell fragments and
clear leukocytes may be seen in tubules as well as in intersti- debris can be seen in the urine sediment; these may be in the
tium. Inflammatory infiltrates in hypersensitivity reactions, form of casts. Necrotic cells may be seen in situ along the
often due to drug exposure, feature eosinophils. Immuno- tubule epithelium or in the tubule lumen, but often overt cell
histologic studies may reveal the presence of immune complexes; necrosis is not prominent. Apoptosis of tubule cells is seen
immune complex deposition around tubules occurs as a primary after injury as well.
Glomerular Diseases
Early postinfectious glomerulonephritis. Numerous polymorphonu- A large epithelial crescent fills Bowman’s space and compresses the
clear leukocytes in glomerular capillary loops contribute to the capillary loops in the glomerular tuft. This silver stain highlights
hypercellular appearance of the glomerulus. There is also a segmental the glomerular mesangium and the basement membrane of the
increase in mesangial cells (hematoxylin and eosin, original magnifica- glomerular capillaries (silver stain, original magnification 400).
tion 400). This reactive inflammatory process occurs in response The patient presented with hematuria and acute renal failure.
to glomerular deposition of immune complexes, including the large Immunostains were negative in this case, a finding consistent with
subepithelial “hump-like” deposits which are typical of post-infec- a pauci-immune process. The differential diagnosis includes small
tious glomerulonephritis. The glomerulonephritis is usually self- vessel vasculitis, and anti-neutrophil cytoplasmic antibody may
limited and reversible, and especially with appropriate treatment of be positive. Crescentic glomerulonephritis may also occur with
the underlying infection, long-term prognosis is excellent [1]. 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 glomeru-
lonephritis 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 syn-
drome). If the cortical necrosis is patchy, recovery of adequate
renal function may occur [3].

A parenchymal infarct in a patient with renal vein thrombosis (hema-
toxylin 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.
A B
A fine-needle aspirate in renal infarction. A, Low magnification shows edge of an infarct is aspirated (May-Grunwald Giemsa, original mag-
many degenerating cells with a “dirty background” containing cellular nification 40). B, Diffusely degenerated and necrotic cells with con-
debris and scattered neutrophils. Compare to acute tubular necrosis, densed and disrupted cytoplasm and pyknotic nuclei, and an adjacent
which has only scattered degenerated or necrotic cells without the neutrophil. No significant numbers of viable tubule epithelial cells
extensive necrosis and cell debris. Neutrophils may be numerous if the 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 mag-
nification 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 hyperchro-
matic 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].

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 Tubulitis, with infiltration of mononuclear cells into the tubular
infiltrate. Eosinophils in the infiltrate suggest a possible hypersensi- epithelium (hematoxylin and eosin, original magnification 400).
tivity reaction (hematoxylin and eosin, original magnification There is a mononuclear infiltrate and edema in the surrounding
400). Drugs are the most common cause of such a reaction, which interstitium. Tubule cells may show evidence of lethal or sublethal
often presents with acute renal failure [6]. Inflammatory cells and injury as the inflammatory cells release damaging enzymes. Tubulitis
cell casts may be seen in the urine sediment in these cases, as is often seen in interstitial nephritis especially if the targets of the
inflammatory cells infiltrate the tubular epithelium. inflammatory reaction are tubular cell antigens or antigens deposited
around the tubules. Immunofluorescence may reveal granular or lin-
ear deposits of immunoglobulin and complement around the tubules.

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. Intra-
tubular 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 B
Fine-needle aspirate of acute infectious interstitial nephritis (acute breakdown. In bacterial infection there are many infiltrating neu-
pyelonephritis). A 25-gauge needle attached to a 10-cc syringe was trophils and there may be associated necrosis of tubule epithelial
utilized to withdraw the aspirate into 4 cc of RPMI-based medi- cells (original magnification 80). B, A neutrophil contains
um. The specimen was then cytocentrifuged and stained with phagocytosed bacteria within the cytoplasm; bacteria stain with
May-Grunwald Giemsa. A, The renal aspirate contains large Giemsa, so are readily detectable in this setting. Adjacent tubule
numbers of intrarenal neutrophils, which are focally undergoing epithelial cells have cytoplasmic granules but do not phagocytize
degenerative changes with cytoplasmic vacuolization and nuclear 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 B
Fine-needle aspirate from patient with intrarenal cytomegalovirus viral infections have a similar appearance, and immunostaining or in
(CMV) infection. A, There are activated and transformed lympho- situ hybridization is required to identify specific viruses (May-
cytes with immature nuclear chromatin and abundant blue cyto- Grunwald Giemsa, original magnification 80). B, Tubular epithe-
plasm that infiltrate the kidney in response to the infection; large lial cells stained with antibody to CMV immediate and early nuclear
granular lymphocytes (NK cells) may be seen as well, but few neu- proteins in active intrarenal CMV infection. With an immunoalka-
trophils. Similar activated lymphocytes, NK cells, and atypical line phosphatase method, cytoplasmic and prominent nuclear stain-
monocytes can be observed within the peripheral blood. The tubule ing for these early proteins are observed in the tubular epithelium. In
epithelial cells are virtually never seen to contain CMV inclusions in very early infection, neutrophils also may have cytoplasmic staining
aspirate material, in contrast to core biopsy specimens. All intrarenal 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 (hema-
toxylin 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 anti-
inflammatory 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.
A B
Fine-needle aspirate of acute allergic interstitial nephritis. A, The present (May-Grunwald Giemsa, original magnification 80).
aspirate contains numerous lymphocytes, occasional activated B, Higher magnification showing the typical infiltrating cells,
lymphocytes, and eosinophils without fully transformed lymphocytes, including a monocyte, activated lymphocyte, and an eosinophil.
corresponding to the inflammatory component within the tubuloint- A neutrophil is present, likely owing to blood contamination
erstitium observed on routine renal biopsy. Monocytes often are (May-Grunwald Giemsa, original magnification 160).
Tubular Diseases
Severe vacuolization of tubular cells in injured tubular epithelium Necrotic tubular cells and cell debris in tubular lumina. One tubule
(hematoxylin and eosin, original magnification 400). The vacuoles shows extensive cell loss, with tubular epithelium lined only by a very
reflect cell injury and derangement of homeostatic mechanisms that flattened layer of cytoplasm. The dilated lumen contains numerous
maintain the normal intracellular milieu. In this case, the vacuoles necrotic tubular cells with pyknotic nuclei. Several tubules contain cell
developed on exposure to intravenous immunoglobulin in a sucrose debris and one contains red blood cells (hematoxylin and eosin, origi-
vehicle; the morphology is reminiscent of the severe changes pro- nal magnification 250). Such changes are more often seen with
duced by osmotic agents. While generally a nonspecific marker of toxic than with ischemic injury [6], unless the latter is very severe.
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].
This micrograph shows sites of cell exfoliation, attenuation of Outer medulla shows in situ cell necrosis and loss in medullary thick
remaining cells, and reactive and regenerative changes (hema- ascending limb (hematoxylin and eosin, original magnification
toxylin and eosin, original magnification 400). Exfoliation 250). Tubules contain cells and cell debris. Changes reflect
occurs with disruption of cell-cell and cell-substrate adhesion, and ischemic injury. Impaction of cells and cast material may lead to
may involve viable as well as non-viable cells [7]. Reactive and tubular obstruction, especially in narrow regions of the nephron.
regenerative changes may include basophilia of cell cytoplasm, Adhesion molecules on the surface of exfoliated cells may contribute
increased nuclear:cytoplasmic ratio, heterogeneity of nuclear size to aggregation of cells within the tubule and adhesion of detached
and appearance, hyperchromatic nuclei and mitotic figures. cells to in situ tubular cells [8].
A B
Fine-needle aspirate showing acute tubular cell injury and necrosis. cytoplasm, and a pyknotic nucleus. Another cell has more advanced
A, The aspirate shows scattered tubular epithelial cells with swelling necrosis with additional cytoplasmic disruption and a very small
and focal degenerative changes, and a minimal associated inflamma- pyknotic nucleus. Compare the adjacent swollen damaged tubular
tory infiltrate. There is no significant background cell debris (May- cell which has not yet undergone necrosis (May-Grunwald Giemsa,
Grunwald Giemsa, original magnification 40). B, One tubular original magnification 160).
cell is degenerated with reduction in cell size, condensed gray-blue

Urine sediment from a patient with acute tubular injury showing
tubular cells and cell casts (Papanicolaou stain, original magnifica-
tion 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 B
Myoglobin casts in the tubules of a patient who abused cocaine. A, (original magnification 250). These casts may obstruct the
Hematoxylin and eosin stained casts have a dark red, coarsely gran- nephron, especially with dehydration and low tubular fluid flow
ular appearance (original magnification 250). B, Immunoperoxi- rates. Rhabdomyolysis with formation of intrarenal myoglobin casts
dase stain for myoglobin confirms positive staining in the casts may also occur with severe trauma, crush injury, or extreme exercise.

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 diffi-
cult 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].
FIGURE 9-26
Disintegrating Apoptosis-schematic of histologic changes in tubular epithelium.
fragments The process begins with condensation of the cytoplasm and of the
nucleus, a process which involves endonucleases, which digest the
Shrunken cell with DNA into ladder-like fragments characteristic of this process. The
peripheral condensed nuclear cell disintegrates into discrete membrane-bound fragments, so-called
chromatin and intact
“apoptotic bodies.” These fragments may be rapidly extruded into
organelles
the tubular lumen or phagocytosed by neighboring epithelial cells
or inflammatory cells. (Modified from Arends, et al. [10];
with permission.)
Phagocytosed
apoptic cell
fragments
Ischemia Toxins
Altered Vascular endothelial Inflammatory Tubular cell injury

permeability injury infiltrate
Sublethal Apoptosis Lethal
Upregulation of Loss of surface area Altered adhesion Changes of repair In situ

adhesion molecules and cell polarity and regeneration necrosis
Interstitial Tubular cell

edema swelling Increased epithelial
permeability
Compression of
peritubular capillaries Loss of tubular
integrity Exfoliation
Loss of normal Impaction in the

transport function tubules
Vacuolization Arteriolar Loss of Obstruction Cast formation

of smooth vasoconstriction distal flow
muscle
cells Glomerular "Backleak" of Increased Tubular dilatation
collapse filtrate intratubular
Increased renal pressure
vascular
resistance
Aggregation of
erythrocytes,fibrin Decrease in glomerular
and/or leukocytes filtration rate
in peritubular Reduced renal
capillaries blood flow
FIGURE 9-27
A schematic showing the relationship between morphologic and Histology reflects the altered hemodynamics, epithelial derange-
functional changes with injury to the renal tubule due to ischemia ments, and obstruction which contribute to loss of renal function.
or nephrotoxins. Morphologic changes are shown in italics. (Modified from Racusen [11]; with permission.)
References
1. Popovic-Rolovic M, Kostic M, Antic-Peco A, et al.: Medium and 7. Racusen LC, Fivush BA, Li Y-L, et al.: Dissociation of tubular
long-term prognosis of patients with acute post-streptococcal detachment and tubular cell death in clinical and experimental
glomerulonephritis. Nephron 1991, 58:393–399. “acute tubular necrosis.” Lab Invest 1991, 64:546–556.
2. Jennette JC: Crescentic glomerulonephritis. In Heptinstall’s Pathology 8. Goligorsky MS, Lieberthal W, Racusen L, Simon EE: Integrin recep-
of the Kidney, edn. 5. Edited by Jennette JC, JL Olson, M Schwarz, tors in renal tubular epithelium: New insights into pathophysiology
FG Silva. New York:Lippincott-Raven, 1998. of acute renal failure. Am J Physiol 1993, 264:F1–F8.
3. Racusen LC, Solez K: Renal cortical necrosis, infarction and 9. Schumer KM, Olsson CA, Wise GJ, Buttyan R: Morphologic,
atheroembolic disease. In Renal Pathology. Edited by Tisher C, biochemical and molecular evidence of apoptosis during the
B Brenner. Philadelphia:Lippincott-Raven, 1993:811. reperfusion phase after brief periods of renal ischemia.
4. Evert BH, Jennette JC, Falk RJ: The pathogenic role of antineutrophil Am J Pathol 1992, 140:831–838.
cytoplasmic autoantibodies. Am J Kidney Dis 1991, 8:188–195. 10. Arends MJ, Wyllie AH: Apoptosis: Mechanisms and role in
5. Remuzzi G, Ruggenenti P: The hemolytic uremic syndrome. Kidney pathology. Int Rev Exp Pathol 1991, 32:225–254.
Int 1995, 47:2–19. 11. Racusen LC: Pathology of acute renal failure: Structure/function
6. Nadasdy T, Racusen LC: Renal injury caused by therapeutic and correlations. Advances in Renal Replacement Therapy, 1997
diagnostic agents, and abuse of analgesics and narcotics. In Heptinstalls 4(Suppl. 2): 3–16.
Pathology of the Kidney, edn. 5. Edited by Jennette JC, JL Olson,
MM Schwartz, FG Silva. New York:Lippincott-Raven, 1998.
Acute Renal Failure in
the Transplanted Kidney
Kim Solez
Lorraine C. Racusen
A
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 new-
onset 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 lympho-
proliferative 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 estab-
lish 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
Acute Rejection
FIGURE 10-1
DIAGNOSTIC POSSIBILITIES IN TRANSPLANT- Diagnostic possibilities in transplant-related acute renal failure.
RELATED ACUTE RENAL FAILURE
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
FIGURE 10-2
Diagnosis of rejection in the Banff classification makes use of two
basic lesions, tubulitis and intimal arteritis. The 1993–1995 Banff
classification depicted in this figure is the standard in use in virtually
lit gr is re
bu de it ve
all current clinical trials and in many individual transplant units. In

tu y ter se
of h an l ar ate,
is) ee
Lesions-tubulitis, intimal arteritis
this construct, rejection is regarded as a continuum of mild, moderate,

it a er
(w ntim od
i –m
and severe forms. The 1997 Banff classification is similar, having the
ild
same threshold for rejection diagnosis, but it recognizes three different

M
histologic types of acute rejection: tubulointersititial, vascular, and

transmural. The quotation marks emphasize the possible overlap of
lit te
Se bul
bu ra
tu
is
features of the various types (eg, the finding of tubulitis should not
ve itis
tu ode
re
M
None Borderline Mild Moderate Severe Rejection

dissuade the pathologist from conducting a thorough search for
intimal arteritis).
is
lit
bu
tu
ild
M
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 sec-
tion 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
FIGURE 10-4 (see Color Plate) FIGURE 10-5

In this figure the tubules with lymphocytic invasion are atrophic Intimal arteritis in a case of acute rejection. Note that more than
with thickened tubular basement membranes. There are 13 or 14 20 lymphocytes are present in the thickened intima. With this
lymphocytes per tubular cross section. This is an example of how a lesion, however, even a single lymphocyte in this site is sufficient
properly performed periodic acid-Schiff (PAS) stain should look. to make the diagnosis. Thus, the pathologist must search for subtle
The Banff classification is critically dependent on proper performance intimal arteritis lesions, which are highly reliable and specific for
of PAS staining. The invading lymphocytes are readily apparent and rejection. (From Solez et al. [1]; with permission.)
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.)

Artery in longitudinal section shows a more florid intimal arteritis Transmural arteritis with fibrinoid change. In addition to the influx of
than that in Figure 10-5. Aggregation of lymphocytes is also seen inflammatory cells there has been proliferation of modified smooth
in the lumen, but this is a nonspecific change. The reporting for muscle cells migrated from the media to the greatly thickened intima.
some clinical trials has involved counting lymphocytes in the most Note the fibrinoid change at lower left and the penetration of the
inflamed artery, but this has not been shown to correlate with clinical media by inflammatory cells at the upper right. Patients with these
severity or outcome, whereas the presence or absence of the lesion types of lesions have a less favorable prognosis, greater graft loss, and
has been shown to have such a correlation. (From Solez et al. [1]; poorer long-term function as compared with patients with intimal
with permission.) arteritis alone. These sorts of lesions are also common in antibody-
mediated rejection (see Fig. 10-9).
FIGURE 10-8
Arterial lesions in acute rejection Diagram of arterial lesions of acute rejection.
1 8 7 The initial changes (1–5) before intimal
Adventitia arteritis (6) occurs are completely nonspecific.
These early changes are probably mechanisti-
3 10 cally related to the diagnostic lesions but can
occur as a completely self-limiting phenome-
non unrelated to clinical rejection. Lesions 7
Media to 10 are those characteristic of “transmural”
2 rejection. Lesion 1 is perivascular inflamma-
tion; lesion 2, myocyte vacuolization; lesion
Endothelium 11
3, apoptosis; lesion 4, endothelial activation
and prominence; lesion 5, leukocyte adher-
Lumen 6
ence to the endothelium; lesion 6 (specific),
penetration of inflammatory cells under the
endothelium (intimal arteritis); lesion 7,
4 5 9
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 Calcium oxalate crystals seen under polarized light. These are very
acute tubular necrosis (ATN) in an allograft. The tubule is difficult to characteristic of transplant acute tubular necrosis (ATN), probably
identify because, in contrast to the appearance in native kidney ATN, because they relate to some degree to the duration of uremia, which
no residual tubular cells survive; the epithelium is 100% necrotic. 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”)

Calcium oxalate crystals seen by electron microscopy in transplant Features of transplant acute tubular necrosis that differentiate it
acute tubular necrosis. from the same condition in native kidney [3].
Cyclosporine Toxicity

Cyclosporine nephrotoxicity with new-onset hyaline arteriolar Bland hyaline arteriolar thickening of donor origin in a renal allograft
thickening in the renin-producing portion of the afferent arteriole recipient never treated with cyclosporine. This phenomenon provides
[5]. This lesion can be highly variable in extent and severity from a strong argument for doing implantation biopsies; otherwise, donor
section to section of the biopsy specimen, and it represents one of changes can be mistaken for cyclosporine toxicity.
the strong arguments for examining multiple sections. The lesion is
reversible if cyclosporine levels are reduced. Tacrolimus (FK506)
produces an identical picture.
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 [7–9]. This figure shows
an expansile plasmacytic infiltrate in a case of PTLD. However,
most cases of PTLD are the result of Epstein-Barr virus–induced
lymphoid proliferation.
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 throm-
bosis in renal allografts and these are as various as the first dose reac-
tion 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.
Peritubular Capillary Basement

Membrane Changes in Chronic Rejection
A B
Peritubular capillary basement membrane ultrastructural changes, of diagnostic utility [16]. Ongoing studies of large numbers of
A, and staining for VCAM-1 as specific markers for chronic rejec- patients using these parameters will test the value of these parame-
tion, B [14–16]. Splitting and multilayering of peritubular capillary ters which may eventually be added to the Banff classification.
basement membranes by electron microscopy holds promise as a A, Multilayering of peritubular capillary basement membrane in a
relatively specific marker for chronic rejection [14,15]. VCAM-1 case of chronic rejection; B, shows staining of peritubular capillaries
staining by immunohistology in these same structures may also be for VCAM-1 by immunoperoxidase in chronic rejection.
References
1. Solez K, Axelsen RA, Benediktsson H, et al.: International standardiza- 9. Wood A, Angus B, Kestevan P, et al.: Alpha interferon gene deletions
tion of criteria for the histologic diagnosis of renal allograft rejection: in post-transplant lymphoma. Br J Haematol 1997, 98(4):1002–1003.
The Banff working classification of kidney transplant pathology. 10. Nickerson P, Jeffrey J, McKenna R, et al.: Do renal allograft function
Kidney Int 1993, 44:411–422. and histology at 6 months posttransplant predict graft function at 2
2. Trpkov K, Campbell P, Pazderka F, et al.: Pathologic features of acute years? Transplant Proc 1997, 29(6):2589–2590.
renal allograft rejection associated with donor-specific antibody, 11. Rush D: Subclinical rejection. Presentation at Fourth Banff
analysis using the Banff grading schema. Transplantation 1996, Conference on Allograft Pathology, March 7–12, 1997.
61(11):1586–1592.
12. Wiener Y, Nakhleh RE, Lee MW, et al.: Prognostic factors and early
3. Solez K, Racusen LC, Marcussen N, et al.: Morphology of ischemic resumption of cyclosporin A in renal allograft recipients with throm-
acute renal failure, normal function, and cyclosporine toxicity in botic microangiopathy and hemolytic uremic syndrome. Clin
cyclosporine-treated renal allograft recipients. Kidney Int 1993, Transplant 1997, 11(3):157–162.
43(5):1058–1067.
13. Frem GJ, Rennke HG, Sayegh MH: Late renal allograft failure
4. Salyer WR, Keren D:Oxalosis as a complication of chronic renal secondary to thrombotic microangiopathy—human immunodeficiency
failure. Kidney Int 1973, 4(1):61–66. virus nephropathy. J Am Soc Nephrol 1994, 4(9):1643–1648.
5. Strom EH, Epper R, Mihatsch MJ: Cyclosporin-associated arteri- 14. Monga G, Mazzucco G, Messina M, et al.: Intertubular capillary
olopathy: The renin producing vascular smooth muscle cells are more changes in kidney allografts: A morphologic investigation on 61 renal
sensitive to cyclosporin toxicity. Clin Nephrol 1995, 43(4):226–231. specimens. Mod Pathol 1992, 5(2):125–130.
6. Trpkov K, Marcussen N, Rayner D, et al.: Kidney allograft with a 15. Mazzucco G, Motta M, Segoloni G, Monga G: Intertubular capillary
lymphocytic infiltrate: Acute rejection, post-transplantation lympho- changes in the cortex and medulla of transplanted kidneys and their
proliferative disorder, neither, or both entities? Am J Kidney Dis 1997, relationship with transplant glomerulopathy: An ultrastructural study
30(3):449–454. of 12 transplantectomies. Ultrastruct Pathol 1994, 18(6):533–537.
7. Sasaki TM, Pirsch JD, D’Alessandro AM, et al.: Increased 2-micro- 16. Solez K, Racusen LC, Abdulkareem F, et al.: Adhesion molecules and
globulin (B2M) is useful in the detection of post-transplant lympho- rejection of renal allografts. Kidney Int 1997, 51(5):1476–1480.
proliferative disease (PTLD). Clin Transplant 1997, 11(1):29–33.
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):254–258.
Renal Injury Due To
Environmental Toxins,
Drugs, and Contrast Agents
Marc E. De Broe
T
he kidneys are susceptible to toxic or ischemic injury for sever-
al 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 com-
mon drugs and exogenous toxins encountered by the nephrologist in
clinical practice are discussed in detail.
The clinical expression of the nephrotoxicity of drugs and chemi-
cals 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, vul-
nerability) of particular segments of the nephron, the multiple trans-
port 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
General Nephrotoxic Factors

FIGURE 11-1
The nephron Sites of renal damage, including factors that
contribute to the kidney’s susceptibility to
damage. ACE—angiotensin-converting
enzyme; NSAID—nonsteroidal anti-inflam-
matory drugs; HgCl2—mercuric chloride.
S1
Cortex
Sites of renal damage
S2
Medullary ray
ACE inhibitors
NSAIDs
Aminoglycosides
S1 Acyclovir
Cisplatinum
S3 HgCl2
S2 Lithium
S3 Ischemia
Outer
stripe
Outer medulla
Vulnerability of the kidney

Inner
stripe
Important blood flow (1/4 cardiac output)
High metabolic activity
Largest endothelial surface by weight
Multiple enzyme systems
Inner
Transcellular transport
medula
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 M4 Intratubular obstruction by precipitation of the agents or its metabolites or byproducts
M2 Direct tubular toxicity M5 Allergic interstitial nephritis
M3 Heme pigment–induced toxicity (rhabdomyolysis) M6 Hemolytic-uremic syndrome
M1 M2 M3 M4 M5* M6 Drugs
✓ ✓ ✓ Cyclosporine, tacrolimus
✓ ✓ Amphotericin B, radiocontrast agents
✓ ✓ Nonsteroidal anti-inflammatory drugs
✓ 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
* 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 glycol–induced toxicity can cause calcium oxalate crystals.
FIGURE 11-2
Drugs and chemicals associated with acute renal failure. (Apapted from Thadhani, et al. [2].)
Aminoglycosides
1. Filtration 2. Binding
+
- + -
Glomerulus
Lysosomal phospholipidosis
- -
ABOVE
threshold: *
lysosomal
swelling, BELOW
3. Adsorptive
pinocytosis disruption * threshold:
or leakage exocytosis
shuttle
4. Lysosomal trapping *
Proximal tubule
and storage
*
Regression of
* drug-induced
changes
Cell necrosis * Aminoglycoside
regeneration * Hydrolase
Toxins
FIGURE 11-3
Renal handling of aminoglycosides: 1) glomerular filtration; After charge-mediated binding, the drug is taken up into the cell
2) binding to the brush border membranes of the proximal in small invaginations of the cell membrane, a process in which
tubule; 3) pinocytosis; and 4) storage in the lysosomes [3]. megalin seems to play a role [6]. Within 1 hour of injection, the
Nephrotoxicity and otovestibular toxicity remain frequent side drug is located at the apical cytoplasmic vacuoles, called endocy-
effects that seriously limit the use of aminoglycosides, a still impor- totic vesicles. These vesicles fuse with lysosomes, sequestering the
tant class of antibiotics. Aminoglycosides are highly charged, poly- unchanged aminoglycosides inside those organelles.
cationic, hydrophilic drugs that cross biologic membranes little, if Once trapped in the lysosomes of proximal tubule cells, amino-
at all [4,5]. They are not metabolized but are eliminated unchanged glycosides electrostatically attached to anionic membrane phospho-
almost entirely by the kidneys. Aminoglycosides are filtered by the lipids interfere with the normal action of some enzymes (ie, phos-
glomerulus at a rate almost equal to that of water. After entering pholipases and sphingomyelinase). In parallel with enzyme inhibi-
the luminal fluid of proximal renal tubule, a small but toxicologi- tion, undigested phospholipids originating from the turnover of cell
cally important portion of the filtered drug is reabsorbed and membranes accumulate in lysosomes, where they are normally
stored in the proximal tubule cells. The major transport of amino- digested. The overall result is lysosomal phospholipidosis due to
glycosides into proximal tubule cells involves interaction with nonspecific accumulation of polar phospholipids as “myeloid bod-
acidic, negatively charged phospholipid-binding sites at the level ies,” so called for their typical electron microscopic appearance.
of the brush border membrane. (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 struc-
tures. 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
µm, in part B, 0.1 µm [7].
A
A 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
C and proliferation, C, in the cortical interstitial compartment.
FIGURE 11-6
200 A, Relationship between constant serum levels and concomitant
renal cortical accumulation of gentamicin after a 6 hour intra-
Vmax= 149.83 + 9.08 µg/g/h
venous infusion in rats. The rate of accumulation is expressed in
micrograms of aminoglycoside per gram of wet kidney cortex per
Renal cortical gentamicin accumulation rate, µg/g/h
Km= 15.01+1.55 µ g/ml

hour, due to the linear accumulation in function of time. Each
150 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].
(Continued on next page)
100
accumulation rate, µ g/g/h
Renal cortical gentamicin
60
40
50
20 V= 6.44 + 4.88 C
r= 0.96
0
0 5 10 15
Serum gentamicin concentration, µg/ml
0
0 10 20 30 40 50 60 70 80 90 100
A Serum gentamicin concentration, µg/ml

1000 B, Kidney cortical concentrations of gentamicin in rats given equal
One injection a day
** daily amounts of aminoglycoside in single injections, three injections,
Renal cortical gentamicin accumulation, µ g/g
Three injections a day ** or by continuous infusion over 8 days. Each block represents the
800 Continuous infusion ** mean of seven rats ±SD. Significance is shown only between cortical
Total daily dose: levels achieved after continuous infusion and single injections (aster-
10 mg/kg i.p. isk—P < 0.05; double asterisk—P < 0.01) [9].
600 **
In rats, nephrotoxicity of gentamicin is more pronounced when the
total daily dose is administered by continuous infusion rather than as a
400 ** 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
200 low ones. A single injection results in high peak serum levels that over-
come the saturation limits of the renal uptake mechanism. The high
plasma concentrations are followed by fast elimination and, finally,
0
absence of the drug for a while. This contrasts with the continuous
1 2 4 6 8
low serum levels obtained with more frequent dosing when the uptake
B Days of administration
at the level of the renal cortex is not only more efficient but remains
available throughout the treatment period. Vmax—maximum velocity.
40 40
Renal cortical concentration after one day, µ g/g
One injection a day Continuous infusion (n–6)
35 Gentamicin 35 Netilmicin P< 0.025 P< 0.025 N.S. P< 0.05

250
4.5 mg/kg/d 5 mg/kg/d
30 30
200
Serum levels, µg/ml
25 25
150
20 20
Single injection Single injection
100
15 15
50
10 Continuous infusion 10 Continuous infusion
0
5 5 Gentamicin Netilmicin Tobramycin Amikacin
B 4.5 mg/kg 5 mg/kg 4.5 mg/kg/d 15 mg/kg/d
0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24 FIGURE 11-7
40 90 Course of serum concentrations, A, and of renal cortical concentra-
tions, B, of gentamicin, netilmicin, tobramycin, and amikacin after
Tobramycin Amikacin
dosing by a 30-minute intravenous injection or continuous infusion
35 80
4.5 mg/kg/d 15 mg/kg/d
over 24 hours [10,11].
70 Two trials in humans found that the dosage schedule had a criti-
30
cal effect on renal uptake of gentamicin, netilmicin [10], amikacin,
60 and tobramycin [11]. Subjects were patients with normal renal
Serum levels, µg/ml
25 function (serum creatinine concentration between 0.9 and 1.2

50 mg/dL, proteinuria lower than 300 mg/24 h) who had renal cancer
20 and submitted to nephrectomy. Before surgery, patients received
40 gentamicin (4.5 mg/kg/d), netilmicin (5 mg/kg/d), amikacin (15
Single injection Single injection
15 mg/kg/d), or tobramycin (4.5 mg/kg/d) as a single injection or as a
30 continuous intravenous infusion over 24 hours. The single-injection
10 schedule resulted in 30% to 50% lower cortical drug concentra-
20 Continuous infusion
tions of netilmicin, gentamicin, and amikacin as compared with
Continuous infusion continuous infusion. For tobramycin, no difference in renal accu-
5 10
mulation could be found, indicating the linear cortical uptake of
0 0 this particular aminoglycoside [8]. These data, which supported
0 4 8 12 16 20 24 0 4 8 12 16 20 24 decreased nephrotoxic potential of single-dose regimens, coincided
Time, hrs with new insights in the antibacterial action of aminoglycosides
A
(concentration-dependent killing of gram-negative bacteria and
prolonged postantibiotic effect) [12]. N.S.—not significant.
FIGURE 11-8
RISK FACTORS FOR AMINOGLYCOSIDE NEPHROTOXICITY Risk factors for aminoglycoside nephro-
toxicity. Several risk factors have been
identified and classified as patient related,
Patient-Related Factors Aminoglycoside-Related Factors Other Drugs aminoglycoside related, or related to con-
current administration of certain drugs.
Older age* Recent aminoglycoside therapy Amphotericin B The usual recommended aminoglycoside
Preexisting renal disease Cephalosporins dose may be excessive for older patients
Female gender Larger doses* Cisplatin because of decreased renal function and
Magnesium, potassium, or Treatment for 3 days or more* Clindamycin decreased regenerative capacity of a dam-
calcium deficiency* aged kidney. Preexisting renal disease
Intravascular volume depletion* Cyclosporine clearly can expose patients to inadvertent
Hypotension* Dose regimen* Foscarnet overdosing if careful dose adjustment is
Hepatorenal syndrome Furosemide not performed. Hypomagnesemia,
Sepsis syndrome Piperacillin hypokalemia, and calcium deficiency may
Radiocontrast agents be predisposing risk factors for conse-
Thyroid hormone quences of aminoglycoside-induced dam-
age [13]. Liver disease is an important
clinical risk factor for aminoglycoside
* Similar to experimental data.
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 Prevention of aminoglycoside nephrotoxicity. Coadministration
NEPHROTOXICITY of other potentially nephrotoxic drugs enhances or accelerates the
nephrotoxicity of aminoglycosides. Comprehension of the phar-
macokinetics and renal cell biologic effects of aminoglycosides,
Identify risk factor allows identification of aminoglycoside-related nephrotoxicity risk
Patient related factors and makes possible secondary prevention of this important
Drug related
clinical nephrotoxicity.
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
Amphotericin B
FIGURE 11-10
Proposed partial model for the amphotericin B (AmB)–induced
Water Lipid
pore in the cell membrane. AmB is an amphipathic molecule: its
Phospho- structure enhances the drug’s binding to sterols in the cell mem-
lipid branes and induces formation of aqueous pores that result in weak-
ening 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,
Cholesterol 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].
C20-C33 heptaene segment
Amphotericin B
Pore
C
O
N
H
FIGURE 11-11
RISK FACTORS IN THE DEVELOPMENT OF Risk factors for development of amphotericin B (AmB) nephrotoxic-
AMPHOTERICIN NEPHROTOXICITY ity. Nephrotoxicity of AmB is a major problem associated with clin-
ical use of this important drug. Disturbances in both glomerular
and tubule function are well described. The nephrotoxic effect of
Age AmB is initially a distal tubule phenomenon, characterized by a loss
Concurrent use of diuretics of urine concentration, distal renal tubule acidosis, and wasting of
Abnormal baseline renal function
potassium and magnesium, but it also causes renal vasoconstriction
leading to renal ischemia. Initially, the drug binds to membrane
Larger daily doses
sterols in the renal vasculature and epithelial cells, altering its mem-
Hypokalemia
brane permeability. AmB-induced vasoconstriction and ischemia to
Hypomagnesemia
very vulnerable sections of the nephron, such as medullary thick
Other nephrotoxic drugs (aminoglycosides, cyclosporine)
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.
FIGURE 11-12
Indication for amphotericin B therapy Proposed approach for management of
Clinical evaluation: Correction: amphotericin B (AmB) therapy. Several new
Is patient salt depleted? Correct salt depletion formulations of amphotericin have been
yes Avoid diuretics developed either by incorporating ampho-
Liberalize dietary sodium
tericin into liposomes or by forming com-
Will salt loading exacerbate underlying disease? yes Weigh risk-benefit ratio plexes to phospholipid. In early studies,
Seek alternatives nephrotoxicity was reduced, allowing an
Does patient require concommitant antibiotics? yes Select drug with high salt content increase of the cumulative dose. Few studies
have established a therapeutic index
Is potassium (K) or magnesium (Mg) depleted? yes Correct abnormalities
between antifungal and nephrotoxic effects
No of amphotericin. To date, the only clinically
Begin amphotericin B with sodium supplement, 150 mEq/d Begin amphotericin B therapy proven intervention that reduces the inci-
dence and severity of nephrotoxicity is salt
supplementation, which should probably be
Routine Monitoring:
given prophylactically to all patients who
Clinical evaluation (cardiovascular/respiratory status; body weight; fluid intake and excretion) can tolerate it. (From Bernardo JF, et al.
Laboratory tests (renal function; serum electrolyte levels; 24 -hours urinary electrolyte excretion)
[16]; with permission.)
Clinical evaluation: Is patient vomiting? yes Increase salt load

No
Laboratory evaluation: Correction:
Is serum creatinine
creratinine>3
>3mg/dL
mg/dLor
orisisrenal
renaldeterioration
deteriorationrapid?
rapid? Interrupt amphotericin B therapy,
yes
resume on improvement
Is K level ,3.5 mEq/L or Mg level <1.6 mEq/L? Use oral or intravenous
yes supplementation
No
Continue amphotericin B therapy and routine monitoring
Close follow-up of serum electrolytes
Cyclosporine
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 trans-
plant recipients, however, the situation is completely different. In
this clinical setting, the clinician must differentiate between cyclo-
sporine injury and acute rejection. The incidence of this acute
cyclosporine renal injury can be enhanced by extended graft preser-
vation, preexisting histologic lesions, donor hypotension, or preop-
erative complications. The gold standard for this important dis-
tinction remains renal biopsy.
In addition, cyclosporine has been associated with hemolytic-ure-
mic syndrome with thrombocytopenia, red blood cell fragmenta-
tion, 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 rejec-
FIGURE 11-13 (see Color Plate) tion-related interstitial edema and cellular infiltrates can be helpful.
Intravascular coagulation in a cyclosporine-treated renal transplant Vanrenterghem and coworkers [19] found a high incidence of
recipient. Cyclosporine produces a dose-related decrease in renal venous thromboembolism shortly after (several of them within
function in experimental animals and humans [17] that is attrib- days) cadaveric kidney transplantation in patients treated with
uted to the drug’s hemodynamic action to produce vasoconstriction cyclosporine, in contrast to those treated with azathioprine. Recent
of the afferent arteriole entering the glomerulus. When severe studies [20] have shown that impaired fibrinolysis, due mainly to
enough, this can decrease glomerular filtration rate. Although the excess plasminogen activator inhibitor (PAI-1), may also contribute
precise pathogenesis of the renal hemodynamic effects of to this imbalance in coagulation and anticoagulation during
cyclosporine are unclear, endothelin, inhibition of nitric oxide, cyclosporine treatment.
Lithium-Induced Acute Renal Failure

FIGURE 11-14
SIGNS AND SYMPTOMS OF Symptoms and signs of toxic effects of lithium. Lithium can cause
TOXIC EFFECTS OF LITHIUM acute functional and histologic (usually reversible) renal injury.
Within 24 hours of administration of lithium to humans or ani-
mals, sodium diuresis occurs and impairment in the renal concen-
Toxic Effect Plasma Lithium Level Signs and Symptoms trating capacity becomes apparent. The defective concentrating
capacity is caused by vasopressin-resistant (exogenous and endoge-
Mild 1–1.5 mmol/L Impaired concentration, lethargy, nous) diabetes insipidus. This is in part related to lithium’s inhibi-
irritability, muscle weakness, tion of adenylate cyclase and impairment of vasopressin-induced
tremor, slurred speech, nausea
generation of cyclic adenosine monophosphatase.
Moderate 1.6–2.5 mmol/L Disorientation, confusion,
Lithium-induced impairment of distal urinary acidification has
drowsiness, restlessness, unsteady
gait, coarse tremor, dysarthria, also been defined.
muscle fasciculation, vomiting Acute lithium intoxication in humans and animals can cause
Severe >2.5 mmol/L Impaired consciousness (with acute renal failure. The clinical picture features nonspecific signs of
progression to coma), delirium, degenerative changes and necrosis of tubule cells [21]. The most
ataxia, generalized fasciculations, distinctive and specific acute lesions lie at the level of the distal
extrapyramidal symptoms, tubule [22]. They consist of swelling and vacuolization of the cyto-
convulsions, impaired renal plasm of the distal nephron cells plus periodic acid-Schiff–positive
function
granular material in the cytoplasm (shown to be glycogen) [23].
Most patients receiving lithium have side effects, reflecting the
drug’s narrow therapeutic index.
FIGURE 11-15
DRUG INTERACTIONS WITH LITHIUM 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 consid-
Salt depletion strongly impairs renal elimination of lithium. ered a prerenal type; consequently, it resolves rapidly with appropri-
Salt loading increases absolute and fractional lithium clearance.
ate fluid therapy. Indeed, the histologic appearance in such cases is
remarkable for its lack of significant abnormalities. Conditions that
Diuretics stimulate sodium retention and consequently lithium reabsorption,
Acetazolamide Increased lithium clearance such as low salt intake and loss of body fluid by way of vomiting,
Thiazides Increased plasma lithium level due to decreased diarrhea, or diuretics, decreasing lithium clearance should be avoid-
lithium clearance ed. With any acute illness, particularly one associated with gastroin-
Loop diuretics Acute increased lithium clearance testinal symptoms such as diarrhea, lithium blood levels should be
Amiloride Usually no change in plasma lithium level; may be closely monitored and the dose adjusted when necessary. Indeed,
used to treat lithium-induced polyuria most episodes of acute lithium intoxication are largely predictable,
and thus avoidable, provided that precautions are taken [25].
Nonsteroidal Increased plasma lithium level due to decreased Removing lithium from the body as soon as possible the is the
anti-inflammatory drugs renal lithium clearance (exceptions are aspirin mainstay of treating lithium intoxication. With preserved renal func-
and sulindac)
tion, excretion can be increased by use of furosemide, up to 40 mg/h,
Bronchodilators (amino- Decreased plasma lithium level due to increased
phylline, theophylline) obviously under close monitoring for excessive losses of sodium and
renal lithium clearance
Angiotensin-converting
water induced by this loop diuretic. When renal function is impaired
May increase plasma lithium level
enzyme inhibitors in association with severe toxicity, extracorporeal extraction is the
Cyclosporine most efficient way to decrease serum lithium levels. One should,
Decreased lithium clearance
however, remember that lithium leaves the cells slowly and that plas-
ma levels rebound after hemodialysis is stopped, so that longer dialy-
sis treatment or treatment at more frequent intervals is required.
Inhibitors of the Renin-Angiotensin System

efferent arteriolar vascular tone and in
Pre-kallikrein general is reversible after withdrawing the
angiotensin-converting enzyme (ACE)
inhibitor [27].
Angiotensinogen Kininogen Activated factor XII Inhibition of the ACE kinase II results
in at least two important effects: depletion
Renin + + Kallikrenin of angiotensin II and accumulation of
+ : stimulation bradykinin [28]. The role of the latter effect
Angiotensin I Angiotensin Bradykinin
converting on renal perfusion pressure is not clear, A.
+ enzyme + To understand the angiotensin I convert-
Kininase II ing enzyme inhibitor–induced drop in
glomerular filtration rate, it is important
Angiotensin II Inactive peptide Arachidonic acid
to understand the physiologic role of the
Increased aldosterone release
+ renin-angiotensin system in the regulation
of renal hemodynamics, B. When renal per-
Potentiation of sympathetic activity fusion drops, renin is released into the plas-
ma and lymph by the juxtaglomerular cells
Increased Ca2+ current Prostaglandins of the kidneys. Renin cleaves angiotensino-
gen to form angiotensin I, which is cleaved
further by converting enzyme to form
Cough? angiotensin II, the principal effector mole-
Vasoconstriction Vasodilation
A cule in this system. Angiotensin II partici-
pates in glomerular filtration rate regulation
in a least two ways. First, angiotensin II
FIGURE 11-16 increases arterial pressure—directly and
Soon after the release of this useful class of antihypertensive drugs, the syndrome of func- acutely by causing vasoconstriction and
tional acute renal insufficiency was described as a class effect. This phenomenon was first more “chronically” by increasing body fluid
observed in patients with renal artery stenosis, particularly when the entire renal mass was volumes through stimulation of renal sodi-
affected, as in bilateral renal artery stenosis or in renal transplants with stenosis to a soli- um retention; directly through an effect on
tary kidney [26]. Acute renal dysfunction appears to be related to loss of postglomerular the tubules, as well as by stimulating thirst
+: vasoconstriction –: vasodilation dietary sodium restriction or sodium

B1. Normal condition depletion as during diuretic therapy, con-
Autoregulation gestive heart failure, cirrhosis, and
+
– +
– nephrotic syndrome. When activated, this
Afferent Efferent reninangiotensin system plays an impor-
Glomerulus tant role in the maintenance of glomerular
arteriole arteriole
pressure and filtration through preferen-
Myogenic reflex (Laplace) tial angiotensin II–mediated constriction
Tubuloglomerular feedback of the efferent arteriole. Thus, under such
Tubule
conditions the kidney becomes sensitive
B2. Perfusion pressure reduced to the effects of blockade of the renin-
but still within autoregulatory range PGE2
(congestive heart failure,
angiotensin system by angiotensin I–con-
–
renal artery stenosis, verting enzyme inhibitor or angiotensin II
diuretic therapy, receptor antagonist.
nephrotic syndrome cirrhosis, The highest incidence of renal failure in
sodium restriction depletion, +
patients treated with ACE inhibitors was
advanced age [age >80]) Local
angiotensin II
associated with bilateral renovascular
disease [27]. In patients with already
B3. Perfusion pressure compromised renal function and congestive
seriously reduced PGE2 heart failure, the incidence of serious
(prerenal azotemia) – changes in serum creatinine during ACE
Intra-
glomerular inhibition depends on the severity of the
pressure pretreatment heart failure and renal failure.
+ + Volume management, dose reduction,
Sympathetic activity Local use of relatively short-acting ACE
angiotensin II angiotensin II inhibitors, diuretic holiday for some days
B
before initiating treatment, and avoidance
of concurrent use of nonsteroidal anti-
FIGURE 11-16 (Continued) inflammatory drug (hyperkalemia) are
and indirectly via aldosterone. Second, angiotensin II preferentially constricts the efferent among the appropriate measures for
arteriole, thus helping to preserve glomerular capillary hydrostatic pressure and, conse- patients at risk.
quently, glomerular filtration rate. Acute interstitial nephritis associated with
When arterial pressure or body fluid volumes are sensed as subnormal, the renin- angiotensin I–converting enzyme inhibition
angiotensin system is activated and plasma renin activity and angiotensin II levels has been described [29]. (Adapted from
increase. This may occur in the context of clinical settings such as renal artery stenosis, Opie [30]; with permission.)
Nonsteroidal Anti-inflammatory Drugs

FIGURE 11-17
Patients at risk for NSAID-induced acute renal failure Mechanism by which nonsteroidal anti-inflammatory drugs
(NSAIDs) disrupt the compensatory vasodilatation response of
↑Renin-angiotensin axis ↑Adrenergic nervous system renal prostaglandins to vasoconstrictor hormones in patients with
↑Angiotensin II ↑Catecholamines 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].
Renal vasoconstriction Sodium chloride and water retention are the most common side
↓Renal function
effects of NSAIDs. This should not be considered drug toxicity
because it represents a modification of a physiologic control
"Normalized" renal function mechanism without the production of a true functional disorder
in the kidney.
Inhibition
– –
by NSAID
Compensatory vasodilation induced by renal

prostaglandin synthesis
FIGURE 11-18
PREDISPOSING FACTORS FOR NSAID- Conditions associated with risk for nonsteroidal anti-inflammatory
INDUCED ACUTE RENAL FAILURE 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 perfu-
Severe heart disease (congestive heart failure) sion to the kidney [32]. Renal prostaglandins play an important
Severe liver disease (cirrhosis) role in the maintenance of homeostasis in these patients, so disrup-
Nephrotic syndrome (low oncotic pressure)
tion of counter-regulatory mechanisms can produce clinically
important, and even severe, deterioration in renal function.
Chronic renal disease
Age 80 years or older
Protracted dehydration (several days)
FIGURE11-19
Physiologic stimulus Inflammatory stimuli Inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) on
pathways of cyclo-oxygenase (COX) and prostaglandin synthesis
Inhibition
- by NSAID - [33]. The recent demonstration of the existence of functionally dis-
tinct isoforms of the cox enzyme has major clinical significance, as
COX-1 COX-2
it now appears that one form of cox is operative in the gastric
constitutive inducible mucosa and kidney for prostaglandin generation (COX-1) whereas
Stomach Kidney Inflammatory sites an inducible and functionally distinct form of cox is operative in
Intestine Platelets (macrophages, the production of prostaglandins in the sites of inflammation and
Endothelium synoviocytes) pain (COX-2) [33]. The clinical therapeutic consequence is that an
NSAID with inhibitory effects dominantly or exclusively upon the
O2 -
cox isoenzyme induced at a site of inflammation may produce the
PGE2 TxA2 PGI2 Inflamma- Proteases
tory PGs desired therapeutic effects without the hazards of deleterious effects
on the kidneys or gastrointestinal tract. PG—prostaglandin;
TxA2—thromboxane A2.
Physiologic functions Inflammation
unusual combination of findings and in the

EFFECTS OF NSAIDS ON RENAL FUNCTION setting of protracted NSAID use is virtually
pathognomic of NSAID-related nephrotic
syndrome.
A focal diffuse inflammatory infiltrate
Renal Syndrome Mechanism Risk Factors Prevention/Treatment [34] can be found around the proximal and dis-
Sodium retension ↓ Prostaglandin NSAID therapy (most Stop NSAID tal tubules. The infiltrate consists primarily
and edema common side effect) of cytotoxic T lymphocytes but also con-
Hyperkalemia ↓ Prostaglandin Renal disease Stop NSAID tains other T cells, some B cells, and plasma
↓ Potassium to Heart failure Avoid use in high-risk patients cells. Changes in the glomeruli are minimal
distal tubule Diabetes and resemble those of classic minimal-
↓ Aldosterone/renin- Multiple myeloma change glomerulonephritis with marked
angiotensin Potassium therapy epithelial foot process fusion.
Potassium-sparing Hyperkalemia, an unusual complication
diuretic of NSAIDs, is more likely to occur in
Stop NSAID
Acute deterioration of ↓ Prostaglandin and Liver disease patients with pre-existing renal impairment,
Avoid use in high-risk patients
renal function disruption of Renal disease
cardiac failure, diabetes, or multiple myelo-
hemodynamic bal- ma or in those taking potassium supple-
Heart failure
ance ments, potassium-sparing diuretic therapy,
Dehydration
Stop NSAID or intercurrent use of an angiotensin-con-
Old age
Dialysis and steroids (?) verting enzyme inhibitor. The mechanism of
Nephrotic syndrome with: ↑ Lymphocyte recruit- Fenoprofen Stop NSAID NSAID hyperkalemia—suppression of
Interstitial nephritis ment and activation prostaglandin-mediated renin release—leads
Avoid long-term
Papillary necrosis Direct toxicity Combination aspirin analgesic use to a state of hyporeninemic hypoaldostero-
and acetaminophen nism. In addition, NSAIDs, particularly
abuse
indomethacin, may have a direct effect on
cellular uptake of potassium.
The renal saluretic response to loop
diuretics is partially a consequence of
FIGURE 11-20 intrarenal prostaglandin production. This
Summary of effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function [31]. component of the response to loop diuretics
All NSAIDs can cause another type of renal dysfunction that is associated with various is mediated by an increase in renal
levels of functional impairment and characterized by the nephrotic syndrome together with medullary blood flow and an attendant
interstitial nephritis. reduction in renal concentrating capacity.
Characteristically, the histology of this form of NSAID–induced nephrotic syndrome Thus, concurrent use of an NSAID may
consists of minimal-change glomerulonephritis with tubulointerstitial nephritis. This is an blunt the diuresis induced by loop diuretics.
Contrast Medium–Associated Nephrotoxicity

FIGURE 11-21
RISK FACTORS THAT PREDISPOSE TO CONTRAST Risk factors that predispose to contrast-associated nephropathy. In
ASSOCIATED NEPHROPATHY 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
Confirmed Suspected Disproved over baseline, is between 2% and 7%. For confirmed high-risk
patients (baseline serum creatinine values greater than 1.5 mg/dL) it
Chronic renal failure Hypertension Myeloma rises to 10% to 35%. In addition, there are suspected risk factors
Diabetic nephropathy Generalized atherosclerosis Diabetes without that should be taken into consideration when considering the value
Severe congestive Abnormal liver nephropathy of contrast-enhanced imaging.
heart failure function tests
Amount and frequency Hyperuricemia
of contrast media Proteinuria
Volume depletion
or hypotension
els, a consensus is developing to the effect that contrast-associat-

Hypersomolar radiocontrast medium ed nephropathy involves combined toxic and hypoxic insults
to the kidney [35]. The initial glomerular vasoconstriction that
follows the injection of radiocontrast medium induces the
↑Endothelin Systemic ↓ATPase liberation of both vasoconstrictor (endothelin, vasopressin) and
↑PGE2 ↑Vasopressin hypoxemia
↑ANF ↑Adenosine ↑Blood viscosity Osmotic load vasodilator (prostaglandin E2 [PGE2], adenosine, atrionatiuretic
↓PGI2 to distal tubule factor {ANP}) substances. The net effect is reduced oxygen deliv-
ery to tubule cells, especially those in the thick ascending limb
of Henle. Because of the systemic hypoxemia, raised blood vis-
↑RBF ↓↓RBF cosity, inhibition of sodium-potassium–activated ATPase and the
– increased osmotic load to the distal tubule at a time of reduced
Calcium oxygen delivery, the demand for oxygen increases, resulting in
antagonists cellular hypoxia and, eventually cell death. Additional factors
Theophylline Net ↓O2 delivery Net ↑O2 consumption
that contribute to the acute renal dysfunction of contrast-associ-
ated 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 accompa-
Cell injury ny cell death. As noted in the figure, calcium antagonists and
theophylline (adenosine receptor antagonist) are thought to
↑TH protein ↑Intrarenal number act to diminish the degree of vasoconstriction induced by con-
of macrophages, T cells trast medium.
Stimulation of mesangium The clinical presentation of contrast-associated nephropathy
involves an asymptomatic increase in serum creatinine within 24
Tubular obstruction Superoxidase hours of a radiographic imaging study using contrast medium,
– –
dismutase 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.
↓RBF ↓GFR Reactive O2 species
lipid peroxidase Of oliguric acute renal failure patients, 32% have persistent
elevations of serum creatinine at recovery and half require per-
manent dialysis. In the absence of oliguric acute renal failure
Contrast associated nephropathy 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
FIGURE 11-22 whose defined risks are not only permanent dialysis but also
A proposed model of the mechanisms involved in radiocontrast death. GFR—glomerular filtration rate; RBF—renal blood flow;
medium–induced renal dysfunction. Based on experimental mod- TH—Tamm Horsfall protein.
Thus it is important to select the least invasive diagnostic proce-

PREVENTION OF CONTRAST dure that provides the most information, so that the patient can
ASSOCIATED NEPHROPATHY 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
Hydrate patient before the study (1.5 mL/kg/h) 12 h before and after.
agents has become an important aspect of imaging. A list of
Hemodynamically stabilize hemodynamics. maneuvers that minimize the risk of contrast-associated
Minimize amount of contrast medium administered. nephropathy is contained in this table. The correction of
Use nonionic, iso-osmolar contrast media for patients at high risk (see Figure 11-21). 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
FIGURE 11-23 media have proven to be protective for high-risk patients.
Prevention of contrast-associated nephropathy. The goal of man- Pretreatment with calcium antagonists is an intriguing but
agement is the prevention of contrast-associated nephropathy. unsubstantiated approach.
References
1. Bennett WM, Porter GA: Overview of clinical nephrotoxicity. In 20. Verpooten GA, Cools FJ, Van der Planken MG, et al.: Elevated plas-
Toxicology of the Kidney, edn 2. Edited by Hook JB, Goldstein RS. minogen activator inhibitor levels in cyclosporin-treated renal allo-
Raven Press, 1993:61–97. graft recipients. Nephrol Dial Transplant 1996, 11:347–351.
2. Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J 21. Vestergaard P, Amdisen A, Hansen AE, Schou M: Lithium treatment
Med 1996, 334:1448–1460. and kidney function. Acta Psychiatry Scand 1979; 60:504–520.
3. De Broe ME: Prevention of aminoglycoside nephrotoxicity. In Proc 22. Johnson GF, Hunt G, Duggin GG, et al.: Renal function and lithium
EDTA-ERA. Edited by Davison AM, Guillou PJ. London:BailliËre treatment: initial and follow-up tests in manic-depressive patients.
Tindal, 1985:959–973. J Affective Disord 1984; 6:249–263.
4. Lietman PS: Aminoglycosides and spectinoycin: aminocylitols. In 23. Coppen A, Bishop ME, Bailey JE, et al.: Renal function in lithium
Principles and Practice of Infectious Diseases, edn 2, Part I. Edited by and non–lithium-treated patients with affective disorders. Acta
Mandel GL, Doublas RG Jr, Bennett JE. New York: John Wiley & Psychiatry Scand 1980; 62:343–355.
Sons, 1985:192–206. 24. Battle DC, Dorhout-Mees EJ: Lithium and the kidney. In Clinical
5. Kaloyanides GJ, Pastoriza-Munoz E: Aminoglycoside nephrotoxicity. nephrotoxins—renal injury from drugs and chemicals. Edited by De
Kidney Int 1980, 18:571–582. Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht:
6. Molitoris BA. Cell biology of aminoglycoside nephrotoxicity: newer Kluwer Academic, 1998:383–395.
aspects. Curr Opin Nephrol Hypertens 1997, 6:384–388. 25. Jorgensen F, Larsen S, Spanager E, et al.: Kidney function and quanti-
7. De Broe ME, Paulus GJ, Verpooten GA, et al.: Early effects of gen- tative histological changes in patients on long-term lithium therapy.
tamicin, tobramycin, and amikacin on the human kidney. Kidney Int Acta Psychiatry Scand 1984, 70:455–462.
1984, 25:643–652. 26. Hricik DE, Browning PJ, Kopelman R, et al.: Captopril-induced func-
8. Giuliano RA, Verpooten GA, Verbist L, et al.: In vivo uptake kinetics tional renal insufficiency in patients with bilateral renal artery stenosis
of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp or renal artery stenosis in a solitary kidney. N Engl J Med 1983,
Ther 1986, 236:470–475. 308:373–376.
9. Giuliano RA, Verpooten GA, De Broe ME: The effect of dosing strat- 27. Textor SC: ACE inhibitors in renovascular hypertension. Cardiovasc
egy on kidney cortical accumulation of aminoglycosides in rats. Am J Drugs Ther 1990; 4:229–235.
Kidney Dis 1986, 8:297–303. 28. de Jong PE, Woods LL: Renal injury from angiotensin I converting
10. Verpooten GA, Giuliano RA, Verbist L, et al.: A once-daily dosage enzyme inhibitors. In Clinical nephrotoxins—renal injury from drugs
schedule decreases the accumulation of gentamicin and netilmicin in and chemicals. Edited by De Broe ME, Porter GA, Bennett WM,
the renal cortex of humans. Clin Pharmacol Ther 1989, 44:1–5. Verpooten GA. Dordrecht: Kluwer Academic, 1998:239–250.
11. De Broe ME, Verbist L, Verpooten GA: Influence of dosage schedule 29. Smith WR, Neil J, Cusham WC, Butkus DE: Captopril associated
on renal cortical accumulation of amikacin and tobramycin in man. J acute interstitial nephritis. Am J Nephrol 1989, 9:230–235.
Antimicrob Chemother 1991, 27 (suppl C):41–47. 30. Opie LH: Angiotensin-converting enzyme inhibitors. New York:
12. Bennett WM, Plamp CE, Gilbert DN, et al.: The influence of dosage Willy-Liss, 1992; 3.
regimen on experimental gentamicin nephrotoxicity: dissociation of 31. Whelton A, Watson J: Nonsteroidal anti-inflammatory drugs: effects
peak serum levels from renal failure. J Infect Dis 1979, 140:576–580. on kidney function. In Clinical Nephrotoxins—Renal Injury From
13. Moore RD, Smith CR, Lipsky JJ, et al.: Risk factors for nephrotoxici- drugs and Chemicals. Edited by De Broe ME, Porter GA, Bennett
ty in patients treated with aminoglycosides. Ann Intern Med 1984, WM, Verpooten GA. Dordrecht: Kluwer Academic, 1998:203–216.
100:352–357.
32. De Broe ME, Elseviers MM: Analgesic nephropathy. N Engl J Med
14. Zager RA: A focus of tissue necrosis increases renal susceptibility to 1998, 338:446–452.
gentamicin administration. Kidney Int 1988; 33:84–90.
33. Mitchell JA, Akarasereenont P, Thiemermann C, et al.: Selectivity of
15. Andreoli TE: On the anatomy of amphotericin B-cholesterol pores in nonsteroidal antiinflammatory drugs as inhibitors of constitutive and
lipid bilayer membranes. Kidney Int 1973, 4:337–45. inducible cyclooxygenase. Proc Natl Acad Sci USA 1993,
16. Bernardo J, Sabra R, Branch RA: Amphotericin B. In Clinical 90(24):11693–11697.
Nephrotoxins—Renal Injury From Drugs and Chemicals. Edited by 34. Bennett WM, Henrich WL, Stoff JS: The renal effects of nonsteroidal
De Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht: anti-inflammatory drugs: summary and recommendations. Am J
Kluwer Academic, 1998:135–151. Kidney Dis 1996, 28(1 Suppl 1):S56–S62.
17. Bennett WM: Mechanisms of acute and chronic nephrotoxicity from 35. Heyman SN, Rosen S, Brezis M: Radiocontrast nephropathy: a para-
immunosuppressive drugs. Renal Failure 1996, 18:453–460. digm for the synergism between toxic and hypoxic insults in the kid-
18. de Mattos AM, Olyaei AJ, Bennett WM: Pharmacology of immuno- ney. Exp Nephrol 1994, 2:153.
suppressive medications used in renal diseases and transplantation. 36. Porter GA, Kremer D: Contrast associated nephropathy: presentation,
Am J Kidney Dis 1996, 28:631–667. pathophysiology and management. In Clinical nephrotoxins—Renal
19. Vanrenterghem Y, Lerut T, Roels L, et al.: Thromboembolic complica- Injury From Drugs and Chemicals. Edited by De Broe ME, Porter
tions and haemostatic changes in cyclosporin-treated cadaveric kidney GA, Bennett WM, Verpooten GA. Dordrecht: Kluwer Academic,
allograft recipients. Lancet 1985, 1:999–1002. 1998:317–331.
Diagnostic Evaluation of
the Patient with Acute
Renal Failure
Brian G. Dwinnell
Robert J. Anderson
A
cute renal failure (ARF) is abrupt deterioration of renal func-
tion 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 dis-
agreement 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 clin-
ical perspective, for persons with normal renal function and serum
creatinine concentration, glomerular filtration rate must be dramati-
cally 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 process-
ing 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 CHAPTER
cause, prompt diagnostic evaluation of each case of ARF is necessary.
12
RATIONALE FOR ORGANIZED PRESENTING FEATURES OF ACUTE RENAL FAILURE

APPROACH TO ACUTE RENAL FAILURE
Common
Common Rising BUN or creatinine
Present in 1%–2% of hospital admissions Oligoanuria
Develops after admission in 1%–5% of noncritically ill patients Less common
Develops in 5%–20% after admission to an intensive care unit Symptoms of uremia
Multiple causes Characteristic laboratory abnormalities
Prerenal
Postrenal
Renal
Therapy dependent upon diagnosing cause FIGURE 12-2
Prerenal: improve renal perfusion Presenting features of acute renal failure (ARF). ARF usually comes
Postrenal: relieve obstruction to clinical attention by the finding of either elevated (or rising)
Renal: identify and treat specific cause blood urea nitrogen (BUN) or serum creatinine concentration. Less
Poor outcomes commonly, decreased urine output ( less than 20 mL per hour) her-
Twofold increased length of stay alds the presence of ARF. It is important to acknowledge, however,
Two- to eightfold increased mortality that at least half of all cases of ARF are nonoliguric [2–6]. Thus,
Substantial morbidity 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 acido-
sis, hyperkalemia, hyperphosphatemia, hypocalcemia, hyper-
FIGURE 12-1
uricemia, hypermagnesemia, anemia).
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 [1–7]. If not diagnosed and treated and reversed quick-
ly, it can lead to substantial morbidity and mortality.
Blood Urea Nitrogen, Creatinine, and Renal Failure

can vary with exogenous protein intake and
OVERVIEW OF BLOOD UREA NITROGEN AND SERUM CREATININE endogenous protein catabolism. Urea nitro-
gen is a small, uncharged molecule that is
not protein bound, and as such, it is readily
Blood Urea Nitrogen Serum Creatinine filtered at the renal glomerulus. Urea nitro-
Source Protein that can be of exogenous Nonenzymatic hydrolysis of creatine gen undergoes renal tubular reabsorption
or endogenous origin released from skeletal muscle by specific transporters. This tubular reab-
Constancy of production Variable More stable sorption limits the value of BUN as a mark-
Renal handling Completely filtered; significant Completely filtered; some tubular secretion er for glomerular filtration. However, the
tubular reabsorption
Value as marker for Modest Good in steady state
BUN usually correlates with the symptoms
glomerular filtration rate of uremia. By contrast, the production of
Correlation with Good Poor creatinine is usually more constant unless
uremic symptoms there has been a marked reduction of skele-
tal muscle mass (eg, loss of a limb, pro-
longed starvation) or diffuse muscle injury.
Although creatinine undergoes secretion
FIGURE 12-3 into renal tubular fluid, this is very modest
Overview of blood urea nitrogen (BUN) and serum creatinine. Given the central role of in degree. Thus, a steady-stable serum crea-
BUN and serum creatinine in determining the presence of renal failure, an understanding tinine concentration is usually a relatively
of the metabolism of these substances is needed. Urea nitrogen derives from the break- good marker of glomerular filtration rate as
down of proteins that are delivered to the liver. Thus, the urea nitrogen production rate noted in Figure 12-5.
Diagnostic Evaluation of the Patient with Acute Renal Failure 12.3
FIGURE 12-4
BLOOD UREA NITROGEN (BUN)-CREATININE RATIO The blood urea nitrogen (BUN)-creatinine ratio. Based on the infor-
mation 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,
> 10 < 10
tubular reabsorption of urea nitrogen is enhanced in low-urine flow
Increased protein intake Starvation states. Thus, a high BUN-creatinine ratio often occurs in prerenal
Catabolic state Advanced liver disease and postrenal (see Fig. 12-6) forms of renal failure. Similarly,
Fever Postdialysis state enhanced delivery of amino acids to the liver (as with catabolism,
Sepsis Drugs that impair tubular secretion corticosteroids, etc.) can enhance urea nitrogen formation and
Trauma Cimetidine increase the BUN-creatinine ratio. A BUN-creatinine ratio lower
Corticosteroids Trimethoprim than 10:1 can occur because of decreased urea nitrogen formation
Tissue necrosis Rhabdomyolysis (eg, in protein malnutrition, advanced liver disease), enhanced creati-
Tetracyclines nine formation (eg, with rhabdomyolysis), impaired tubular secretion
of creatinine (eg, secondary to trimethoprim, cimetidine), or relative-
Diminished urine flow
ly enhanced removal of the small substance urea nitrogen by dialysis.
Prerenal state
Postrenal state
FIGURE 12-5
CORRELATION OF STEADY-STATE SERUM Correlation of steady-state serum creatinine concentration and
CREATININE CONCENTRATION AND glomerular filtration rate (GFR).
GLOMERULAR FILTRATION RATE (GFR)
Creatinine (mg/dL) GFR (mL/min)

1 100
2 50
4 25
8 12.5
16 6.25
FIGURE 12-6
Renal Failure Categories of renal failure. Once the presence of renal failure is
ascertained by elevated blood urea nitrogen (BUN) or serum creati-
nine value, the clinician must decide whether it is acute or chronic.
Favors Favors When previous values are available for review, this judgment is
acute chronic made relatively easily. In the absence of such values, the factors
depicted here may be helpful. Hemoglobin potentially undergoes
Normal Kidney size Small nonenzymatic carbamylation of its terminal valine [8]. Thus, simi-
lar to the hemoglobin A1C value as an index of blood sugar con-
Normal Carbamylated hemoglobin High trol, the level of carbamylated hemoglobin is an indicator of the
degree and duration of elevated BUN, but, this test is not yet wide-
Absent Broad casts on urinalysis Present ly available. The presence of small kidneys strongly suggests that
renal failure is at least in part chronic. From a practical standpoint,
History of kidney disease, because even chronic renal failure often is partially reversible, the
Absent hypertension, Present clinician should assume and evaluate for the presence of acute
abnormal urinalysis
reversible factors in all cases of acute renal failure.
Often Anemia, metabolic acidosis, Usually

present hyperkalemia, hyperphosphatemia present
Usually Sometimes,
complete Reversibility with time partial
Categorization of Causes of Acute Renal Failure

abdominal surgery, muscle crush injury,
Acute renal failure 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 cri-
teria for prerenal ARF are delineated in
Prerenal Renal Postrenal Figure 12-9. Once prerenal forms of ARF
causes causes causes have been ruled out, postrenal forms (ie,
obstruction to urine flow) should be consid-
ered. Obstruction to urine flow is a less
common (5% to 15% of cases) cause of
ARF but is nearly always amenable to ther-
Vascular Glomerulo- Interstitial Tubular
disorders nephritis nephritis necrosis apy. The site of obstruction can be
intrarenal (eg, crystals or proteins obstruct-
ing the terminal collecting tubules) or
extrarenal (eg, blockade of the renal pelvis,
ureters, bladder, or urethra). The diagnosis
Ischemia Toxins Pigments of postrenal forms of ARF is supported by
data outlined in Figure 12-10. After pre-
and postrenal forms of ARF have been con-
FIGURE 12-7 sidered, attention should focus on the kid-
Acute renal failure (ARF). This figure depicts the most commonly used schema to classify ney. When considering renal forms of ARF,
and diagnostically approach the patient with ARF [1, 6, 9]. The most common general it is helpful to think in terms of renal
cause of ARF (60% to 70% of cases) is prerenal factors. Prerenal causes include those sec- anatomic compartments (vasculature,
ondary to renal hypoperfusion, which occurs in the setting of extracellular fluid loss (eg, glomeruli, interstitium, and tubules). Acute
with vomiting, nasogastric suctioning, gastrointestinal hemorrhage, diarrhea, burns, heat disorders involving any of these compart-
stroke, diuretics, glucosuria), sequestration of extracellular fluid (eg, with pancreatitis, ments can lead to ARF.
FIGURE 12-8
VASOMOTOR MECHANISMS CONTRIBUTING TO ACUTE RENAL FAILURE Vasomotor mechanisms contributing to acute
renal failure (ARF). Most prerenal forms of
ARF have operational one or more of the
Decreased Renal vasomotor mechanisms depicted here [6].
Perfusion Pressure Afferent Arteriolar Constriction Efferent Arteriolar Dilation Collectively, these factors lead to diminished
glomerular filtration and ARF. NSAIDs—
Extracellular fluid volume loss Sepsis Converting enzyme inhibitors nonsteroidal anti-inflammatory drugs.
or sequestration Medications (NSAIDs, cyclosporine, Angiotensin II receptor antagonists
Impaired cardiac output contrast medium, amphotericin,
Antihypertensive medications alpha-adrenergic agonists)
Sepsis Hypercalcemia
Postoperative state
Hepatorenal syndrome
FIGURE 12-9
DIAGNOSIS OF POSSIBLE PRERENAL CAUSES OF ACUTE RENAL FAILURE Diagnosis of possible prerenal causes of
acute renal failure (ARF). Prerenal events
are the most common factors that lead to
History Examination Laboratory/Other contemporary ARF. The historical, physical
examination, and laboratory and other
Extracellular fluid loss or sequestra- Orthostatic hypotension Normal urinalysis investigations involved in identifying a pre-
tion from skin, gastrointestinal and tachycardia Urinary indices compatible with normal renal form of ARF are outlined here [1].
and/or renal source (see Fig. 12-15) Dry mucous membranes tubular function (see Fig. 12-14) BUN—blood urea nitrogen.
Orthostatic lightheadedness No axillary moisture Elevated BUN-creatinine ratio
Thirst Decreased skin turgor Improved renal function with correction
Oliguria Evidence of congestive of the underlying cause
Symptoms of heart failure heart failure Rarely, chest radiography, cardiac ultra-
Edema Presence of edema sound, gated blood pool scan, central
venous and/or Swan-Ganz wedge
pressure recordings
FIGURE 12-10
DIAGNOSIS OF POSSIBLE POSTRENAL CAUSES OF ACUTE RENAL FAILURE Diagnosis of possible postrenal causes of
acute renal failure (ARF). Postrenal causes
of ARF are less common (5% to 15% of
History Examination Laboratory/Other ARF population) but are nearly always
amenable to therapy. This figure depicts the
Very young or very old age Distended bladder Abnormal urinalysis historical, physical examination and tests
Nocturia Enlarged prostate Elevated BUN-creatinine ratio that can lead to an intrarenal (crystal depo-
Decreased size or force of urine stream Abnormal pelvic examination Elevated postvoiding sition) or extrarenal (blockade of the col-
Anticholinergic or alpha-adrenergic residual volume lecting system) form of obstructive uropa-
agonist medications Abnormal renal ultrasound, thy [1, 6, 9, 10]. BUN—blood urea nitro-
Bladder, prostate, pelvic, or CT or MRI findings gen; CT—computed tomography;
intra-abdominal cancer Improvement after drainage MRI—magnetic resonance imaging.
Fluctuating urine volume
Oligoanuria
Suprapubic pain
Urolithiasis
Medication known to produce
crystalluria (sulfonamides, acyclovir,
methotrexate, protease inhibitors)
FIGURE 12-11
POSTOPERATIVE ACUTE RENAL FAILURE Postoperative acute renal failure (ARF).
The postoperative setting of ARF is very
common. This figure depicts data on the
Frequency Predisposing Factors Preventive Strategies frequency, predisposing factors, and poten-
tial strategies for preventing postoperative
Elective surgery 1%–5% Comorbidity results in decreased Avoid nephrotoxins ARF [11, 12].
Emergent or vascular renal reserve Minimize hospital-acquired infections
surgery 5%–10% The surgical experience decreases (invasive equipment)
renal function (volume shifts, Selective use of volume expansion,
vasoconstriction) vasodilators, inotropes
A second insult usually occurs Preoperative hemodynamic optimization
(sepsis, reoperation, nephrotoxin, in selected cases
volume/cardiac issue) Increase tissue oxygenation delivery to
supranormal levels in selected cases
Diagnostic Steps in Evaluating Acute Renal Failure

are helpful in differentiating between prere-
STEPWISE APPROACH TO DIAGNOSIS OF ACUTE RENAL FAILURE nal (intact tubular function) and acute
tubular necrosis (impaired tubular function)
as the cause of renal failure. Sometimes,
Step 1 Step 2 Step 3 Step 4 further evaluation (usually ultrasonography,
less commonly computed tomography or
History Consider urinary diagnostic Consider selected Consider renal biopsy
indices (see Fig. 12-16) therapeutic trials magnetic resonance imaging) is needed to
Record review Consider empiric therapy
Consider need for further for suspected diagnosis exclude the possibility of bilateral ureteric
Physical examination
evaluation to exclude obstruction (or single ureteric obstruction
Urinary bladder catherization
urinary tract obstruction in patients with a single kidney).
(if oligoanuric)
Consider need for more data Occasionally, additional studies such as
Urinalysis (see Fig. 12-15)
to assess intravascular volume central venous pressure or left ventricular
or cardiac output status filling pressure determinations are needed
Consider need for additional to better assess whether prerenal factors are
blood tests contributing to the ARF. When the cause of
Consider need for evaluation of the ARF continues to be difficult to ascer-
renal vascular status tain 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, addi-
FIGURE 12-12 tional blood analyses and other tests
Stepwise approach to diagnosis of acute renal failure (ARF). The multiple causes, predis- described in Figures 12-18 through 12-20
posing factors, and clinical settings demand a logical, sequential approach to each case of may be indicated. Sometimes, selected ther-
ARF. This figure presents a four-step approach to assessing ARF patients in an effort to apeutic trials (eg, volume expansion,
delineate the cause in a timely and cost-effective manner. Step 1 involves a focused history, maneuvers to increase cardiac index,
record review, and examination. The salient features of these analyses are noted in more ureteric stent or nephrostomy tube relief of
detail in Figure 12-13. In many cases, a single bladder catheterization is needed to assess obstruction) are necessary to document the
the degree of residual volume, which should be less than 30 to 50 mL. Urinalysis is a criti- cause of ARF definitively. Empiric therapy
cal part of the initial evaluation of all patients with ARF. Generally, a relatively normal (eg, corticosteroids for suspected acute
urinalysis suggests either a prerenal or postrenal cause, whereas a urinalysis containing allergic interstitial nephritis) is given as
cells and casts is most compatible with a renal cause. A detailed schema of urinalysis inter- both a diagnostic and a therapeutic maneu-
pretation in the setting of ARF is depicted in Figure 12-15. Usually, after Step 1 the clini- ver in selected cases. Rarely, despite all
cian has a reasonably good idea of the likely cause of the ARF. Sometimes, the information efforts, the cause of the ARF remains
noted under Step 2 is needed to ascertain definitively the cause of the ARF. More details of unknown and renal biopsy is necessary to
Step 2 are depicted in Figure 12-14. Oftentimes, urinary diagnostic indices (see Fig. 12-16), establish a definitive diagnosis.
FIRST STEP IN EVALUATION OF ACUTE RENAL FAILURE
History Physical examination

Disorders that suggest or predispose to renal failure: hypertension, diabetes mellitus, Skin: rash suggestive of allergy, palpable purpura of vasculitis, livedo reticularis and
human immunodeficiency virus, vascular disease, abnormal urinalyses, family history digital infarctions suggesting atheroemboli
of renal disease, medication use, toxin or environmental exposure, infection, heart fail- Eyes: hypertension, diabetes mellitus, Hollenhorst plaques, vasculitis, candidemia
ure, vasculitis, cancer Lungs: rales, rubs
Disorders that suggest or predispose to volume depletion: vomiting, diarrhea, pancreati- Heart: evidence of heart failure, pericardial disease, jugular venous pressure
tis, gastrointestinal bleeding, burns, heat stroke, fever, uncontrolled diabetes mellitus,
diuretic use, orthostatic hypotension, nothing-by-mouth status, nasogastric suctioning Vascular system: bruits, pulses, abdominal aortic aneurysm
Disorders that suggest or predispose to obstruction: stream abnormalities, nocturia, anti- Abdomen: flank or suprapubic masses, ascites, costovertebral angle pain
cholingeric medications, stones, urinary tract infections, bladder or prostate disease, Extremities: edema, pulses, compartment syndromes
intra-abnominal malignancy, suprapubic or flank pain, anuria, fluctuating urine volumes Nervous system: focal findings, asterixis, mini-mental status examination
Symptoms of renal failure: anorexia, vomiting, reversed sleep pattern, puritus Consider bladder catheterization
Record review Urinalysis (see Fig. 12-13)
Recent events (procedures, surgery)
Medications (see Fig. 12-22)
Vital signs
Intake and output
Body weights
Blood chemistries and hemogram
FIGURE 12-13
First step in evaluation of acute renal failure.
FIGURE 12-14
SECOND STEP IN EVALUATION Second step in evaluation of acute renal failure.
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, antineu-
trophilic cytoplasmic antibodies, antinuclear antibodies, serologic tests for hepati-
tis, 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
Urinalysis in acute renal failure
Normal Abnormal
RBC WBC Eosinophils RTE cells Crystalluria Low grade

RBC casts WBC casts Pigmented proteinuria
Proteinuria casts
Prerenal, Glomerulopathy, Pyelonephritis, Allergic ATN, Uric acid, Plasma cell

postrenal, vasculitis, interstitial interstitial myoglobinuria, drugs or toxins dyscrasia
high oncotic thrombotic nephritis nephritis, hemoglobinuria
pressure microangiopathy atheroemboli,
(dextran, glomerulopathy
mannitol)
FIGURE 12-15
Urinalysis in acute renal failure (ARF). A normal urinalysis suggests White blood cells (WBCs) can also be present in small numbers in
a prerenal or postrenal form of ARF; however, many patients with the urine of patients with ARF. Large numbers of WBCs and WBC
ARF of postrenal causes have some cellular elements on urinalysis. casts strongly suggest the presence of either pyelonephritis or acute
Relatively uncommon causes of ARF that usually present with interstitial nephritis. Eosinolphiluria (Hansel’s stain) is often present
oligoanuria and a normal urinalysis are mannitol toxicity and large in either allergic interstitial nephritis or atheroembolic disease [13,
doses of dextran infusion. In these disorders, a “hyperoncotic state” 14]. Renal tubular epithelial (RTE) cells and casts and pigmented
occurs in which glomerular capillary oncotic pressure, combined granular casts typically are present in pigmenturia-associated ARF
with the intratubular hydrostatic pressure, exceeds the glomerular (see Fig. 12-21) and in established acute tubular necrosis (ATN).
capillary hydrostatic pressure and stop glomerular filtration. Red The presence of large numbers of crystals on urinalysis, in conjunc-
blood cells (RBCs) can be seen with all renal forms of ARF. When tion with the clinical history, may suggest uric acid, sulfonamides, or
RBC casts are present, glomerulonephritis or vasculitis is most likely. protease inhibitors as a cause of the renal failure.
FIGURE 12-16
Urinary diagnostic indices Urinary diagnostic indices in acute renal failure (ARF). These
in acute renal failure 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
Prerenal Renal of these is completely sensitive or specific in differentiating the prer-
enal from the ATN form of ARF. Second, often a continuum exists
Hyaline casts Urinalysis Abnormal between early prerenal conditions and late prerenal conditions that
>1.020 Specific gravity ~1.010 lead to ischemic ATN. Most of the data depicted here are derived
>500 Uosm (mOsm/kg H2O) >300 from patients relatively late in the progress of ARF when the serum
<20 Una (mEq/L) >40 creatinine concentrations were 3 to 5 mg/dL. Third, there is often a
<1 FE Na (%) >2
relatively large “gray area,” in which the various indices do not give
<7 FE uric acid (%) >15
<7 FE lithium (%) >20
definitive results. Finally, some of the indices (eg, fractional excre-
tion 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/P—urine-plasma ratio.
Vascular Mechanisms Involved in Acute Renal Failure

FIGURE 12-17
VASCULAR CAUSES OF ACUTE RENAL FAILURE 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
Arterial Venous of ARF is to consider the anatomic compartments of the kidney.
Thus, disorders of the renal vasculature (see Fig. 12-18), glomeru-
Large vessels Occlusion lus (see Fig. 12-19), interstitium (see Fig. 12-20) and tubules can all
Renal artery stenosis Clot result in identical clinical pictures of ARF [1]. This figure depicts
Thrombosis Tumor the disorders of the renal arterial and venous systems that can
Cross-clamping result in ARF [15].
Emboli
Atheroemboli
Endocarditis
Atrial fibrillation
Mural thrombus
Tumor
Small vessels
Cortical necrosis malignant hypertension
Scleroderma
Vasculitis
Antiphospholipid syndrome
Thrombotic microangiopathies
Hemolytic-uremic syndrome
Thrombotic thrombocytopenic purpura
Postpartum
Medications (mitomycin C, cyclosporine, tacrolimus)
FIGURE 12-18
DIAGNOSIS OF POSSIBLE VASCULAR CAUSE OF ACUTE RENAL FAILURE Diagnosis of a possible vascular cause of
acute renal failure (ARF). This figure depicts
the historical, physical examination, and
History Examination Laboratory/Other testing procedures that often lead to diagno-
sis of a “vascular cause” of ARF [1, 15, 16].
Factors that predispose to vascular disease Marked hypertension Thrombocytopenia
(smoking, hypertension, diabetes mellitus, Atrial fibrillation Microangiopathic hemolysis
hyperlipidemia) Scleroderma Coagulopathy
Claudication, stroke, myocardial infarction Palpable purpura Urinalysis with hematuria and
Surgical procedure on aorta Abdominal low-grade proteinuria
Catheterization procedure involving aorta aortic aneurysm Abnormal renal isotope scan
Selected clinical states (scleroderma, pregnancy) Diminished pulses and/or Doppler ultrasonography
Selected medications, toxins (cyclosporine, Infarcted toes Renal angiography
mitomycin C, cocaine, tacrolimus) Hollendhorst plaques Renal or extrarenal tissue analysis
Constitutional symptoms Vascular bruits
Stigmata of
bacterial endocarditis
Illeus
Acute Glomerulonephritis
FIGURE 12-19
DIAGNOSIS OF A POSSIBLE ACUTE GLOMERULAR Diagnosis of a possible acute glomerular
PROCESS AS THE CAUSE OF ACUTE RENAL FAILURE process as the cause of acute renal failure
(ARF). Acute glomerulonephritis is a rela-
tively rare cause of ARF in adults. In the
History Examination Laboratory/Other pediatric age group, acute glomerulonephri-
tis and a disorder of small renal arteries
Recent infection Hypertension Urinalysis with hematuria, red cell (hemolytic-uremic syndrome) are relatively
Sudden onset of edema, dyspnea Edema casts, and proteinuria common causes. This figure depicts the his-
Systemic disorder Rash Serologic or culture evidence of torical, examination, and laboratory find-
(eg, lupus erythematosus, Wegener’s recent infection
Arthropathy ings that collectively may support a diagno-
granulomatosis, Goodpasture’s syndrome) Laboratory evidence of immune-
Prominent sis of acute glomerulonephritis as the cause
No evidence of other causes of renal failure pulmonary findings mediated process (low complement,
cryoglobulinemia, antinuclear anti- of ARF [16, 17].
Stigmata of bacterial
body, anti-DNA, rheumatoid factor,
endocarditis or
anti–glomerular basement mem-
visceral abscess
brane antibody, antineutrophilic
cytoplasmic antibody)
Renal tissue examination
Interstitial Nephritis
FIGURE 12-20
DIAGNOSIS OF POSSIBLE ACUTE INTERSTITIAL Diagnosis of possible acute interstitial
NEPHRITIS AS THE CAUSE OF ACUTE RENAL FAILURE nephritis as the cause of acute renal failure
(ARF). This figure outlines the historical,
physical examination and other investiga-
History Examination Laboratory/Other tive methods that can lead to identification
of acute interstitial nephritis as the cause
Medication exposure Fever Abnormal urinalysis (white blood cells or cell casts, of ARF [18].
Severe pyelonephritis Rash eosinophils, eosinophilic casts, low-grade proteinuria,
Systemic infection Back or flank pain 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
Acute Tubular Necrosis
DIAGNOSIS OF POSSIBLE PIGMENT-ASSOCIATED FORMS OF ACUTE RENAL FAILURE
Myoglobinuria Hemoglobinuria
History Examination Laboratory History Examination Laboratory
Trauma to muscles Can be normal Serum creatinine disproportionately Condition associated with Can be normal Normocytic anemia
Condition known Muscle edema, elevated related to BUN intravascular hemolysis Pallor High red cell LDH fraction
to predispose to weakness, pain Elevated (10-fold) enzymes (red cell trauma, antibody- Flank pain Reticulocytosis
nontraumatic Neurovascular (CK, SGOT, LDH, adolase) mediated hemolysis, direct red
Low haptoglobin
rhabdomyolysis entrapment or com- Elevations of plasma potassium, cell toxicity, sickle cell disease)
Urinalysis with pigmented
Muscle pain partment syndromes uric acid, phosphorus, and granular casts, () stick
or stiffness in severe cases hypocalcemia reaction for blood in absence
Dark urine Flank pain Urinalysis with pigmented granular of hemataria and reddish
casts, () stick reaction for blood brown or pink plasma
in the absence of hematuria, and
myoglobin test if available
Clear plasma
FIGURE 12-21
Diagnosis of possible pigment-associated forms of acute renal failure of ATN is supported by the absence of other causes of ARF, the pres-
(ARF). Once prerenal and postrenal forms of ARF have been ruled ence of one or more predisposing factors, and the presence of urinary
out and renal vascular, glomerular, and interstitial processes seem diagnostic indices and urinalysis suggested of ATN (see Figs. 12-15
unlikely, a diagnosis of acute tubular necrosis (ATN) is probable. A and 12-16). A pigmenturic disorder (myloglobinuria or hemoglobin-
diagnosis of ATN is thus one of exclusion (of other causes of ARF). uria) can predispose to ARF. This figure depicts the historical, physi-
In the majority of cases when ATN is present, one or more of the cal examination, and supporting diagnostic tests that often lead to a
three predisposing conditions have been identified to be operational. diagnosis of pigment-associated ARF [19]. BUN—blood urea nitro-
These conditions include renal ischemia due to a prolonged prerenal gen; CK—creatinine kinase; SGOT—serum glutamic-oxaloacetic
state, nephrotoxin exposure, and sometimes pigmenturia. A diagnosis transaminase; LDH—lactic dehydrogenase.
Nephrotoxin Acute Renal Failure

FIGURE 12-22
NEPHROTOXIC ACUTE RENAL FAILURE 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 mecha-
Prerenal Vasoconstriction Crystalluria nisms to induce renal dysfunction [6, 20, 21]. CEI—converting
Diuretics NSAIDs Sulfonamides enzyme inhibitor; NSAID—nonsteroidal anti-inflammatory drugs.
Interleukin 2 Radiocontrast agents Methotrexate
CEIs Cyclosporine Acyclovir
Antihypertensive agents Tacrolimus Triamterene
Amphotericin Ethylene glycol
Tubular toxicity
Protease inhibitors
Aminoglyosides Endothelial injury
Cisplatin Cyclosporine Glomerulopathy
Vancomycin Mitomycin C Gold
Foscarnet Tacrolimus Penicillamine
Pentamidine Cocaine NSAIDs
Radiocontrast Conjugated estrogens Interstitial nephritis
Amphotercin Quinine Multiple
Heavy metals
References
1. Anderson RJ, Schrier RW: Acute renal failure. In Diseases of the 12. Kellerman PS: Perioperative care of the renal patient. Arch Intern Med
Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1994, 154:1674–1681.
1997:1069–1113. 13. Nolan CR, Anger MS, Kelleher SP: Eosinophiluria —a new method of
2. Hou SH, Bushinsky D, Wish JB, Harrington JT: Hospital-acquired detection and definition of the clinical spectrum. N Engl J Med 1986,
renal insufficiency: A prospective study. Am J Med 1983, 315:1516–1519.
74:243–248. 14. Wilson DM, Salager TL, Farkouh ME: Eosinophiluria in atheroem-
3. Shusterman N, Strom BL, Murray TG, et al.: Risk factors and out- bolic renal disease. Am J Med 1991, 91:186–191.
come of hospital-acquired acute renal failure. Am J Med 1987, 15. Abuelo JG: Diagnosing vascular causes of acute renal failure. Ann
83:65–71. Intern Med 1995, 123:601–614.
4. Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure 16. Falk RJ, Jennette JC: ANCA small-vessel vasculitis. J Am Soc Nephrol
on mortality. JAMA 1996, 275:1489–1494. 1997, 8:314–322.
~ F, Pascual J: Epidemiology of acute renal failure: A prospective,
5. Liano 17. Kobrin S, Madacio MP: Acute poststreptococcal glomerulonephritis
multicenter, community-based study. Kid Int 1996, 50:811–818. and other bacterial infection-related glomerulonephritis. In Diseases
6. Thadhani R, Pascual M, Bonventre JV: Acute renal failure. New Engl of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little,
J Med 1996, 334:1448–1460. Brown; 1997:1579–1594.
7. Feest TG, Round A, Hamad S: Incidence of severe acute renal failure 18. Eknoyan G: Acute tubulointerstitial nephritis. In Diseases of the
in adults: Results of a community-based study. Br Med J 1993, Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown;
306:481–483. 1997:1249–1272.
8. Davenport A: Differentiation of acute from chronic renal impairment 19. Don BR, Rodriguez RA, Humphreys MH: Acute renal failure associ-
by detection of carbamylated hemoglobin. Lancet 1993, ated with pigmenturia as crystal deposits. In Diseases of the Kidney.
341:1614–1616. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown;
9. Mendell JA, Chertow GM: A practical approach to acute renal fail- 1997:1273–1302.
ure. Med Clin North Am 1997, 81:731–748. 20. Chaudbury O, Ahmed Z: Drug-induced nephrotoxicity. Med Clin
10. Kopp JB, Miller KD, Mican JM, et al.: Crystalluria and urinary tract North Am 1997, 81:705–717.
abnormalities associated with indinovir. Ann Intern Med 1997, 21. Palmer B, Henrich WL: Nephrotoxicity of nonsteroidal anti-inflamma-
127:119–125. tory agents, analgesics, and angiotensin converting enzyme inhibitors. In
11. Charlson ME, MacKenzie CR, Gold JP, Shires T: Postoperative Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston:
changes in serum creatinine. Ann Surg 1989, 209:328–335. Little, Brown; 1997:1167–1188.
Pathophysiology of Ischemic
Cytoskeletal Aspects
Bruce A. Molitoris
Robert Bacallao
I
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 dysfunc-
tion 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 mem-
brane 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 CHAPTER
functionally different with respect to many parameters, including
enzymes, ion channels, hormone receptors, electrical resistance,
13
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
and maintenance of this specialized organization is a dynamic induced by ischemia can be mimicked by F-actin disassembly
and ATP dependent multistage process involving the formation mediated by cytochalasin D [11]. Although these correlations
and maintenance of cell-cell and cell-substratum attachments are highly suggestive of a central role for actin alterations in the
and the targeted delivery of plasma membrane components to pathophysiology of ischemia-induced surface membrane dam-
the appropriate domains [5]. These processes are very dependent age they fall short in providing mechanistic data that directly
on the cytoskeleton, in general, and the cytoskeletal membrane relate actin cytoskeletal changes to cell injury.
interactions mediated through F-actin (see Fig. 13-2, 13-3), in Proximal tubule cell injury during ischemia is also known to
particular. be principally responsible for the reduction in GFR. Figure 13-5
Ischemia in vivo and cellular ATP depletion in cell culture illustrates the three known pathophysiologic mechanisms that
models (“chemical ischemia”) are known to produce character- relate proximal tubule cell injury to a reduction in GFR.
istic surface membrane structural, biochemical, and functional Particularly important is the role of the cytoskeleton in mediating
abnormalities in proximal tubule cells. These alterations occur these three mechanisms of reduced GFR. First, loss of apical
in a duration-dependent fashion and are illustrated in Figures membrane into the lumen and detachment of PTC result in sub-
13-2 and 13-3 and listed in Figure 13-4. Ischemia-induced strate for cast formation. Both events have been related to actin
alterations in the actin cytoskeleton have been postulated to cytoskeletal and integrin polarity alterations [12–15]. Cell
mediate many of the aforementioned surface membrane detachment and the loss of integrin polarity are felt to play a
changes [2,6,7]. This possible link between ischemia-induced central role in tubular obstruction (Fig. 13-6). Actin cytoskeletal-
actin cytoskeletal alterations and surface membrane structural mediated tight junction opening during ischemia occurs and
and functional abnormalities is suggested by several lines. First, results in back-leak of glomerular filtrate into the blood. This
the actin cytoskeleton is known to play fundamental roles in results in ineffective glomerular filtration (Fig. 13-7). Finally,
surface membrane formation and stability, junctional complex abnormal proximal sodium ion reabsorption results in large
formation and regulation, Golgi structure and function, and distal tubule sodium delivery and a reduction in GFR via tubu-
cell–extracellular membrane attachment [2,4,5,8]. Second, loglomerular feedback mechanisms [2,16,17].
proximal tubule cell actin cytoskeleton is extremely sensitive to In summary, ischemia-induced alterations in proximal tubule
ischemia and ATP depletion [9,10]. Third, there is a strong cell surface membrane structure and function are in large part
correlation between the time course of actin and surface mem- responsible for cell and organ dysfunction. Actin cytoskeletal
brane alterations during ischemia or ATP depletion [2,9,10]. dysregulation during ischemia has been shown to be responsi-
Finally, many of the characteristic surface membrane changes ble for much of the surface membrane structural damage.
FIGURE 13-1
RELATIONSHIP BETWEEN THE CLINICAL AND CELLULAR Relationship between the clinical and cellular phases of ischemic
PHASES OF ISCHEMIC ACUTE RENAL FAILURE 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
Clinical Phases Cellular Phases through vascular and cellular adaptive responses. The initiation
phase occurs when renal blood flow decreases to a level that results
Prerenal azotemia Vascular and cellular adaptation in severe cellular ATP depletion that, in turn, leads to acute cell
↓ ↓ injury. Severe cellular ATP depletion causes a constellation of cellular
Initiation ATP depletion, cell injury alterations culminating in proximal tubule cell injury, cell death, and
↓ ↓ organ dysfunction [2]. During the clinical phase known as mainte-
Maintenance Repair, migration, apoptosis, proliferation nance, cells undergo repair, migration, apoptosis, and proliferation in
↓ ↓ an attempt to re-establish and maintain cell and tubule integrity [3].
Recovery Cellular differentiation 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 13.3
A B C
D E F
FIGURE 13-2
Ischemic acute renal failure in the rat kidney. Light A, B, trans-
mission electron, C, D, and immunofluorescence E, F, micro-
MV scopy of control renal cortical sections, A, C, E, and after mod-
erate 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
ZO 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 interac-
tion with the surface membrane at the zonula occludens (ZO,
ZA tight junction) zonula adherens (ZA, occludens junction), inter-
actions with ankyrin to mediate Na+, K+-ATPase [2] stabilization
MT
x and cell adhesion molecule attachment [5,8]. The actin cyto-
N skeleton 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
x actin-bundling proteins [19] to mediate amplification of the api-
HD cal surface membrane via microvilli (MV). The actin bundle
attaches to the surface membrane by the actin-binding proteins
ECM myosin I and ezrin [19,20].
G
FIGURE 13-3
Proximal tubule cell Fate of an injured proximal tubule cell.
The fate of a proximal tubule cell after an
ischemic episode depends on the extent and
ADP ATP duration of the ischemia. Cell death can
+
+P
1 K occur immediately via necrosis or in a more
programmed fashion (apoptosis) hours to
Ischemia Necrosis days after the injury. Fortunately, most cells
Death recover either in a direct fashion or via
+ Na+
d Na d an intermediate undifferentiated cellular
ate ure
nti Inj
+ Recovery +
re K ADP K ADP Apoptosis pathway. Again, the severity of the injury
D iffe ATP +P ATP +P
1 1 determines the route taken by a particular
ECM cell. Adjacent cells are often injured to
Na+ 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
d the initiation phase. ECM—extracellular
ate
enti
iffe
r membrane; Na+—sodium ion; K+—potassi-
d
Un um ion; P1—phosphate.
FIGURE 13-4
ISCHEMIA INDUCED PROXIMAL TUBULE CELL ALTERATIONS Ischemia induced proximal tubule cell
alterations.
Alterations References
Surface Membrane Alterations
1. Microvilli fusion, internalization, fragmentation and luminal shedding resulting in loss of [21]
surface membrane area and tubular obstruction
2. Loss of surface membrane polarity for lipids and proteins [2,22,23]
3. Junctional complex dissociation with unregulated paracellular permeability (backleak) [6,24–27]
4. Reduced PTC vectorial transport [28]
Actin Cytoskeletal Alterations
1. Polymerization of actin throughout the cell cytosol [6,16,29]
2. Disruption and delocalization of F-actin structures including stress fibers, cortical actin [2,7,16]
and the junctional ring
3. Accumulation of intracellular F-actin aggregates containing surface membrane pro- [20,30]
teins—myosin I, the tight junction proteins ZO-1, ZO-2, cingulin
4. Disruption and dissociation of the spectrin cytoskeleton [31,32]
5. Disruption of microtubules during early reflow in vivo [33]
6. The cytoskeleton of proximal tubule cells, as compared to distal tubule cells, is more [6,16,34]
sensitive to ischemia in vivo and ATP depletion in vitro
FIGURE 13-5
A Normal
Mechanisms of proximal tubule cell—medi-
Afferent arteriole Efferent arteriole ated reductions in glomerular filtration rate
(GFR) following ischemic injury. A, GFR
Glomerular depends on four factors: 1) adequate blood
plasma flow flow to the glomerulus; 2) an adequate
glomerular capillary pressure as determined
by afferent and efferent arteriolar resis-
Glomerular tance; 3) glomerular permeability; and
hydrostatic 4) low intratubular pressure. B, Afferent
pressure
Glomerular arteriolar constriction diminishes GFR by
filtration reducing blood flow—and, therefore,
Intratubular glomerular capillary pressure. This occurs
pressure in response to a high distal sodium delivery
and is mediated by tubular glomerular
feedback. C, Obstruction of the tubular
B Afferent C D
arteriolar Obstruction Backleak lumen by cast formation increases tubular
constriction 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
Glomerular Obstructing Leakage of the blood stream. This is believed to occur
pressure cast filtrate through open tight junctions.
RG
RG
RGD
RG
D
RGD RG RG
D
D
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
A rat kidneys. The desquamated cells can adhere to injured cells or
aggregate, causing tubule obstruction.

cRGDDFLG cRDADFV C, When cyclic peptides that contain the RGD canonical binding
1400
x x cRGDDFV Control site of integrins are perfused intra-arterially, the peptides amelio-
1200 rate the extent of acute renal failure, as demonstrated by a higher
glomerular filtration rate (GFR) in rats receiving peptide containing
1000 *** **
x the RGD sequence. B, Proposed mechanism of renal protection by
cyclic RGD peptides. By adhering to the RGD binding sites of the
GFR, µl/min
x x integrins located on the apical plasma membrane or distributed

800
randomly on desquamated cells, the cyclic peptide blocks cellular
* aggregation and tubular obstruction [12–15]. (Courtesy of MS
600 **
x Goligorski, MD.)
400
200
0
C 0 Pre-Op Day 1 Day 2 Day 3
TER vs. Time

80
ATP depleted
ATP depleted
70
Control
Repletion buffer added

60
50
TER, Ω -cm2
40
30
20
10
A 0
0 10 20 30 40 60 90 120 150
C Time,min
FIGURE 13-7
Functional and morphologic changes in tight junction integrity asso-
ciated 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 cross-
clamp [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 reple-
tion [36]. Paracellular resistance to electron movement
B

(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 periph-
ery of cells at cell contact sites, forming a con-
tinuous linear contour. E, In ATP–depleted
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 junc-
tion shows a continuous ridge like structure in
D E freeze fracture preparations [38]. In ATP
depleted cells the strands are disrupted, form-
ing aggregates (arrows). Note that the contin-
uous strands are no longer present and large
gaps are observable.
Acknowledgment
These studies were in part supported by the National Institute Association Established Investigator Award (BAM), a VA
of Diabetes and Digestive and Kidney Diseases Grants DK Merrit Review Grant (BAM), and a NKF Clinical Scientist
41126 (BAM) and DK4683 (RB) and by an American Heart Award (RB).
References
1. ~o F, Pascual J, Madrid Acute Renal Failure Study Group:
Lian 20. Wagner MC, Molitoris BA: ATP depletion alters myosin Ib cellular
Epidemiology of acute renal failure: A prospective, multicenter, location in LLC-PK1 cells. Am J Physiol 1997, 272:C1680–C1690.
community-based study. Kidney Int 1996, 50:811–818. 21. Venkatachalam MA, Jones DB, Rennke HG, et al.: Mechanism of
2. Molitoris BA, Wagner MC: Surface membrane polarity of proximal proximal tubule brush border loss and regeneration following mild
tubular cells: Alterations as a basis for malfunction. Kidney Int 1996, ischemia. Lab Invest 1981, 45:355–365.
49:1592–1597. 22. Ritter D, Dean AD, Guan ZH, et al.: Polarized distribution of renal
3. Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl natriuretic peptide receptors in normal physiology and ischemia.
J Med 1996, 334:1448–1457. Am J Physiol 1995, 269:F918–F925.
4. Drubin DG, Nelson WJ: Origins of cell polarity. Cell 1996, 23. Alejandro VSJ, Nelson WJ, Huie P, et al.: Postischemic injury, delayed
84:335–344. function and Na+/K+-ATPase distribution in the transplanted kidney.
5. Mays RW, Nelson WJ, Marrs JA: Generation of epithelial cell polarity: Kidney Int 1995, 48:1308–1315.
Roles for protein trafficking, membrane-cytoskeleton, and E-cad- 24. Donohoe JF, Venkatachalam MA, Benard DB, et al.: Tubular leakage
herin–mediated cell adhesion. Cold Spring Harbor Symposia on and obstruction after renal ischemia: Structural-functional correla-
Quantitative Biol 1995, 60:763–773. tions. Kidney Int 1978, 13:208–222.
6. Bacallao R, Garfinkel A, Monke S, et al.: ATP depletion: A novel 25. Molitoris BA, Falk SA, Dahl RH: Ischemic-induced loss of epithelial
method to study junctional properties in epithelial tissues. I. polarity. Role of the tight junction. J Clin Invest 1989, 84:1334–1339.
Rearrangement of the actin cytoskeleton. J Cell Sci 1994, 26. Mandel LJ, Bacallao R, Zampighi G: Uncoupling of the molecular
107:3301–3313. fence and paracellular gate functions in epithelial tight junctions.
7. Kroshian VM, Sheridan AM, Lieberthal W: Functional and cytoskeletal Nature 1993, 361:552–555.
changes induced by sublethal injury in proximal tubular epithelial 27. Kwon O, Nelson J, Sibley RK, et al.: Backleak, tight junctions and
cells. Am J Physiol 1994, F21–F30. cell-cell adhesion in postischemic injury to the renal allograft
8. Fish EM, Molitoris BA: Alterations in epithelial polarity and the (Abstract). J Am Soc Nephrol 1996, 7:A2907.
pathogenesis of disease states. N Engl J Med 1994, 330:1580–1588. 28. Molitoris BA. Na+-K+-ATPase that redistributes to apical membrane
9. Glaumann B, Glauman H, Berezesky IK, et al.: Studies on the cellular during ATP depletion remains functional. Am J Physiol 1993,
recovery from injury II. Ultrastructural studies on the recovery of the 265:F693–F597.
pars convoluta of the proximal tubule of the rat kidney from tempo- 29. Kellerman PS: Exogenous adenosine triphosphate (ATP) proximal
rary ischemia. Virchows Arch B 1977, 24:1–18. tubule microfilament structure and function in vivo in a maleic acid
10. Kellerman PS, Norenberg SL, Jones GM: Early recovery of the actin model of ATP depletion. J Clin Invest 1993, 92:1940–1949.
cytoskeleton during renal ischemic injury in vivo. Am J Kidney Dis 30. Tsukamoto T, Nigam SK: ATP depletion causes tight junction proteins
1996, 16:33–42. to form large, insoluble complexes with cytoskeletal proteins in renal
11. Kellerman PS, Clark RAF, Hoilien CA, et al.: Role of microfilaments epithelial cells. J Biol Chem 1997, 273:F463–F472.
in the maintenance of proximal tubule structural and functional 31. Molitoris BA, Dahl R, Hosford M: Cellular ATP depletion induces
integrity. Am J Physiol 1990, 259:F279–F285. disruption of the spectrin cytoskeletal network. Am J Physiol 1996,
12. Noiri E, Gailit J, Gurrath M, et al.: Cyclic RGD peptides ameliorate 271:F790–F798.
ischemic acute renal failure in rats. Kidney Int 1994, 46:1050–1058. 32. Edelstein CL, Ling H, Schrier RW: The nature of renal cell injury.
13. Noiri E, Goligorsky MS, Som P: Radiolabeled RGD peptides as diag- Kidney Int 1997, 51:1341–1351.
nostic tools in acute renal failure and tubular obstruction. J Am Soc 33. Abbate M, Bonventre JV, Brown D: The microtubule network of renal
Nephrol 1996, 7:2682–2688. epithelial cells is disrupted by ischemia and reperfusion. Am J Physiol
14. Romanov V, Noiri E, Czerwinski G, et al.: Two novel probes reveal 1994, 267:F971–F978.
tubular and vascular RGD binding sites in the ischemic rat kidney. 34. Sheridan AM, Schwartz JH, Kroshian VM, et al.: Renal mouse proxi-
Kidney Int 1997, 52:92–102. mal tubular cells are more susceptible than MDCK cells to chemical
15. Goligorsky MS, Noiri E, Romanov V, et al.: Therapeutic potential of anoxia. Am J Physiol 1993, 265:F342–F350.
RGD peptides in acute renal failure. Kidney Int 1997, 51:1487–1493. 35. Molitoris BA, Falk SA, Dahl RH: Ischemia-induced loss of epithelial
16. Molitoris BA, Dahl R, Geerdes AE: Cytoskeleton disruption and polarity. Role of the tight junction. J Clin Invest 1989, 84:1334–1339.
apical redistribution of proximal tubule Na+,K+-ATPase during 36. Doctor RB, Bacallao R, Mandel LJ: Method for recovering ATP
ischemia. Am J Physiol 1992, 263:F488–F495. content and mitochondrial function after chemical anoxia in renal
17. Alejandro V, Scandling JD, Sibley RK, et al.: Mechanisms of filtration cell cultures. Am J Physiol 1994, 266:C1803–C1811.
failure during postischemic injury of the human kidney: A study of 37. Stevenson BR, Siliciano JD, Mooseker MS, et al.: Identification of
the reperfused renal allograft. J Clin Invest 1995, 95:820–831. ZO-1: A high molecular weight polypeptide associated with the tight
18. Bacallao R, Fine LG: Molecular events in the organization of renal junction (zonula occludens) in a variety of epithelia. J Cell Biol 1986,
tubular epithelium: From nephrogenesis to regeneration. Am J Physiol 103:755–766.
1989, 257:F913–F924. 38. Mandel LJ, Bacallao R, Zampighi G: Uncoupling of the molecular
19. Molitoris BA: Putting the actin cytoskeleton into perspective: patho- ‘fence’ and paracellular ‘gate’ functions in epithelial tight junctions.
physiology of ischemic alterations. Am J Physiol 1997, Nature 1993, 361:552–555.
272:F430–F433.
Pathophysiology
of Ischemic Acute
Renal Failure
Michael S. Goligorsky
Wilfred Lieberthal
A
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 sec-
ondary 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 con-
sequence 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
Vasoactive Hormones
Ischemic or toxic insult
Tubular injury and

Hemodynamic changes dysfunction
Afferent arteriolar Mesangial Reduced tubular Backleak of Tubular obstruction

vasoconstriction contraction reabsorption of NaCl glomerular filtrate
Reduced GPF and P Reduced glomerular Increased delivery of Backleak of urea, Compromises patency
filtration surface area NaCl to distal nephron creatinine, of renal tubules and
available for filtration (macula densa) and and reduction in prevents the recovery
and a fall in Kf activation of TG feedback "effective GFR" of renal function
FIGURE 14-1
Pathophysiology of ischemic and toxic acute renal which directly reduce GFR. Tubular injury reduces
failure (ARF). The severe reduction in glomerular GFR by causing tubular obstruction and by allow-
filtration rate (GFR) associated with established ing backleak of glomerular filtrate. Abnormalities in
ischemic or toxic renal injury is due to the com- tubular reabsorption of solute may contribute to
bined effects of alterations in intrarenal hemody- intrarenal vasoconstriction by activating the tubu-
namics and tubular injury. The hemodynamic alter- loglomerular (TG) feedback system. GPF—glomeru-
ations associated with ARF include afferent arteriolar plasmaflow; P—glomerular pressure; Kf—
lar constriction and mesangial contraction, both of glomerular ultrafiltration coefficient.
FIGURE 14-2
Ischemic or toxic injury Vasoactive hormones that may be responsible for the hemodynamic abnormalities in acute
to the kidney 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 mecha-
Increase in Deficiency of nisms responsible for the hemodynamic alterations in ARF involve an increase in the
vasoconstrictors vasodilators intrarenal activity of vasoconstrictors and a deficiency of important vasodilators. A num-
ber of vasoconstrictors have been implicated in the reduction in renal blood flow in ARF.
Angiotensin II The importance of individual vasoconstrictor hormones in ARF probably varies to some
Endothelin extent with the cause of the renal injury. A deficiency of vasodilators such as endothelium-
Thromboxane derived nitric oxide (EDNO) and/or prostaglandin I2 (PGI2) also contributes to the renal
Adenosine PGI2
EDNO hypoperfusion associated with ARF. This imbalance in intrarenal vasoactive hormones
Leukotrienes
Platelet-activating favoring vasoconstriction causes persistent intrarenal hypoxia, thereby exacerbating tubu-
factor lar injury and protracting the course of ARF.
Imbalance in vasoactive hormones

causing persistent intrarenal
vasoconstriction
Persistent medullary hypoxia

Pathophysiology of Ischemic Acute Renal Failure 14.3
FIGURE 14-3
Glomerular basement The mesangium regulates single-nephron glomerular filtration rate
membrane (SNGFR) by altering the glomerular ultrafiltration coefficient (Kf).
This schematic diagram demonstrates the anatomic relationship
Glomerular capillary
between glomerular capillary loops and the mesangium. The
endothelial cells mesangium is surrounded by capillary loops. Mesangial cells (M)
M are specialized pericytes with contractile elements that can respond
to vasoactive hormones. Contraction of mesangium can close and
Glomerular epithelial prevent perfusion of anatomically associated glomerular capillary
M cells loops. This decreases the surface area available for glomerular fil-
tration and reduces the glomerular ultrafiltration coefficient.
Mesangial cell contraction
Angiotensin II
Endothelin–1
Thromboxane Mesangial cell relaxation
Sympathetic nerves Prostacyclin
EDNO
FIGURE 14-4
A, The topography of juxtaglomerular apparatus (JGA), including
macula densa cells (MD), extraglomerular mesangial cells (EMC),
Afferent arteriole
and afferent arteriolar smooth muscle cells (SMC). Insets schemati-
Periportal cally illustrate, B, the structure of JGA; C, the flow of information
cell within the JGA; and D, the putative messengers of tubuloglomeru-
lar feedback responses. AA—afferent arteriole; PPC—peripolar cell;
Extraglomerular EA—efferent arteriole; GMC—glomerular mesangial cells.
mesangial cells (Modified from Goligorsky et al. [1]; with permission.)
Macula densa
cells Glomerus
AA
MD
AA AA
MD MD SMC+GC PPC
PPC G
PPC EMC GMC
G G
EMC GMC EMC GMC
Chloride
Adenosine EA
PGE2
EA EA Angiotensin
Nitric oxide
Osmolarity
B C D Unknown?
FIGURE 14-5
The normal tubuloglomerular (TG) feedback mechanism The tubuloglomerular (TG) feedback mech-
anism. A, Normal TG feedback. In the nor-
4. Afferent arteriolar and mesangial 3. Renin is released from specialized
contraction reduce SNGFR back toward cells of JGA and the intrarenal renin mal kidney, the TG feedback mechanism is
control levels. angiotensin system generates release a sensitive device for the regulation of the
of angiotensin II locally. 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
2. The composition of filtrate induces vasocontriction of the glomerular
1. SNGFR increases passing the macula densa is arterioles and contraction of the mesangial
causing increase altered and stimulates the JGA. cells. These events return SNGFR back
in delivery of solute
to the distal nephron. 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 proxi-
mal 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:
A
SNGFR is reduced below normal levels. It
is likely that vasoconstrictors other than
angiotensin II, as well as vasodilator hor-
Role of TG feedback in ARF mones (such as PGI2 and nitric oxide) are
also involved in modulating TG feedback.
4. Afferent arteriolar and mesangial 3. Local release of Abnormalities in these vasoactive hormones
contraction reduce SNGFR below angiotensin II in ARF may contribute to alterations in TG
normal levels. is stimulated.
feedback in ARF.
1. Renal epithelial cell injury 2. The composition of filtrate

reduces reabsorption passing the macula densa is
of NaCl by proximal tubules. altered and stimulates the JGA.
B
FIGURE 14-6
Osswald's Hypothesis
Metabolic basis for the adenosine hypothesis. A, Osswald’s
Increased ATP hydrolysis (increased distal Na+ load) 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];
Increased generation of adenosine
with permission.)
Activation of JGA
Afferent arteriolar vasoconstriction
Nerve endings
[Na+] ATP Na+

Adenosine
Renin- ↓ Renin
Adenosine containing
cells secretion
ANG II
Vascular
–
[Cl ] smooth ↓ GFR
muscle
ANG I
Signal Transmission Mediator(s) Effects

A
Adenosine nucleotide metabolism
ATP ADP AMP Adenosine
A1 A2
Receptors
e
se
se
as
Transporter
P-
P-
id
AT
AD
ot
cle
nu
5'-
Phosphorylation
or
degradation
ATP ADP AMP Adenosine Inosine Hypo-

xanthine
Salvage Degradation
pathway pathway
Uric acid Xanthine

B
FIGURE 14-7
20 Elevated concentration of adenosine, inosine,
15 and hypoxanthine in the dog kidney and
Adenosine,
nmoles/mL
10 urine after renal artery occlusion. (Modified

5 from Miller et al. [3]; with permission.)
0
25
20
nmoles/mL
Inosine,
15
10
5
0
30
25
Hypoxanthine,
20
nmoles/mL
15
10
5
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Volume collected, mL
Post Ischemia
Glomerul I
SNGFR: 17.4±1.7 nL/min
PFR: 66.6±5.6 nL/min
Glomeruli II
SNGFR: 27.0±3.1 nL/min
B Anti-endothelin PFR: 128.7±14.4 nL/min
FIGURE 14-8
Endothelin (ET) is a potent renal vasoconstrictor. Endothelin (ET)
is a 21 amino acid peptide of which three isoforms—ET-1, ET-2
and ET-3—have 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 vaso-
constrictor known. Infusion of ET-1 into the kidney induces pro-
found 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
A 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. SNGFR—sin-
gle nephron glomerular filtration rate; PFR—glomerular renal plas-
ma flow rate. (From Kon et al. [4]; with permission.)
FIGURE 14-9
Pre–proendothelin–1
Biosynthesis of mature endothelin-1 (ET-1). The mature ET-1
NH2 COOH peptide is produced by a series of biochemical steps. The precur-
sor of active ET is pre-pro ET, which is cleaved by dibasic pair-
53 74 92 203
specific endopeptidases and carboxypeptidases to yield a
39–amino acid intermediate termed big ET-1. Big ET-1, which
Lys–Arg Arg–Arg has little vasoconstrictor activity, is then converted to the mature
21–amino acid ET by a specific endopeptidase, the endothelin-
Dibasic pair–specific converting enzyme (ECE). ECE is localized to the plasma mem-
endopeptidase(s) brane of endothelial cells. The arrows indicate sites of cleavage
of pre-pro ET and big ET.
NH3 Big endothelin

COOH
Trp–Val Endothelin converting

enzyme (ECE)
Leu Ser Ser

Met Cys Ser Cys NH3
Mature endothelin
Asp
Lys
Glu
Cys Val Tyr Phe Cys His Leu Asp Ile Ile Trp COOH
FIGURE 14-10
Plasma ET Regulation of endothelin (ET) action; the
Mature ET role of the ET receptors. Pre-pro ET is pro-
duced and converted to big ET. Big ET is
converted to mature, active ET by endothe-
lin-converting enzyme (ECE) present on the
E ETB receptor endothelial cell membrane. Mature ET
EC
secreted onto the basolateral aspect of the
Endothelium NO PGI2 endothelial cell binds to two ET receptors
(ETA and ETB); both are present on vascu-
lar smooth muscle (VSM) cells. Interaction
of ET with predominantly expressed ETA
receptors on VSM cells induces vasocon-
striction. ETB receptors are predominantly
ECE located on the plasma membrane of
endothelial cells. Interaction of ET-1 with
these endothelial ETB receptors stimulates
Mature ET production of nitric oxide (NO) and prosta-
cyclin by endothelial cells. The production
Cyclic Cyclic of these two vasodilators serves to counter-
ETA receptor ETB receptor
GMP AMP balance the intense vasoconstrictor activity
Vascular
smooth of ET-1. PGI2—prostaglandin I2.
muscle
Vasoconstriction Vasodilation
FIGURE 14-11
Ischemia Vehicle
Endothelin-1 (ET-1) receptor blockade ameliorates severe ischemic
10 BQ123(0.1mg/kg • min, for 3h)
BQ123 acute renal failure (ARF) in rats. The effect of an ETA receptor
Number of rats
8 antagonist (BQ123) on the course of severe postischemic ARF was

6 examined in rats. BQ123 (light bars) or its vehicle (dark bars) was
administered 24 hours after the ischemic insult and the rats were
4
followed for 14 days. A, Survival. All rats that received the vehicle
2 were dead by the 3rd day after ischemic injury. In contrast, all rats
0 that received BQ123 post-ischemia survived for 4 days and 75%
A Basal 24h 1 2 3 4 5 6 14 recovered fully. B, Glomerular filtration rate (GFR). In both groups
control of rats GFR was extremely low (2% of basal levels) 24 hours after
ischemia. In BQ123-treated rats there was a gradual increase in
150
Ischemia GFR that reached control levels by the 14th day after ischemia.
120 C, Serum potassium. Serum potassium increased in both groups but
GFR, mL/h
BQ123(0.1mg/kg • min, for 3h)

90 reached significantly higher levels in vehicle-treated compared to the
60 BQ123-treated rats by the second day. The severe hyperkalemia
30 likely contributed to the subsequent death of the vehicle treated
0
rats. In BQ123-treated animals the potassium fell progressively after
B Basal 24h 1 2 3 4 5 6 14 the second day and reached normal levels by the fourth day after
control ischemia. (Adapted from Gellai et al. [5]; with permission.)
10 BQ123(0.1mg/kg • min, for 3h)

Plasma K+, mEq/L
Ischemia
8
6
4
2
0
Basal 24h 1 2 3 4 5 6 14
control
C Posttreatment days
FIGURE 14-12
Production of prostaglandins. Arachidonic acid is released from the
Lipid Membrane plasma membrane by phospholipase A2. The enzyme cycloxygenase
catalyses the conversion of arachidonate to two prostanoid interme-
diates (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
Phospholipase A2
cell type. In endothelial cells prostacyclin (PGI2) (in the circle) is the
Arachidonic acid major metabolite of cycloxygenase activity. Prostacyclin, a potent
vasodilator, is involved in the regulation of vascular tone. TXA2 is
NSAID Cycloxygenase not produced in endothelial cells of normal kidneys but may be pro-
duced in increased amounts and contribute to the pathophysiology
PGG2 of some forms of acute renal failure (eg, cyclosporine A–induced
Prostaglandin nephrotoxicity). The production of all prostanoids and TXA2 is
intermediates blocked by nonsteroidal anti-inflammatory agents (NSAIDs), which
inhibit cycloxygenase activity.
Thromboxane
PGH2
TxA2
PGF2 PGI2 PGE2

Prostacyclin
FIGURE 14-13
Aorta
Endothelin (ET) receptor blockade ameliorates acute cyclosporine-
induced nephrotoxicity. Cyclosporine A (CSA) was administered
Cyclosporine A intravenously to rats. Then, an ET receptor anatgonist was infused
in circulation directly into the right renal artery. Glomerular filtration rate (GFR)
Intra–arterial
infusion of ETA and renal plasma flow (RPF) were reduced by the CSA in the left
receptor antagonist
CSA
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.)
Right renal Left renal

artery artery
GFR and RPF: GFR and RPF:

near normal Reduced 20-25%
below normal
Right kidney Left kidney
FIGURE 14-14
Normal basal state
Prostacyclin is important in maintaining
Circulating levels of vasoconstrictors: Low renal blood flow (RBF) and glomerular fil-
tration rate (GFR) in “prerenal” states.
Afferent arteriolar tone
normal A, When intravascular volume is normal,
prostacyclin production in the endothelial
Intrarenal levels of prostacyclin: Low cells of the kidney is low and prostacyclin
Intraglomerular P plays little or no role in control of vascular
normal
tone. B, The reduction in absolute or
“effective” arterial blood volume associated
with all prerenal states leads to an increase
A GFR normal in the circulating levels of a number of of
vasoconstrictors, including angiotensin II,
Intravascular volume depletion
catecholamines, and vasopressin. The
Circulating levels of vasoconstrictors: High increase in vasoconstrictors stimulates
phospholipase A2 and prostacyclin produc-
tion in renal endothelial cells. This increase
normal or mildly reduced
in prostacyclin production partially coun-
Intrarenal levels of prostacyclin: High teracts the effects of the circulating vaso-
constrictors and plays a critical role in
Intraglomerular P
normal or mildly reduced
maintaining normal or nearly normal RBF
and GFR in prerenal states. C, The effect of
cycloxygenase inhibition with nonsteroidal
B GFR anti-inflammatory drugs (NSAIDs) in pre-
normal or mildly reduced renal states. Inhibition of prostacyclin
production in the presence of intravascular
Intravascular volume depletion volume depletion results in unopposed
and NSAID administration action of prevailing vasoconstrictors and
Circulating levels of vasoconstrictors: High results in severe intrarenal vascasoconstric-
tion. NSAIDs can precipitate severe acute
renal failure in these situations.
severely increased
Intrarenal levels of prostacyclin: Low

Intraglomerular P
severely reduced
GFR
C severely reduced
A. VASODILATORS USED IN EXPERIMENTAL ACUTE RENAL FAILURE (ARF)
Time Given in
Vasodilator ARF Disorder Relation to Induction Observed Effect
Propranolol Ischemic Before, during, after ↓Scr, BUN if given before,
during; no effect if given after
Phenoxybenzamine Toxic Before, during, after Prevented fall in RBF
Clonidine Ischemic After ↓Scr, BUN
Bradykinin Ischemic Before, during ↑RBF, GFR
Acetylcholine Ischemic Before, after ↑RBF; no change in GFR
Prostaglandin E1 Ischemic After ↑RBF; no change in GFR
Prostaglandin E2 Ischemic, toxic Before, during ↑GFR
Prostaglandin I2 Ischemic Before, during, after ↑GFR
Saralasin Toxic, ischemic Before ↑RBF; no change in Scr, BUN
Captopril Toxic, ischemic Before ↑RBF; no change in Scr, BUN
Verapamil Ischemic, toxic Before, during, after ↑RBF, GFR in most studies
Nifedipine Ischemic Before ↑GFR
Nitrendipine Toxic Before, during ↑GFR
Diliazem Toxic Before, during, after ↑GFR; ↓recovery time
Chlorpromazine Toxic Before ↑GFR; ↓recovery time
Atrial natriuretic Ischemic, toxic After ↑RBF, GFR
peptide
BUN—blood urea nitrogen; GFR—glomerular filtration rate; RBF—renal blood flow; Scr–serum creatinine.
B. VASODILATORS USED TO ALTER COURSE

OF CLINICAL ACUTE RENAL FAILURE (ARF)
Vasodilator ARF Disorder Observed Effect Remarks

Dopamine Ischemic, toxic Improved V, Scr if used early Combined with furosemide
Phenoxybenzamine Ischemic, toxic No change in V, RBF
Phentolamine Ischemic, toxic No change in V, RBF
Prostaglandin A1 Ischemic No change in V, Scr Used with dopamine
Prostaglandin E1 Ischemic ↑RBF, no change v, Ccr Used with NE
Dihydralazine Ischemic, toxic ↑RBF, no change V, Scr
Verapamil Ischemic ↑Ccr or no effect
Diltiazem Transplant, toxic ↑Ccr or no effect Prophylactic use
Nifedipine Radiocontrast No effect
Atrial natriuretic Ischemic ↑Ccr
peptide
Ccr—creatinine clearance; NE—norepinephrine; RBF—renal blood flow; Scr—serum creatinine; V—urine 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.)
NH2 + NH2 NH2 + NOH NH2 + O Modular structure of nitric oxide synthases
H BH4 ARG CaM FMN FAD NADPH
NADPH NADP+ 1/
2 NADPH /2 NADP
1 +
Target domain Oxygenase domain Reductase domain
O2 H 2O O2 H 2O
NH NH NH Dimerization site(s) 13–14 18–20
+ • NO nNOS
2–3 4–5 6 7–9 10–12 1516–17 21–23 24–29
BH4 BH4 nitric oxide 11–12 16–18
eNOS
+
NH3 COO– +
NH3 COO– +
NH3 COO– 1 2–3 4 5–7 8–10 1314–15 19–21 22–26
M 12–13
G
A L-arginine N -hydroxy-L-arginine L-citrulline iNOS
2–3 4–5 6 7–9 10–11 13 14–18 19–21 22–26
2–3 4–8 9–12 13–16
FIGURE 14-16 Mammalian P450 Reductases
Chemical reactions leading to the generation of nitric oxide (NO), Bacterial Flavodoxins
Plant Ferredoxin NADPH Reductases
A, and enzymes that catalize them, B. (Modified from Gross [8]; B. mega P450
with permission.) DHF Reductases
B Mammalian Syntrophins (GLGF Motif)
L-arginine
M
DNA damage Cell death
NOS L-citrulline NO concentration Activation of Apoptosis
mM apoptotic signal
Nitric oxide Thiols Induction of stress proteins
GTP
Heme- & iron- Inactivation of enzymes
Smooth muscle GC Vasodilatation µM containing proteins
ROIs Antioxidant
cGMP Guanylate cyclase cGMP (cellular signal)
nM
Inhibition of B Time Consequences
Target cell
Immune cells iron-containing
death
enzymes
FIGURE 14-17
CNS and PNS Neurotransmission
Hemoglobin 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, Endothelium-
NO3– + NO2– dependent vasodilators, such as acetylcholine and the calcium
ionophore A23187, act by stimulating eNOS activity thereby
cGMP increasing endothelium-derived nitric oxide (EDNO) production.
In contrast, other vasodilators act independently of the endotheli-
A Urine excretion um. Some endothelium-independent vasodilators such as nitroprus-
side and nitroglycerin induce vasodilation by directly releasing nitric
oxide in vascular smooth muscle cells. NO released by these agents,
Leukocyte like EDNO, induces vasodilation by stimulating the production of
– migration cyclic guanosine monophosphate (cGMP) in vascular smooth mus-
Endothelium-dependent
vasodilators cle (VSM) cells. Atrial natriuretic peptide (ANP) is also an endothe-
Platelet
– lium-independent vasodilator but acts differently from NO. ANP
+ aggregation
NO• directly stimulates an isoform of guanylyl cyclase (GC) distinct from
+
Shear stress soluble GC (called particulate GC) in VSM. CNS—central nervous
L-Arginine + NOS system; GTP—guanosine triphosphate; NOS—nitric oxide synthase;
PGC—particulate guanylyl cyclase; PNS—peripheral nervous sys-
NO• tem; ROI—reduced oxygen intermediates; SGC—soluble guanylyl
cyclase. (A, From Reyes et al. [9], with permission; B, from Kim
Nitroglycerin ANP et al. [10], with permission.)
+ +
sGC + pGC
GTP cGMP
Relaxation
C
FIGURE 14-18
Ischemia (I) Impaired production of endothelium-dependent nitric oxide (EDNO) contributes to the
alone vasoconstriction associated with established acute renal failure (ARF). Ischemia-reperfu-
sion injury in the isolated erythrocyte-perfused kidney induced persistant intarenal vaso-
I + ANP constriction. The endothelium-independent vasodilators (atrial natriuretic peptide [ANP]
and nitroprusside) administered during the reflow period caused vasodilation and restored
I+ the elevated intrarenal vascular resistance (RVR) to normal. In marked contrast, two
nitroprusside endothelium-dependent vasodilators (acetylcholine and A23187) had no effect on renal
I+ vascular resistance after ischemia-reflow. These data suggest that EDNO production is
Acetylcholine impaired following ischemic injury and that this loss of EDNO activity contributes to the
vasoconstriction associated with ARF. (Adapted from Lieberthal [11]; with permission.)
I + A23187
0 20 40 60 80
Increase in RVR above control, %
60 150
O2 BUN
50 *
Hypoxia 100
mg/dL
*
40 *
30 P<.001
50
Hypoxia + L-NAME
20 P<.001
0
Percent LDH release
Control 3.0
10
0 Cr
2.5
1.5
60 O2 Hypoxia + L-Arg
mg/dL
P<.05
50 *
1.0 *
P<.01 Hypoxia *
40
P<.001
30 0.5
P<.001
20
Control 0
10 Ischemia
Control
0
S
SCR
AS
Vehicle
0 10 20 30 40 50
A Time, min B
FIGURE 14-19
P<.001 Deleterious effects of nitric oxide (NO) on the viability of renal
50 tubular epithelia. A, Hypoxia and reoxygenation lead to injury of
tubular cells (filled circles); inhibition of NO production improves
40 the viability of tubular cells subjected to hypoxia and reoxygena-
tion (triangles in upper graph), whereas addition of L-arginine
LDH release, %
enhances the injury (triangles in lower graph). B, Amelioration of

30 ischemic injury in vivo with antisense oligonucleotides to the
NS iNOS: blood urea nitrogen (BUN), and creatinine (CR) in rats sub-
20 jected to 45 minutes of renal ischemia after pretreatment with anti-
sense phosphorothioate oligonucleotides (AS) directed to iNOS or
with sense (S) and scrambled (SCR) constructs. C, Resistance of
10
proximal tubule cells isolated from iNOS knockout mice to hypox-
ia-induced injury. LDH—lactic dehydrogenase. (A, From Yu et al.
0 [12], with permission; B, from Noiri et al. [13], with permission;
Normoxia Hypoxia Normoxia Hypoxia C, from Ling et al. [14], with permission.)
C Wild type mice iNOS knockout mice
Iothalamate Radiocontrast
100 100
Chronic renal
Normal kidneys
Cortex
50 50 insufficiency
Percent of baseline
0 0
Iothalamate Compensatory increase in Increased Reduced or absent
200
PGI2 and EDNO release endothelin increase in PGI2 or EDNO
150
Medulla
100 100
50 50
Iothalamate Mild vasoconstriction Severe vasoconstriction
0 0
0 20 40 60 0 20 40 60
Minutes Minutes
No pretreatment Pretreatment with
No loss of GFR Acute renal failure
A (n = 6) L-NAME (n = 6) B
FIGURE 14-20
Proposed role of nitric oxide (NO) in radiocontrast-induced acute the normal kidney. The vasodilators counteract the effects of the
renal failure (ARF). A, Administration of iothalamate, a radiocon- vasoconstrictors so that intrarenal vasoconstriction in response to
trast dye, to rats increases medullary blood flow. Inhibitors of radiocontrast is usually modest and is associated with little or no
either prostaglandin production (such as the NSAID, loss of renal function. However, in situations when there is pre-
indomethacin) or inhibitors of NO synthesis (such as L-NAME) existing chronic renal insufficiency (CRF) the vasodilator response
abolish the compensatory increase in medullary blood flow that to radiocontrast is impaired, whereas production of endothelin and
occurs in response to radiocontrast administration. Thus, the stim- other vasoconstrictors is not affected or even increased. As a result,
ulation of prostaglandin and NO production after radiocontrast radiocontrast administration causes profound intrarenal vasocon-
administration is important in maintaining medullary perfusion striction and can cause ARF in patients with CRF. This hypothesis
and oxygenation after administration of contrast agents. B, would explain the predisposition of patients with chronic renal
Radiocontrast stimulates the production of vasodilators (such as dysfunction, and especially diabetic nephropathy, to contrast-
prostaglandin [PGI2] and endothelium-dependent nitric oxide induced ARF. (A, Adapted from Agmon and Brezis [15], with per-
[EDNO]) as well as endothelin and other vasoconstrictors within mission; 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, Patho-
physiologic mechanisms ignited by the elevation of cytosolic calci-
um concentration. (A, Adapted from Goligorsky [17], with permis-
sion; B, from Edelstein and Schrier [18], with permission.)
Pre NE Post NE
* 60 NS Verapamil before NE
400 100 P<.001
40
* * P<.05
Estimated [Ca2+]i , nM
80
Pl stained nuclei, %
*
20
* * *
CIn, mL/min
* 60
300 * 0
40 60 Verapamil after NE
NS
200 * Significant 20
vs. time 0 40
P<.02
150 0 P<.001
Hypoxia 20
0 10 20 30 0
A Time, min B Control 1h 24 h
FIGURE 14-22
Pathophysiologic sequelae of the elevated cytosolic calcium (C2+). verapamil before injection of norepinephrine (cross-hatched bars) sig-
A, The increase in cytosolic calcium concentration in hypoxic rat nificantly attenuated the drop in inulin clearance induced by norepi-
proximal tubules precedes the tubular damage as assessed by propidi- nephrine alone (open bars). (A, Adapted from Kribben et al. [19], with
um iodide (PI) staining. B, Administration of calcium channel inhibitor permission; B, adapted from Burke et al. [20], with permission.)
FIGURE 14-23
Dynamics of heat shock
proteins (HSP) in stressed
cells. Mechanisms of acti-
vation and feedback con-
trol of the inducible heat
shock gene. In the nor-
mal unstressed cell, heat
shock factor (HSF) is
rendered inactive by
association with the con-
stitutively expressed
HSP70. After hypoxia or
ATP depletion, partially
denatured proteins (DP)
become preferentially
associated with HSC73,
releasing HSF and allow-
ing 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 trimer-
ized 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.)
Free Radical Pathways in the Mitochondrion

Catalase/GPx complex?
Hydrogen H2O 2
peroxide
Hydrogen
H 2O 2 Outer Hydroperoxyl peroxide
membrane radical
Inner HO2
membrane
–
O2 HO2
Superoxide Hepatocyte
(and other cells) Plasma EC–SOD
anion
(From glycolysis/ Proteinase?
TCA cycle) Golgi
– e–
Mn-SOD 2O2 complex
O2
(tetramer) Tissue EC–SOD
+ Endoplasmic
Matrix 2H+ reticulum Secretory vesicle
Heparin +
Mitochondrion sulfate 2H+
Chromosome proteoglycans
(chrom) 4
Manganese H 2O 2
superoxide
dismatase
(Mn-SOD) mRNA Extracellular GPx +
superoxide subunit O2
dismutase
(EC-SOD) Se GPx
chrom 6 mRNA (tetramer)
Catalase H2O+O2
mRNA Glutathione
chrom 3 +GSSG (dimer)
Glutathione
peroxidase
chrom 21 (GPx) mRNA
chrom 11
Cu,Zn–SOD +2GSH Glutathione
(dimer) (monomer)
Catalase
subunit
Peroxisome Plasma
+O2 membrane
Copper–zinc 2O2– +2H+ damaged
superoxide (enlarged below)
dismutase
(Cu,Zn–SOD) mRNA
Perxisome reactions Lipid peroxidation of plasma membrane
Oxidative enzyme Phospholipid 2GSH's + LOOH LOH+
(eg, urate oxidase) GSSG+ Free
hydroperoxide
RH2 glutathione radical
LO
+ Catalase peroxidase
OH
O2 (tetramer) (PHGPx) R
Lipid
peroxide
LH
LO
Inside O RH
H
Heme cell L Lipid

Lipid
LH LOO radical
Hydrogen 2H2O+O2 LH
peroxide LH
LOOH O
LH
L LOO Outside
LOOH H cell
LH
e– Lipid
Vitamin E (a-Tocopherol–)
inhibits lipid peroxidation chain collpases
chain reaction (now hydrophilic)
FIGURE 14-24
Cellular sources of reactive oxygen species (ROS) defense systems from free radicals. Superoxide and hydro-
gen 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 gentamycin-
induced 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-reperfu-
sion 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.)
FIGURE 14-25
EVIDENCE SUGGESTING A ROLE FOR Evidence suggesting a role for reactive oxygen metabolites in acute
REACTIVE OXYGEN METABOLITES IN renal failure. The increased ROS production results from two
ISCHEMIC ACUTE RENAL FAILURE major sources: the conversion of hypoxanthine to xanthine by xan-
thine dehydrogenase and the oxidation of NADH by NADH oxi-
dase(s). During the period of ischemia, oxygen deprivation results
Enhanced generation of reactive oxygen metabolites and xanthine oxidase and in the massive dephosphorylation of adenine nucleotides to hypox-
increased conversion of xanthine dehydrogenase to oxidase occur in in vitro and in anthine. Normally, hypoxanthine is metabolized by xanthine dehy-
vivo models of injury. drogenase which uses NAD+ rather than oxygen as the acceptor of
Lipid peroxidation occurs in in vitro and in vivo models of injury, and this can be pre- electrons and does not generate free radicals. However, during
vented by scavengers of reactive oxygen metabolites, xanthine oxidase inhibitors, or ischemia, xanthine dehydrogenase is converted to xanthine oxi-
iron chelators. dase. When oxygen becomes available during reperfusion, the
Glutathione redox ratio, a parameter of “oxidant stress” decreases during ischemia and metabolism of hypoxanthine by xanthine oxidase generates super-
markedly increases on reperfusion. oxide. Conversion of NAD+ to its reduced form, NADH, and the
Scavengers of reative oxygen metabolites, antioxidants, xanthine oxidase inhibitors, accumulation of NADH occurs during ischemia. During the reper-
and iron chelators protect against injury. fusion period, the conversion of NADH back to NAD+ by NADH
A diet deficient in selenium and vitamin E increases susceptibility to injury. oxidase also results in a burst of superoxide production. (From
Inhibition of catalase exacerbates injury, and transgenic mice with increased superoxide Ueda et al. [23]; with permission.)
dismutase activity are less susceptible to injury.
250 3.0
FIGURE 14-26
24 Effect of different scavengers of reactive
16
2.5 oxygen metabolites and iron chelators on,
200
Plasma urea nitrogen, mg/dL
A, blood urea nitrogen (BUN) and, B, crea-

*P < 0.001 2.0 *P < 0.001 tinine in gentamicin-induced acute renal
Creatinine, mg/dL
150 failure. The numbers shown above the error

1.5 bars indicate the number of animals in each
100 group. Benz—sodium benzoate; Cont—con-
1.0 trol group; DFO—deferoxamine; DHB—
16* 8* 6* 5* 4* 2,3 dihydroxybenzoic acid; DMSO—
50 8*
8* dimethyl sulfoxide; DMTU—dimethylth-
6* 13* 4* 0.5
26 18 iourea; Gent—gentamicin group. (From
0 0.0 Ueda et al. [23]; with permission.)
O
HB
HB
FO
FO
nz
nz
U
U
t
t
t
t
Con
Con
Gen
Gen
MT
MT
MS
MS
+Be
+Be
+D
+D
+D
+D
+D
+D
+D
+D
A B
FIGURE 14-27
Superoxide Production of the hydroxyl radical: the Haber-Weiss reaction. Superoxide is converted to
O2– +Fe3+ hydrogen peroxide by superoxide dismutase. Superoxide and hydrogen peroxide per se
are not highly reactive and cytotoxic. However, hydrogen peroxide can be converted to
Iron stores the highly reactive and injurious hydroxyl radical by an iron-catalyzed reaction that
(Ferritin) requires the presence of free reduced iron. The availability of free “catalytic iron” is a
Release of Hydrogen critical determinant of hydroxyl radical production. In addition to providing a source of
free iron Peroxide hydroxyl radical, superoxide potentiates hydroxyl radical production in two ways: by
(H2O2) releasing free iron from iron stores such as ferritin and by reducing ferric iron and recy-
Fe2+ cling 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+).
Fe3+ The further oxidation of metheme results in the production of an oxyferryl moiety
OH Hydroxyl (Fe4+=O), which is a long-lived, strong oxidant which likely plays a role in the cellular
Radical injury associated with hemoglobinuria and myoglobinuria.
(OH–) 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 myeloper-
oxidase, which is specific to leukocytes, converts hydrogen peroxide to another highly
reactive and injurious oxidant, hypochlorous acid.
FIGURE 14-28
:O–O• + •N–O :O–O–N–O 22 kcal/mol Initiation LH + OH• H2O + L• Cell injury: point of convergence between
...Large Gibbs energy
the reduced oxygen intermediates–generat-
ONOO– Propagation L• + O2 LOO• ing and reduced nitrogen intermediates–
:O2•– 6.7 x 109 M–1•s–1 [NO] ...Faster than SOD generating pathways, A, and mechanisms
O 2 + H 2O 2 of lipid peroxidation, B.
1 x 109 M–1•s–1 [SOD] LOO• + LH LOOH + L•
H
O O O O Termination L• + L• L–L
N O N O N O•
OH
...Peroxynitrous LOO• + NO• LOONO
A OH• acid in trans B
ONOO–
Cortex Medulla
X X: SOD, Cu2+, Fe3+
XO
NO2•
Tyr
116 KD 116 KD
NO2
OH R Nitrotyrosine
A
66 KD 66 KD
C CI LN C CI LN
Free
R R' radical
Unsaturated fatty acid R R'
• O2
O O
Free OO•
Control Control Ischemia L-Nil + Ischemia R • R' radical
R R'
B O2 Lipid based
peroxyradical (LOO•)
OO• O O
FIGURE 14-29 OH
O
Detection of peroxynitrite production and lipid peroxidation in R R'
ischemic acute renal failure. A, Formation of nitrotyrosine as an HNE
indicator of ONOO- production. Interactions between reactive
oxygen species such as the hydroxyl radical results in injury to Ab
the ribose-phosphate backbone of DNA. This results in single- HNE OH
O OH
O
and 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 X X
the ribose-phosphate backbone of DNA, nuclear DNA fragmenta- Protein
tion (single- and double-strand breaks) and activation of poly- (X: Cys, His, Lys) Formation of stable
D hemiacetal adducts
(ADP)-ribose synthase. B, Immunohistochemical staining of kid-
neys with antibodies to nitrotyrosine. C, Western blot analysis of
nitrotyrosine. D, Reactions describing lipid peroxidation and for- process is called lipid peroxidation. In addition to impairing the
mation of hemiacetal products. The interaction of oxygen radi- structural and functional integrity of cell membranes, lipid perox-
cals with lipid bilayers leads to the removal of hydrogen atoms idation can lead to a self-perpetuating chain reaction in which
from the unsaturated fatty acids bound to phospholipid. This additional ROS are generated.
Cortex Medulla
Control Control Ischemia L-Nil + Ischemia

E
E, Immunohistochemical staining of kidneys with antibodies to C CI LN C CI LN
HNE–modified proteins. F, Western blot analysis of HNE expres-
sion. C—control; CI—central ischemia; LN—ischemia with L-Nil
pretreatment (Courtesy of E. Noiri, MD.) F
Leukocytes in Acute Renal Failure

FIGURE 14-30
Leukocyte adhesion molecules Role of adhesion molecules in mediating
Inactive leukocyte
β2 integrins (LFA1 or Mac1) leukocyte attachment to endothelium.
Selections
A, The normal inflammatory response is
Endothelial adhesion molecules mediated by the release of cytokines that
Activated leukocyte ICAM induce leukocyte chemotaxis and activation.
Ligand for leukocyte selections 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,
Firm adhesion of
Selection–mediated
leukocytes
rolling of leukocytes
(integrin–mediated)
Diapedesis
Release of
oxidants
Tissue injury proteases
A elastases

B. LEUKOCYTE ADHESION MOLECULES B. Selectin-mediated leukocyte-endothelial interaction results in
AND THEIR LIGANDS POTENTIALLY the rolling of leukocytes along the endothelium and facilitates the
IMPORTANT IN ACUTE RENAL FAILURE 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
Major Families Cell Distribution cells. Immobilization of leukocytes is necessary for diapedesis of
leukocytes between endothelial cells into parenchymal tissue.
Selectins Leukocytes release proteases, elastases, and reactive oxygen radi-
L-selectin Leukocytes cals that induce tissue injury. Activated leukocytes also elaborate
P-selectin Endothelial cells cytokines such as interleukin 1 and tumor necrosis factor which
E-selectin Endothelial cells attract additional leukocytes to the site, causing further injury.
Carbohydrate ligands for selectins
Sulphated polysacharides Endothelium
Oligosaccharides Leukocytes
Integrins
CD11a/CD18 Leukocytes
CD11b/CD18 Leukocytes
Immunoglobulin G–like ligands
for integrins
Intracellular adhesion molecules (ICAM) Endothelial cells
FIGURE 14-31
125
Anti-ICAM Anti-ICAM Neutralizing anti–ICAM antibody amelio-
antibody 2 antibody rates the course of ischemic renal failure
100 Vehicle Vehicle
with blood urea nitrogen, A, and plasma
Blood urea nitrogen
creatinine, B. Rats subjected to 30 minutes

Plasma creatinine
1.5
75 of bilateral renal ischemia or a sham-opera-
tion were divided into three groups that
1
50 received either anti-ICAM antibody or its
vehicle. Plasma creatinine levels are shown
25 0.5 at 24, 48, and 72 hours. ICAM antibody
ameliorates the severity of renal failure at
0 0 all three time points. (Adapted from Kelly
0 24 48 72 0 24 48 72 96 et al. [24]; with permission.)
A Time following ischemia-reperfusion, d B Time following ischemia-reperfusion, d
1250 FIGURE 14-32

Vehicle Neutralizing anti-ICAM-1 antibody reduces myeloperoxidase activity
Anti-ICAM in rat kidneys exposed to 30 minutes of ischemia. Myeloperoxidase
1000
antibody is an enzyme specific to leukocytes. Anti-ICAM antibody reduced
Myeloperoxidase activity
myeloperoxidase activity (and by inference the number of leuko-

750 cytes) in renal tissue after 30 minutes of ischemia. (Adapted from
Kelly et al. [24]; with permission.)
500
250
0
0 4 24 48 72
Time after reperfusion, hrs
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 lyzoso-
mal 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 membrane–bound 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 bod-
ies with intact plasma membranes ensures that apoptosis does not cause any surrounding
inflammatory reaction.
A B
FIGURE 14-34
Hypothetical schema of cellular events trig-
Induction phase
gering apoptotic cell death. (From Kroemer

et al. [25]; with permission.)
[Ca2+]i ? ? ?
Signal transduction pathways
Mitochondrion Regulation by
Hcl-2 and
Mitochondrial permeability transition its relatives
? Activation of
Positive feedback loop ICE/ced-3-like
Effector phase
proteases ?
Consequences of permeability transition:
Disruption of ∆ψm and mitochondrial biogenesis
Breakdown of energy metabolism
Uncoupling of respiratory chain
Calcium release frommitochondrial matrix
Hyperproduction of superoxide anion
Depletion of glutathione
?
ROS Increase in ATP NAD/NADH Tyrosin kinases

effects [Ca2+]i depletion depletion G-proteins ?
Degradation phase
Cytoplasmic effects Nucleus

Disruption of anabolic reactions Activation of endonucleases
Dilatation of ER Activation of repair enzymes
Activation of proteases (ATP depletion)
Disruption of intracellular calcium Activation of poly(ADP) ribosly
compartimentalization transferase (NAD depletion)
Disorganization of cytoskeleton Chromatinolysis, nucleolysis
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).
FIGURE 14-36
DNA fragmentation in apoptosis vs necrosis. DNA is made up of nucleosomal units. Each
Nucleosome nucleosome of DNA is about 200 base pairs in size and is surrounded by histones. Between
~200 bp 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
Internucleosome breaks in DNA between nucleosomes. No fragmentation occurs in nucleosomes because the
"Linker" regions
DNA is “protected” by the histones. Because of the size of nucleosomes, the DNA is frag-
mented 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.
DNA fragmentation 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.
Apoptosis Necrosis Electrophoresis of DNA from necrotic cells results in a smear pattern.
Loss
of
histones
800 bp 600 bp 400 bp 200 bp
DNA electrophoresis
Apoptic Necrotic
"ladder" "smear"
pattern pattern
FIGURE 14-37
POTENTIAL CAUSES OF APOPTOSIS Potential causes of apoptosis in acute renal failure (ARF). The
IN ACUTE RENAL FAILURE 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
Loss of survival factors constant external signals, called survival signals, to remain viable,
Deficiency of renal growth factors (eg, IGF-1, EGF, HGF) the loss of these survival signals can trigger apoptosis. In ARF, a
Loss of cell-cell and cell-matrix interactions
deficiency of growth factors and loss of cell-substrate adhesion are
potential causes of apoptosis. The death pathways induced by
Receptor-mediated activators of apoptosis
engagement of tumour necrosis factor (TNF) with the TNF recep-
Tumor necrosis factor
tor or Fas with its receptor (Fas ligand) are well known causes of
Fas/Fas ligand
apoptosis in immune cells. TNF and Fas can also induce apoptosis
Cytotoxic events
in epithelial cells and may contribute to cell death in ARF.
Ischemia; hypoxia; anoxia
Oxidant injury
Nitric oxide
Cisplati
FIGURE 14-38
Apoptotic Trigger Apoptosis is mediated by a highly coordinated and genetically pro-
grammed pathway. The response to an apoptotic stimulus can be
divided into a commitment and execution phases. During the com-
mitment phase the balance between a number of proapoptotic and
Commitment phase antiapoptotic mechanisms determine whether the cell survives or
dies by apoptosis. The BCL-2 family of proteins consists of at least
Anti-apoptic factors Pro-apoptic factors 12 isoforms, which play important roles in this commitment phase.
Some of the BCL-2 family of proteins (eg, BCL-2 and BCL-XL) pro-
BclXL BAD tect cells from apoptosis whereas other members of the same family
Bcl–2 Bax (eg, BAD and Bax) serve proapoptotic functions. Apoptosis is exe-
cuted by a final common pathway mediated by a class of cysteine
proteases-caspases. Caspases are proteolytic enzymes present in cells
Execution phase
in an inactive form. Once cells are commited to undergo apoptosis,
Crma
these caspases are activated. Some caspases activate other caspases
Caspase activation in a hierarchical fashion resulting in a cascade of caspase activation.
p35
Eventually, caspases that target specific substrates within the cell are
? Point of no return?
activated. Some substrates for caspases that have been identified
Proteolysis of multiple include nuclear membrane components (such as lamin), cytoskeletal
intracellular substrates elements (such as actin and fodrin) and DNA repair enzymes and
transcription elements. The proteolysis of this diverse array of sub-
strates in the cell occurs in a predestined fashion and is responsible
for the characteristic morphologic features of apoptosis.
Apoptosis
FIGURE 14-39
Stress Therapeutic approaches, both experimental
and in clinical use, to prevent and manage
acute renal failure based on its pathogenetic
Loss of tubular mechanisms. ETR—ET receptor; GFR—
• Restoration of Hemodynamic integrity and • Avoidance and
fluid and compromise glomerular filtration rate; HGF—hepatocyte
function discontinuation
electrolyte of nephrotoxins growth factor 1; IGF-1—insulin-like growth
balance • Survival factors factor 1; Kf—glomerular ultrafiltration coef-
• ETR antagonists PMN Back (HGF, IGF-1) ficient; NOS—nitric oxide synthase; PMN—
Kf RBF Obstruction
• Ca channel infiltration leak • ATP-Mg polymorphonuclear leukocytes; RBF—renal
inhibitors • T4
• ATP-Mg
blood flow; T4—thyroxine.
• ETR • Dopamine • ICAM-1 • Mannitol • IGF-1l • NOS inhibitors
antagonists • ANP antibody • Lasix • T4
• Ca channel • IGF-1 • RGD • ANP • HGF
inhibitors • RGD
GFR and
maintenance
phase
Restoration Reparation of
of renal tubular integrity
hemodynamics and function
Recovery
References
1. Goligorsky M, Iijima K, Krivenko Y, et al.: Role of mesangial cells in 14. Ling H, Gengaro P, Edelstein C, et al.: Injurious isoform of NOS in
macula densa-to-afferent arteriole information transfer. Clin Exp mouse proximal tubular injury. Kidney Int, 1998, 53:1642
Pharm Physiol 1997, 24:527–531. 15. Agmon Y, et al.: Nitric oxide and prostanoids protect the renal outer
2. Osswald H, Hermes H, Nabakowski G: Role of adenosine in signal medulla from radiocontrast toxicity in the rat. J Clin Invest 1994,
transmission of TGF. Kidney Int 1982, 22(Suppl. 12):S136–S142. 94:1069–1075.
3. Miller W, Thomas R, Berne R, Rubio R: Adenosine production in the 16. Agmon Y, Brezis M: NO and the medullary circulation. In: Nitric
ischemic kidney. Circ Res 1978, 43(3):390–397. Oxide and the Kidney. Edited by Goligorsky M, Gross S. New
4. Kon V, et al.: Glomerular actions of endothelin in vivo. J Clin Invest York:Chapman and Hall, 1997.
1989, 83:1762–1767. 17. Goligorsky MS: Cell biology of signal transduction. In: Hormones,
5. Gellai M, Jugus M, Fletcher T, et al.: Reversal of postischemic acute autacoids, and the kidney. Edited by Goldfarb S, Ziyadeh F. New
renal failure with a selective endothelin A receptor antagonist in the York:Churchill Livingstone, 1991.
rat. J Clin Invest 1994, 93:900–906. 18. Edelstein C, Schrier RW: The role of calcium in cell injury. In: Acute
6. Fogo, et al.: Endothelin receptor antagonism is protective in vivo in Renal Failure: New Concepts and Therapeutic Strategies. Edited by
acute cyclosporine toxicity. Kidney Int 1992, 42:770–774. Goligorsky MS, Stein JH. New York:Churchill Livingstone, 1995.
7. Conger J: NO in acute renal failure. In: Nitric Oxide and the Kidney. 19. Kribben A, Wetzels J, Wieder E, et al.:Evidence for a role of cytosolic
Edited by Goligorsky M, Gross S. New York:Chapman and Hall, free calcium in hypoxia-induced proximal tubule injury. J Clin Invest
1997. 1994, 93:1922.
8. Gross S: Nitric oxide synthases and their cofactors. In: Nitric Oxide 20. Burke T, Arnold P, Gordon J, Schrier RW: Protective effect of
and the Kidney. Edited by Goligorsky M, Gross S. New intrarenal calcium channel blockers before or after renal ischemia.
York:Chapman and Hall, 1997. J Clin Invest 1984, 74:1830.
9. Reyes A, Karl I, Klahr S: Role of arginine in health and in renal dis- 21. Kashgarian M: Stress proteins induced by injury to epithelial cells. In:
ease. Am J Physiol 1994, 267:F331–F346. Acute Renal Failure: New Concepts and therapeutic strategies. Edited
10. Kim Y-M, Tseng E, Billiar TR: Role of NO and nitrogen intermediates by Goligorsky MS, Stein JH. New York:Churchill Livingstone, 1995.
in regulation of cell functions. In: Nitric Oxide and the Kidney. Edited 22. J NIH Research
by Goligorsky M, Gross S. New York:Chapman and Hall, 1997. 23. Ueda N, Walker P, Shah SV: Oxidant stress in acute renal failure.
11. Lieberthal W:Renal ischemia and reperfusion impair endothelium- In: Acute Renal Failure: New Concepts and Therapeutic Strategies.
dependent vascular relaxation. Am J Physiol 1989, 256:F894–F900. Edited by Goligorsky MS, Stein JH. New York:Churchill
12. Yu L, Gengaro P, Niederberger M, et al.: Nitric oxide: a mediator in Livingstone, 1995.
rat tubular hypoxia/reoxygenation injury. Proc Natl Acad Sci USA 24. Kelly KJ, et al.: Antibody to anyi-cellular adhesion molecule-1 pro-
1994, 91:1691–1695. tects the kidney against ischemic injury. Proc Natl Acad Sci USA
13. Noiri E, Peresleni T, Miller F, Goligorsky MS: In vivo targeting of 1994, 91:812–816.
iNOS with oligodeoxynucleotides protects rat kidney against 25. Kroemer G, Petit P, Zamzami N, et al.: The biochemistry of pro-
ischemia. J Clin Invest 1996, 97:2377–2383. grammed cell death. FASEB J 1995, 9:1277–1287.
Pathophysiology of
Nephrotoxic Acute
Renal Failure
Rick G. Schnellmann
Katrina J. Kelly
H
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 environ-
mental pollutants that cause nephrotoxicity has increased, it has
become clear that chemicals with very diverse chemical structures pro-
duce nephrotoxicity. For example, the heavy metal HgCl2, the myco-
toxin 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 dif-
ferent toxicants. Nevertheless, there are similarities between chemical-
induced acute tubular injury and ischemia/reperfusion injury.
The tubular cells of the kidney are particularly vulnerable to toxi-
cant-mediated injury due to their disproportionate exposure to circu-
lating chemicals and transport processes that result in high intracellu-
lar 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 macromole-
cule(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
CHAPTER
stress both lipid peroxidation and protein oxidation have been shown
15
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 depen-
dence of renal function on aerobic metabolism. The loss of ATP leads
to disruption of cellular ion homeostasis with decreased cellular Following exposure to a chemical insult those cells sufficiently
K+ content, increased Na+ content and membrane depolariza- injured die by one of two mechanisms, apoptosis or oncosis.
tion. Increased cytosolic free Ca2+ concentrations can occur in Clinically, a vast number of nephrotoxicants can produce a
the early or late phase of cell injury and plays a critical role lead- variety of clinical syndromes-acute renal failure, chronic renal
ing to cell death. The increase in Ca2+ can activate calcium acti- failure, nephrotic syndrome, hypertension and renal tubular
vated neutral proteases (calpains) that appear to contribute to defects. The evolving understanding of the pathophysiology of
the cell injury that occurs by a variety of toxicants. During the toxicant-mediated renal injury has implications for potential
late phase of cell injury, there is an increase in Cl- influx, fol- therapies and preventive measures. This chapter outlines some
lowed by the influx of increasing larger molecules that leads to of the mechanisms thought to be important in toxicant-mediat-
cell lysis. Two additional enzymes appear to play an important ed renal cell injury and death that leads to the loss of tubular
role in cell injury, particularly oxidative injury. Phospholipase A2 epithelial cells, tubular obstruction, “backleak” of the glomeru-
consists of a family of enzymes in which the activity of the lar filtrate and a decreased glomerular filtration rate. The recov-
cytosolic form increases during oxidative injury and contributes ery from the structural and functional damage following chemi-
to cell death. Caspases are a family of cysteine proteases that are cal exposures is dependent on the repair of sublethally-injured
activated following oxidative injury and contribute to cell death. and regeneration of noninjured cells.
Clinical Significance of Toxicant-Mediated

Acute Renal Failure
CLINICAL SIGNIFICANCE OF REASONS FOR THE KIDNEY’S

TOXICANT–MEDIATED RENAL FAILURE SUSCEPTIBILITY TO TOXICANT INJURY
Nephrotoxins may account for approximately 50% of all cases of acute and chronic Receives 25% of the cardiac output
renal failure. Sensitive to vasoactive compounds
Nephrotoxic renal injury often occurs in conjunction with ischemic acute renal failure. Concentrates toxicants through reabsorptive and secretive processes
Acute renal failure may occur in 2% to 5% of hospitalized patients and 10% to 15% of Many transporters result in high intracellular concentrations
patients in intensive care units. Large luminal membrane surface area
The mortality of acute renal failure is approximatley 50% which has not changed Large biotransformation capacity
significantly in the last 40 years.
Baseline medullary hypoxia
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.
FIGURE 15-2
Reasons for the kidney’s susceptibility to toxicant injury.
FIGURE 15-1
Clinical significance of toxicant-mediated renal failure.
FIGURE 15-3
FACTORS THAT PREDISPOSE THE Factors that predispose the kidney to toxicant injury.
KIDNEY TO TOXICANT INJURY
Preexisting renal dysfunction

Dehydration
Diabetes mellitus
Exposure to multiple nephrotoxins
Pathophysiology of Nephrotoxic Acute Renal Failure 15.3
EXOGENOUS AND ENDOGENOUS CHEMICALS THAT CAUSE ACUTE RENAL FAILURE
Antibiotics Immunosuppressive agents Vasoactive agents Other drugs

Aminoglycosides (gentamicin, tobramycin, Cyclosporin A Nonsteroidal anti-inflammatory Acetaminophen
amikacin, netilmicin) Tacrolimus (FK 506) drugs (NSAIDs) Halothane
Amphotericin B Antiviral agents Ibuprofen Methoxyflurane
Cephalosporins Acyclovir Naproxen Cimetidine
Ciprofloxacin Cidovir Indomethacin Hydralazine
Demeclocycline Foscarnet Meclofenemate Lithium
Penicillins Valacyclovir Aspirin Lovastatin
Pentamidine Heavy metals Piroxicam Mannitol
Polymixins Cadmium Angiotensin-converting Penicillamine
Rifampin Gold enzyme inhibitors Procainamide
Sulfonamides Mercury Captopril Thiazides
Tetracycline Lead Enalopril Lindane
Vancomycin Arsenic Lisinopril Endogenous compounds
Chemotherapeutic agents Bismuth Angiotensin receptor antagonists Myoglobin
Adriamycin Uranium Losartan Hemoglobin
Cisplatin Organic solvents Calcium
Methotraxate Ethylene glycol Uric acid
Mitomycin C Carbon tetrachloride Oxalate
Nitrosoureas Unleaded gasoline Cystine
(eg, streptozotocin, Iomustine)
Radiocontrast media
Ionic (eg, diatrizoate, iothalamate)
Nonionic (eg, metrizamide)
FIGURE 15-4
Exogenous and endogenous chemicals that cause acute renal failure.
FIGURE 15-5
Proximal convoluted tubule Nephrotoxicants may act at different sites in the kidney, resulting
(S1/S2 segments) in altered renal function. The sites of injury by selected nephrotoxi-
Aminoglycosides cants are shown. Nonsteroidal anti-inflammatory drugs (NSAIDs),
Cephaloridine Glomeruli angiotensin-converting enzyme (ACE) inhibitors, cyclosporin A,
Cadmium chloride Interferon–α and radiographic contrast media cause vasoconstriction. Gold,
Potassium dichromate Gold interferon-alpha, and penicillamine can alter glomerular function
Penicillamine and result in proteinuria and decreased renal function. Many
Proximal straight tubule nephrotoxicants damage tubular epithelial cells directly.
Renal vessels (S3 segment) Aminoglycosides, cephaloridine, cadmium chloride, and potassium
NSAIDs Cisplatin dichromate affect the S1 and S2 segments of the proximal tubule,
ACE inhibitors Mercuric chloride whereas cisplatin, mercuric chloride, and dichlorovinyl-L-cysteine
Cyclosporin A Dichlorovinyl–L–cysteine affect the S3 segment of the proximal tubule. Cephalosporins, cad-
mium chloride, and NSAIDs cause interstitial nephritis whereas
phenacetin causes renal papillary necrosis.
Interstitium
Papillae Cephalosporins
Phenacetin Cadmium
NSAIDs
Renal vasoconstriction Prerenal azotemia

Intravascular Sympathetic
Increased tubular pressure volume tone
n Tubular obstruction "Back-leak" of glomerular filtrate

E e
Intratubular Functional Capillary permeability Hypertension
x p GFR
h casts abnormalties Endothelin
p
o r Nitric oxide
o Tubular damage Endothelial injury Thromboxane Renal and systemic
s
t Prostaglandins vasoconstriction
u
r o Intrarenal factors Persistent medullary hypoxia
e x Physical constriction
i of medullary vessels Vascular smooth muscle
Hemodynamic Glomerular sensitivity to vasoconstrictors
t c hydrostatic
alterations
o a pressure
n
t Intrarenal Striped interstitial
Cyclosporin A Angiotensin II fibrosis
vasoconstriction Perfusion pressure
Efferent tone
Afferent tone
Glomerular factors Tubular cell injury GFR
Glomerular ultrafiltration
Obstruction Postrenal failure FIGURE 15-7
Renal injury from exposure to cyclosporin A. Cyclosporin A is one
FIGURE 15-6 example of a toxicant that acts at several sites within the kidney.
Mechanisms that contribute to decreased glomerular filtration rate It can injure both endothelial and tubular cells. Endothelial injury
(GFR) in acute renal failure. After exposure to a nephrotoxicant, results in increased vascular permeability and hypovolemia, which
one or more mechanisms may contribute to a reduction in the activates the sympathetic nervous system. Injury to the endotheli-
GFR. These include renal vasoconstriction resulting in prerenal um also results in increases in endothelin and thromboxane A2
azotemia (eg, cyclosporin A) and obstruction due to precipitation and decreases in nitric oxide and vasodilatory prostaglandins.
of a drug or endogenous substances within the kidney or collecting Finally, cyclosporin A may increase the sensitivity of the vascula-
ducts (eg, methotrexate). Intrarenal factors include direct tubular ture to vasoconstrictors, activate the renin-angiotensin system, and
obstruction and dysfunction resulting in tubular backleak and increase angiotensin II levels. All of these changes lead to vasocon-
increased tubular pressure. Alterations in the levels of a variety of striction and hypertension. Vasoconstriction in the kidney con-
vasoactive mediators (eg, prostaglandins following treatment with tributes to the decrease in glomerular filtration rate (GFR), and
nonsteroidal anti-inflammatory drugs) may result in decreased the histologic changes in the kidney are the result of local ischemia
renal perfusion pressure or efferent arteriolar tone and increased and hypertension.
afferent arteriolar tone, resulting in decreased in glomerular hydro-
static pressure. Some nephrotoxicants may decrease glomerular
function, leading to proteinuria and decreased renal function.
Renal Cellular Responses to Toxicant Exposures

FIGURE 15-8
Nephrotoxic insult The nephron’s response to a nephrotoxic insult. After a population
to the nephron of cells are exposed to a nephrotoxicant, the cells respond and ulti-
mately the nephron recovers function or, if cell death and loss is
Uninjured cells Injured cells Cell death
extensive, nephron function ceases. Terminally injured cells under-
go cell death through oncosis or apoptosis. Cells injured sublethal-
ly undergo repair and adaptation (eg, stress response) in response
Compensatory Cellular Cellular Cellular to the nephrotoxicant. Cells not injured and adjacent to the injured
hypertrophy adaptation proliferation repair 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
Re-epithelialization Cellular adaptation
injury. Finally the uninjured cells may also undergo adaptation in
response to nephrotoxicant exposure.
Differentiation
Structural and functional recovery of the nephron

Intact tubular epithelium Loss of polarity, tight junction

integrity, cell–substrate adhesion,
simplification of brush border
Toxic injury Cell death
Necrosis Apoptosis
α
β Sloughing of viable
and nonviable cells
with intraluminal
cell-cell adhesion
Cytoskeleton
Extracellular matrix
Cast formation
Na+/K+=ATPase
and tubuler
β1 Integrin obstruction
RGD peptide
FIGURE 15-9
After injury, alterations can occur in the cytoskeleton and in may be sloughed into the tubular lumen. Adhesion of sloughed
the normal distribution of membrane proteins such as Na+, K+- cells to other sloughed cells and to cells remaining adherent to
ATPase and 1 integrins in sublethally injured renal tubular the basement membrane may result in cast formation, tubular
cells. These changes result in loss of cell polarity, tight junction obstruction, and further compromise the glomerular filtration
integrity, and cell-substrate adhesion. Lethally injured cells rate. (Adapted from Fish and Molitoris [1], and Gailit et al. [2];
undergo oncosis or apoptosis, and both dead and viable cells with permission.)
FIGURE 15-10
Sublethally Migrating Cell
Potential sites where nephrotoxicants can interfere with the struc-
injured cells spreading cells proliferation
tural and functional recovery of nephrons.
Basement
membrane
Toxicant inhibition Toxicant inhibition Toxicant inhibition
of cell repair of cell migration/spreading of cell proliferation
140
120
100
Percent of control
Oncosis Apoptosis
80
60
Cell number/confluence
40 Mitochondrial function
Active Na+ transport
20 +
Na -coupled glucose transport
GGT activity Blebbing Budding
0
0 1 2 3 4 5 6
Time after exposure, d
FIGURE 15-11 Necrosis

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 mitochon-
drial function active (Na+) transport and Na+-coupled glucose
transport occurred 24 hours after oxidant exposure. The activity Phagocytosis Phagocytosis
of the brush border membrane enzyme -glutamyl transferase inflammation by macrophages
(GGT) was not affected by oxidant exposure. Cell proliferation or nearby cells
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 physio- FIGURE 15-12
logic functions are diminished after oxidant injury and that a hier- Apoptosis and oncosis are the two generally recognized forms of
archy exists in the repair process: migration or spreading followed cell death. Apoptosis, also known as programmed cell death and
by cell proliferation forms a monolayer and antedates the repair of cell suicide, is characterized morphologically by cell shrinkage, cell
physiologic functions. (Data from Nowak et al. [3].) 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 mor-
phologically by cell and organelle swelling, plasma membrane bleb-
bing, 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 break-
down and cell debris. (From Majno and Joris [4]; with permission.)
Mechanisms of Toxicant-Mediated Cellular Injury

Transport and biotransformation
FIGURE 15-13
Toxicant whose primary
Toxicants in general mechanism of action is The general relationship between oncosis and apoptosis after
ATP depletion 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
Oncosis Oncosis nephrotoxicant is ATP depletion, oncosis may be the predominant
cause of cell death with limited apoptosis occurring.
Cell death
Cell death
Apoptosis
Apoptosis
Toxicant concentration Toxicant concentration

FIGURE 15-14
GSH-Hg-GSH The importance of cellular transport in mediating toxicity.
GSH-Hg-GSH Proximal tubular uptake of inorganic mercury is thought to be the
GSH-Hg-GSH result of the transport of mercuric conjugates (eg, diglutathione
CYS-Hg-CYS γ-GT Urine
GLY-CYS-Hg-CYS-GLY ? mercury conjugate [GSH-Hg-GSH], dicysteine mercuric conjugate
CYS-Hg-CYS Acivicin [CYS-Hg-CYS]). At the luminal membrane, GSH-Hg-GSH appears
Dipeptidase to be metabolized by (-glutamyl transferase ((-GT) and a dipepti-
Lumen +
CYS-Hg-CYS Na
dase to form CYS-Hg-CYS. The CYS-Hg-CYS may be taken up by
Neutral amino an amino acid transporter. At the basolateral membrane, mercuric
–
R-Hg-R–
acid transporter conjugates appear to be transported by the organic anion trans-
Proximal +
tubular cell CYS-Hg-CYS Na CYS-Hg-CYS porter. (-Ketoglutarate and the dicarboxylate transporter seem to
GSH-Hg-GSH
play important roles in basolateral membrane uptake of mercuric
Na+ α-Ketoglutarate α-Ketoglutarate conjugates. Uptake of mercuric-protein conjugates by endocytosis
Dicarboxylate Organic anion
transporter transporter may play a minor role in the uptake of inorganic mercury trans-
port. PAH—para-aminohippurate. (Courtesy of Dr. R. K. Zalups.)
α-Ketoglutarate Organic anions
Na+
Blood (PAH or
Dicarboxylic α-Ketoglutarate probenecid)
acids –
R-Hg-R–
CYS-Hg-CYS
GSH-Hg-GSH
FIGURE 15-15
Toxicant Covalent and noncovalent binding versus oxidative stress mecha-
nisms of cell injury. Nephrotoxicants are generally thought to pro-
duce cell injury and death through one of two mechanisms, either
Biotransformation
alone or in combination. In some cases the toxicant may have a
high affinity for a specific macromolecule or class of macromole-
High-affinity binding Reactive intermediate Redox cycling cules that results in altered activity (increase or decrease) of these
to macromolecules molecules, resulting in cell injury. Alternatively, the parent nephro-
toxicant may not be toxic until it is biotransformed into a reactive
Covalent binding Increased reactive intermediate that binds covalently to macromolecules and in turn
Altered activity of to macromolecules oxygen species alters their activity, resulting in cell injury. Finally, the toxicant may
critical macromolecules increase reactive oxygen species in the cells directly, after being bio-
transformed into a reactive intermediate or through redox cycling.
Damage to critical Oxidative damage to
critical macromolecules
The resulting increase in reactive oxygen species results in oxida-
macromolecules
tive damage and cell injury.
Cell injury
Cell repair Cell death
FIGURE 15-16
Plasma RSG Plasma RSG
This figure illustrates the renal proximal tubular uptake, biotransfor-
R + SG Glomerular filtration mation, and toxicity of glutathione and cysteine conjugates and mer-
1. 2. capturic acids of haloalkanes and haloalkenes (R). 1) Formation of a
6.
R-SG R-SG R-SG 3. glutathione conjugate within the renal cell (R-SG). 2) Secretion of the
Na+ R-SG into the lumen. 3) Removal of the -glutamyl residue (-Glu)
4. γ-Glu by -glutamyl transferase. 4) Removal of the glycinyl residue (Gly) by
Plasma 7. 5. Gly a dipeptidase. 5) Luminal uptake of the cysteine conjugate (R-Cys).
R-Cys R-Cys R-Cys
R-Cys 12. NH3+H3CCOCO2H Basolateral membrane uptake of R-SG (6), R-Cys (7), and a mercap-
Na+ turic acid (N-acetyl cysteine conjugate; R-NAC)(8). 9) Secretion of
10. 11. R-SH 13.
R-NAC into the lumen. 10) Acetylation of R-Cys to form R-NAC.
Covalent binding
11) Deacetylation of R-NAC to form R-Cys. 12) Biotransformation
8. Cell injury
Plasma of the penultimate nephrotoxic species (R-Cys) by cysteine conjugate
R-NAC R-NAC R-NAC
R-NAC 9. -lyase to a reactive intermediate (R-SH), ammonia, and pyruvate.
Na+
Basolateral Brush border 13) Binding of the reactive thiol to cellular macromolecules (eg, lipids,
membrane membrane proteins) and initiation of cell injury. (Adapted from Monks and Lau
FIGURE 15-17
Covalent binding of a nephrotoxicant
metabolite in vivo to rat kidney tissue, local-
ization of binding to the mitochondria, and
identification of three proteins that bind to
the nephrotoxicant. A, Binding of tetrafluo-
roethyl-L-cysteine (TFEC) metabolites in vivo
to rat kidney tissue detected immunohisto-
chemically. 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
A B fractionation of renal cortical mitochondria
from untreated and TFEC treated rats and
Representative immunoblot analysis revealed numerous pro-
starting Submitochondrial fractions teins that bind to the nephrotoxicant (inner-
material A. Untreated B. TFEC (30 mg/kg) inner membrane, matrix-soluble matrix,
Mr (kDa) outer-outer membrane, inter-intermembrane
space). The identity of three of the proteins
228
that bound to the nephrotoxicant: P84,
P99 109 mortalin (HSP70-like); P66, HSP 60; and
P84 P42, aspartate aminotransferase. Mr—rela-
P66 70
tive molecular weight. (From Hayden et al.
P52
P42 44 [6], and Bruschi et al. [7]; with permission.)
Matrix
Inner
Outer
Matrix
Inter
Inner
Outer
Inter
Lipid peroxidation and mitochondrial dysfunction

HH R
FIGURE 15-18
A simplified scheme of lipid peroxidation. The first step, hydrogen
HO• Lipid abstraction from the lipid by a radical (eg, hydroxyl), results in the
H 2O formation of a lipid radical. Rearrangement of the lipid radical
Hydrogen abstraction results in conjugated diene formation. The addition of oxygen
•H R
results in a lipid peroxyl radical. Additional hydrogen abstraction
Lipid radical results in the formation of a lipid hydroperoxide. The Fenton reac-
Diene conjugation tion produces a lipid alkoxyl radical and lipid fragmentation,
R resulting in lipid aldehydes and ethane. Alternatively, the lipid per-
• oxyl radical can undergo a series of reactions that result in the for-
H Lipid radical, conjugated diene mation of malondialdehyde.
O2 Oxygen addition
R R
•O–O H Lipid peroxyl radical
O O
LH Hydrogen abstraction
L•
R
O O Lipid hydroperoxide
HOO H
Fe(II) Fenton reaction
Malondialdehyde
Fe(III) HO•
R
•O H Lipid alkoxyl radical
Fragmentation
H R
• H
H
H O Lipid aldehyde
LH • H
L H
H Ethane
H
50 100
Control Control
TBHP (0.5 mmol) DCVC
40 TBHP + DEF (1 mM) 80 DCVC + DEF (1 mM)
TBHP + DPPD (2 µM) DCVC + DPPD (50µM)
LDH release, %
LDH release, %
30 60
20 40
10 20
0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
A Time, h B Time, h
1.2 2.0
+1 mM DEF
1.0 +50 µM DPPD
1.6
nmol MDA•mg protein–1
nmol MDA•mg protein–1

Lipid peroxidation,
Lipid peroxidation,
0.8
1.2
0.6
0.8
0.4
0.4
0.2
0.0 0.0
C Control TBHP +1 mM DEF +2 µM DPPD D Control DCVC
FIGURE 15-19
A–D, Similarities and differences between oxidant-induced and peroxidation and cell death caused by TBHP. In contrast,
halocarbon-cysteine conjugate–induced renal proximal tubular while DEF and DPPD completely blocked the lipid peroxidation
lipid peroxidation and cell death. The model oxidant t-butylhy- caused by DCVC, cell death was only delayed. These results
droperoxide (TBHP) and the halocarbon-cysteine conjugate suggest that the iron-mediated oxidative stress caused by TBHP
dichlorovinyl-L-cysteine (DCVC) caused extensive lipid peroxi- is responsible for the observed toxicity, whereas the iron-mediat-
dation after 1 hour of exposure and cell death (lactate dehydro- ed oxidative stress caused by DCVC accelerates cell death. One
genase (LDH) release) over 6-hours’ exposure. The iron chelator reason that cells die in the absence of iron-mediated oxidative
deferoxamine (DEF) and the antioxidant N,N’-diphenyl-1, stress is that DCVC causes marked mitochondrial dysfunction.
4-phenylenediamine (DPPD) completely blocked both the lipid (Data from Groves et al. [8], and Schellmann [9].)
FIGURE 15-20
ALTERATION OF RENAL TUBULAR CELL Mechanisms by which nephrotoxicants can alter renal tubular
ENERGETICS AFTER EXPOSURE TO TOXICANTS cell energetics.
Decreased oxygen delivery secondary to vasoconstriction

Inhibition of mitochondrial respiration
Increased tubular cell oxygen consumption
FIGURE 15-21
Substrates Some of the mitochondrial targets of nephro-
11 toxicants: 1) nicotinamide adenine dinu-
Cephaloridine Atractyloside cleotide (NADH) dehydrogenase; 2) succi-
TCA Ochratoxin A nate dehydrogenase; 3) coenzyme
cycle Q–cytochrome C reductase; 4) cytochrome
ADP C; 5) cytochrome C oxidase; 6) cytochrome
Bromohydroquinone 9
ATP Aa3; 7) H+-Pi contransporter; 8) F0F1-
Dichlorovinyl–L–cysteine ATPase; 9) adenine triphosphate/diphosphate
1
Tetrafluoroethyl–L–cysteine H+ ATP (ATP/ADP) translocase; 10) protonophore
Pentachlorobutadienyl–L–cysteine 8
2 H+ (uncoupler); 11) substrate transporters.
Citrinin 3
Ochratoxin A H+
Hg2+ CN– 4 Oligomycin
5
H+
Pi Pi
6 7
H+
Matrix
O2 H 2O Ochratoxin A
10
Pentachlorobutadienyl–L–cysteine
H+ Inner membrane
Citrinin
FCCP Outer membrane
Disruption of ion homeostasis
Na+ H 2O
100
Na+ 90
Relative cellular changes
80 Na+
Na+ Na+ ATPase
Na+ ATPase 70
ATP 60
– – Cl–
ATP – Cl– 50 QO2 Membrane
– potential
40
Cl– Cl –
– K+ – 30 K+
– H 2O
K + – 20
10
ATP
A K+ B Antimycin A K+ 0
0 5 10 15 20 25 30
Antimycin A Time, min
FIGURE 15-22
Early ion movements after mitochondrial dysfunction. A, A control
renal proximal tubular cell. Within minutes of mitochondrial inhibi- FIGURE 15-23
tion (eg, by antimycin A), ATP levels drop, resulting in inhibition of A graphic of the phenomena diagrammed in Figure 15-22.
the Na+, K+-ATPase. B, Consequently, Na+ influx, K+ efflux, mem-
brane depolarization, and a limited degree of cell swelling occur.
FIGURE 15-24
Na+
The late ion movements after mitochondrial dysfunction that leads
Na+
to cell death/lysis. A, Cl- influx occurs as a distinct step subsequent
ATPase
Na+
to Na+ influx and K+ efflux. B, Following Cl- influx, additional
Na+ ATPase Na+ and water influx occur resulting in terminal cell swelling.
ATP Ultimately cell lysis occurs.
ATP Cl– Cl–
Cl– Cl–
K+
K+
H 2O
A Antimycin A K+ B Antimycin A K+
FIGURE 15-25
100
A graph of the phenomena depicted in Figures 15-22 through 15-
90 24, illustrating the complete temporal sequence of events following
Relative cellular changes
80 +
Na mitochondrial dysfunction. QO2—oxygen consumption.
70
60 Cl–
H 2O
50 QO2 Membrane
potential
40
30 K+ Ca++
20
10
ATP
0
0 5 10 15 20 25 30
Antimycin A Time, min
Disregulation of regulatory enzymes
BIOCHEMICAL CHARACTERISTICS OF CALPAIN

er
ATP Ca 2+
Ca2+
(1 mM)
Ca2+ Endopeptidase
(100 nM) Heterodimer: 80-kD catalytic subunit, 30-kD regulatory subunit
—Calpain and -calpain are ubiquitously distributed cytosolic isozymes
ATP —Calpain and -calpain have identical regulatory subunits but distinctive catalytic
Mitochondria Ca2+ 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 15-26
A simplified schematic drawing of the regulation of cytosolic
free Ca2+. 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 cytoso-
lic substrates. Calpains may also undergo Ca2+-mediated transloca-
tion 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.)
35 40
30 35
30
LDH release, %
LDH release, %
25
25
20
20
15
15
10 10
5 5
0 0
A CON TFEC +C12 BHQ +C12 TBHP +C12 B CON TFEC +PD BHQ +PD TBHP +PD
FIGURE 15-29
A, B, Dissimilar types of calpain inhibitors block renal proximal domain on the enzyme. The toxicants used were the haloalkane
tubular toxicity of many agents. Renal proximal tubular suspen- cysteine conjugate tetrafluoroethyl-L-cysteine (TFEC), the alkylat-
sions were pretreated with the calpain inhibitor 2 (CI2) or ing quinone bromohydroquinone (BHQ), and the model oxidant t-
PD150606 (PD). CI2 is an irreversible inhibitor of calpains that butylhydroperoxide (TBHP). The release of lactate dehydrogenase
binds to the active site of the enzyme. PD150606 is a reversible (LDH) was used as a marker of cell death. CON—control. (From
inhibitor of calpains that binds to the calcium (Ca2+)-binding 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 deple-
tion. 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 a–d represent an alternate
pathway that results in extracellular Ca2+ entry. (Data from Waters et al. [12,13,14].)
FIGURE 15-31
PROPERTIES OF PHOSPHOLIPASE A2 GROUP Biochemical characteristics of several identi-
fied phospholipase A2s.
Characteristics Secretory Cytosolic Ca2+-Independent

Localization Secreted Cytosolic Cytosolic Membrane
Molecular mass ~14 kDa ~85 kDa ~40 kDa unknown
Arachidonate preference
Ca2+ required mM (M None None
Ca2+ role Catalysis Memb. Assoc. None None
50 80
LLC-cPLA2 LLC-cPLA2
70
LLC-vector LLC-PK1
40
60
LDH release, % total

LLC-vector
AA release, %
30 50
40
20 30
20
10
10
0 0
30 60 90 120 0.0 0.1 0.2 0.3 0.4 0.5
A Time, min B [H2O2], mmol
FIGURE 15-32
80
LLC-cPLA2 The importance of the cytosolic phospholipase A2 in oxidant
70 injury. A, Time-dependent release of arachidonic acid (AA)
LLC-sPLA2
60 from LLC-PK1 cells exposed to hydrogen peroxide (0.5 mM).
LDH release, % total
LLC-vector
50
B and C, The concentration-dependent effects of hydrogen perox-
ide on LLC-PK1 cell death (using lactate dehydrogenase [LDH]
40 release as marker) after 3 hours’ exposure. Cells were transfected
30 with 1) the cytosolic PLA2 (LLC-cPLA2), 2) the secretory PLA2
20 (LLC-sPLA2), 3) vector (LLC-vector), or 4) were not transfected
(LLC-PK1). Cells transfected with cytosolic PLA2 exhibited
10
greater AA release and cell death in response to oxidant exposure
0 than cells transfected with the vector or secretory PLA2 or not
0.0 0.1 0.2 0.3 0.4 0.5 transfected. These results suggest that activation of cytosolic
C [H2O2], mmol PLA2 during oxidant injury contributes to cell injury and death.
(From Sapirstein et al. [15]; with permission.)
50
200
100
Residual double-stranded DNA, %
∆ Increase in caspase activity,
40
150 75
Cell death, %
units/mg protein
30
100 50
20
50 25 10
0 0
0
cin A
cin A
r II
r II
rI
rI
trol
trol
0 10 20 30
bito
bito
bito
bito
Con
Con
imy
imy
Time of antimycin A treatment,

Inhi
Inhi
Inhi
Inhi
Ant
Ant
A min B C
FIGURE 15-33
Potential role of caspases in cell death in LLC-PK1 cells exposed to Inhibitor 1 is IL-1 converting enzyme inhibitor 1 (YVAD-CHO) and
antimycin A. A, Time-dependent effects of antimycin A treatment on inhibitor II is CPP32/apopain inhibitor (DEVD-CHO). These results
caspase activity in LLC-PK1 cells. B, C, The effect of two capase suggest that caspases are activated after mitochondrial inhibition and
inhibitors on antimycin A–induced DNA damage and cell death, respec- that caspases may contribute to antimycin A–induced DNA damage
tively. Antimycin A is an inhibitor of mitochondrial electron transport. and cell death. (From Kaushal et al. [16]; with permission.)
References
1. Fish EM, Molitoris BA: Alterations in epithelial polarity and the 10. Suzuki K, Ohno S: Calcium activated neutral protease: Structure-func-
pathogenesis of disease states. N Engl J Med 1994, 330:1580. tion relationship and functional implications. Cell Structure Function
2. Gailit J, Colfesh D, Rabiner I, et al.: Redistribution and dysfunction 1990, 15:1.
of integrins in cultured renal epithelial cells exposed to oxidative 11. Suzuki K, Sorimachi H, Yoshizawa T, et al.: Calpain: Novel family
stress. Am J Physiol 1993, 264:F149. members, activation, and physiologic function. Biol Chem Hoppe-
3. Nowak G, Aleo MD, Morgan JA, Schnellmann RG: Recovery of cellu- Seyler 1995, 376:523.
lar functions following oxidant injury. Am J Physiol 1998, 274:F509. 12. Waters SL, Sarang SS, Wang KKW, Schnellmann RG: Calpains medi-
4. Majno G, Joris I: Apoptosis, oncosis and necrosis. Am J Pathol 1995, ate calcium and chloride influx during the late phase of cell injury. J
146:3. Pharmacol Exp Ther 1997, 283:1177.
5. Monks TJ, Lau SS: Renal transport processes and glutathione conju- 13. Waters SL, Wong JK, Schnellmann RG: Depletion of endoplasmic
gate–mediated nephrotoxicity. Drug Metab Dispos 1987, 15:437. reticulum calcium stores protects against hypoxia- and mitochondrial
inhibitor–induced cellular injury and death. Biochem Biophys Res
6. Hayden PJ, Ichimura T, McCann DJ, et al.: Detection of cysteine con-
Commun 1997, 240:57.
jugate metabolite adduct formation with specific mitochondrial pro-
teins using antibodies raised against halothane metabolite adducts. 14. Waters SL, Miller GW, Aleo MD, Schnellmann RG: Neurosteroid
J Biol Chem 1991, 266:18415. inhibition of cell death. Am J Physiol 1997, 273:F869.
7. Bruschi SA, West KA, Crabb JW, et al.: Mitochondrial HSP60 (P1 15. Sapirstein A, Spech RA, Witzgall R, Bonventre JV: Cytosolic phospho-
protein) and a HSP70-like protein (mortalin) are major targets for lipase A2 (PLA2), but not secretory PLA2, potentiates hydrogen perox-
modification during S-(1,1,2,2-tetrafluoroethyl)-L-cysteine–induced ide cytotoxicity in kidney epithelial cells. J Biol Chem 1996,
nephrotoxicity. J Biol Chem 1993, 268:23157. 271:21505.
8. Groves CE, Lock EA, Schnellmann RG: Role of lipid peroxidation in 16. Kaushal GP, Ueda N, Shah SV: Role of caspases (ICE/CED3 proteases)
renal proximal tubule cell death induced by haloalkene cysteine conju- in DNA damage and cell death in response to a mitochondrial
gates. Toxicol Appl Pharmacol 1991, 107:54. inhibitor, antimycin A. Kidney Int 1997, 52:438.
9. Schnellmann RG: Pathophysiology of nephrotoxic cell injury. In
Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW.
Boston:Little Brown; 1997:1049.
Cellular Features of
Injury and Repair
Kevin T. Bush
Hiroyuki Sakurai
Tatsuo Tsukamoto
Sanjay K. Nigam
A
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 charac-
teristic of renal epithelial cells [1–7]. 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 [7–12].
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 perme-
ability barrier, and thus of functional renal tubules, is critically depen-
dent on the establishment of functional tight junctions. The tight junc-
CHAPTER
tion is an apically oriented structure that functions as both the “fence”
that separates apical and basolateral plasma membrane domains and
16
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 physio-
logical conditions remains ill-understood; however, utilization of the
“calcium switch” model with cultured renal epithelial cells has protein, E-cadherin) are membrane proteins. Matrix proteins and
helped to elucidate some of the critical features of tight junction their integrin receptors may need to be resynthesized, along with
bioassembly. In this model for tight junction reassembly, signal- growth factors and cytokines, all of which pass through the endo-
ing events involving G proteins, protein kinase C, and calcium plasmic reticulum (ER). The rate-limiting events in the biosynthe-
appear necessary for the reestablishment of tight junctions sis and assembly of these proteins occur in the ER and are cat-
[13–19]. Tight junction injury and recovery, like that which alyzed by a set of ER-specific molecular chaperones, some of
occurs after ischemia and reperfusion, has similarly been mod- which are homologs of the cytosolic heat-shock proteins [20]. The
eled by subjecting cultured renal epithelial cells to ATP deple- levels of mRNAs for these proteins may increase 10-fold or more
tion (“chemical anoxia”) followed by repletion. While there are in the ischemic kidney, to keep up with the cellular need to syn-
many similarities to the calcium switch, biochemical studies thesize and transport these new membrane proteins, as well as
have recently revealed major differences, for example, in the secreted ones.
way tight junction proteins interact with the cytoskeleton [12]. If the ischemic insult is sufficiently severe, cell death and/or
Thus, important insights into the basic and applied biology of detachment leads to loss of cells from the epithelium lining the
tight junctions are likely to be forthcoming from further analy- kidney tubules. To recover from such a severe insult, cell regen-
sis of the ATP depletion-repletion model. Nevertheless, it is like- eration, differentiation, and possibly morphogenesis, are neces-
ly that, as in the calcium switch model, tight junction reassem- sary. To a limited extent, the recovery of kidney tubule function
bly is regulated by classical signaling pathways that might after such a severe ischemic insult can be viewed as a recapitu-
potentially be pharmacologically modulated to enhance recov- lation of various steps in renal development. Cells must prolif-
ery after ischemic insults. erate and differentiate, and, in fact, activation of growth fac-
More prolonged insults can lead to greater, but still sublethal, tor–mediated signaling pathways (some of the same ones
injury. Key cellular proteins begin to break down. Many of these involved in kidney development) appears necessary to amelio-
(eg, the tight junction protein, occludin, and the adherens junction rate renal recovery after acute ischemic injury [21–30].
The Ischemic Epithelial Cell

FIGURE 16-1
Functional renal tubules Ischemic acute renal failure (ARF). Flow chart illustrates the cellu-
lar basis of ischemic ARF. As described above, renal tubule epithe-
Uninjured cells lial cells undergo a variety of biochemical and structural changes in
Ischemic insult response to ischemic insult. If the duration of the insult is suffi-
ciently short, these alterations are readily reversible, but if the
Injured cells insult continues it ultimately leads to cell detachment and/or cell
death. Interestingly, unlike other organs in which ischemic injury
↓ATP; ↑[CA2+]i; ↑Free radicals; Other changes? 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.
Tight junction Apical-basolateral Microfilament
disruption polarity disruption disruption
Dysfunctional renal tubular epithelial cells
Remove insult Continued insult
Cell loss
Cellular
(detachment
repair
or death)
Cell regenertation,
differentiation, and
morphogenesis
Remove insult
Acute Renal Failure: Cellular Features of Injury and Repair 16.3
FIGURE 16-2
Typical renal epithelial cell. Diagram of a typical renal epithelial
cell. Sublethal injury to polarized epithelial cells leads to multiple
Brush lesions, including loss of the permeability barrier and apical-basolat-
border eral polarity [7–12]. To recover, cells must reestablish intercellular
junctions and repolarize to form distinct apical and basolateral
domains characteristic of functional renal epithelial cells. These
Tight
junction
junctions include those necessary for maintaining the permeability
barrier (ie, tight junctions), maintaining cell-cell contact (ie,
Adherens Terminal web adherens junctions and desmosomes), and those involved in cell-cell
junction Actin cortical ring communication (ie, gap junctions). In addition, the cell must estab-
lish 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
Desmosome Intermediate
injury to tubule cells new cells may have to replace those lost during
filaments the ischemic insult, and these new cells must differentiate into
epithelial cells to restore proper function to the tubules.
Gap
junction
Na+, K+, ATPase

Integrins
Extracellular matrix
FIGURE 16-3
Symplekin Occludin 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
7H6 p130 basolateral plasma membrane domains of the cells, allowing for vectorial transport of ions
Cingulin ZO–1 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 criti-
cally important to the proper functioning of renal tubules. The tight junction is comprised
ZO–2
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, 32–37].
Actin These proteins include the transmembrane protein occludin [35, 38] and the cytosolic pro-
filaments
teins 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
Fodrin Paracellular tight junction also appears to interact with the actin-based cytoskeleton, probably in part
space through ZO-1–fodrin interactions.
Reassembly of the Permeability Barrier

mechanisms underlying tight junction dys-
function in ischemia and how tight junction
Reutilization of existing Synthesis of new integrity recovers after the insult [6, 12, 42].
junctional components junctional components
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 reassem-
Polarized renal Nonpolarized renal Nonpolarized renal Cell death bly of the tight junction can proceed with
epithelial cells epithelial cells epithelial cells existing (disassembled) components after
Apoptosis Necrosis ATP repletion. This model of short-term ATP
Intact intercellular Compromised Damaged disassembled
junctions intercellular junctions intercellular junctions
depletion-repletion is probably most relevant
to transient sublethal ischemic injury of renal
tubule cells. However, in a model of
Short-term Long-term Severe longterm ATP depletion (2.5 to 4 hours),
ATP depletion ATP depletion ATP depletion
0–1 h 2.5-4 h 6+ h that probably is most relevant to prolonged
Deplete Replete Replete ischemic (though still sublethal) insult to the
ATP ATP ATP
renal tubule, it is likely that reestablishment
of the permeability barrier (and thus of
FIGURE 16-4 tubule function) depends on the production
Cell culture models of tight junction disruption and reassembly. The disruption of the perme- (message and protein) and bioassembly of
ability barrier, mediated by the tight junction, is a key lesion in the pathogenesis of tubular new tight junction components. Many of
dysfunction after ischemia and reperfusion. Cell culture models employing ATP depletion these components (membrane proteins) are
and repletion protocols are a commonly used approach for understanding the molecular assembled in the endoplasmic reticulum.
occludin ZO-1 fodrin occludens 1 (ZO-1), and the transmembrane protein occludin are
integral components of the tight junction that are intimately asso-
ciated at the apical border of epithelial cells. This is demonstrated
control here by indirect immunofluorescent localization of these two pro-
teins in normal kidney epithelial cells. After 1 hour of ATP deple-
tion this association appears to change, occludin can be found in
the cell interior, whereas ZO-1 remains at the apical border of the
ATP depletion (1 hr) plasma membrane. Interestingly, the intracellular distribution of
the actin-cytoskeletal–associated protein fodrin also changes after
ATP depletion. Fodrin moves from a random, intracellular distrib-
ution and appears to become co-localized with ZO-1 at the apical
ATP repletion (3hrs) border of the plasma membrane. These changes are completely
reversible after ATP repletion. These findings suggest that disrup-
tion of the permeability barrier could be due, at least in part, to
altered association of ZO-1 with occludin. In addition, the appar-
FIGURE 16-5 ent co-localization of ZO-1 and fodrin at the level of the tight
Immunofluorescent localization of proteins of the tight junction junction suggests that ZO-1 is becoming intimately associated
after ATP depletion and repletion. The cytosolic protein zonula with the cytoskeleton.
FIGURE 16-6
Occludin Occludin
ATP depletion causes disruption of tight junctions. Diagram of the
ZO–1 Fodrin ZO–1 changes induced in tight junction structure by ATP depletion. ATP
depletion causes the cytoplasmic tight junction proteins zonula
Fodrin Ischemia
ZO–2 ZO–2 occludens 1 (ZO-1) and ZO-2 to form large insoluble complexes,
ATP depletion probably in association with the cytoskeletal protein fodrin [12],
Actin
Actin though aggregation may also be significant. Furthermore, occludin,
filament
filament 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.
Membrane vesicle?
FIGURE 16-7
Madin-Darby canine kidney (MDCK) cell calcium switch. Insight into the molecular mecha-
nisms 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
Low calcium (LC) 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 cell-
cell 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,
A B MDCK cells undergo significant changes in
cell shape and make extensive cell-cell con-
tact 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 junc-
tions [12, 13, 16–19, 37, 44–46]. An
C D analogous set of signaling events is likely
responsible for tight junction reassembly
after ischemia. (From Stuart and Nigam
FIGURE 16-9
Signalling molecules that may be involved in tight junction assembly. Model of the poten-
tial 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
PKC
(Rab/Rho), and tyrosine kinases [13–16, 18, 37, 44–53]. Although it is not clear how this
P-Tyr process is initiated, it depends on cell-cell contact and involves wide-scale changes in levels
of intracellular free calcium. Receptor/CAM—cell adhesion molecule; DAG—diacylglyc-
P-Ser erol; ER—endoplasmic reticulum; G—alpha subunit of GTP-binding protein; IP3—inosi-
tol trisphosphate. (From Denker and Nigam [19]; with permission.)
P
Gα
Effector
DAG 2+
Tyr-kinases Ca
+
?TP IP3
Rab/Rho
?Receptor/CAM
ER
The Endoplasmic Reticulum Stress Response in Ischemia

mRNA FIGURE 16-10
Protein processing in the endoplasmic reticu-
Ribosome lum (ER). To recover from serious injury,
cells must synthesize and assemble new mem-
Secretion- brane (tight junction proteins) and secreted
Free chaperones competent (growth factors) proteins. The ER is the ini-
To
reutilization protein Golgi tial site of synthesis of all membrane and
secreted proteins. As a protein is translocated
Dissociation of into the lumen of the ER it begins to interact
chaperones
with a group of resident ER proteins called
ATP
ADP molecular chaperones [20, 54–57]. Molecular
chaperones bind transiently to and interact
Protein folding
with these nascent polypeptides as they fold,
Peptidyl-prolyl isomerization
assemble, and oligomerize [20, 54, 58]. Upon
N-linked glycosylation ein n Misassembled
ot tio successful completion of folding or assembly,
Disulfide bond formation Pr riza protein
e the molecular chaperones and the secretion-
m
go
oli competent protein part company via a reac-
tion that requires ATP hydrolysis, and the
Degradation chaperones are ready for another round of
Misfolded protein folding [20, 59–61]. If a protein is
protein
recognized as being misfolded or misassem-
Resident ER bled it is retained within the ER via stable
proteolytic pathway?
association with the molecular chaperones
and is ultimately targeted for degradation
To proteasome? [62]. Interestingly, some of the more charac-
teristic features of epithelial ischemia include
loss of cellular functions mediated by pro-
teins that are folded and assembled in the ER
(ie, cell adhesion molecules, integrins, tight
junctional proteins, transporters). This sug-
gests that proper functioning of the protein-
folding machinery of the ER could be critical-
ly important to the ability of epithelial cells
to withstand and recover from ischemic
insult. ADP—adenosine diphosphate.
FIGURE 16-11
45' Ischemia 15' Ischemia Ischemia upregulates endoplasmic reticulum
(ER) molecular chaperones. Molecular
chaperones of the ER are believed to func-
GAPDH GAPDH tion normally to prevent inappropriate
intra- or intermolecular interactions during
the folding and assembly of proteins [20,
54]. However, ER molecular chaperones are
BiP BiP 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
grp94 grp94
[20, 54]. In fact, the messages encoding the
ER molecular chaperones are known to
increase in response to intraorganelle accu-
ERp72 ERp72 mulation of such malfolded proteins [11,
20, 54, 55]. Here, Northern blot analysis of
1 2 3 1 2 3 total RNA from either whole kidney or cul-
A A
B tured epithelial cells demonstrates that
ischemia or ATP depletion induces the
mRNAs that encode the ER molecular
Kidney Cell Line Thyroid Cell Line chaperones, including immunoglobulin
binding protein (BiP), 94 kDa glucose regu-
28 S lated protein (grp94), and 72 kDa endo-
GAPDH rRNA plasmic reticulum protein (Erp72) [11].
BiP This suggests not only that ischemia or ATP
depletion causes the accumulation of mal-
BiP folded proteins in the ER but that a major
grp94 effect of ischemia and ATP depletion could
be perturbation of the “folding environ-
grp94 ment” of the ER and disruption of protein
processing. GAPDH—glyceraldehyde-3-
ERp72
phosphate dehydrogenase; Hsp70—70 kDa
ERp72 heat-shock protein. (From Kuznetsov et al.
Hsp70
Hsp70
1 2 3 4 5 6 1 2 3 4
C D
C
FIGURE 16-12
Antimycin A ATP depletion perturbs normal endoplas-
mic reticulum (ER) function. Because ATP
10M
and a proper redox environment are neces-

1M
5M
MED
PBS
sary 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 condi-
tions. Here, Western blot analysis of the
Tg
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
1 2 3 4 5 A for 1 hour completely blocks the secretion
A B of thyroglobulin (Tg) from these cells.

B–D, Moreover, indirect immunofluores-
cence 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]. MED—control media; PBS—phos-
phate-buffered saline. (From Kuznetsov et
al. [11]; with permission.)
C D
FIGURE 16-13
Antimycin A ATP depletion increases the stability of chaperone-folding
MED PBS 1 5 10 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, 65–73]. The dis-
Tg sociation 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 chap-
erones with a model ER secretory protein is examined by Western
grp94 blot analysis of thyroglobulin (Tg) immunoprecipitates from thy-
roid 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 deple-
tion causes stabilization of the interactions between molecular
BiP
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
ERp72 part, on the ability of the cell to rescue the protein-folding and -
assembly apparatus of the ER. Control media (MED) and phos-
phate buffered saline (PBS)—no ATP depletion; 1, 5, 10M
1 2 3 4 5 antimycin A—ATP-depleting conditions. (From Kuznetsov et al.
Growth Factors and Morphogenesis
Basement membrane
degrading proteinases
Integrin receptors for

interstitial matrix
Cytoskeletal
rearrangement
Terminal Proteinases
nephron
Cell-surface receptors
Arcade for proteinases
(uPA-R, ? for MMPs)
Lack of integrin-mediated
basement membrane
initiated signaling
A B
FIGURE 16-14
Kidney morphogenesis. Schematics demonstrate the development of the ureteric bud and
Uninduced mesenchyme metanephric mesenchyme during kidney organogenesis. During embryogenesis, mutual inductive
events between the metanephric mesenchyme and the ureteric bud give rise to primordial struc-
tures 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
Condensing cells 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 pro-
teins. 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.
S-shaped body
The metanephric mesenchyme not only induces ureteric bud branching but is also induced by the
C ureteric bud to epithelialize and differentiate into the proximal through distal tubule [74–76].
(From Stuart and Nigam [80] and Stuart et al. [81]; with permission.)
FIGURE 16-15
Tubulogenesis in vitro Potential of in vitro tubulogenesis research. Flow chart indicates
relevance of in vitro models of kidney epithelial cell branching
Basic research Applied research tubulogenesis to basic and applied areas of kidney research. While
results from such studies provide critical insight into kidney devel-
opment, this model system might also contribute to the elucidation
Renal development Renal diseases of mechanisms involved in kidney injury and repair for a number
of diseases, including tubular epithelial cell regeneration secondary
Renal injury and repair to acute renal failure. Moreover, these models of branching tubulo-
genesis could lead to therapies that utilize tubular engineering as
Renal cystic diseases artificial renal replacement therapy [82].
Urogenital abnormalities
Hypertension
Artificial kidneys
FIGURE 16-16
Cellular response to growth factors. Schematic representation of
Cell proliferation
Mitogenesis 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.
Cell movement Among these properties are the ability to regulate or activate
Motogenesis
numerous cellular signaling responses, including proliferation
(mitogenesis), motility (motogenesis), and differentiation (morpho-
Growth Cell organization genesis). These characteristics allow growth factors to play critical
Morphogenesis roles in a number of complex biological functions, including
factor
embryogenesis, angiogenesis, tissue regeneration, and malignant
Cell survival transformation [83].
Antiapoptosis
DD
Remodeling of cell substratum
A B
C D
FIGURE 16-17
Motogenic effect of growth factors—hepatocyte growth factor type of cultured renal epithelial cell with HGF induced the dissoci-
(HGF) induces cell “scattering.” During development or regenera- ation of islands of cells into individual cells. This phenomenon is
tion the recruitment of cells to areas of new growth is vital. referred to as scattering. HGF was originally identified as scatter
Growth factors have the ability to induce cell movement. Here, factor, based on its ability to induce the scattering of MDCK cells
subconfluent monolayers of either Madin-Darby canine kidney [83]. Now, it is known that HGF and its receptor, the transmem-
(MDCK) C, D, or murine inner medullary collecting duct brane tyrosine kinase c-met, play important roles in development,
(mIMCD) A, B, cells were grown for 24 hours in the absence, regeneration, and carcinogenesis [83]. (From Cantley et al. [84];
A, C, or presence B, D, of 20 ng/mL HGF. Treatment of either with permission.)
the branching and tubulogenesis of renal epithelial cells. Analyzing

Growth the role of single factors (ie, extracellular matrix, growth factors,
factors cell-signaling processes) involved in ureteric bud branching tubulo-
genesis 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 sus-
pended 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
FIGURE 16-18 generation of branching epithelial tubules and has provided crucial
Three-dimensional extracellular matrix gel tubulogenesis model. insights into the potential roles that these various factors play in
Model of the three-dimensional gel culture system used to study epithelial cell branching morphogenesis [77, 79, 84–87].
(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 tubulo-
A B genic activity [86–93]. Interestingly, many
of these same growth factors have been
FIGURE 16-19 shown to be effective in the recovery of
An example of the branching tubulogenesis of renal epithelial cells cultured in three- renal function after acute ischemic insult
dimensional extracellular matrix gels. Microdissected mouse embryonic kidneys [21–30]. (From Barros et al. [87]; with
(11.5 to 12.5 days) were cocultured with A, murine inner medullary collecting duct permission.)
FIGURE 16-20
Development of cell lines derived from embryonic kidney. Flow
chart of the establishment of ureteric bud and metanephric mes-
enchymal cell lines from day 11.5 mouse embryo. Although the
results obtained from the analysis of kidney epithelial cells—
Pregnant SV40–transgenic mouse 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
Isolate embryos
the mechanisms of epithelial cell branching tubulogenesis, ques-
tions can be raised about the applicability to embryonic develop-
Dissect out embryonic kidney ment 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
Isolate metanephric mesenchyme Isolate ureteric bud 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.
Culture to obtain immortalized cells
A B C
FIGURE 16-21
Ureteric bud cells undergo branching tubulogenesis in three- vitro model with the greatest relevance to early kidney develop-
dimensional extracellular matrix gels. Cell line derived from ment [94]. A, UB cells grown for 1 week in the presence of condi-
ureteric bud (UB) and metanephric mesenchyme from day 11.5 tioned media collected from cells cultured from the metanephric
mouse embryonic kidney undergo branching tubulogenesis in mesenchyme. Note the formation of multicellular cords. B, After
three-dimensional extracellular matrix gels. Here, UB cells have 2 weeks’ growth under the same conditions, UB cells have formed
been induced to form branching tubular structures in response to more substantial tubules, now with clear lumens. C, Interestingly,
“conditioned” media collected from the culture of metanephric after 2 weeks of culture in a three-dimensional gel composed
mesenchymal cells. During normal kidney morphogenesis, these entirely of growth factor–reduced Matrigel, ureteric bud cells have
two embryonic cell types undergo a mutually inductive process not formed cords or tubules, only multicellular cysts. Thus, chang-
that ultimately leads to the formation of functional nephrons ing the matrix composition can alter the morphology from tubules
[74–76]. This model system illustrates this process, ureteric bud to cysts, indicating that this model might also be relevant to renal
cells being induced by factors secreted from metanephric mes- cystic disease, much of which is of developmental origin. (From
enchymal cells. Thus, this system could represent the simplest in Sakurai et al. [94]; with permission.)
Free HGF and empty HGF binding to Dimerization of c-Met

c-Met receptor c-Met receptor receptor and activation
of Gab 1
C–Met C–Met C–Met Growth factor
HGF HGF HGF
HGF binding
HGF HGF HGF HGF
HGF
Plasma Plasma Plasma

membrane membrane membrane
Gab-1 Gab-1 Gab-1 Gab-1 Gab-1 Gab-1 Up-regulation of proteases

Mitogenic response
Branching morphogenesis Motogenic response
Transduction of Gab-1
Alteration of cytoskeleton
signal leading to Other responses
branching tubulogenesis
FIGURE 16-23
Mechanism of growth factor action. Proposed model for the gener-
FIGURE 16-22
alized response of epithelial cells to growth factors, which the
Signalling pathway of hepatocyte growth factor action. Diagram of depends on their environment. Epithelial cells constantly monitor
the proposed intracellular signaling pathway involved in hepatocyte their surrounding environment via extracellular receptors (ie, inte-
growth factor (HGF)–mediated tubulogenesis. Although HGF is per- grin receptors) and respond accordingly to growth factor stimula-
haps the best-characterized of the growth factors involved in epithe- tion. If the cells are in the appropriate environment, growth factor
lial cell-branching tubulogenesis, very little of its mechanism of binding induces cellular responses necessary for branching tubulo-
action is understood. However, recent evidence has shown that the genesis. There are increases in the levels of extracellular proteinases
HGF receptor (c-Met) is associated with Gab-1, a docking protein and of structural and functional changes in the cytoarchitecture
believed to be involved in signal transduction [96]. Thus, on binding that enable the cells to form branching tubule structures.
to c-Met, HGF activates Gab-1–mediated signal transduction, which,
by an unknown mechanism, affects changes in cell shape and cell
movement or cell-cell–cell-matrix interactions. Ultimately, these alter-
ations lead to epithelial cell–branching tubulogenesis.
GROWTH FACTORS IN DEVELOPMENTAL AND RENAL RECOVERY
Growth Factor Expression Following Renal Ischemia Effect of Exogenous Administration Branching/Tubulogenic Activity
HGF Increased [97] Enhanced recovery [103] Facilatory [109,110]
EGF Unclear [98,99] Enhanced recovery [104,105] Facilatory [111]
HB-EGF Increased [100] Undetermined Facilatory [111]
TGF- Unclear Enhanced recovery [106] Facilatory [111]
IGF Increased [101] Enhanced recovery [107,108] Facilatory [112,113]
KGF Increased [102] Undetermined Undetermined
bFGF Undetermined Undetermined Facilatory [112]
GDNF Undetermined Undetermined Facilatory [114]
TGF- Increased† [98] Undetermined Inhibitory for branching [115]
PDGF Increased† [98] Undetermined 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 tubulogenesis or to affect recovery of kidney tubules after ischemic
describes the roles of different growth factors in renal injury or in or other injury. Interestingly, growth factors that facilitate branch-
branching tubulogenesis. A large variety of growth factors have ing tubulogenesis in vitro also enhance the recovery of injured
been tested for their ability either to mediate ureteric branching renal tubules.
References
1. Zager RA, Gmur DJ, Bredl CR, et al.: Regional responses within the 13. Nigam SK, Denisenko N, Rodriguez-Boulan E, Citi S: The role of phos-
kidney to ischemia: Assessment of adenine nucleotide and catabolite phorylation in development of tight junctions in cultured renal epithelial
profiles. Biochim Biophys Acta 1990, 1035:29–36. (MDCK) cells. Biochem Biophys Res Commun 1991, 181:548–553.
2. Hays SR: Ischemic acute renal failure. Am J Med Sci 1992, 14. Nigam SK, Rodriguez-Boulan E, Silver RB: Changes in intracellular
304:93–108. calcium during the development of epithelial polarity and junctions.
3. Toback FG: Regeneration after acute tubular necrosis. Kidney Int Proc Natl Acad Sci USA 1992, 89:6162–6166.
1992, 41:226–246. 15. Stuart RO, Sun A, Panichas M, et al.: Critical role for intracellular
4. Liu S, Humes HD: Cellular and molecular aspects of renal repair in calcium in tight junction biogenesis. J Cellular Physiology 1994,
acute renal failure. Curr Opin Nephrol Hypertension 1993, 2:618–624. 159:423–433.
5. Doctor RB, Bennett V, Mandel LJ: Degradation of spectrin and ankyrin 16. Stuart RO, Nigam SK: Regulated assembly of tight junctions by pro-
in the ischemic rat kidney. Am J Physiol 1993, 264:C1003–C1013. tein kinase C. Proc Natl Acad Sci USA 1995, 92:6072–6076.
6. Doctor RB, Bacallao R, Mandel LJ: Method for recovering ATP con- 17. Stuart RO, Sun A, Bush KT, Nigam SK: Dependence of epithelial
tent and mitochondrial function after chemical anoxia in renal cell intercellular junction biogenesis on thapsigargin-sensitive intracellular
cultures. Am J Physiol 1994, 266:C1803–C1811. calcium stores. J Biol Chem 1996, 271:13636–13641.
7. Edelstein CL, Ling H, Schrier RW: The nature of renal cell injury. 18. Denker BM, Saha C, Khawaja S, Nigam SK: Involvement of a het-
Kidney Int 1997, 51:1341–1351. erotrimeric G protein subunit in tight junction biogenesis. J Biol
8. Fish EM, Molitoris BA: Alterations in epithelial polarity and the Chem 1996, 271:25750–25753.
pathogenesis of disease states. N Engl J Med 1994, 330:1580–1587. 19. Denker BM, Nigam SK: Molecular structure and assembly of the tight
9. Mandel LJ, Bacallao R, Zampighi G: Uncoupling of the molecular junction. Am J Physiol 1998, 274:F1–F9.
‘fence’ and paracellular ‘gate’ functions in epithelial tight junctions.
20. Gething M-J, Sambrook J: Protein folding in the cell. Nature 1992,
Nature 1993, 361:552–555.
355:33–45.
10. Goligorsky MS, Lieberthal W, Racusen L, Simon EE: Integrin recep-
tors in renal tubular epithelium: New insights into pathophysiology of 21. Humes HD, Cielinski DA, Coimbra T, et al.: Epidermal growth factor
acute renal failure. Am J Physiol 1993, 264:F1–F8. enhances renal tubule cell regeneration and repair and accelerates the
recovery of renal function in postischemic acute renal failure. J Clin
11. Kuznetsov G, Bush KT, Zhang PL, Nigam SK: Perturbations in matu-
Invest 1989, 84:1757–1761.
ration of secretory proteins and their association with endoplasmic
reticulum chaperones in a cell culture model for epithelial ischemia. 22. Humes HD, Beals TF, Cieslinski DA, et al.: Effects of transforming
Proc Natl Acad Sci USA 1996, 93:8584–8589. growth factor–beta, transforming growth factor-alpha, and other growth
12. Tsukamoto T, Nigam SK: Tight junction proteins become insoluble, factors on renal proximal tubule cells. Lab Invest 1991, 64:538–545.
form large complexes and associate with fodrin in an ATP depletion 23. Miller SB, Martin DR, Kissane J, Hammerman MR: Insulin-like
model for reversible junction disassembly. J Biol Chem 1997, growth factor I accelerates recovery from ischemic acute tubular
272:16133–16139. necrosis in the rat. Proc Natl Acad Sci USA 1992, 89:11876–11880.
24. Border W, Noble N: Transforming growth factor beta in tissue fibro- 47. Tsukita S, Oishi K, Akiyama T, et al.: Specific proto-oncogenic tyro-
sis. N Engl J Med 1994, 331:1286–1292. sine kinase of src family are enriched in cell-to-cell adherens junctions
25. Kawaida K, Matsumoto K, Shimazu H, Nakamura T: Hepatocyte where the level of tyrosine phosphorylation is elevated. J Cell Biol
growth factor prevents acute renal failure and accelerates renal regen- 1991, 113:867–879.
eration in mice. Proc Natl Acad Sci USA 1994, 91:4357–4361. 48. Citi S: Protein kinase inhibitors prevent junction dissociation induced
26. Miller S, Martin D, Kissane J, Hammerman M: Hepatocyte growth by low extracellular calcium in MDCK epithelial cells. J Cell Biol
factor accelerates recovery from acute ischemic renal injury in rats. 1992, 117:169–178.
Am J Physiol 1994, 266:F129–F134. 49. Reynolds AB, Daniel J, McCrea PD, et al.: Identification of a new
27. Miller S, Martin D, Kissane J, Hammerman M: Rat models for clini- catenin: The tyrosine kinase substrate pl20cas associates with E-cad-
cal use of insulin-like growth factor I in acute renal failure. Am J herin complexes. Molec Cell Biol 1994, 14:8333–8342.
Physiol 1994, 266:F949–F956. 50. Weber E, Berta G, Tousson A, et al.: Expression and polarized target-
28. Noiri E, Romanov V, Forest T, et al.: Pathophysiology of renal tubu- ing of a Rab3 isoform in epithelial cells. J Cell Biol 1994,
lar obstruction: Therapeutic role of synthetic RGD peptides in acute 125:583–594.
renal failure. Kidney Int 1995, 48:1375–1385. 51. Zahraoui A, Joberty G, Arpin M, et al.: A small rab GTPase is dis-
29. Rahman SN, Butt AR, DuBose TD, et al.: Differential clinical effects tributed in cytoplasmic vesicles in non-polarized cells but colocalizes
of anaritide atrial natiuretic peptide (ANP) in oliguric and non-olig- with the tight junction marker ZO-1 in polarized epithelial cells. J
uric ATN. J Am Soc Nephrol 1995, 6:474. Cell Biol 1994, 124:101–115.
30. Franklin S, Moulton M, Hammerman MR, Miller SB: Sustained 52. Citi S, Denisenko N: Phosphorylation of the tight junction protein
improvement of renal function and amelioration of symptoms in cingulin and the effects of protein kinase inhibitors and activators in
patients with chronic renal failure (CRF) treated with insulin-like MDCK epithelial cells. J Cell Sci 1995, 108:2917–2926.
growth factor I (IGF-I). J Am Soc Nephrol 1995, 6:387. 53. Nilsson M, Fagman H, Ericson LE: Ca2+-dependent and Ca2+-inde-
31. Farquhar M, Palade GE: Junctional complexes in various epithelia. J pendent regulation of the thyroid epithelial junction complex by pro-
Cell Biol 1963, 17:375–412. tein kinases. Exp Cell Res 1996, 225:1–11.
32. Anderson JM, Itallie CMV: Tight junctions and the molecular basis 54. Braakman I, Helenius J, Helenius A: Role of ATP and disulphide
for regulation of paracellular permeability. Am J Physiol 1995, bonds during protein folding in the endoplasmic reticulum. Nature
269:G467–G475. 1992, 356:260–262.
33. Citi S, Sabanay H, Jakes R, et al.: Cingulin, a new peripheral compo- 55. Bush KT, Hendrickson BA, Nigam SK: Induction of the FK506–bind-
nent of tight junctions. Nature 1988, 333:272–276. ing protein, FKBP13, under conditions which misfold proteins in the
34. Zhong Y, Saitoh T, Minase T, et al.: Monoclonal antibody 7H6 reacts endoplasmic reticulum. Biochem J 1994, 303:705–708.
with a novel tight junction–associated protein distinct from ZO-1, 56. Kuznetsov G, Chen LB, Nigam SK: Several endoplasmic reticulum
cingulin and ZO-2. J Cell Biol 1993, 120:477–483. stress proteins, including ERp72, interact with thyroglobulin during
35. Furuse M, Hirose T, Itoh M, et al.: Occludin: A novel integral mem- its matulation. J Biol Chem 1994, 269:22990–22995.
brane protein localizing at tight junctions. J Cell Biol 1993, 57. Nigam SK, Goldberg AL, Ho S, et al.: A set of ER proteins with prop-
123:1777–1788. erties of molecular chaperones includes calcium binding proteins and
36. Jesaitis LA, Goodenough DA: Molecular characterization and tissue members of the thioredoxin superfamily. J Biol Chem 1994,
distribution of ZO-2, a tight junction protein homologous to ZO-1 269:1744–1749.
and Drosophila discs–large tumor suppressor protein. J Cell Biol 58. Knittler MR, Haas IG: Interaction of BIP with newly synthesized
1994, 124:949–961. immunoglobulin light chain molecules: cycles of sequential binding
37. Balda MS, Gonzalez-Mariscal L, Matter K, et al.: Assembly of the and release. EMBO J 1992, 11:1573–1581.
tight junction: The role of diacylglycerol. J Cell Biol 1993,
59. Pelham H: Speculations on the functions of the major heat shock and
123:293–302.
glucose regulated proteins. Cell 1986, 46:959–961.
38. Furuse M, Itoh M, Hirase T, et al.: Direct association of occludin with
60. Pelham HR: Heat shock and the sorting of luminal ER proteins.
ZO-1 and its possible involvement in the localization of occludin at
Embo J 1989, 8:3171–3176.
tight junctions. J Cell Biol 1994, 127:1617–1626.
61. Ellis R, Van Der Vies S: Molecular chaperones. Annu Rev Biochem
39. Balda M, Whitney J, Flores C, et al.: Functional dissociation of para-
cellular permeability and transepithelial resistance and disruption of 1991, 60:321–347.
the apical-basolateral intramembrane diffusion barrier by expression 62. Fra A, Sitia R: The endoplasmic reticulum as a site of protein degra-
of a mutant tight junction protein. J Cell Biol 1996, 134:1031–1049. dation. Subcell Biochem 1993, 21:143–168.
40. Citi S, Sabanay H, Kendrick-Jones J, Geiger B: Cingulin: 63. Hwang C, Sinskey A, Lodish H: Oxidized redox state of glutathione
Characterization and localization. J Cell Sci 1989, 93:107–122. in the endoplasmic reticulum. Science 1992, 257:1496–1502.
41. Keon BH, Schafer S, Kuhn C, et al.: Symplekin, a novel type of tight 64. Gaut J, Hendershot L: The modification and assembly of proteins in
junction plaque protein. J Cell Biol 1996, 134:1003–1018. the endoplasmic reticulum. Curr Opin Cell Biol 1993, 5:589–595.
42. Canfield PE, Geerdes AM, Molitoris BA: Effect of reversible ATP 65. Bole DG, Hendershot LM, Kearny JF: Posttranslational association of
depletion on tight-junction integrity in LLC-PK1 cells. Am J Physiol immunoglobulin heavy chain binding protein with nascent heavy
1991, 261:F1038–F1045. chains in nonsecreting and secreting hybridomas. J Cell Biol 1986,
43. Rodriguez-Boulan E, Nelson WJ: Morphogenesis of the polarized 102:1558–1566.
epithelial cell phenotype. Science 1989, 245:718–725. 66. Gething MJ, McCammon K, Sambrook J: Expression of wild-type
44. Balda MS, Gonzalez-Mariscal L, Contreras RG, et al.: Assembly and and mutant forms of influenza hemagglutinin: The role of folding in
sealing of tight junctions: Possible participation of G-proteins, phos- intracellular transport. Cell 1986, 46:939–950.
pholipase C, protein kinase C and calmodulin. J Membrane Biol 67. Dorner AJ, Bole DG, Kaufman RJ: The relationship of N-linked gly-
1991, 122:193–202. cosylation and heavy chain–binding protein association with the secre-
45. de Almeida JB, Holtzman EJ, Peters P, et al.: Targeting of chimeric G- tion of glycoproteins. J Cell Biol 1987, 105:2665–2674.
alpha-i proteins to specific membrane domains. J Cell Sci 1994, 68. Ng DT, Randall RE, Lamb RA: Intracellular maturation and transport
107:507–515. of the SV5 type II glycoprotein hemagglutinin-neuraminidase: Specific
46. Dodane V, Kachar B: Identification of isoforms of G proteins and and transient association with GRP78-BiP in the endoplasmic reticu-
PKC that colocalize with tight junctions. J Membrane Biol 1996, lum and extensive internalization from the cell surface. J Cell Biol
149:199–209. 1989, 109:3273–3289.
69. Rothman JE: Polypeptide chain binding proteins: catalysts of protein 93. Sakurai H, Nigam SK: TGF- selectively inhibits branching morpho-
folding and related processes in cells. Cell 1989, 59:591–601. genesis but not tubulogenesis. Am J Physiol 1997, 272:F139–F146.
70. Blount P, Merlie JP: BIP associates with newly synthesized subunits of 94. Sakurai H, Barros EJ, Tsukamoto T, et al.: An in vitro tubulogenesis
the mouse muscle nicotinic receptor. J Cell Biol 1991, system using cell lines derived from the embryonic kidney shows
113:1125–1132. dependence on multiple soluble growth factors. Proc Natl Acad Sci
71. Melnick J, Aviel S, Argon Y: The endoplasmic reticulum stress protein USA 1997, 94:6279–6284.
GRP94, in addition to BiP, associates with unassembled immunoglob- 95. Barasch J, Pressler L, Connor J, Malik A: A ureteric bud cell line
ulin chains. J Biol Chem 1992, 267:21303–21306. induces nephrogenesis in two steps by two distinct signals. Am J
72. Pind S, Riordan J, Williams D: Participation of the endoplasmic retic- Physiol 1996, 271:F50–F61.
ulum chaperone calnexin (p88, IP90) in the biogenesis of the cystic 96. Weidner K, Di Cesare S, Sachs M, et al.: Interaction between Gab1
fibrosis transmembrane conductance regulator. J Biol Chem 1994, and the c-Met receptor tyrosine kinase is responsible for epithelial
269:12784–12788. morphogenesis. Nature 1996, 384:173–176.
73. Kuznetsov G, Chen L, Nigam S: Multiple molecular chaperones com- 97. Igawa T, Matsumoto K, Kanda S, et al.: Hepatocyte growth factor
plex with misfolded large oligomeric glycoproteins in the endoplasmic may function as a renotropic factor for regeneration in rats with acute
reticulum. J Biol Chem 1997, 272:3057–3063. renal injury. Am J Physiol 1993, 265:F61–F69.
74. Saxen L: Organogenesis of the Kidney. Cambridge: Cambridge 98. Schaudies RP, Johnson JP: Increased soluble EGF after ischemia is
University Press; 1987. accompanied by a decrease in membrane-associated precursors.
75. Brenner BM: Determinants of epithelial differentiation during early Am J Physiol 1993, 264:F523–F531.
nephrogenesis. J Am Soc Nephrol 1990, 1:127–139. 99. Salido EC, Lakshmanan J, Fisher DA, et al.: Expression of epidermal
76. Nigam SK, Aperia A, Brenner BM: Development and maturation of growth factor in the rat kidney. An immunocytochemical and in situ
the kidney. In The Kidney. Edited by Brenner BM. Philadelphia: WB hybridization study. Histochemistry 1991, 96:65–72.
Saunders; 1996. 100.Homma T, Sakai M, Cheng HF, et al.: Induction of heparin-binding
77. Montesano R, Schaller G, Orci L: Induction of epithelial tubular mor- epidermal growth factor-like growth factor mRNA in rat kidney after
phogenesis in vitro by fibroblast-derived soluble factors. Cell 1991, acute injury. J Clin Invest 1995, 96:1018–1025.
66:697–711.
101.Metejka GL, Jennische E: IGF-I binding and IGF-I mRNA expression
78. Montesano R, Matsumoto K, Nakamura T, Orci L: Identification of a in the post-ischemic regenerating rat kidney. Kidney Int 1992,
fibroblast-derived epithelial morphogen as hepatocyte growth factor. 42:1113–1123.
Cell 1991, 67:901–908.
102.Ichimura T, Finch PW, Zhang G, et al.: Induction of FGF-7 after
79. Santos OFP, Nigam SK: HGF-induced tubulogenesis and branching of kidney damage: a possible paracrine mechanism for tubule repair.
epithelial cells is modulated by extracellular matrix and TGF-. Dev Am J Physiol 1996, 271:F967–F976.
Biol 1993, 160:293–302.
103.Kawaida K, Matsumoto K, Shimazu H, Nakamura T: Hepatocyte
80. Stuart RO, Barros EJG, Ribeiro E, Nigam SK: Epithelial tubulogenesis growth factor prevents acute renal failure and accelerates renal
through branching morphogenesis: Relevance to collecting system regeneration in mice. Proc Natl Acad Sci USA 1994, 91:4357–4361.
development. J Am Soc Nephrol 1995, 6:1151–1159.
104.Humes HD, Cielski DA, Coimbra T, et al.: Epidermal growth factor
81. Stuart RO, Nigam SK: Development of the tubular nephron. Semin enhances renal tubule cell regeneration and repair and accelerates the
Nephrol 1995, 15:315–326. recovery of renal function in postischemic acute renal failure. J Clin
82. Sakurai H, Nigam SK: In vitro branching tubulogenesis: Implications Invest 1989, 84:1757–1761.
for developmental and cystic disorders, nephron number, renal repair 105.Coimbra T, Cielinski DA, Humes HD: Epidermal growth factor accel-
and nephron engineering. Kidney Int 1998, 54:14–26.
erates renal repair in mercuric chloride nephrotoxicity. Am J Physiol
83. Matsumoto K, Nakamura T: Emerging multipotent aspects of hepato- 1990, 259:F438–F443.
cyte growth factor. J Biochem 1996, 119:591–600.
106.Reiss R, Cielinski DA, Humes HD: Kidney Int 1990, 37:1515–1521.
84. Cantley LG, Barros EJG, Gandhi M, et al.: Regulation of mitogenesis,
107.Miller SB, Martin DR, Kissane J, Hammerman MR: Insulin-like
motogenesis, and tubulogenesis by hepatocyte growth factor in renal
growth factor I accelerates recovery from ischemic acute tubular
collecting duct cells. Am J Phisiol 1994, 267:F271–F280.
necrosis in the rat. Proc Natl Acad Sci USA 1992, 89:11876–11880.
85. Perantoni AO, Williams CL, Lewellyn AL: Growth and branching
morphogenesis of rat collecting duct anlagen in the absence of 108.Rabkin R, Sorenson A, Mortensen D, Clark R: J Am Soc Nephrol
metanephric mesenchyme. Differentiation 1991, 48:107–113. 1992, 3:713.
86. Santos OF, Barros EJ, Yang X-M, et al.: Involvement of hepatocyte 109.Montesano R, Schaller G, Orci L: Induction of epithelial tubular
growth factor in kidney development. Dev Biol 1994, 163:525–529. morphogenesis in vitro by fibroblast-derived soluable factors.
Cell 1991, 66:697–711.
87. Barros EJG, Santos OF, Matsumoto K, et al.: Differential tubulogenic
and branching morphogenetic activities of growth factors: 110.Santos OFP, Nigam SK: Modulation of HGF-induced tubulogenesis
Implications for epithelial tissue development. Proc Natl Acad Sci and branching by multiple phosphorylation mechanisms. Dev Biol
USA 1995, 92:4412–4416. 1993, 159:535–548.
88. Rogers S, Ryan G, Hammerman MR: Insulin-like growth factors I 111.Sakurai H, Tsukamoto T, Kjelsberg CA, et al.: EGF receptor ligands
and II are produced in metanephros and are required for growth and are a large fraction of in vitro branching morphogens secreted by
development in vitro. J Cell Biol 1991, 113:1447–1453. embryonic kidney. Am J Physiol 1997, 273:F463–F472.
89. Rogers SA, Ryan G, Hammerman MR: Metanephric transforming 112.Sakurai H, Barros EJG, Tsukamoto T, et al.: An in vitro tubulogenesis
growth factor alpha is required for renal organogenesis in vitro. Am J system using cell lines derived from the embrionic kidney shows
Physiol 1992, 262:F533–F539. dependence on multiple soluble growth factors. Proc Natl Acad Sci
USA 1997, 94:6297–6284.
90. Liu Z, Wada J, Alvares K, et al.: Distribution and relevance of insulin-
like growth factor I receptor in metanephric development. Kidney Int 113.Rogers SA, Ryan G, Hammerman MR: Cell Biol 113:1447–1453.
1993, 44:1242–1250. 114.Vega QC, Worby CA, Lechner MS, et al.: Glial cell line-derived
91. Liu J, Baker J, Perkins A, et al.: Mice carrying null mutations of the neurotrophic factor activates the receptor tyrosine kinase RET and
genes encoding insulin-like growth factor I (IGF-1) and type I IGF promotes kidney morphogenesis. Proc Natl Acad Sci USA 1996,
receptor (IGF1R). Cell 1993, 75:59–72. 93:10657–10661.
92. Sakurai H, Tsukamoto T, Kjelsberg C, et al.: EGF receptor ligands are 115.Sakurai H, Nigam SK: Transforming growth factor-beta selectively
a large fraction of in vitro branching morphogens secreted by embry- inhibits branching morphogenesis but not tubulogenesis. Am J Physiol
onic kidney. Am J Physiol 1997, 273:F463–F472. 1997, 272:F139–F146.
Molecular Responses
and Growth Factors
Steven B. Miller
Babu J. Padanilam
T
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 thera-
pies 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 mol-
ecular 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 molec-
ular basis that regulates this process is poorly-understood. After an CHAPTER
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
17
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 prolifer-
ate to reepithelialize the damaged nephron segments. Thus, several
different processes are required to achieve structural and func- and 3) some damaged cells may actually die—not as a result of
tional integrity of the kidney after a toxic or ischemic insult: the initial insult but through a process of programmed cell death
1) uninjured cells must proliferate and reepithelialize damaged known as apoptosis. Figure 17-1 provides a schematic represen-
nephron segments; 2) nonlethally damaged cells must recover; tation of the renal response to an ischemic or toxic injury.
Subcellular Cellular Nephron/Kidney

Plasma
Cytosol Organelles membrane 1
1 Growth factors Cell
Noninjured
cells proliferation
Brush
ER blebbing border Dysfunction ± Reepithelialization
Insult ↓ATP Nonlethally
1
Mitochondrial sloughing of nephron
↑Ca2+ injured cells
morphological
switching changes
Loss of
membrane
protein 2 2 Recovery of
orientation Cellular
Cell death nephron structure
recovery
and function
FIGURE 17-1
Schematic representation of some of the events pursuant to a stimulating cells to undergo mitosis. Nonlethally injured cells
renal insult and epithelial cell repair. Subcellular; Initial events have the potential to follow one of two pathways. In the appro-
include a decrease in cellular ATP and an increase in intracellu- priate setting, perhaps stimulated by growth factors, these cells
lar free calcium. There is blebbing of the endoplasmic reticulum may recover with restoration of cellular integrity and function
with mitochondrial swelling and dysfunction. The brush border (Pathway 2); however, if the injury is significant the cell may still
of the proximal tubules is sloughed into the tubule lumen, and die, but through a process of programmed cell death or apopto-
there is redistribution of membrane proteins with the loss of cel- sis. The third population of cells are those with severe injury
lular polarity. Cellular; At a cellular level this results in three that undergo necrotic cell death. Nephron/Kidney; With the
populations of tubule cells, depending on the severity of the reepithelialization of damaged nephron segments and cellular
insult. Some cells are intact and are poised to participate in the recovery of structural and functional integrity, renal function is
proliferative process (Pathway 1). Growth factors participate by 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 fac-
tors may be 1) produced by the tubule epithelium itself and act
locally in an autocrine, juxtacrine or paracrine manner; 2) pro-
duced 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
Basement membrane 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
GROWTH FACTORS IN ACUTE RENAL FAILURE 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
EGF HGF
have efficacy in ischemia models and in a variety of toxic models
Ischemic and toxic Ischemic and toxic
of ARF. In addition, both IGF-I and HGF are beneficial when ther-
Established ARF
IGF-I apy is delayed and ARF is “established” after an ischemic insult.
Ischemic and toxic IGF-I has the additional advantage in that it also ameliorates the
Pretreatment and established ARF course of renal failure when given prophylactically before an acute
ischemic insult.
ARF—acute renal failure; EGF—epidermal growth factor; HGF—hepatocyte growth
factor; IGF-I—insulin-like growth factor.
FIGURE 17-4
Prepro-EGF DCT
Expression of messenger RNA (mRNA) for prepro–epidermal
mRNA
growth factor (EGF) in kidney. This schematic depicts the localiza-
tion of mRNA for prepro-EGF under basal states in kidney.
PCT Prepro-EGF mRNA is localized to the medullary thick ascending
limbs (MTAL) and distal convoluted tubules (DCT).
Immunohistochemical studies demonstrate that under basal condi-
tions the peptide is located on the luminal membrane with the
CTAL
active peptide actually residing within the tubule lumen. It is specu-
lated that, during pathologic states, preformed EGF is either trans-
ported or routed to the basolateral membrane or can enter the
interstitium via backleak. After a toxic or ischemic insult, expres-
sion of EGF is rapidly suppressed and can remain low for a long
time. Likewise, total renal content and renal excretion of EGF
OMCD decreases. CTAL—cortical thick ascending limb; IMCD—inner
MTAL medullary collecting duct; OMCD—outer medullary collecting
duct; and PCT—proximal convoluted tubule.
IMCD
FIGURE 17-5
GROWTH FACTOR PRODUCTION Production of epidermal growth factor (EGF), insulin-like growth
factor (IGF-I), and hepatocyte growth factor (HGF) by various tis-
sues. EGF, IGF-I, and HGF have all been demonstrated to improve
outcomes in various animal models of acute renal failure (ARF).
EGF IGF-I
All three growth-promoting factors are produced in the kidneys
Submandibular salivary glands Liver
and in a variety of other organs. The local production is probably
Kidney Lung
most important for recovery from an acute renal insult. The influ-
Others Kidney
ence of production in other organs in the setting of ARF has yet to
HGF Heart be determined. This chapter deals primarily with local production
Liver Muscle and actions of EGF, IGF-I, and HGF.
Spleen Other organs
Kidney
Lung
Other organs
FIGURE 17-6
EGF-receptor DCT
Receptor binding for epidermal growth factor (EGF). EGF binding
binding
in kidney under basal conditions is extensive. The most significant
specific binding occurs in the proximal convoluted (PCT) and
PCT 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
CTAL
EGF system may be responsible for the beneficial effect of exoge-
nously administered EGF is the setting of acute renal failure.
GLOM CTAL—cortical thick ascending loop.
OMCD
MTAL
IMCD
DAG activates protein kinase C; IP3 raises

the intracellular calcium (Ca2+) levels by
EGF
inducing its release from intracellular
stores. Ca2+ is involved in the activation of
the calmodulin-dependent CAM-kinase,
P P which is a serine/threonine kinase.
P P A more important signal transduction
pathway activated by PTKs concerns the
ras pathway. The ras cycle is connected to
GAP activated receptors via the adapter protein
PKC PI3K SHC Grb2 and the guanosine diphosphate-
guanosine triphosphate exchange factor Sos
PLCγ Grb2 SOS
PIP
(son of sevenless). GDP-ras, upon phospho-
PI-3,4 P2 rylation, is converted to its activated form,
DAG + IP3 PIP2 GTP-ras. The activated ras activates anoth-
Ras- er Ser/Thr kinase called raf-1, which in turn
Signal GDP Ras-
Ca2+ transduction GTP activates another kinase, the mitogen acti-
vated protein kinase kinase (MAPKK).
MAPKK activates the serine/threonine
CamK RAF kinases, and extracellular signal-regulated
kinases Erk1 and 2. Activation of Erk1/2
MAPKK leads to translocation into the nucleus,
where it phosphorylates key transcription
ERK1/ ERK2
factors such as Elk-1, and c-myc.
Gene transcription Phosphorylated Elk-1 associates with serum
response factor (SRF) and activates tran-
Growth differentiation scription of c-fos. The protein products of
c-fos and c-jun function cooperatively as
components of the mammalian transcrip-
FIGURE 17-7 tion factor AP-1. AP-1 binds to specific
Epidermal growth factor (EGF)–mediated signal transduction pathways. The EGF receptor DNA sequences in putative promoter
triggers the phospholipase C-gamma (PLC-gamma), phosphatidylinositol-3 kinase (PI3K), sequences of target genes and regulates gene
and mitogen-activated protein kinase (MAPK) signal transduction pathways described in transcription. Similarly, c-myc forms a het-
the text that follows. erodimer with another immediate early
Growth factors exert their downstream effects through their plasma membrane–bound gene max and regulates transcription.
protein tyrosine kinase (PTK) receptors. All known PTK receptors are found to have four The expression of c-fos, c-jun, and Egr-1 is
major domains: 1) a glycosylated extracellular ligand-binding domain; 2) a transmembrane found to be upregulated after ischemic renal
domain that anchors the receptor to the plasma membrane; 3) an intracellular tyrosine injury. Immunohistochemical analysis showed
kinase domain; and 4) regulatory domains for the PTK activity. Upon ligand binding, the the spatial expression of c-fos and Egr-1 to be
receptors dimerize and autophosphorylate, which leads to a cascade of intracellular events in thick ascending limbs, where cells are
resulting in cellular proliferation, differentiation, and survival. undergoing minimal proliferation as com-
The tyrosine phosphorylated residues in the cytoplasmic domain of PTK are of utmost pared with the S3 segments of the proximal
importance for its interactions with cytoplasmic proteins involved in EGF–mediated signal tubules. This may suggest that the expression
transduction pathways. The interactions of cytoplasmic proteins are governed by specific of immediate early genes after ischemic injury
domains termed Src homology type 2 (SH2) and type 3 (SH3) domains. The SH2 domain is not associated with cell proliferation.
is a conserved 100–amino acid sequence initially characterized in the PTK-Src and binds to Several mechanisms control the specificity
tyrosine phosphorylated motifs in proteins; the SH3 domain binds to their targets through of RTK signaling: 1) the specific ligand-
proline-rich sequences. SH2 domains have been found in a multitude of signal transducers receptor interaction; 2) the repertoire of
and docking proteins such as growth factor receptor–bound protein 2 (Grb2), phophatidy- substrates and signaling molecules associat-
linositol-3 kinase (p85-PI3K), phospholipase C-gamma (PLC-gamma), guanosine triphos- ed with the activated RTK; 3) the existence
phatase (GTPase)–activating protein of ras (ras-GAP), and signal transducer and activator of tissue-specific signaling molecules; and 4)
of transcription 3 (STAT-3). the apparent strength and persistence of the
Upon ligand binding and phosphorylation of PTKs, SH2–domain containing proteins biochemical signal. Interplay of these fac-
interact with the receptor kinase domain. PLC-gamma on interaction with the PTK, tors can determine whether a given ligand-
becomes phosphorylated and catalyzes the turnover of phosphatidylinositol (PIP2) to receptor interaction lead to events such as
two other second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG). growth, differentiation, scatter or survival.
IGF-1 DCT IGF-receptor DCT

mRNA binding
PCT PCT
CTAL CTAL
GLOM GLOM
OMCD OMCD
MTAL MTAL
IMCD IMCD

Expression of mRNA for insulin-like growth factor I (IGF-I). Receptor binding for insulin-like growth factor I (IGF-I).
Under basal conditions, a variety of nephron segments can produce IGF-I binding sites are conspicuous throughout the normal
IGF-I. Glomeruli (GLOM), medullary and cortical thick ascending kidney. Binding is higher in the structures of the inner medulla
limbs (MTAL/CTAL), and collecting ducts (OMCD, IMCD) are all than in the cortex. After an acute ischemic insult, there is a
reported to produce IGF-I. Within hours of an acute ischemic renal marked increase in IGF-I binding throughout the kidney. The
insult, the expression of IGF-I decreases; however, 2 to 3 days after increase appears to be greatest in the regenerative zones, which
the insult, when there is intense regeneration, there is an increase in include structures of the cortex and outer medulla. These find-
the expression of IGF-I in the regenerative cells. In addition, ings suggest an important trophic effect of IGF-I in the setting
extratubule cells, predominantly macrophages, express IGF-I in the of acute renal injury. CTAL/MTAL—cortical/medullary thick
regenerative period. This suggests that IGF-I works by both ascending loop; DCT/PCT—distal/proximal convoluted tubule;
autocrine and paracrine mechanisms during the regenerative GLOM—glomerulus; OMCD/IMCD—outer/inner medullary col-
process. DCT/PCT—distal/proximal convoluted tubule. lecting duct.
FIGURE 17-10
Diagram of intracellular signaling pathways
IGF-I
mediated by the insulin-like growth factor I
IGF-IR (IGF-IR) receptor. IGF-IR when bound to
IGF-I undergoes autophosphorylation on its
tyrosine residues. This enhances its intrinsic
Other tyrosine kinase activity and phosphorylates
substrates multiple substrates, including insulin recep-
SHC tor substrate 1 (IRS-1), IRS-2, and Src
homology/collagen (SHC). IRS-1 upon
Grb2
phosphorylation associates with the p85
SOS P110 subunit of the PI3-kinase (PI3K) and phos-
p85 phorylates PI3-kinase. PI3K upon phospho-
Crk II PI3-kinase rylation converts phosphoinositide-3 phos-
signaling
IRS-1/IRS-2 phate (PI-3P) into PI-3,4-P2, which in turn
activates a serine-thronine kinase Akt (pro-
C3G Akt tein kinase B). Activated Akt kinase phos-
SYP phorylates the proapoptotic factor Bad on a
Grb2 nck BAD
serine residue, resulting in its dissociation
SOS Cell survival from B-cell lymphoma-X (Bcl-XL) . The
Phosphotyrosine
released Bcl-XL is then capable of suppress-
Ras dephosphorylation ing cell death pathways that involve the
Growth,
activity of apoptosis protease activating fac-
differentiation tor (Apaf-1), cytochrome C, and caspases.
A number of growth factors, including
Raf-1 platelet-derived growth factor (PDGF) and
MEKs
S6-kinase IGF 1 promotes cell survival. Activation of
the PI3K cascade is one of the mechanisms
Gene by which growth factors mediate cell sur-
ERKs expression
TF vival. Phosphorylated IRS-1 also associates
with growth factor receptor bound protein
EGF-R 2 (Grb2), which bind son of sevenless (Sos)
MBP
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 sub-
strates for IGF-I are phosphotyrosine phos-
phatases and SH2 domain containing tyro-
sine phosphatase (Syp). Figure 17-7 has
details on the other signaling pathways in
this figure. MBP—myelin basic protein;
nck—an adaptor protein composed of SH2
and SH3 domains; TF—transcription factor.
FIGURE 17-11
HGF mRNA DCT
Expression of hepatocyte growth factor (HGF) mRNA and HGF
HGF receptor
mRNA receptor mRNA in kidney. While the liver is the major source of
circulating HGF, the kidney also produces this growth-promoting
PCT peptide. Experiments utilizing in situ hybridization, immunohisto-
chemistry, and reverse transcription–polymerase chain reaction
(RT-PCR) have demonstrated HGF production by interstitial cells
but not by any nephron segment. Presumably, these interstitial
CTAL
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, partic-
ipating in regeneration via a paracrine mechanism; however, its
OMCD expression is also rapidly induced in spleen and lung in animal
MTAL
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,
IMCD 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.
FIGURE 17-12
Pro-HGF
convertase Model of hepatocyte growth factor
Membrane bound Mature (HGF)/c-met signal transduction. In the
Pro-HGF HGF extracellular space, single-chain precursors
Matrix soluble of HGF bound to the proteoglycans at the
pro-HGF
cell surface are converted to the active form
by urokinase plasminogen activator (uPA),
uPa HGFR
Extracellular while the matrix soluble precursor is
processed by a serum derived pro-HGF
convertase. HGF, upon binding to its recep-
tor c-met, induces its dimerization as well
Cytosol as autophosphorylation of tyrosine
GTP-γas Urokinase S S Antiapoptosis residues. The phosphorylated residue binds
Raf-1 receptor BAG-1
Y
to various adaptors and signal transducers
Y PIP2
Y Y such as growth factor receptor bound pro-
SHC PLC-γ tein-2 (Grb2), p85-PI3 kinase, phospholi-
PKC λ, β, γ
DAG activation
P
pase C-gamma (PLC-gamma), signal trans-
P P Y Y
mSos1 IP3 ducer and activator of transcription-3
Grb2
(STAT-3) and Src homology/collagen (SHC)
P Y Y P via Src homology 2 (SH2) domains and
Gab 1 triggers various signal transduction path-
p85 ways. A common theme among tyrosine
MAP kinases C-SγC PI3K kinase receptors is that phosphorylation of
kinases (MEK S) STAT3 different specific tyrosine residues deter-
mines which intracellular transducer will
bind the receptor and be activated. In the
case of HGF receptor, phosphorylation of a
Focal single multifunctional site triggers a
MAP kinases adhesion
TF
Scatter pleiotropic response involving multiple sig-
(ERK5)
SRE nal transducers. The synchronous activation
of several signaling pathways is essential to
TF conferring the distinct invasive growth abil-
Nuclear
membrane ity of the HGF receptor. HGF functions as
Growth
a scattering (dissociation/motility) factor for
TF
epithelial cells, and this ability seems to be
Transcription
mediated through the activation of STAT-3.
Gene
Phosphorylation of adhesion complex
regulatory proteins such as ZO-1, beta-
catenin, 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 associ-
ation independent from tyrosine residues.
FIGURE 17-13
DETERMINANT MECHANISMS FOR Mechanisms by which growth factors may possibly alter outcomes
OUTCOMES OF ACUTE RENAL FAILURE 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 set-
ting of experimental ARF. While the results are the same, the
Mitogenic Anabolic
respective mechanisms of actions of each of these growth factors
Morphogenic Alter leukocyte function
are probably quite different. Many investigators have examined
Cell migration Alter inflammatory process
individual growth factors for a variety of properties that may be
Hemodynamic Apoptosis
beneficial in the setting of ARF. This table lists several of the prop-
Cytoprotective Others erties examined to date. Suffice it to say that the mechanisms by
which the individual growth factors alter the course of experimen-
tal ARF is still unknown.
acute renal insult there is an initial decrease in both insulin-like

growth factor (IGF-I) peptide and mRNA, which recovers over sev-
ACTIONS OF GROWTH FACTORS
eral days but only after the regenerative process is under way. The
IN ACUTE RENAL FAILURE
pattern with epidermal growth factor (EGF) is different in that a
transient increase in available mature peptide from cleavage of pre-
formed EGF is followed by a pronounced and prolonged decrease in
Actions IGF-I EGF ↓↓ both peptide and message. Both peptide and message for hepatocyte
Protein ↓/↑ ↑/↓ growth factor (HGF) are transiently increased in kidney after a toxic
mRNA ↓/↑ ↓ or an ischemic insult. The receptors for all three growth factors are
↑
increased after injury, which may be crucial to the response to exoge-
Receptiors ↑
nous administration.
Vascular ↑ ↓
The mechanism by which the different growth factors act in the set-
Anabolic ↑ ←→
ting of acute renal injury is quite variable. IGF-I is known to increase
Mitogenic ↑ ↑↑↑ renal blood flow and glomerular filtration rate in both normal ani-
Apoptosis ↓ mals 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
FIGURE 17-14 parameters. Finally, both EGF and HGF are potent mitogens for renal
Selected actions of growth factors in the setting of acute renal failure proximal tubule cells, the nephron segment is most often damaged by
(ARF). After an acute renal injury, a spectrum of molecular respons- ischemic acute renal injury, whereas IGF-I is only a modest mitogen.
es occur involving the local expression of growth factors and their Likewise, both EGF and HGF appear to be more effective than IGF-I
receptors. In addition, there is considerable variation in the mecha- at inhibiting apoptosis in the setting of acute renal injury, but it is not
nisms by which the growth factors are beneficial for ARF. After an clear whether this is an advantage or a disadvantage.
Clinical Use of Growth Factors in Acute Renal Failure
+Vehicle
HGF +IGF-I *
4
↑ *
Serum creatinine, mg/dL
↑ *
↑ *
2
←→
*
←→ *
↑↑↑
0
0 2 4 6
Time after ischemia, d
FIGURE 17-15
Rationale for the use of insulin-like growth factor IGF-I in the set-
ting of acute renal failure (ARF). Of the growth factors that have FIGURE 17-16
been demonstrated to improve outcomes after acute renal injury, Serial serum creatinine values in rats with ischemic acute renal failure
the most progress has been made with IGF-I. From this table, it is (ARF) treated with insulin-like growth factor (IGF-I) or vehicle. This is
evident that IGF-I has a broad spectrum of activities, which makes the original animal experiment that demonstrated a benefit from IGF-I
it a logical choice for treatment of ARF. An agent that increased in the setting of ARF. In this study, IGF-I was administered beginning
renal plasma flow and glomerular filtration rate and was mito- 30 minutes after the ischemic insult (arrow). Data are expressed as
genic for proximal tubule cells and anabolic would address several mean ± standard error. Significant differences between groups are indi-
features of ARF. cated 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.)
FIGURE 17-17
280
+ Vehicle Body weights of rats with ischemic acute renal failure (ARF) treat-
+ IGF-I ed with insulin-like growth factor (IGF-I) or vehicle. Unlike epider-
* mal growth factor or hepatocyte growth factor (HGF), IGF-I is
*
anabolic even in the setting of acute renal injury. These data are
* *
Body weight, g
from the experiment described in Figure 17-16. As the data in this

220
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 aster-
isks. (From Miller et al. [2]; with permission.)
160
0 2 4 6
Time after ischemia, d
A B
FIGURE 17-18
Photomicrograph of kidneys from rats with acute renal failure cations, and papillary proliferations the tubule lumen of proxi-
(ARF) treated with insulin-like growth factor (IGF-I) or vehicle. mal tubules. The kidney obtained from the IGF-I–treated rat (B)
These photomicrographs are of histologic sections stained with appears almost normal, showing evidence of regeneration and
hematoxylin and eosin originating from kidneys of rats that restoration of normal renal architecture. In this experiment the
received vehicle or IGF 1 after ischemic renal injury. Kidneys histologic appearance of kidneys from the IGF-I–treated animals
were obtained 7 days after the insult. There is evidence of con- was statistically better than that of the vehicle-treated controls,
siderable residual injury in the kidney from the vehicle-treated as determined by a pathologist blinded to therapy. (From Miller
rat (A): dilation and simplification of tubules, interstitial calcifi- et al. [2]; with permission.)
over- and underexpression of IGF-I, this is the first growth fac-

tor 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.
RATIONALE FOR INSULIN-LIKE GROWTH In the area of acute renal failure there are now two reported tri-
FACTOR I (IGF-I) IN ACUTE RENAL FAILURE als 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 dysfunc-
tion, defined as a reduction of the glomerular filtration rate as
compared with a preoperative baseline, at each of three measure-
ments 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
FIGURE 17-19 impractical to perform a single center trial with enough power to
Reported therapeutic trials of insulin-like growth factor (IGF-I) obtain differences in clinically important end-points. Thus, this
in humans. Based on the compelling animal data and the fact trial was intended only to offer “proof of concept” that IGF-I is
that there are clearly identified disease states involving both useful for patients with acute renal injuries.
35 *P<0.05 Chi square Receptors are present on proximal tubules

Renal dysfunction, %
30 Regulates proximal tubule metabolism and transport

25 *
20
15 Increases renal plasma flow and glomerular filtration rates
10 Mitogenic for proximal tubule cells
5 Enhanced expression after acute renal injury
0 Anabolic
Placebo IGF-I
Treatment groups
THERAPEUTIC TRIALS OF INSULIN-LIKE
GROWTH FACTOR I IN HUMANS
FIGURE 17-20
Incidence of postoperative renal dysfunction treated with insulin
(IGF-I) or placebo. IGF-I significantly reduced the incidence of post- FIGURE 17-21
operative renal dysfunction in these high-risk patients. Renal dys- Summary of an abstract describing the trial of insulin-like growth
function occurred in 33% of those who received placebo but in only factor (IGF-I) in the treatment of patients with established acute
22% of patients treated with IGF-I. The groups were well-matched renal failure (ARF). Based on the accumulated animal and human
with respect to age, sex, type of operation, ischemia time, and base- data, a multicenter, double-blind, randomized, placebo-controlled
line renal function as defined by serum creatinine or glomerular fil- trial was performed to examine the effects of IGF-I in patients with
tration rate. The IGF-I was tolerated well: no side effects were established ARF. Enrolled patients had ARF of a wide variety of
attributed to the drug. Secondary end-points such as discharge, causes, including surgery, trauma, hypertension, sepsis, and nephro-
serum creatinine, length of hospitalization, length of stay in the toxic injury. Approximately 75 patients were enrolled, treatment
intensive care unit, or duration of intubation were not significantly being initiated within 6 days of the renal insult. Renal function was
different between the two groups. (Adapted from Franklin, et al. evaluated by iodothalimate clearance. Unfortunately, at an interim
[3]; with permission.) 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 hormone–resistant short stature Corticosteroid therapy

Postoperative state
Laron-type dwarfism
Insulin-dependent and non–insulin-dependent diabetes mellitus
Anabolic agent in catabolic states
Acute renal failure
AIDS (Protein wasting malnutrition)
Chronic renal failure
Burns
LACK OF EFFECT OF RECOMBINANT

FIGURE 17-22
Advantages of insulin-like growth factor (IGF-I) in the treatment of
FIGURE 17-23
acute renal failure. The limited data obtained to date on the use of
IGF-I for acute renal failure demonstrate that the peptide is well- Limitations in the use of growth factors to treat acute renal failure
tolerated and may be useful in selected patient populations. (ARF). The disappointing results of several recent clinical trials of
Additional human trials are ongoing including use in the settings of ARF therapy reflect the fact that our understanding of its pathophysi-
renal transplantation and chronic renal failure. ology 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 regenera-
tive 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
FIGURE 17-24
HUMAN IGF-I IN PATIENTS WITH ARF* A list of genes
whose expression
is induced at
Multicenter, double- *No difference between the groups were observed in final values or changes in values for glomerular filtration various time points
blind, randomized, by ischemic renal
placebo-controlled 1 Hour 1 Day 2 Days 5 Days References injury. The molecu-
ARF secondary to lar response of
surgery, trauma, ↑ ←→ Bardella et al. [5] the kidney to an
hypertensive ↑ ←→ Ouellette et al. [6] ischemic insult is
nephropathy, sep- ↑ ←→ Bonventre et al. [7] complex and is
sis, or drugs
←→ ↓ ↓ ↓ Witzgall et al. [8] the subject of
Treated within the investigations by
first 6 days for 14
days ↑ ↑ ↑ ↑ Safirstein et al. [9]
several laboratories.
Evaluated renal func- ↑ ←→ “ (Continued on
tion and mortality ↑ Goes et al. [10] next page)
↑ ↑ “
↑ “
↑ ↑ “
↑ ↑ Singh et al. [11]
↑ ↑ “
↑ ↑ “
↑ ↑ “
↑ ↑ ←→ ←→ Soifer et al. [12]
↑ (6 h) ↑ ↑ Firth and Ratcliffe [13]
↓ (6 h) ↓ ↓ “
(Table continued on next page)
Well-tolerated
Safe in short-term studies GROWTH

I FACTOR LIMITATIONS N ACUTE
Experience with diseases of RENAL
overexpression and under- FAILURE
expression
Lack of basic knowledge
Did not worsen outcomes of the pathophysiology
IGF-I—insulin-like growth of ARF
factor. 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 pop-
ulations

Several genes have already been identified to be altered as a result of ischemic injury. It is not clear at
induced or down-regulated after ischemia and reper- present if the varied expression of these genes plays a
fusion. This table lists genes whose expression is role in cell injury, survival, or proliferation.
FIGURE 17-25
ARF—acute renal failure. 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
MOLECULAR RESPONSE TO RENAL
proliferation. A better understanding of the various factors and
ISCHEMIC/REPERFUSION INJURY
the signal transduction pathways transduced by them that con-
tribute to cell death can lead to development of therapeutic
Genes strategies to interfere with the process of cell death. Similarly,
Transcription factors identification of factors that are involved in initiating cell migra-
c-jun tion, dedifferentiation, and proliferation may lead to therapy
c-fos aimed at accelerating the regeneration program. To identify the
Egr-1 various factors involved in cell injury and regeneration, powerful
Kid 1 methods for identification and cloning of differentially expressed
genes are critical. One such method that has been used exten-
Cytokines
sively by several laboratories is the differential display poly-
JE
merase chain reaction (DD-PCR).
KC
In this schematic, mRNA is derived from kidneys of sham-
IL-2
operated (controls) and ischemia-injured rats, some pretreated
IL-10
with insulin-like growth factor (IGF-I). The mRNAs are reverse
IFN-
transcribed using an anchored deoxy thymidine-oligonucleotide
GM-CSF
(oligo-dT) primer (Example: dT[12]-MX, where M represent G,
MIP-2
A, or C, and X represents one of the four nucleotides). An
IL-6
anchored primer limits the reverse transcription to a subset of
IL-11
mRNAs. The first strand cDNA is then PCR amplified using an
LIF
arbitrary 10 nucleotide-oligomer primer and the anchored
PTHrP
primer. The PCR reaction is performed in the presence of
Endothelin 1
radioactive or fluorescence-labeled nucleotides, so that the
Endothelin 3
amplified fragments can be displayed on a sequencing gel. Bands
of interest can be excised from the gel and used for further char-
acterization. ARF—acute renal failure.
FIGURE 17-26
Sham ARF Schematic representation of a differential display gel in which
Sham +IGF-1 ARF
+ IGF-1
mRNA from kidneys is reverse-transcribed and polymerase chain
reaction (PCR) amplified (see Figure 17-25). The PCR amplifica-
1
tion is conducted in the presence of radioactive nucleotides. The
cDNA fragments corresponding to the 3’ end of the mRNA species
2 are displayed by running them on a sequencing gel, followed by
autoradiography. The arrows show bands corresponding to mRNA
3 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-I–dependent manner; 3) in response
to induction of ischemic injury; and 4) to genes that are down-reg-
4 ulated after induction of ischemic injury. ARF—acute renal failure.
References
1. Toback GF: Regeneration after acute tubular necrosis. Kidney Int 17. Ishibashi K, et al.: Expressions of receptor for hepatocyte growth
1992, 41:226–246. factor in kidney after unilateral nephrectomy and renal injury.
2. Miller SB, Martin DR, Kissane J, Hammerman, MR: Insulin-like Biochem Biophys Res Commun 1993, 187:1454–1459.
growth factor I accelerates recovery from ischemic acute tubular 18. Safirstein R, et al.: Changes in gene expression after temporary renal
necrosis in the rat. Proc Natl Acad Sci USA 1992, 89:11876–11880. ischemia. Kidney Int 1990, 37:1515–1521.
3. Franklin SC, Moulton M, Sicard GA, et al.: Insulin-like growth factor 19. Basile DP, et al.: Increased transforming growth factor-beta 1 expres-
I preserves renal function postoperatively. Am J Physiol 1997, sion in regenerating rat renal tubules following ischemic injury. Amer
272:F257–F259. J Physiol 1996, 270:F500–F509.
4. Kopple JD, Hirschberg R, Guler H-P, et al.: Lack of effect of recombi- 20. Padanilam BJ, Hammerman MR: Ischemia-induced receptor for acti-
nant human insulin-like growth factor I (IGF-I) in patients with acute vated C kinase (RACK1) expression in rat kidneys. Amer J Physiol
renal failure (ARF). J Amer Soc Nephro 1996, 7:1375. 1997, 272:F160–F166.
5. Bardella L, Comolli R: Differential expression of c-jun, c-fos and hsp 21. Pombo CM, et al.: The stress-activated protein kinases are major
70 mRNAs after folic acid and ischemia reperfusion injury: effect of
c-Jun amino-terminal kinases activated by ischemia and reperfusion.
antioxidant treatment. Exp Nephrol 1994, 2:158–165.
J Biol Chem 1994, 269:26546–26551.
6. Ouellette AJ, et al.: Expression of two “immediate early” genes, Egr-1
22. Safirstein R: Gene expression in nephrotoxic and ischemic acute renal
and c-fos, in response to renal ischemia and during compensatory
failure [editorial]. J Am Soc Nephrol 1994, 4:1387–1395.
renal hypertrophy in mice. J Clin Invest 1990, 85:766–771.
7. Bonventre JV, et al.: Localization of the protein product of the imme- 23. Safirstein R, Zelent AZ, Price PM: Reduced renal prepro-epidermal
diate early growth response gene, Egr-1, in the kidney after ischemia growth factor mRNA and decreased EGF excretion in ARF. Kid Int
and reperfusion. Cell Regulation 1991, 2:251–60. 1989, 36:810–815.
8. Witzgall R, et al.: Kid-1, a putative renal transcription factor: regula- 24. Raju VS, Maines, MD: Renal ischemia/reperfusion up-regulates heme
tion during ontogeny and in response to ischemia and toxic injury. oxygenase-1 (HSP32) expression and increases cGMP in rat heart.
Mol Cell Biol 1993, 13:1933–1942. J Pharmacol Exp Ther 1996, 277:1814–1822.
9. Safirstein R, et al.: Expression of cytokine-like genes JE and KC is 25. Van Why SK, et al.: Induction and intracellular localization of HSP-72
increased during renal ischemia. Amer J Physiol 1991, 261:F1095–F1101. after renal ischemia. Am J Physiol 1992, 263:F769–F775.
10. Goes N, et al.: Ischemic acute tubular necrosis induces an extensive 26. Padanilam BJ, Martin DR, Hammerman MR: Insulin-like growth
local cytokine response. Evidence for induction of interferon-gamma, factor I–enhanced renal expression of osteopontin after acute
transforming growth factor-beta 1, granulocyte-macrophage ischemic injury in rats. Endocrinology 1996, 137:2133–2140.
colony–stimulating factor, interleukin-2, and interleukin-10. 27. Walker PD: Alterations in renal tubular extracellular matrix compo-
Transplantation 1995, 59:565–572. nents after ischemia-reperfusion injury to the kidney. Lab Invest 1994,
11. Singh AK, et al.: Prominent and sustained upregulation of MIP-2 and 70:339–345.
gp130 signaling cytokines in murine renal ischemic-reperfusion injury. 28. Van Why SK, et al.: Expression and molecular regulation of Na+-K+-
J Am Soc Nephrol 1997, 8:595A. ATPase after renal ischemia. Am J Physiol 1994, 267:F75–F85.
12. Soifer NE, et al.: Expression of parathyroid hormone–related protein
29. Wang Z, et al.: Ischemic-reperfusion injury in the kidney: overexpres-
in the rat glomerulus and tubule during recovery from renal ischemia.
sion of colonic H+-K+-ATPase and suppression of NHE-3. Kidney Int
J Clin Invest 1993, 92:2850–2857.
1997, 51:1106–1115.
13. Firth JD, Ratcliffe PJ: Organ distribution of the three rat endothelin
messenger RNAs and the effects of ischemia on renal gene expression. 30. McKanna JA, et al.: Localization of p35 (annexin I, lipocortin I) in
J Clin Invest 1992, 90:1023–1031. normal adult rat kidney and during recovery from ischemia. J Cell
Physiol 1992, 153:467–76.
14. Witzgall R, et al.: Localization of proliferating cell nuclear antigen,
vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for 31. Nakamura H, et al.: Subcellular characteristics of phospholipase A2
a heterogeneous genetic response among nephron segments, and a activity in the rat kidney. Enhanced cytosolic, mitochondrial, and
large pool of mitotically active and dedifferentiated cells. J Clin Invest microsomal phospholipase A2 enzymatic activity after renal ischemia
1994, 93:2175–2188. and reperfusion. J Clin Invest 1991, 87:1810–1818.
15. Basile DP, Liapis H, Hammerman MR: Expression of bcl-2 and bax in 32. Lewington AJP, Padanilam BJ, Hammerman MR: Induction of calcy-
regenerating rat renal tubules following ischemic injury. Am J Physiol clin after ischemic injury to rat kidney. Am J Physiol 1997,
1997, 272:F640–F647. 273(42):F380–F385.
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):1113–1123.
Nutrition and Metabolism
in Acute Renal Failure
Wilfred Druml
A
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 sup-
port for ARF, however, differ from those for patients with chronic renal
failure (CRF), because diets or infusions that satisfy minimal require-
ments 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 var-
ious 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 abnormali-
ties 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 require-
ments (and outcome) are not renal dysfunction per se but the degree of
hypercatabolism caused by the disease associated with ARF, the nutri-
tional state, and the type and frequency of dialysis therapy. Pre-exist-
ing or hospital-acquired malnutrition has been identified as an impor-
tant 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, immunocom-
petence, and wound healing for a patient who has acquired ARF—in
may instances among other complications. At the same time the spe-
cific metabolic alterations and demands in ARF and the impaired
excretory renal function must be respected to limit uremic toxicity. CHAPTER
In this chapter the multiple metabolic alterations associated with
ARF are reviewed, methods for estimating nutrient requirements are
18
discussed and, current concepts for the type and composition of nutri-
tional programs are summarized. This information is relevant for
designing nutritional support in an individual patient with ARF.
FIGURE 18-1
NUTRITION IN ACUTE RENAL FAILURE 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
Goals a minimal intake of nutrients (to minimize uremic toxicity or to
Preservation of lean body mass retard progression of renal failure, as recommended for CRF) but
Stimulation of wound healing and reparatory functions rather an optimal amount of nutrients should be provided for cor-
Stimulation of immunocompetence rection and prevention of nutrient deficiencies and for stimulation
Acceleration of renal recovery (?) of immunocompetence and wound healing in the mostly hypercata-
But not (in contrast to stable CRF) bolic patients with ARF [1].
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
FIGURE 18-2
METABOLIC PERTURBATIONS Metabolic perturbations in acute renal failure (ARF). In most
IN ACUTE RENAL FAILURE instances ARF is a complication of sepsis, trauma, or multiple
organ failure, so it is difficult to ascribe specific metabolic alter-
ations to ARF. Metabolic derangements will be determined by the
Determined by Plus acute uremic state plus the underlying disease process or by com-
plications such as severe infections and organ dysfunctions and,
Renal dysfunction (acute uremic state) Specific effects of renal
last but not least by the type and frequency of renal replacement
Underlying illness replacement therapy
therapy [1, 2].
The acute disease state, such as Nonspecific effects of extracorporeal
circulation (bioincompatibility)
Nevertheless, ARF does not affect only water, electrolyte, and acid
systemic inflammatory response
base metabolism: it induces a global change of the metabolic envi-
syndrome (SIRS)
ronment with specific alterations in protein and amino acid, carbo-
Associated complications (such as
infections) hydrate, and lipid metabolism [2].
Metabolic Alterations in Acute Renal Failure

Energy metabolism
FIGURE 18-3
Energy metabolism in acute renal failure (ARF). In experimental ani-
mals 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 un-
complicated 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 deter-
mined 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 process-
es 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 18.3
FIGURE 18-4
ESTIMATION OF ENERGY REQUIREMENTS Estimation of energy requirements. Energy requirements of
patients with acute renal failure (ARF) have been grossly over-
estimated in the past and energy intakes of more than 50 kcal/kg
Calculation of resting energy expenditure (REE) (Harris Benedict equation): of body weight (BW) per day (ie, about 100% above resting
Males: 66.47 (13.75 BW) (5 height) (6.76 age) energy expenditure (REE) haven been advocated [6]. Adverse
Females: 655.1 (9.56 BW) (1.85 height) (4.67 age)
effects of overfeeding have been extensively documented during
the last decades, and it should be noted that energy intake must
The average REE is approximately 25 kcal/kg BW/day
not exceed the actual energy consumption. Energy requirements
Stress factors to correct calculated energy requirement for hypermetabolism:
can be calculated with sufficient accuracy by standard formulas
Postoperative (no complications) 1.0
such as the Harris Benedict equation. Calculated REE should be
Long bone fracture 1.15–1.30
multiplied with a stress factor to correct for hypermetabolic
Cancer 1.10–1.30
disease; however, even in hypercatabolic conditions such as sepsis
Peritonitis/sepsis 1.20–1.30 or multiple organ dysfunction syndrome, energy requirements
Severe infection/polytrauma 1.20–1.40 rarely exceed 1.3 times calculated REE [1].
Burns ( approxim. REE % burned body surface area) 1.20–2.00
Corrected energy requirements (kcal/d) REE stress factor
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 metabol-
ic alterations in ARF is activation of protein catabolism with
excessive release of amino acids from skeletal muscle and sus-
tained negative nitrogen balance [7, 8]. Not only is protein break-
down 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 pro-
tein degradation is increased, even in the presence of insulin [9].
(From [8]; with permission.)
FIGURE 18-6
Protein metabolism in acute renal failure (ARF): impairment of of the curves, insulin sensitivity is maintained (see also Fig. 18-14).
cellular amino acid transport. A, Amino acid transport into skele- This abnormality can be linked both to insulin resistance and to
tal muscle is impaired in ARF [10]. Transmembranous uptake of a generalized defect in ion transport in uremia; both the activity
the amino acid analogue methyl-amino-isobutyrate (MAIB) is and receptor density of the sodium pump are abnormal in adi-
reduced in uremic tissue in response to insulin (muscle tissue pose cells and muscle tissue [11]. B, The impairment of rubidium
from uremic animals, black circles, and from sham-operated ani- uptake (Rb) as a measure of Na-K-ATPase activity is tightly cor-
mals, open circles, respectively). Thus, insulin responsiveness is related to the reduction in amino acid transport. (From [10,11];
reduced in ARF tissue, but, as can be seen from the parallel shift with permission.)
FIGURE 18-7
Protein catabolism in acute renal failure (ARF). Amino acids are erated hepatic gluconeogenesis, which cannot be suppressed by
redistributed from muscle tissue to the liver. Hepatic extraction of exogenous substrate infusions (see Fig. 18-15). In the liver, protein
amino acids from the circulation—hepatic gluconeogenesis, A, and synthesis and secretion of acute phase proteins are also stimulated.
ureagenesis, B, from amino acids all are increased in ARF [12]. Circles—livers from acutely uremic rats; squares—livers from sham
The dominant mediator of protein catabolism in ARF is this accel- operated rats. (From Fröhlich [12]; with permission.).
A major stimulus of muscle protein catabolism in ARF is insulin

CONTRIBUTING FACTORS TO PROTEIN resistance. In muscle, the maximal rate of insulin-stimulated
CATABOLISM IN ACUTE RENAL FAILURE 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
Impairment of metabolic functions by uremia toxins
and oxidation of amino acids independently of azotemia, and
Endocrine factors
nitrogen balance can be improved by correcting the metabolic
Insulin resistance
acidosis [13]. These findings were not uniformly confirmed for
Increased secretion of catabolic hormones (catecholamines,
ARF in animal experiments [14].
glucagon, glucocorticoids)
Several additional catabolic factors are operative in ARF. The
Hyperparathyroidism
secretion of catabolic hormones (catecholamines, glucagon,
Suppression of release or resistance to growth factors
glucocorticoids), hyperparathyroidism which is also present in ARF
Acidosis
(see Fig. 18-22), suppression of or decreased sensitivity to growth
Systemic inflammatory response syndrome (activation of cytokine network) factors, the release of proteases from activated leukocytes—all can
Release of proteases stimulate protein breakdown. Moreover, the release of inflammato-
Inadequate supply of nutritional substrates ry mediators such as tumor necrosis factor and interleukins have
Loss of nutritional substrates (renal replacement therapy) 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
FIGURE 18-8 findings suggest that, in addition, both activation of protein
Protein catabolism in acute renal failure (ARF): contributing factors. breakdown and inhibition of muscular protein synthesis are
The causes of hypercatabolism in ARF are complex and multifold induced by hemodialysis [15].
and present a combination of nonspecific mechanisms induced by Last (but not least), of major relevance for the clinical situation
the acute disease process and underlying illness and associated com- is the fact that inadequate nutrition contributes to the loss of lean
plications, specific effects induced by the acute loss of renal function, body mass in ARF. In experimental animals, starvation potentiates
and, finally, the type and intensity of renal replacement therapy. the catabolic response of ARF [7].
FIGURE 18-9
Amino acid pools and amino acid utilization in acute renal failure extraction of amino acids observed in animal experiments,
(ARF). As a consequence of these metabolic alterations, imbal- overall amino acid clearance and clearance of most glucoplastic
ances in amino acid pools in plasma and in the intracellular com- amino acids is enhanced. In contrast, clearances of PHE, proline
partment occur in ARF. A typical plasma amino acid pattern is (PRO), and, remarkably, VAL are decreased [16, 17]. ALA—
seen [16]. Plasma concentrations of cysteine (CYS), taurine (TAU), alanine; ARG—arginine; ASN—asparagine; ASP—aspartate;
methionine (MET), and phenylalanine (PHE) are elevated, where- CIT—citrulline; GLN—glutamine; GLU—glutamate; GLY—
as plasma levels of valine (VAL) and leucine (LEU) are decreased. glycine; HIS—histidine; ORN—ornithine; PRO—proline; SER—
Moreover, elimination of amino acids from the intravascular serine; THR—threonine; TRP—tryptophan; TYR—tyrosine.
space is altered. As expected from the stimulation of hepatic (From Druml et al. [16]; with permission.)
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 degrada-
tion. 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, metabol-
ic clearance progressively decreases with falling creatinine clearance
FIGURE 18-10 (open circles, 7 healthy subjects and a patient with unilateral
Metabolic functions of the kidney and protein and amino acid nephrectomy*) but extrarenal clearance in the absence of renal
metabolism in acute renal failure (ARF). Protein and amino acid function (black circles) is sufficient for rapid utilization of the
metabolism in ARF are also affected by impairment of the meta- dipeptide and release of tyrosine [21]. (From Druml et al. [21];
bolic functions of the kidney itself. Various amino acids are synthe- with permission.)
patients: histidine, arginine, tyrosine, serine, cysteine [19]. Infusion

of arginine-free amino acid solutions can cause life-threatening com-
plications 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 meta-
bolic functions in regulating nitrogen metabolism, supporting
immune functions, and preserving the gastrointestinal barrier.
Thus, it can become conditionally indispensable in catabolic ill-
ness [23]. Because free glutamine is not stable in aqueous solu-
tions, dipeptides containing glutamine are used as a glutamine
source in parenteral nutrition. The utilization of dipeptides in
FIGURE 18-11 part depends on intact renal function, and renal failure can impair
Amino acids in nutrition of acute renal failure (ARF): Conditionally hydrolysis (see Fig. 18-10) [24]. No systematic studies have been
essential amino acids. Because of the altered metabolic environment published on the use of glutamine in patients with ARF, and it
of uremic patients certain amino acids designated as nonessential must be noted that glutamine supplementation increases nitrogen
for healthy subjects may become conditionally indispensable to ARF intake considerably.
Protein requirements
FIGURE 18-12
ESTIMATING THE EXTENT OF PROTEIN CATABOLISM Estimation of protein catabolism and nitrogen balance. The extent
of protein catabolism can be assessed by calculating the urea nitro-
gen appearance rate (UNA), because virtually all nitrogen arising
Urea nitrogen appearance (UNA) (g/d) from amino acids liberated during protein degradation is converted
Urinary urea nitrogen (UUN) excretion to urea. Besides urea in urine (UUN), nitrogen losses in other body
Change in urea nitrogen pool
fluids (eg, gastrointestinal, choledochal) must be added to any
change in the urea pool. When the UNA rate is multiplied by 6.25,
(UUN V) (BUN2 BUN1) 0.006 BW
it can be converted to protein equivalents. With known nitrogen
(BW2 BW1) BUN2/100
intake from the parenteral or enteral nutrition, nitrogen balance
If there are substantial gastrointestinal losses, add urea nitrogen in secretions:
can be estimated from the UNA calculation.
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
body weight per day) was derived from a study in which, unfortu-
nately, 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
FIGURE 18-13 further ameliorate nitrogen balance.
Amino acid and protein requirements of patients with acute renal Chima and coworkers measured a mean PCR of 1.7 g kg body
failure (ARF). The optimal intake of protein or amino acids is weight per day in 19 critically ill ARF patients and concluded that
affected more by the nature of the underlying cause of ARF and protein needs in these patients range between 1.4 and 1.7 g/kg per
the extent of protein catabolism and type and frequency of dialysis day [28]. Similarly, Marcias and coworkers have obtained a protein
than by kidney dysfunction per se. Unfortunately, only a few stud- catabolic rate (PCR) of 1.4 g/kg per day and found an inverse
ies have attempted to define the optimal requirements for protein relationship between protein and energy provision and PCR and
or amino acids in ARF: again recommended protein intake of 1.5 to 1.8 g/kg per day [29].
In nonhypercatabolic patients, during the polyuric phase of ARF Similar conclusions were drawn by Ikitzler in evaluating ARF
protein intake of 0.97 g/kg body weight per day was required to patients on intermittent hemodialysis therapy [30]. (From Kierdorf
achieve a positive nitrogen balance [25]. A similar number (1.03g/kg et al. [27]; with permission.)
Glucose metabolism
FIGURE 18-14
Glucose metabolism in acute renal failure (ARF): Peripheral insulin than impaired insulin sensitivity as the cause of defective glucose
resistance. ARF is commonly associated with hyperglycemia. The metabolism. The factors contributing to insulin resistance are more
major cause of elevated blood glucose concentrations is insulin or less identical to those involved in the stimulation of protein
resistance [31]. Plasma insulin concentration is elevated. Maximal breakdown (see Fig. 18-8). Results from experimental animals sug-
insulin-stimulated glucose uptake by skeletal muscle is decreased by gest a common defect in protein and glucose metabolism: tyrosine
50 %, A, and muscular glycogen synthesis is impaired, B. However, release from muscle (as a measure of protein catabolism) is closely
insulin concentrations that cause half-maximal stimulation of glu- correlated with the ratio of lactate release to glucose uptake [9].
cose uptake are normal, pointing to a postreceptor defect rather (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 pro-
tein breakdown) in ARF is accelerated hepatic gluconeogenesis, main-
ly 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 hepat-
ic glucose formation can only be decreased, but not halted, by sub-
strate supply. As can be seen from this experimental study, even dur-
ing 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 catab-
olism and preserve lean body mass. (From Cianciaruso et al. [32];
with permission.)
Lipid metabolism
FIGURE 18-16
Lipid metabolism in acute renal failure (ARF). Profound alterations
of lipid metabolism occur in patients with ARF. The triglyceride con-
tent 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 impair-
ment 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]. FFA—free
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-den-
sity 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 triglyc-
erides 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 emul-
sions 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.)
Electrolytes and micronutrients

FIGURE 18-18
CAUSES OF ELECTROLYTE DERANGEMENTS Electrolytes in acute renal failure (ARF): causes of hyperkalemia
IN ACUTE RENAL FAILURE and hyperphosphatemia. ARF frequently is associated with hyper-
kalemia and hyperphosphatemia. Causes are not only impaired
renal excretion of electrolytes but release during catabolism, altered
Hyperkalemia Hyperphosphatemia distribution in intracellular and extracellular spaces, impaired
cellular uptake, and acidosis. Thus, the type of underlying disease
Decreased renal elimination Decreased renal elimination
and degree of hypercatabolism also determine the occurrence and
Increased release during catabolism Increased release from bone
severity of electrolyte abnormalities. Either hypophosphatemia or
2.38 mEq/g nitrogen Increased release during catabolism:
hyperphosphatemia can predispose to the development and
0.36 mEq/g glycogen 2 mmol/g nitrogen
maintenance of ARF [37].
Decreased cellular uptake/ Decreased cellular uptake/utilization
increased release and/or increased release from cells
Metabolic acidosis: 0.6 mmol/L rise/0.1
decrease in pH

Electrolytes in acute renal failure (ARF): hypophosphatemia and Micronutrients in acute renal failure (ARF): water-soluble vitamins.
hypokalemia. It must be noted that a considerable number of Balance studies on micronutrients (vitamins, trace elements) are not
patients with ARF do not present with hyperkalemia or hyperphos- available for ARF. Because of losses associated with renal replace-
phatemia, but at least 5% have low serum potassium and more ment therapy, requirements for water-soluble vitamins are expected
than 12% have decreased plasma phosphate on admission [38]. to be increased also in patients with ARF. Malnutrition with deple-
Nutritional support, especially parenteral nutrition with low elec- tion of vitamin body stores and associated hypercatabolic underly-
trolyte content, can cause hypophosphatemia and hypokalemia in ing disease in ARF can further increase the need for vitamins.
as many as 50% and 19% of patients respectively [39,40]. Depletion of thiamine (vitamin B1) during continuous hemofiltra-
In the case of phosphate, phosphate-free artificial nutrition causes tion and inadequate intake can result in lactic acidosis and heart
hypophosphatemia within a few days, even if the patient was hyper- failure [42]. This figure depicts the evolution of plasma lactate con-
phosphatemic on admission (black circles) [41]. Supplementation of centration before and after administration of 600 mg thiamine in
5 mmol per day was effective in maintaining normal plasma phos- two patients. Infusion of 600 mg of thiamine reversed the metabol-
phate concentrations (open squares), whereas infusion of more than ic abnormality within a few hours. An exception to this approach
10 mmol per day resulted in hyperphosphatemia, even if the patients to treatment is ascorbic acid (vitamin C); as a precursor of oxalic
had decreased phosphate levels on admission (open circles). acid the intake should be kept below 200 mg per day because any
Potassium or phosphate depletion increases the risk of developing excessive supply may precipitate secondary oxalosis [43]. (From
ARF and retards recovery of renal function. With modern nutrition- Madl et al. [42]; with permission.)
al 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.)

Micronutrients in acute renal failure (ARF): fat-soluble vitamins Hypocalcemia and the vitamin D–parathyroid hormone (PTH) axis
(A, E, K). Despite the fact that fat-soluble vitamins are not lost dur- in acute renal failure (ARF). ARF is also frequently associated with
ing hemodialysis and hemofiltration, plasma concentrations of vita- hypocalcemia secondary to hypoalbuminemia, elevated serum phos-
mins A and E are depressed in patients with ARF and requirements phate, plus skeletal resistance to calcemic effect of PTH and impair-
are increased [44]. Plasma concentrations of vitamin K (with broad ment of vitamin-D activation. Plasma concentration of PTH is
variations of individual values) are normal in ARF. Most commer- increased. Plasma concentrations of vitamin D metabolites, 25-OH
cial multivitamin preparations for parenteral infusions contain the vitamin D3 and 1,25-(OH)2 vitamin D3, are decreased [44]. In ARF
recommended daily allowances of vitamins and can safely be used caused by rhabdomyolysis rebound hypercalcemia may develop during
in ARF patients. (From Druml et al. [44]; with permission.) 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 organism’s 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 reple-
tion of antioxidant status exerts the opposite effect [45]. These
data argue for a crucial role of reactive oxygen species and peroxi-
dation of lipid membrane components in initiating and mediating
ischemia or reperfusion injury.
In patients with multiple organ dysfunction syndrome and associ-
ated ARF (lightly shaded bars) various factors of the oxygen radi-
cal 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 pro-
foundly 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 supplemen-
tation of antioxidant micronutrients for patients with ARF.
(Adapted from Druml et al. [46]; with permission.)
Metabolic Impact of Renal Replacement Therapy

(arteriovenous) hemofiltration (CHF) and continuous hemodialysis
have gained wide popularity. CRRTs are associated with multiple
METABOLIC EFFECTS OF CONTINUOUS
metabolic effects in addition to “renal replacement” [47].
RENAL REPLACEMENT THERAPY
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
Amelioration of uremia intoxication (renal replacement)
lactate as anions, oxidation of which in part compensates for the
Plus
heat loss. This lactate load can result in hyperlactemia in the pres-
Heat loss
ence of liver dysfunction or increased endogenous lactate formation
Excessive load of substrates (eg, lactate, glucose)
such as in circulatory shock.
Loss of nutrients (eg, amino acids, vitamins) Several nutrients with low protein binding and small molecular
Elimination of short-chain proteins (hormones, mediators?) weight (sieving coefficient 0.8 to 1.0), such as vitamins or amino
Induction or activation of mediator cascades acids are eliminated during therapy. Amino acid losses can be esti-
Stimulation of protein catabolism? mated from the volume of the filtrate and average plasma concen-
tration, 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
FIGURE 18-24 acid input, but it can be even higher during continuous hemodiafil-
Metabolic impact of extracorporeal therapy. The impact of hemodial- tration [48].
ysis therapy on metabolism is multifactorial. Amino acid and protein With the large molecular size cut-off of membranes used in hemofil-
metabolism are altered not only by substrate losses but also by activa- tration, small proteins such as peptide hormones are filtered. In view
tion of protein breakdown mediated by release of leukocyte-derived of their short plasma half-life hormone losses are minimal and proba-
proteases, of inflammatory mediators (interleukins and tumor necro- bly not of pathophysiologic importance. Quantitatively relevant elimi-
sis factor) induced by blood-membrane interactions or endotoxin. nation of mediators by CRRT has not yet been proven. On the other
Dialysis can also induce inhibition of muscle protein synthesis [15]. hand, prolonged blood-membrane interactions can induce conse-
In the management of patients with acute renal failure (ARF), con- quences of bioincompatibility and activation of various endogenous
tinuous renal replacement therapies (CRRT), such as continuous cascade systems.
Nutrition, Renal Function, and Recovery
FIGURE 18-25
A, B, Impact of nutritional interventions on renal function and Infusion of amino acids raised renal cortical protein synthesis as
course of acute renal failure (ARF). Starvation accelerates protein evaluated by 14C-leucine incorporation and depressed protein breakdown
breakdown and impairs protein synthesis in the kidney, whereas in rats with mercuric chloride–induced ARF [49]. On the other hand, in a
refeeding exerts the opposite effects [49]. In experimental animals, similar model of ARF, infusions of varying quantities of essential amino
provision of amino acids or total parenteral nutrition accelerates acids (EAA) and nonessential amino acids (NEAA) did not provide any
tissue repair and recovery of renal function [50]. In patients, protection of renal function and in fact increased mortality [52]. However,
however, this has been much more difficult to prove, and only one in balance available evidence suggests that provision of substrates may
study has reported on a positive effect of TPN on the resolution enhance tissue regeneration and wound healing, and potentially, also
of ARF [51]. renal tubular repair [49]. (From Toback et al. [50]; with permission.)
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 para-
dox [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 nephro-
toxic and ischemic models of ARF, whereas inhibitors of nitric
oxide synthase exert an opposite effect [56,57]. In myoglobin-
induced ARF the drop in renal blood flow (black circles, ARF con-
trols) 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 ischemic ARF, A, but also reduces the increase in BUN and
course of acute renal failure (ARF). Various other endocrine-meta- improves nitrogen balance, B, [58]. (open circles) ARF plus vehi-
bolic interventions (eg, thyroxine, human growth hormone [HGH], cle; (black circles, sham-operated rats plus vehicle; open squares,
epidermal growth factor, insulin-like growth factor 1 [IGF-1]) have ARF plus rhIGF-I; black squares, sham operated rats plus rhIGF-
been shown to accelerate regeneration after experimental ARF I.) Unfortunately, efficacy of these interventions was not uniform-
[51]. In a rat model of postischemic ARF, treatment with IGF-1 ly confirmed in clinical studies [59, 60]. (From Ding et al. [58];
starting 5 hours after induction of ARF accelerates recovery from with permission.)
Decision Making, Patient Classification,

and Nutritional Requirements
underlying illness involved. In any patient with evidence of mal-
nourishment, nutritional therapy should be instituted regardless of
DECISIONS FOR NUTRITION IN PATIENTS
whether the patient will be likely to eat. If a well-nourished patient
WITH ACUTE RENAL FAILURE
can resume a normal diet within 5 days, no specific nutritional sup-
port is necessary. The degree of accompanying catabolism is also a
factor. For patients with underlying diseases associated with excess
Decisions dependent on
protein catabolism, nutritional support should be initiated early.
Patients ability to resume oral diet (within 5 days?)
If there is evidence of malnourishment or hypercatabolism, nutri-
Nutritional status
tional therapy should be initiated early, even if the patient is likely to
Underlying illness/degree of associated hypercatabolism
eat before 5 days. Modern nutritional strategies should be aimed at
1. What patient with acute renal failure needs nutritional support? avoiding the development of deficiency states and of “hospital-
2. When should nutritional support be initiated? acquired malnutrition.” During the acute phase of ARF (the first
3. At what degree of impairment in renal function should the nutritional regimen 24 hours after trauma or surgery) nutritional support should be
be adapted for renal failure?
withheld because nutrients infused during this “ebb phase” are not
4. In a patient with multiple organ dysfunction, which organ determines the type of utilized, could increase oxygen requirements, and aggravate tissue
nutritional support?
injury and renal dysfunction.
5. Is enteral or parenteral nutrition the most appropriate method for providing
The nutritional regimen should be adapted for renal failure when
nutritional support?
renal function is impaired. The multiple metabolic alterations char-
acteristic 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
FIGURE 18-28 mg/dL) the nutritional regimen should be adapted to ARF.
Nutrition in patients with acute renal failure (ARF): decision mak- With the exception of severe hepatic failure and massively deranged
ing. Not every patient with ARF requires nutritional support. It is amino acid metabolism (hyperammonemia) or protein synthesis (deple-
important to identify those who will benefit and to define the opti- tion of coagulation factors) renal failure is the major determinant of the
mal time to initiate therapy [1]. nutritional regimen in patients with multiple organ dysfunction.
The decision to initiate nutritional support is influenced by the Enteral feeding is preferred for all patients, including those with ARF.
patient’s ability to cover nutritional requirements by eating, in addi- Nevertheless, for a large portion of patients, parenteral nutrition—total
tion to the nutritional status of the patient as well as the type of or partial—will 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 >6 g 6–12 g >12 g
(above nitrogen intake)
Clinical setting (examples) Drug toxicity Elective surgery Severe injury or
± infection sepsis
Mortality 20 % 60% >80%
Dialysis or hemofiltration frequency Rare As needed Frequent
Route of nutrient Oral Enteral or parenteral Enteral or parenteral
administration
Energy recommendations 25 25–30 25–35
(kcal/kg BW/d)
Energy substrates Glucose Glucose + fat Glucose fat
Glucose (g/kg BW/d) 3.0–5.0 3.0–5.0 3.0–5.0 (max. 7.0)
Fat (g/kg BW/d) 0.5–1.0 0.8–1.5
Amino acids/protein (g/kg/d) 0.6–1.0 0.8–1.2 1.0–1.5
EAA (NEAA) EAA NEAA EAA NEAA
Nutrients used Foods Enteral formulas Enteral formulas
Glucose 50%–70% Glucose 50%–70% +
fat emulsions 10% fat emulsions 10%
or 20% or 20%
EAA + specific NEAA solutions (general or “nephro”)
Multivitamin and multitrace element preparations
BW—body weight; EAA—essential amino acids; NEAA—nonessential 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 catabo-
lism 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 (aminogly-
cosides, 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 feed-
ing 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 nutri-
tion, hemodialysis or continuous hemofiltration plus blood pressure and ventilatory sup-
port. 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.)
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 stom-
ach or jejunum [61]. Feeding solutions can be administered by pump intermittently or con-
tinuously. 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.)
SPECIFIC ENTERAL FORMULAS FOR NUTRITIONAL SUPPORT OF PATIENTS WITH RENAL FAILURE
Travasorb Salvipeptide Survimed

Amin-Aid renal* nephro† renal‡ Suplena§ Nepro§
Volume (mL) 750 1050 500 1000 500 500
Calories (kcal) 1467 1400 1000 1320 1000 1000
(cal/mL) 1.96 1.35 2.00 1.32 2.00 2.00
Energy distribution
Protein:fat:carbohydrates (%) 4:21:75 7:12:81 8:22:70 6:10:84 6:43:51 14:43:43
kcal/g N 832:1 389:1 313:1 398:1 418:1 179:1
Proteins (g) 14.6 24.0 20.0 20.8 15.0 35
EAA (%) 100 60 23
NEAA (%) — 30 20
Hydrolysate (%) — — 23 100
Full protein (%) — — 34 — 100 100
Nitrogen (g) 1.76 3.6 3.2 3.32 2.4 5.6
Carbohydrates (g) 274 284 175 276 128 108
Monodisaccharides (%) 100 100 3 10 12
Oligosaccharides (%) — — 28
Polysaccharides (%) — — 69 88 90
Fat (g) 34.6 18.6 24 15.2 48 47.8
LCT (%) 30 50 100 100
Essential GA (%) 18 31 52 22
MCT (%) 70 50 30 0 0
Nonprotein (cal/g N) 502 363 288 374 393 154
Osmol (mOsm/kg) 1095 590 507 600 635 615
Sodium (mmol/L) 11 — 7.2 15.2 32 34.0
Potassium (mmol/L) — — 1.5 8 27.0 28.5
Phosphate (mmol) — 16.1 6.13 6.4 11.0 11.0
Vitamins b a a a a a
Minerals b b a a 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
EAA—essential amino acids; FA—fatty acids; LCT—long-chain triglycerides; MCT—medium-chain triglycerides; N—nitrogen; NEAA—non-essential amino acids.
FIGURE 18-31
Enteral feeding formulas. There are standardized tube feeding for- with ARF. The protein content is lower and is confined to high-
mulas designed for subjects with normal renal function that can quality proteins (in part as oligopeptides and free amino acids), the
also be given to patients with acute renal failure (ARF). electrolyte concentrations are restricted. Most formulations contain
Unfortunately, the fixed composition of nutrients, including pro- recommended allowances of vitamins and minerals.
teins and high content of electrolytes (especially potassium and In part, these enteral formulas are made up of components that
phosphate) often limits their use for ARF. increase the flexibility in nutritional prescription and enable adapta-
Alternatively, enteral feeding formulas designed for nutritional tion to individual needs. The diets can be supplemented with addi-
therapy of patients with chronic renal failure (CRF) can be used. tional electrolytes, protein, and lipids as required. Recently, ready-to-
The preparations listed here may have advantages also for patients use liquid diets have also become available for renal failure patients.
Parenteral Nutrition
RENAL FAILURE FLUID—ALL-IN-ONE SOLUTION
Component Quantity Remarks

Glucose 40%–70% 500 mL In the presence of severe insulin resistance
switch to D30W
Fat emulsion 10%–20% 500 mL Start with 10%, switch to 20% if triglycerides
are < 350 mg/dL
Amino acids 6.5%–10% 500 mL General or special “nephro” amino acid
solutions, including EAA and NEAA
Water-soluble vitamins Daily Limit vitamin C intake < 200 mg/d
Fat-soluble vitamins* Daily
Trace elements* Twice weekly Caveats: toxic effects
Electrolytes As required Caveats: hypophosphatemia or hypokalemia
after initiation of TPN
Insulin As required 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, NEAA—essential and
nonessential amino acids; TPN—total parenteral nutrition.
AMINO ACID SOLUTIONS FOR THE TREATMENT OF ACUTE RENAL FAILURE (“NEPHRO” SOLUTIONS)
Aminess Aminosyn NephrAmine Nephrotect

Rose-Requirements RenAmin (Clintec) (Clintec) RF (Abbott) (McGaw) (Fresenius)
Amino acids (g/L) 65 52 52 54 100
( g/%) 6.5 5.2 5.2 5.4 10
Volume (mL) 500 400 1000 1000 500
(mOsm/L) 600 416 475 435 908
Nitrogen (g/L) 10 8.3 8.3 6.5 16.3
Essential amino acids (g/L)
Isoleucine 1.40 5.00 5.25 4.62 5.60 5.80
Leucine 2.20 6.00 8.25 7.26 8.80 12.80
Lysine acetate/HCl 1.60 4.50 6.00 5.35 6.40 12.00
Methionine 2.20 5.00 8.25 7.26 8.80 2.00
Phenylalanine 2.20 4.90 8.25 7.26 8.80 3.50
Threonine 1.00 3.80 3.75 3.30 4.00 8.20
Tryptophan 0.50 1.60 1.88 1.60 2.00 3.00
Valine 1.60 8.20 5.20 6.40 8.70
Nonessential amino acids (g/L)
Alanine 5.60 6.20
Arginine 6.30 6.00 6.00 8.20
Glycine 3.00 6.30*
Histidine 4.20 4.12 4.29 2.50 9.80
Proline 3.50 3.00
Serine 3.00 7.60
Tyrosine 0.40 3.00†
Cysteine 0.20 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 tions or in special proportions designed to counteract the
failure (ARF). The most controversial choice regards the type of metabolic changes of renal failure (“nephro” solutions), includ-
amino acid solution to be used: either essential amino acids (EAAs) ing the amino acids that might become conditionally essential
exclusively, solutions of EAA plus nonessential amino acids in ARF.
(NEAAs), or specially designed “nephro” solutions of different Because of the relative insolubility of tyrosine in water, dipep-
proportions of EAA and specific NEAA that might become “condi- tides containing tyrosine (such as glycyl-tyrosine) are contained in
tionally essential” for ARF (see Fig. 18-11). modern nephro solutions as the tyrosine source [22, 23]. One
Use of solutions of EAA alone is based on principles established for should be aware of the fact that the amino acid analogue N-acetyl
treating chronic renal failure (CRF) with a low-protein diet and an tyrosine, which previously was used frequently as a tyrosine
EAA supplement. This may be inappropriate as the metabolic adapta- source, cannot be converted into tyrosine in humans and might
tions to low-protein diets in response to CRF may not have occurred even stimulate protein catabolism [21].
in patients with ARF. Plus, there are fundamental differences in the Despite considerable investigation, there is no persuasive evi-
goals of nutritional therapy in the two groups of patients, and conse- dence that amino acid solutions enriched in branched-chain amino
quently, infusion solutions of EAA may be sub-optimal. acids exert a clinically significant anticatabolic effect. Systematic
Thus, a solution should be chosen that includes both essential studies using glutamine supplementation for patients with ARF are
and nonessential amino acids (EAA, NEAA) in standard propor- lacking (see Fig. 18-11).
FIGURE 18-34
Energy substrates in total parenteral nutrition (TPN) in acute
renal failure (ARF): glucose and lipids. Because of the well-docu-
mented 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 effects—such as aggravation of tissue injury, glycation of pro-
teins, activation of protein catabolism, among others [2]. When
intake is increased above 5 g/kg of body weight per day infused glu-
cose 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
et al. [63]; with permission.)
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 steato-
sis, 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 pre-
vent the use of lipid emulsions. Instead, the amount infused should be adjusted to meet the
patient’s 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, plas-
ma 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 triglyceride-
lowering 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
FIGURE 18-36
SUGGESTED SCHEDULE FOR MINIMAL Complications and monitoring of nutritional support in acute renal
MONITORING OF PARENTERAL NUTRITION failure (ARF).
Complications: Technical problems and infectious complica-
tions originating from the central venous catheter, chemical
Metabolic Status incompatibilities, and metabolic complications of parenteral
nutrition are similar in ARF patients and in nonuremic subjects.
Variables Unstable Stable However, tolerance to volume load is limited, electrolyte derange-
Blood glucose 1–6 daily Daily ments can develop rapidly, exaggerated protein or amino acid
Osmolality Daily 2 weekly intake stimulates excessive blood urea nitrogen (BUN) and waste
Electrolytes (Na+, K+, Cl+) Daily Daily product accumulation and glucose intolerance, and decreased fat
Calcium, phosphate, magnesium Daily 3 weekly clearance can cause hyperglycemia and hypertriglyceridemia.
Daily BUN increment Daily Daily Thus, nutritional therapy for ARF patients requires more fre-
Urea nitrogen appearance rate Daily 2 weekly quent monitoring than it does for other patient groups, to avoid
Triglycerides Daily 2 weekly
metabolic complications.
Monitoring: This table summarizes laboratory tests that moni-
Blood gas analysis, pH Daily 1 weekly
tor parenteral nutrition and avoid metabolic complications.
Ammonia 2 weekly 1 weekly
The frequency of testing depends on the metabolic stability of
Transaminases bilirubin 2 weekly 1 weekly
the patient. In particular, plasma glucose, potassium, and phos-
phate should be monitored repeatedly after the start of parenter-
al nutrition.
References
1. Druml W: Nutritional support in acute renal failure. In Nutrition and 14. Kuhlmann MK, Shahmir E, Maasarani E, et al.: New experimental
the Kidney. Edited by Mitch WE, Klahr S. Philadelphia: Lippincott- model of acute renal failure and sepsis in rats. JPEN 1994,
Raven, 1998. 18:477–485.
2. Druml W, Mitch WE: Metabolism in acute renal failure. Sem Dial 15. Bergström J: Factors causing catabolism in maintenance hemodialysis
1996, 9:484–490. patients. Miner Electrolyte Metab 1992, 18:280–283.
3. Om P, Hohenegger M: Energy metabolism in acute uremic rats. 16. Druml W, Bürger U, Kleinberger G, et al.: Elimination of amino acids
Nephron 1980, 25:249–253. in acute renal failure. Nephron 1986, 42:62–67.
4. Schneeweiss B, Graninger W, Stockenhuber F, et al.: Energy metabolism 17. Druml W, Fischer M, Liebisch B, et al.: Elimination of amino acids in
in acute and chronic renal failure. Am J Clin Nutr 1990, 52:596–601. renal failure. Am J Clin Nutr 1994, 60:418–423.
5. Soop M, Forsberg E, Thˆrne A, Alvestrand A: Energy expenditure in 18. Mitch WE, Chesney RW: Amino acid metabolism by the kidney.
postoperative multiple organ failure with acute renal failure. Clin Miner Electrolyte Metab 1983, 9:190–202.
Nephrol 1989, 31:139–145. 19. Laidlaw SA, Kopple JD: Newer concepts of indispensable amino
6. Spreiter SC, Myers BD, Swenson RS: Protein-energy requirements in acids. Am J Clin Nutr 1987, 46:593–605.
subjects with acute renal failure receiving intermittent hemodialysis. 20. Naschitz JE, Barak C, Yeshurun D: Reversible diminished insulin
Am J Clin Nutr 1980, 33:1433–1437. requirement in acute renal failure. Postgrad Med J 1983, 59:269–271.
7. Mitch WE: Amino acid release from the hindquarter and urea appear- 21. Druml W, Lochs H, Roth E, et al.: Utilisation of tyrosine dipeptides
ance in acute uremia. Am J Physiol 1981, 241:E415–E419. and acetyl-tyrosine in normal and uremic humans. Am J Physiol
8. Salusky IB, Flügel-Link RM, Jones MR, Kopple JD: Effect of acute 1991, 260:E280–E285.
uremia on protein degradation and amino acid release in the rat hemi- 22. Druml W, Roth E, Lenz K, et al.: Phenylalanine and tyrosine metabo-
corpus. Kidney Int 1983, 24(Suppl. 16):S41–S42. lism in renal failure. Kidney Int 1989, 36(Suppl 27):S282–S286.
9. Clark AS, Mitch WE: Muscle protein turnover and glucose uptake in 23. Fürst P. Stehle P: The potential use of dipeptides in clinical nutrition.
acutely uremic rats. J Clin Invest 1983, 72:836–845. Nutr Clin Pract 1993, 8:106–114.
10. Maroni BJ, Karapanos G, Mitch WE: System A amino acid transport 24. Hübl W, Druml W, Roth E, Lochs H: Importance of liver and kidney
in incubated muscle: Effects of insulin and acute uremia. Am J Physiol for the utilization of glutamine-containing dipeptides in man.
1986, 251:F74–F80. Metabolism 1994, 43:1104–1107.
11. Druml W, Kelly RA, Mitch WE, May RC: Abnormal cation transport 25. Hasik J, Hryniewiecki L, Baczyk K, Grala T: An attempt to evaluate
in uremia. J Clin Invest 1988, 81:1197–1203. minimum requirements for protein in patients with acute renal failure.
12. Fröhlich J, Hoppe-Seyler G, Schollmeyer P, et al.: Possible sites of inter- Pol Arch Med Wewn 1979, 61:29–36.
action of acute renal failure with amino acid utilization for gluconeoge- 26. Lopez-Martinez J, Caparros T, Perez-Picouto F: Nutrition parenteral
nesis in isolated perfused rat liver. Eur J Clin Invest 1977, 7:261–268. en enfermos septicos con fracaso renal agudo en fase poliurica. Rev
13. May RC, Kelly RA, Mitch WE: Mechanisms for defects in muscle Clin Esp 1980, 157:171–178.
protein metabolism in rats with chronic uremia: The influence of 27. Kierdorf H: Continuous versus intermittent treatment: Clinical results
metabolic acidosis. J Clin Invest 1987; 79:1099–1103. in acute renal failure. Contrib Nephrol 1991, 93:1–12.
28. Chima CS, Meyer L, Hummell AC, et al.: Protein catabolic rate in 47. Druml W: Impact of continuous renal replacement therapies on
patients with acute renal failure on continuous arteriovenous hemofil- metabolism. Int J Artif Organs 1996, 19:118–120.
tration and total parenteral nutrition. J Am Soc Nephrol 1993, 48. Frankenfeld DC, Badellino MM, Reynolds HN, et al.: Amino acid
3:1516–1521. loss and plasma concentration during continuous hemodiafiltration.
29. Macias WL, Alaka KJ, Murphy MH, et al.: Impact of nutritional regi- JPEN 1993, 17:551–561.
men on protein catabolism and nitrogen balance in patients with 49. Toback FG: Regeneration after acute tubular necrosis. Kidney Int
acute renal failure. JPEN 1996, 20:56–62. 1992, 41:226–246.
30. Ikizler TA, Greene JH, Wingard RL, Hakim RM: Nitrogen balance in 50. Toback FG, Dodd RC, Maier ER, Havener LJ: Amino acid adminis-
acute renal failure patients. J Am Soc Nephrol 1995, 6:466A. tration enhances renal protein metabolism after acute tubular necro-
31. May RC, Clark AS, Goheer MA, Mitch WE: Specific defects in sis. Nephron 1983, 33:238–243.
insulin-mediated muscle metabolism in acute uremia. Kidney Int 51. Abel RM, Beck CH, Abbott WM, et al.: Improved survival from acute
1985, 28:490–497. renal failure after treatment with intravenuous essential amino acids
32. Cianciaruso B, Bellizzi V, Napoli R, et al.: Hepatic uptake and release and glucose: Results of a prospective double-blind study. N Engl J
of glucose, lactate and amino acids in acutely uremic dogs. Med 1973, 288:695–699.
Metabolism 1991, 40:261–290. 52. Oken DE, Sprinkel M, Kirschbaum BB, Landwehr DM: Amino acid
33. Druml W, Laggner A, Widhalm K, et al.: Lipid metabolism in acute therapy in the treatment of experimental acute renal failure in the rat.
Kidney Int 1980, 17:14–23.
renal failure. Kidney Int 1983, 24(Suppl 16):S139–S142.
53. Zager RA, Venkatachalam MA: Potentiation of ischemic renal injury
34. Druml W, Fischer M, Sertl S, et al.: Fat elimination in acute renal fail-
by amino acid infusion. Kidney Int 1983, 24:620–625.
ure: Long-chain versus medium-chain triglycerides. Am J Clin Nutr
1992, 55:468–472. 54. Brezis M, Rosen S, Spokes K, et al.: Transport-dependent anoxic cell
injury in the isolated perfused rat kidney. Am J Pathol 1984,
35. Druml W, Zechner R, Magometschnigg D, et al.: Post-heparin lipolyt- 116:327–341.
ic activity in acute renal failure. Clin Nephrol 1985, 23:289–293.
55. Heyman SN, Rosen S, Silva P, et al.: Protective action of glycine in
36. Adolph M, Eckart J, Metges C, et al.: Oxidative utilization of lipid cisplatin nephrotoxicity. Kidney Int 1991, 40:273–279.
emulsions in septic patients with and without acute renal failure. Clin
Nutr 1995, 14(Suppl 2):35A. 56. Schramm L, Heidbreder E, Lopau K, et al.: Influence of nitric oxide
on renal function in toxic renal failure in the rat. Miner Electrolyte
37. Dobyan DC, Bulger RE, Eknoyan G: The role of phosphate in the Metab 1996, 22:168–177.
potentiation and amelioration of acute renal failure. Miner Electrolyte
57. Wakabayashi Y, Kikawada R: Effect of L-arginine on myoglobin-
Metab 1991, 17:112–115.
induced acute renal failure in the rabbit. Am J Physiol 1996,
38. Druml W, Lax F, Grimm G, et al.: Acute renal failure in the elderly— 270:F784–F789.
1975–1990. Clin Nephrol 1994, 41:342–349.
58. Ding H, Kopple JD, Cohen A, Hirschberg R: Recombinant human
39. Kurtin P, Kouba J: Profound hypophosphatemia in the course of acute insulin-like growth factor-1 accelerates recovery and reduces catabo-
renal failure. Am J Kidney Dis 1987, 10:346–349. lism in rats with ischemic acute renal failure. J Clin Invest 1993,
40. Marik PE, Bedigian MK: Refeeding hypophosphatemia in critically ill 91:2281–2287.
patients in an intensive care unit. Arch Surg 1996, 131:1043–1047. 59. Franklin SC, Moulton M, Sicard GA, et al.: Insulin-like growth factor
41. Kleinberger G, Gabl F, Gassner A, et al.: Hypophosphatemia during 1 preserves renal function postoperatively. Am J Physiol 1997,
parenteral nutrition in patients with renal failure. Wien Klin 272:F257–F259.
Wochenschr 1978, 90:169–172. 60. Hirschberg R, Kopple JD, Guler HP, Pike M: Recombinant human
42. Madl Ch, Kranz A, Liebisch B, et al.: Lactic acidosis in thiamine defi- insulin-like growth factor-1 does not alter the course of acute renal
ciency. Clin Nutr 1993, 12:108–111. failure in patients. 8th Int. Congress Nutr Metabol Renal Disease,
Naples 1996.
43. Friedman AL, Chesney RW, Gilbert EF, et al.: Secondary oxalosis as a
61. Druml W, Mitch WE: Enteral nutrition in renal disease. In Enteral
complication of parenteral alimentation in acute renal failure. Am J
and Tube Feeding. Edited by Rombeau JL, Rolandelli RH.
Nephrol 1983, 3:248–252.
Philadelphia: WB Saunders, 1997:439–461.
44. Druml W, Schwarzenhofer M, Apsner R, Hörl WH: Fat soluble vita-
62. Roberts PR, Black KW, Zaloga GP: Enteral feeding improves outcome
mins in acute renal failure. Miner Electrolyte Metab 1998, 24:220–226. and protects against glycerol-induced acute renal failure in the rat.
45. Zurovsky Y, Gispaan I: Antioxidants attenuate endotoxin-induced Am J Respir Crit Care Med 1997, 156:1265–1269.
acute renal failure in rats. Am J Kidney Dis 1995, 25:51–57. 63. Wennberg A, Norbeck HE, Sterner G, Lundholm K: Effects of intra-
46. Druml W, Bartens C, Stelzer H, et al.: Impact of acute renal failure on venous nutrition on lipoprotein metabolism, body composition,
antioxidant status in multiple organ failure syndrome. JASN 1993, weight gain and uremic state in experimental uremia in rats. J Nutr
4:314A. 1991, 121:1439–1446.
Supportive Therapies:
Intermittent Hemodialysis,
Continuous Renal
Replacement Therapies,
and Peritoneal Dialysis
Ravindra L. Mehta
O
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, ther-
apeutic 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 out-
comes from ARF. This chapter outlines current concepts in the use of
dialysis techniques for ARF.
CHAPTER
19
Dialysis Methods
run) that does not need to be pretreated, the unique characteristics of
the regeneration process allow greater flexibility in custom tailoring
DIALYSIS MODALITIES FOR ACUTE RENAL FAILURE
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
Intermittent therapies Continuous therapies cost of the sterile replacement fluid [3]. Several modifications have
Hemodialysis (HD) Peritoneal (CAPD, CCPD) been made in this therapy, including the provision of on-line prepara-
Single-pass Ultrafiltration (SCUF) tion of sterile replacement solutions. Proponents of this modality
Sorbent-based Hemofiltration (CAVH, CVVH) claim a greater degree of hemodynamic stability and improved middle
Peritoneal (IPD) Hemodialysis (CAVHD, CVVHD) molecule clearance, which may have an impact on outcomes.
Hemofiltration (IHF) Hemodiafiltration (CAVHDF, CVVHDF) As a more continuous technique, peritoneal dialysis (PD) is an
Ultrafiltration (UF) CVVHDF 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 equili-
FIGURE 19-1 brated PD is utilized [4]. Dialysate is instilled and drained manually
Several methods of dialysis are available for renal replacement thera- and continuously every 3 to six hours, and fluid removal is achieved
py. While most of these have been adapted from dialysis procedures by varying the concentration of dextrose in the solutions.
developed for end-stage renal disease several variations are available Alternatively, the process can be automated with a cycling device
specifically for ARF patients [1] . programmed to deliver a predetermined volume of dialysate and
Of the intermittent procedures, intermittent hemodialysis (IHD) is drain the peritoneal cavity at fixed intervals. The cycler makes the
currently the standard form of therapy worldwide for treatment of process less labor intensive, but the utility of PD in treating ARF in
ARF in both intensive care unit (ICU) and non-ICU settings. The vast the ICU is limited because of: 1) its impact on respiratory status
majority of IHD is performed using single-pass systems with moder- owing to interference with diaphragmatic excursion; 2) technical dif-
ate blood flow rates (200 to 250 mL/min) and countercurrent ficulty of using it in patients with abdominal sepsis or after abdomi-
dialysate flow rates of 500 mL/min. Although this method is very effi- nal surgery; 3) relative inefficiency in removing waste products in
cient, it is also associated with hemodynamic instability resulting from “catabolic” patients; and 4) a high incidence of associated peritoni-
the large shifts of solutes and fluid over a short time. Sorbent system tis. Several continuous renal replacement therapies (CRRT) have
IHD that regenerates small volumes of dialysate with an in-line evolved that differ only in the access utilized (arteriovenous [non-
Sorbent cartridge have not been very popular; however, they are a pumped: SCUF, CAVH, CAVHD, CAVHDF] versus venovenous
useful adjunct if large amounts of water are not available or in disas- [pumped: CVVH, CVVHD, CVVHDF]), and, in the principal
ters [2]. These systems depend on a sorbent cartridge with multiple method of solute clearance (convection alone [UF and H], diffusion
layers of different chemicals to regenerate the dialysate. In addition to alone [hemodialyis (HD)], and combined convection and diffusion
the advantage of needing a small amount of water (6 L for a typical [hemodiafiltration (HDF)]).
CRRT techniques: SCUF CRRT techniques: CAVH – CVVH

A–V SCUF V–V SCUF CAVH R CVVH R
A V A V
V P V V P V
Uf UFC Uf Uf Uf
Qb = 50–100 mL/min Qb = 50–200 mL/min Qb = 50–100 mL/min Qb = 50–200 mL/min
Qf = 2–6 mL/min Qf = 2–8 mL/min Qf = 8–12 mL/min Qf = 10–20 mL/min
Mechanisms of function Mechanisms of function
Treatment Pressure profile Membrane Reinfusion Diffusion Convection Treatment Pressure profile Membrane Reinfusion Diffusion Convection
SCUF TMP=30mmHg CAVH–CVVH TMP=50mmHg
0 High–flux No Low Low 0 High–flux Yes Low High
in out in out
A B
FIGURE 19-2
Schematics of different CRRT techniques. A, Schematic repre- continuous arteriovenous or venovenous hemofiltration
sentation of SCUF therapy. B, Schematic representation of (CAVH/CVVH) therapy.
Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis 19.3
CRRT techniques: CAVHD – CVVHD CRRT techniques: CAVHDF – CVVHDF

CAVHD CVVHD CAVHDF R CVVHDF P
A P A
V V P V
V V V
Dial. Out Dial. in Dial. Out Dial. in Dial. Out Dial. In Dial. Out Dial. In
+Uf +Uf
Qb = 50–100 mL/min Qf=1–3 mL/min Qb = 50–100 mL/min Qf=1–5 mL/min Qb = 50–100 Qd=10–20 mL/min Qb = 100–200 Qd=20–40 mL/min
Qd= 10–20 mL/min Qd=10–30 mL/min Qf = 8–12 mL/min Qf = 10–20 mL/min
Mechanisms of function Mechanisms of function
Treatment Pressure profile Membrane Reinfusion Diffusion Convection Treatment Pressure profile Membrane Reinfusion Diffusion Convection
CAVHD–CVVHD TMP=50mmHg CAVHDF–CVVHDF TMP=50mmHg
0 Low–flux No High Low 0 High–flux Yes High High
C D

C, Schematic representation of continuous arteriovenous/ P—peristaltic pump; Qb—blood flow; Qf—ultrafiltration
venovenous hemodialysis (CAVHD-CVVHD) therapy. rate; TMP—transmembrane pressure; in—dilyzer inlet; out—
D, Schematic representation of continuous arteriovenous/ dialyzer outlet; UFC—ultrafiltration control system; Dial—
venovenous hemodiafiltration (CAVHDF/CVVHDF) therapy. dialysate; Qd—dialysate flow rate. (From Bellomo et al. [5];
A—artery; V—vein; Uf—ultrafiltrate; R—replacement fluid; with permission.)
CONTINUOUS RENAL REPLACEMENT THERAPY: COMPARISON OF TECHNIQUES
SCUF CAVH CVVH CAVHD CAVHDF CVVHD CVVHDF PD

Access AV AV VV AV AV VV VV Perit. Cath.
Pump No No Yes No No Yes Yes No†
Filtrate (mL/h) 100 600 1000 300 600 300 800 100
Filtrate (L/d) 2.4 14.4 24 7.2 14.4 7.2 19.2 2.4
Dialysate flow (L/h) 0 0 0 1.0 1.0 1.0 1.0 0.4
Replacement fluid (L/d) 0 12 21.6 4.8 12 4.8 16.8 0
Urea clearance (mL/min) 1.7 10 16.7 21.7 26.7 21.7 30 8.5
Simplicity* 1 2 3 2 2 3 3 2
Cost* 1 2 4 3 3 4 4 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 terminolo- Diffusion-based techniques similar to intermittent hemodialysis
gy for continuous renal replacement therapy (CRRT) techniques (HD) are based on the principle of a solute gradient between the
has been subject to individual interpretation. Recognizing this lack blood and the dialysate. If both diffusion and convection are used
of standardization an international group of experts have proposed in the same technique the process is termed hemodiafiltration
standardized terms for these therapies [5]. The basic premise in the (HDF). In this instance, both dialysate and a replacement solution
development of these terms is to link the nomenclature to the oper- are used, and small and middle molecules can both be removed
ational characteristics of the different techniques. In general all easily. The letters UF, H, HD, and HDF identify the operational
these techniques use highly permeable synthetic membranes and characteristics in the terminology. Based on these principles, the
differ in the driving force for solute removal. When arteriovenous terminology for these techniques is easier to understand. As shown
(AV) circuits are used, the mean arterial pressure provides the in Figure 19-1 the letter C in all the terms describes the continuous
pumping mechanism. Alternatively, external pumps generally utilize nature of the methods, the next two letters [AV or VV] depict the
a venovenous (VV) circuit and permit better control of blood flow driving force and the remaining letters [UF, H, HD, HDF] represent
rates. The letters AV or VV in the terminology serve to identify the the operational characteristics. The only exception to this is the
driving force in the technique. Solute removal in these techniques is acronym SCUF (slow continuous ultrafiltration), which remains as
achieved by convection, diffusion, or a combination of these two. a reminder of the initiation of these therapies as simple techniques
Convective techniques include ultrafiltration (UF) and hemofiltra- harnessing the power of AV circuits. (Modified from Mehta [7];
tion (H) and depend on solute removal by solvent drag [6]. with permission.)
Operational Characteristics
Anticoagulation
Surface Anticoagulation in Dialysis for ARF
Contact Platelet Patient Dialyzer Membrane

activation activation Uremia Geometry
Drug therapy Manufacture
Propagation
Dialysis
Initiation
FIXa Procoagulant technique

surface
Dialyzer preparation
Anticoagulation
Blood flow access
Thrombin
Fibrin
FIGURE 19-5
Factors influencing dialysis-related thrombogenicity. One of the
major determinants of the efficacy of any dialysis procedure in acute
FIGURE 19-4 renal failure (ARF) is the ability to maintain a functioning extracor-
Pathways of thrombogenesis in extracorporeal circuits. (Modified poreal circuit. Anticoagulation becomes a key component in this
from Lindhout [8]; with permission.) regard and requires a balance between an appropriate level of anti-
coagulation 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
Heparin CRRT
Modalities for anticoagulation for continuous renal replacement
Anticoagulant Replacement Dialysate
therapy. While systemic heparin is the anticoagulant most com-
heparin solutions 1.5% dianeal
(~400µ/h) (A & B alternating) (1000mL/h)
monly used for dialysis, other modalities are available. The utiliza-
tion of these modalities is largely influenced by prevailing local
experience. Schematic diagrams for heparin, A, and citrate, B, anti-
Arterial Venous
Filter coagulation techniques for continuous renal replacement therapy
catheter catheter (CRRT). A schematic of heparin and regional citrate anticoagula-
(d)
(a) (b) (c) tion for CRRT techniques. Regional citrate anticoagulation mini-
3–way
stop cock
mizes the major complication of bleeding associated with heparin,
Ultrafiltrate but it requires monitoring of ionized calcium. It is now well-recog-
(effluent dialysate nized that the longevity of pumped or nonpumped CRRT circuits
A plus net ultrafiltrate)
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),
Citrate CRRT Dialysate Calcium whereas in pumped circuits (CVVH/HD/HDF) blood flow is main-
NA 117, K4, Mg 1., 1 mEq/10 mL tained; however, the constant pressure across the membrane results
Cl 122.5 mEq/L; (~40 mL/h) in a layer of protein forming over the membrance reducing its effi-
dextrose 0.1%–2.5% cacy. This process is termed concentration repolarization [10].
Anticoagulant Replacement zero alkali CAVH/CVVH—continuous arteriovenous/venovenous hemofiltra-
Central
4%% trisodium citrate solution zero calcium tion. (From Mehta RL, et al. [11]; with permission.)
(~170 mL/h) 0.9%% saline (1000 mL/h) line
Arterial Venous
Filter
catheter catheter
(a) (b) (d) (c)
3–way
stop cock Ultrafiltrate
(effluent dialysate
B plus net ultrafiltrate)
Solute Removal
Membrane Membrane
Blood Dialysate Blood Dialysate
Middle
molecules
Small
molecules
Diffusion Convection
Concentration gradient based transfer. Movement of water across the membrane
Small molecular weight substances (<500 Daltons) carries solute across the membrane.
A are transferred more rapidly. B Middle molecules are removed more efficiently.
FIGURE 19-7
Membrane
Blood Dialysate Mechanisms of solute removal in dialysis. The success of any dialysis
procedure depends on an understanding of the operational character-
istics 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.
Adsorption
Several solutes are removed from circulation by
adsorption to the membrane. This process is
C influenced by the membrane structure and charge.
number of exchanges and the dwell time of

each exchange. In continuous arteriovenous
DETERMINANTS OF SOLUTE REMOVAL IN DIALYSIS
and venovenous hemodialysis in most situa-
TECHNIQUES FOR ACUTE RENAL FAILURE
tions ulrafiltration rates of 1 to 3 L/hour are
utilized; however recently high-volume
hemofiltration with 6 L of ultrafiltrate pro-
IHD CRRT PD duced every hour has been utilized to
Small solutes (MW <300) Diffusion: Diffusion: Diffusion: remove middle– and large–molecular weight
Qb Qd Qd cytokines in sepsis [12]. Fluid balance is
Membrane width Convection: Convection: achieved by replacing the ultrafiltrate
Qd Qf Qf removed by a replacement solution. The
Middle molecules (MW 500–5000) Diffusion composition of the replacement fluid can be
Convection: Convection: Convection: varied and the solution can be infused
Qf Qf Qf before or after the filter.
SC SC SC Diffusion-based techniques (hemodialysis)
LMW proteins (MW 5000–50,000) Convection Convection Convection
are based on the principle of a solute gradi-
ent between the blood and the dialysate. In
Diffusion Adsorption
IHD, typically dialysate flow rates far exceed
Adsorption
blood flow rates (200 to 400 mL/min,
Large proteins (MW >50,000) Convection Convection Convection
dialysate flow rates 500 to 800 mL/min) and
dialysate flow is single pass. However, unlike
IHD, the dialysate flow rates are significant-
ly slower than the blood flow rates (typical-
FIGURE 19-8 ly, rates are 100 to 200 mL/min, dialysate
Determinants of solute removal in dialysis techniques for acute renal failure. Solute removal flow rates are 1 to 2 L/hr [17 to 34mL/min]),
in these techniques is achieved by convection, diffusion, or a combination of these two. resulting in complete saturation of the
Convective techniques include ultrafiltration (UF) and hemofiltration (H) and they depend dialysate. As a consequence, dialysate flow
on solute removal by solvent drag [6]. As solute removal is solely dependent on convective rates become the limiting factor for solute
clearance it can be enhanced only by increasing the volume of ultrafiltrate produced. While removal and provide an opportunity for
ultrafiltration requires fluid removal only, to prevent significant volume loss and resulting clearance enhancement. Small molecules are
hemodynamic compromise, hemofiltration necessitates partial or total replacement of the preferentially removed by these methods. If
fluid removed. Larger molecules are removed more efficiently by this process and, thus, both diffusion and convection are used in
middle molecular clearances are superior. In intermittent hemodialysis (IHD) ultrafiltration the same technique (hemodiafiltration, HDF)
is achieved by modifying the transmembrane pressure and generally does not contribute sig- both dialysate and a replacement solution
nificantly to solute removal. In peritoneal dialysis (PD) the UF depends on the osmotic gra- are used and small and middle molecules can
dient achieved by the concentration of dextrose solution (1.55% to 4.25%) utilized the both be easily removed.
FIGURE 19-9
Dialyste flow, L/h Dialysis time Ultrafiltrate volume, Cycling Manual Comparison of weekly urea clearances with different dialysis tech-
1.5 1 4 h/d 4 h qod L/d treatment time, hrs
40 48 niques. Although continuous therapies are less efficient than inter-
352 20 15 mittent techniques, overall clearances are higher as they are utilized
Dialysate inflow, L/wk
160 96 continuously. It is also possible to increase clearances in continuous
302 techniques by adjustment of the ultrafiltration rate and dialysate
268
flow rate. In contrast, as intermittent dialysis techniques are opera-
tional at maximum capability, it is difficult to enhance clearances
except by increasing the size of the membrane or the duration of
140 therapy. CAV/CVVHDF—continuous arteriovenous/venovenous
hemodiafiltration; IHD—intermittent hemodialysis; CAVH—con-
84
72 tinuous arteriovenous hemodialysis; PD—peritoneal dialysis.
CAVHDF/CVVHDF IHD CAVH PD

COMPARISON OF DIALYSIS PRESCRIPTION DRUG DOSING IN CRRT*

AND DOSE DELIVERED IN CRRT AND IHD
Drug Normal Dose (mg/d) Dose in CRRT (mg)

Dialysis Prescription Amikacin 1050 250 qd–bid
IHD CRRT Netilmycin 420 100–150 qd
Membrane characteristics Variable permeability High permeability Tobramycin 350 100 qd
Anticoagulation Short duration Prolonged Vancomycin 2000 500 qd–bid
Blood flow rate ≥200 mL/min <200 mL/min Ceftazidime 6000 1000 bid
Dialysate flow ≥500 mL/min 17–34 mL/min Cefotaxime 12,000 2000 bid
Duration 3–4 hrs Days Ceftriaxone 4000 2000 qd
Clearance High Low Ciprofloxacin 400 200 qd
Imipenem 4000 500 tid–qid
Dialysis Dose Delivered Metronidazole 2100 500 tid–qid
IHD CRRT Piperacillin 24,000 4000 tid
Patient factors Digoxin 0.29 0.10 qd
Hemodynamic stability +++ + Phenobarbital 233 100 bid–qid
Recirculation +++ + Phenytoin 524 250 qd–bid
Infusions ++ + Theophylline 720 600–900 qd
Technique factors
Blood flow +++ ++ * Reflects doses for continuous venovenous hemofiltration with ultrafiltration rate of
Concentration repolarization + +++ 20 to 30 mL/min.
Membrane clotting + +++
Duration +++ +
FIGURE 19-11
Other factors
Drug dosing in continuous renal replacement (CRRT) techniques.
Nursing errors + +++
Drug removal in CRRT techniques is dependent upon the molecular
Interference + ++++
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
FIGURE 19-10 the continuous removal in CRRT. (Modified from Kroh et al. [13];
Comparison of dialysis prescription and dose delivered in continu- with permission.)
ous 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 charac-
teristics; however, it must be recognized that there may be a signifi-
cant difference between the dialysis dose prescribed and that deliv-
ered. 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.
NUTRITIONAL ASSESSMENT AND SUPPORT WITH RENAL REPLACEMENT TECHNIQUES
Parameters: Initial Assessment IHD CAVH/CVVH CAVHD/CVVHDF

Energy assessment HBE x AF x SF, or indirect calorimetry Same Same
Dialysate dextrose absorption Negligible Not applicable 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
0.1–0.15% dextrose
Protein assessment
Visceral proteins Serum prealbumin Same Same
Nitrogen balance: N2 in–N2 out Nitrogen in: protein in TPN +/enteral Nitrogen in: same Nitrogen in: same
solutions/6.25
Nitrogen out: urea nitrogen appearance Nitrogen out: ultrafiltrate urea Nitrogen out: ultrafiltrate/dialysate urea
nitrogen losses nitrogen losses
UUN† UUN† UUN†
Insensible losses Insensible losses Insensible losses
Dialysis amino acid losses Ultrafiltrate amino acid losses Ultrafiltrate/dialysate amino acid losses
(1.0–1.5 N2/dialysis therapy) (1.5–2.0 N2/D) (1.5–2.0 N2/D)
Nutrition support prescription: Renal formulas with limited fluid, potas- Standard TPN/enteral formulations. Standard TPN/enteral formulations when 0.1–0.15%
TPN/enteral nutrition sium, phosphorus, and magnesium No fluid or electrolyte restrictions. dextrose dialysate used
Modified formulations when 1.5–2.5% dextrose
dialysate used
TPN: Low-dextrose solutions to prevent carbohy-
drate 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.
Reassessment of requirements and
efficacy of nutrition support
Energy assessment Weekly HBE x AF x SF*, or Same Same
indirect calorimetry
Serum prealbumin Weekly Same Same
Nitrogen balance Weekly Same Same
* 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 tech- absorption occurs form the dialysate in hemodialysis and hemodi-
niques. A key feature of dialysis support in acute renal failure is to afiltration modalities and can result in hyperglycemia. Intermittent
permit an adequate amount of nutrition to be delivered to the dialysis techniques are limited by time in their ability to allow
patient. The modality of dialysis and operational characteristics unlimited nutritional support. (From Monson and Mehta [14];
affect the nutritional support that can be provided. Dextrose with permission.)
Fluid Control
patients with acute renal failure in the
intensive care setting. In the presence of a
OPERATING CHARACTERISTICS OF CRRT:
failing kidney, fluid removal is often a chal-
FLUID REMOVAL VERSUS FLUID REGULATION
lenge that requires large doses of diuretics
with a variable response. It is often neces-
sary in this setting to institute dialysis for
Fluid Removal Fluid Regulation volume control rather than metabolic con-
Ultrafiltration rate (UFR) To meet anticipated needs Greater than anticipated needs trol. CRRT techniques offer a significant
Fluid management Adjust UFR Adjust amount of replacement fluid advantage over intermittent dialysis for
Fluid balance Zero or negative balance Positive, negative, or zero balance fluid control [14,15]; however, if not car-
Volume removed Based on physician estimate Driven by patient characteristics ried out appropriately they can result in
Application Easy, similar to intermittent hemodialysis Requires specific tools and training major complications. To utilize these thera-
pies for their maximum potential it is neces-
sary to recognize the factors that influence
fluid balance and have an understanding of
the principles of fluid management with
FIGURE 19-13 these techniques. In general it is helpful to
Operating characteristics of continuous renal replacement (CRRT): fluid removal versus consider dialysis as a method for fluid
fluid regulation. Fluid management is an integral component in the management of removal and fluid regulation.
hours instead of 3 to 4 hours. In Level 2

the ultrafiltrate volume every hour is delib-
APPROACHES FOR FLUID MANAGEMENT IN CRRT
erately set to be greater than the hourly
intake, and net fluid balance is achieved by
hourly replacement fluid administration. In
Approaches Level 1 Level 2 Level 3 this method a greater degree of control is
UF volume Limited Increase intake Increase intake possible and fluid balance can be set to
Replacement Minimal Adjusted to achieve Adjusted to achieve achieve any desired outcome. The success
fluid balance fluid balance of this method depends on the ability to
Fluid balance 8h Hourly Hourly achieve ultrafiltration rates that always
Targeted exceed the anticipated intake. This allows
UF pump Yes Yes/No Yes/No flexibility in manipulation of the fluid bal-
Examples SCUF/CAVHD CAVH/CVVH CAVHDF/CVVHDF ance, so that for any given hour the fluid
CVVHD CAVHDF/CVVHDF CVVH status could be net negative, positive, or
Advantages balanced. A key advantage of this tech-
Simplicity +++ ++ + nique is that the net fluid balance achieved
Achieve fluid balance + +++ +++ at the end of every hour is truly a reflec-
Regulate volume changes + ++ +++ tion of the desired outcome. Level 3
CRRT as support + ++ +++ extends the concept of the Level 2 inter-
Disadvantages
vention to target the desired net balance
every hour to achieve a specific hemody-
Nursing effort + ++ +++
namic parameter (eg, central venous pres-
Errors in fluid balance +++ ++ +
sure, pulmonary artery wedge pressure, or
Hemodynamic instability ++ ++ +
mean arterial pressure). Once a desired
Fluid overload +++ + +
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
FIGURE 19-14 calls for more effort and consequently
Approaches for fluid management in continuous renal replacement therapy (CRRT). results in improved outcomes. SCUF—
CRRT techniques are uniquely situated in providing fluid regulation, as fluid manage- ultrafiltration; CAVHD/CVVHD—continu-
ment can be achieved with three levels of intervention [16]. In Level 1, the ultrafiltrate ous arteriovenous/venovenous hemodialy-
(UF) volume obtained is limited to match the anticipated needs for fluid balance. This sis; CAVH/CVVH—continuous arteriove-
calls for an estimate of the amount of fluid to be removed over 8 to 24 hours and subse- nous/venovenous hemofiltration;
quent calculation of the ultrafiltration rate. This strategy is similar to that commonly CAVHDF/CVVHDF—continuous arteri-
used for intermittent hemodialysis and differs only in that the time to remove fluid is 24 ovenous/venovenous hemodiafiltration.
FIGURE 19-15
COMPOSITION OF REPLACEMENT FLUID AND DIALYSATE FOR CRRT Composition of dialysate and replacement
fluids used for continuous renal replace-
ment therapy (CRRT). One of the key fea-
Replacement Fluid tures of any dialysis method is the manipu-
lation of metabolic balance. In general, this
Investigator Golper [19] Kierdorf [20] Lauer [21] Paganini [22] Mehta [11] Mehta [11] is achieved by altering composition of
Na+ 147 140 140 140 140.5 154 dialysate or replacement fluid . Most com-
Cl- 115 110 — 120 115.5 154 mercially available dialysate and replace-
HCO3- 36 34 — 6 25 — ment solutions have lactate as the base;
K+ 0 0 2 2 0 — however, bicarbonate-based solutions are
Ca2+ 1.2 1.75 3.5 4 4 — being utilized more and more [17,18].
Mg2+ 0.7 0.5 1.5 2 — —
Glucose 6.7 5.6 — 10 — —
Acetate — — 41 40 — —
Dialysate
Component (mEq/L) 1.5% Dianeal Hemosol AG 4D Hemosol LG 4D Baxter Citrate
Sodium 132 140 140 140 117
Potassium — 4 4 2 4
Chloride 96 119 109.5 117 121
Lactate 35 — 40 30 —
Acetate — 30 — — —
Calcium 3.5 3.5 4 3.5 —
Magnesium 1.5 1.5 1.5 1.5 1.5
Dextrose (g/dL) 1.5 0.8 .11 0.1 0.1–2.5
FIGURE 19-16
Replacement 17 mL/min
Prefilter Prefilter Postfilter Effect of site of delivery of replacement fluid: pre- versus postfilter
Prepump Prepump BFR 100 mL/min continuous venovenous hemofiltration with ultrafiltration rate of 1
BFR 83 mL/min BFR 117 mL/min 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 proce-
Filter dure. There is a significant effect of fluid delivered prepump or
postpump, as the amount of blood delivered to the filter is reduced
Blood pump
in prepump dilution. BFR—blood flow rate.
BFR 100 mL/min
Ultrafiltrate
FIGURE 19-17
50 Prefilter prepump 47.6 Pre- versus postfilter replacement fluid: effect on filtration fraction.
Prefilter postpump 41.6 Prefilter replacement tends to dilute the blood entering the circuit
40 35.7
Postfilter 32.2 32.2 and enhances filter longevity by reducing the filtration fraction;
30 26.3 however, in continuous venovenous hemofiltration (CVVH) circuits
%
22.6 23.9
20 19.5 the overall clearance may be reduced as the amount of solute deliv-
ered to the filter is reduced.
10
0
CVVH 1L/h CVVH 3L/h CVVH 6L/h
Applications and Indications for Dialytic Intervention

important consideration in this regard is to
recognize that the patient with ARF is
INDICATIONS AND TIMING OF DIALYSIS FOR ACUTE RENAL FAILURE:
somewhat different than the one with end-
RENAL REPLACEMENT VERSUS RENAL SUPPORT
stage renal disease (ESRD). The rapid
decline of renal function associated with
multiorgan failure does not permit much
Renal Replacement Renal Support of an adaptive response which character-
Purpose Replace renal function Support other organs izes the course of the patient with ESRD.
Timing of intervention Based on level of biochemical markers Based on individualized need As a consequence, the traditional indica-
Indications for dialysis Narrow Broad
tions for renal replacement may need to be
redefined. For instance, excessive volume
Dialysis dose Extrapolated from ESRD Targeted for overall support
resuscitation, a common strategy for mul-
tiorgan failure, may be an indication for
dialysis, even in the absence of significant
elevations in blood urea nitrogen. In this
FIGURE 19-18 respect, it may be more appropriate to
Dialysis intervention in acute renal failure (ARF): renal replacement versus renal sup- consider dialysis intervention in the inten-
port. An important consideration in the management of ARF is defining the goals of sive care patient as a form of renal support
therapy. Several issues must be considered, including the timing of the intervention, the rather than renal replacement. This termi-
amount and frequency of dialysis, and the duration of therapy. In practice, these issues nology serves to distinguish between the
are based on individual preferences and experience, and no immutable criteria are fol- strategy for replacing individual organ
lowed [7,23]. Dialysis intervention in ARF is usually considered when there is clinical function and one to provide support for
evidence of uremia symptoms or biochemical evidence of solute and fluid imbalance. An all organs.
FIGURE 19-19
POTENTIAL APPLICATIONS FOR CONTINUOUS Potential applications for continuous renal
RENAL REPLACEMENT THERAPY replacement therapy (CRRT). CRRT tech-
niques are increasingly being utilized as sup-
port modalities in the intensive care setting
Renal Replacement Renal Support Extrarenal Applications and are particularly suited for this function.
The freedom to provide continuous fluid
Acute renal failure Fluid management Cytokine removal ? sepsis management permits the application of
Chronic renal failure Solute control Heart failure unlimited nutrition, adjustments in hemody-
Acid-base adjustments Cancer chemotherapy namic parameters, and achievement of
Nutrition Liver support steady-state solute control, which is difficult
Burn management Inherited metabolic disorders with intermittent therapies. It is thus possi-
ble to widen the indications for renal inter-
vention and provide a customized approach
for the management of each patient.
FIGURE 19-20
RELATIVE ADVANTAGES () AND DISADVANTAGES () OF CRRT, IHD, AND PD Advantages () and disadvantages () of
dialysis techniques. CRRT—continuous
renal replacement therapy; IHD—intermit-
Variable CRRT IHD PD tent hemodialysis; PD—peritoneal dialysis.
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
FIGURE 19-21
DETERMINANTS OF THE CHOICE OF TREATMENT Determinants of the choice of treatment modality for acute renal
MODALITY FOR ACUTE RENAL FAILURE failure. The primary indication for dialysis intervention can be a
major determinant of the therapy chosen because different thera-
pies vary in their efficacy for solute and fluid removal. Each tech-
Patient nique has its advantages and limitations, and the choice depends
Indication for dialysis on several factors. Patient selection for each technique ideally
Presence of multiorgan failure
should be based on a careful consideration of multiple factors [1].
The general principle is to provide adequate renal support without
Access
adversely affecting the patient. The presence of multiple organ fail-
Mobility and location of patient
ure may limit the choice of therapies; for example, patients who
Anticipated duration of therapy
have had abdominal surgery may not be suitable for peritoneal
Dialysis process
dialysis because it increases the risk of wound dehiscence and infec-
Components (eg, membrane, anticoagulation)
tion. Patients who are hemodynamically unstable may not tolerate
Type (intermittent or continuous) intermittent hemodialysis (IHD). Additionally, the impact of the
Efficacy for solute and fluid balance chosen therapy on compromised organ systems is an important
Complications consideration. Rapid removal of solutes and fluid, as in IHD, can
Outcome result in a disequilibrium syndrome and worsen neurologic status.
Nursing and other support Peritoneal dialysis may be attractive in acute renal failure that com-
Availability of machines plicates acute pancreatitis, but it would contribute to additional
Nursing support protein losses in the hypoalbuminemic patient with liver failure.
FIGURE 19-22
RECOMMENDATION FOR INITIAL DIALYSIS Recommendation for initial dialysis modality
MODALITY FOR ACUTE RENAL FAILURE (ARF) for acute renal failure (ARF). Patients with
multiple organ failure (MOF) and ARF can
be treated with various continuous therapies
Indication Clinical Condition Preferred Therapy or IHD. Continuous therapies provide better
hemodynamic stability; however, if not moni-
Uncomplicated ARF Antibiotic nephrotoxicity IHD, PD tored carefully they can lead to significant
Fluid removal Cardiogenic shock, CP bypass SCUF, CAVH volume depletion. In general, hemodynami-
Uremia Complicated ARF in ICU CVVHDF, CAVHDF, IHD cally unstable, catabolic, and fluid-over-
Increased intracranial pressure Subarachnoid hemorrhage, CVVHD, CAVHD loaded patients are best treated with continu-
hepatorenal syndrome ous therapies, whereas IHD is better suited
Shock Sepsis, ARDS CVVH, CVVHDF, CAVHDF for patients who require early mobilization
Nutrition Burns CVVHDF, CAVHDF, CVVH and are more stable. It is likely that the mix
Poisons Theophylline, barbiturates Hemoperfusion, IHD, CVVHDF of modalities used will change as evidence
Electrolyte abnormalities Marked hyperkalemia IHD, CVVHDF linking the choice of modality to outcome
ARF in pregnancy Uremia in 2nd, 3rd trimester PD 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 individu-
alized approach for management of ARF.
Outcomes
FIGURE 19-23
CRRT CRRT
Efficacy of continuous renal replacement
100 IHD 6 IHD
S Creat, mg/dL
therapy (CRRT) versus intermittent

BUN, mg/dL
5
80 4
hemodialysis (IHD): effect on blood urea
3 nitrogen, A, and creatinine levels, B, in
60 acute renal failure.
2
40 1
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9
Days B Days
A
FIGURE 19-24
Survivors
Blood urea nitrogen (BUN) levels in survivors and non-survivors in acute renal failure
50 Non-survivors
treated with continuous renal replacement therapy (CRRT). It is apparent that CRRT tech-
Urea, mmol/L
40 niques offer improved solute control and fluid management with hemodynamic stability,
however a relationship to outcome has not been demonstrated. In a recent retrospective
30 analysis van Bommel [24] found no difference in BUN levels among survivors and non-
20 survivors with ARF While it is clear that lower solute concentrations can be achieved with
0 1 2 3 4 5 6 CRRT whether this is an important criteria impacting on various outcomes from ARF still
Days 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.
1 Low Kt/V
0.8 High Kt/V BIOCOMPATIBLE MEMBRANES IN INTERMITTENT HEMODIALYSIS (IHD)
AND ACUTE RENAL FAILURE (ARF): EFFECT ON OUTCOMES
Survival, %
CCF score
0.6
0.4
0.2 BCM Group BICM Group Probability
0 Patients, n 72 81
0 5 10 15 20 All patients recover of renal function 46 (64%) 35 (43%) 0.001
Cleveland clinic ICU ARF score Survival 41 (57%) 37 (46%) 0.03
Patients nonoliguric before hemodialysis 39 46
FIGURE 19-25 Development of oliguria with dialysis 17 (44%) 32 (70%) 0.03
Effect of dose of dialysis in acute renal fail- Recovery of renal function 31 (79%) 21 (46%) 0.0004
ure (ARF) on outcome from ARF. Survival 28 (74%) 22 (48%) 0.003
Patients oliguric before hemodialysis 33 35
Recovery of renal function 15 (45%) 14 (40%) ns
Survival 12 (36%) 15 (43%) 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 recov-
ery of renal function with biocompatible membranes; however, this effect was not significant
in oliguric patients. Further investigations are required in this area. NS—not 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] Retrospective 31 90 27 70 20 ns
Alarabi [33] Retrospective 40 55 40 45 10 ns
Mehta [34] Retrospective 24 85 18 72 13 ns
Kierdorf [20] Retrospective 73 93 73 77 16 < 0.05
Bellomo [35] Retrospective 167 70 84 59 11 ns
Bellomo [36] Retrospective 84 70 76 45 25 < 0.01
Kruczynski [37] Retrospective 23 82 12 33 49 < 0.01
Simpson [38] Prospective 58 82 65 70 12 ns
Kierdorf [39] Prospective 47 65 48 60 4.5 ns
Mehta [40] Prospective 82 41.5 84 59.5 18 ns
FIGURE 19-27
Continuous renal replacement therapy (CRRT) versus intermittent major studies done in this area do not show a survival advantage for
hemodialysis (IHD): effect on mortality. Despite significant advances CRRT [29,30]. Although several investigators have not been able to
in the management of acute renal failure (ARF) over the last four demonstrate an advantage of these therapies in influencing mortality,
decades, the perception is that the associated mortality has not we believe this may represent the difficulty in changing a global out-
changed significantly [26]. Recent publications suggest that there come which is impacted by several other factors [31]. It is probably
may have been some improvement during the last decade [27]. Both more relevant to focus on other outcomes such as renal functional
IHD and peritoneal dialysis (PD) were the major therapies until a recovery rather than mortality. We believe that continued research is
decade ago, and they improved the outcome from the 100% mortali- required in this area; however, there appears to be enough evidence
ty of ARF to its current level. The effect of continuous renal replace- to support the use of CRRT techniques as an alternative that may be
ment therapy on overall patient outcome is still unclear [28] . The preferable to IHD in treating ARF in an intensive care setting.
Future Directions
1 Blood delivered 4 Postfiltered blood

to lumen of fibers delivered to extracapillary
in filter device (only one fiber shown) space of RAD
Filter unit
6 Transported and synthesized
Reabsorber unit elements added to postfiltered
blood, returned to general
circulation
2 Filtrate conveyed 3 Filtrate delivered

to tubule lumens to interiors of
fibers in RAD 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 devel-
oped 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 multi-
organ 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 pro-
vided by dialysis [44]. These devices are likely to be utilized in combination with CRRT to truly provide com-
plete RRT in the near future. (From Humes HD [44]; with permission.)
References
1. Mehta RL: Therapeutic alternatives to renal replacement therapy for 10. Ronco C, Brendolan A, Crepaldi C, et al.: Importance of hollow fiber
critically ill patients in acute renal failure. Semin Nephro 1994, geometry in CAVH. Contrib Nephrol 1991, 15:175–178.
14:64–82. 11. Mehta RL, McDonald BR, Aguilar MM, Ward DM: Regional citrate
2. Shapiro WB: The current status of Sorbent hemodialysis. Semin Dial anticoagulation for continuous arteriovenous hemodialysis in critically
1990, 3:40–45. ill patients. Kidney Int 1990, 38:976–981.
3. Botella J, Ghezzi P, Sanz-Moreno C, et al.: Multicentric study on 12. Grootendorst AF, Bouman C, Hoeben K, et al.: The role of continu-
paired filtration dialysis as a short, highly efficient dialysis technique. ous renal replacement therapy in sepsis multiorgan failure. Am J
Nephrol Dial Transplant 1991, 6:715–721. Kidney Dis 1996, 28(5) S3:S50–S57.
4. Steiner RW: Continuous equilibration peritoneal dialysis in acute renal 13. Kroh UF, Holl TJ, Steinhausser W: Management of drug dosing in
failure. Perit Dial Intensive 1989, 9:5–7. continuous renal replacement therapy. Semin Dial 1996, 9:161–165.
5. Bellomo R, Ronco C, Mehta RL: Nomenclature for continuous renal 14. Monson P, Mehta RL: Nutritional considerations in continuous renal
replacement therapies. Am J Kidney Dis 1996, 28(5)S3:2–7. replacement therapies. Semin Dial 1996, 9:152–160.
6. Henderson LW: Hemofiltration: From the origin to the new wave. Am 15. Golper TA: Indications, technical considerations, and strategies for
J Kidney Dis 1996, 28(5)S3:100–104. renal replacement therapy in the intensive care unit. J Intensiv Care
7. Mehta RL: Renal replacement therapy for acute renal failure: Med 1992, 7:310–317.
Matching the method to the patient. Semin Dial 1993, 6:253–259. 16. Mehta RL: Fluid management in continuous renal replacement thera-
8. Lindhout T: Biocompatability of extracorporeal blood treatment. py. Semin Dial 1996, 9:140–144.
Selection of hemostatic parameters. Nephrol Dial Transplant 1994, 17. Palevsky PM: Continuous renal replacement therapy component selec-
9(Suppl. 2):83–89. tion: replacement fluid and dialysate. Semin Dial 1996, 9:107–111.
9. Ward RA: Effects of hemodialysis on corpulation and platelets: Are 18. Thomas AN, Guy JM, Kishen R, et al.: Comparison of lactate and
we measureing membrane biocompatability? Nephrol Dial Transplant bicarbonate buffered haemofiltration fluids: Use in critically ill
1995, 10(Suppl. 10):12–17. patients. Nephrol Dial Transplant 1997, 12(6):1212–1217.
19. Golper TA: Continuous arteriovenous hemofiltration in acute renal 33. Alarabi AA, Danielson BG, Wikstrom B, Wahlberg J: Outcome of
failure. Am J Kidney Dis 1985, 6:373–386. continuous arteriovenous hemofiltration (CAVH) in one centre. Ups J
20. Kierdorf H: Continuous versus intermittent treatment: clinical results Med Sci 1989, 94:299–303.
in acute renal failure. Contrib Nephrol 1991, 93:1–12. 34. McDonald BR, Mehta RL: Decreased mortality in patients with acute
21. Lauer renal failure undergoing continuous arteriovenous hemodialysis.
Contrib Nephrol 1991, 93:51–56.
22. Paganini EP: Slow continuous hemofiltration and slow continuous
ultrafiltration. Trans Am Soc Artif Intern Organs 1988, 34:63–66. 35. Bellomo R, Mansfield D, Rumble S, et al.: Acute renal failure in criti-
cal illness. Conventional dialysis versus acute continuous hemodiafil-
23. Schrier RW, Abraham HJ: Strategies in management of acute renal
tration. Am Soc Artif Intern Organs J 1992, 38:654–657.
failure in the intensive therapy unit. In Current Concepts in Critical
Care: Acute Renal Failure in the Intensive Therapy Unit. Edited by 36. Bellomo R, Boyce N: Continuous venovenous hemodiafiltration com-
Bihari D, Neild G. Berlin:Springer-Verlag, 1990:193–214. pared with conventional dialysis in critically ill patients with acute
24. Van Bommel EFH, Bouvy ND, So KL, et al.: High risk surgical acute renal failure. Am Soc Artif Intern Organs J 1993, 39:794–797.
renal failure treated by continuous arterio venous hemodiafiltration: 37. Kruczynski K, Irvine-Bird K, Toffelmire EB, Morton AR: A compari-
Metabolic control and outcomes in sixty patients. Nephron 1995, son of continuous arteriovenous hemofiltration and intermittent
70:185–196. hemodialysis in acute renal failure patients in the intensive care unit.
25. Paganini EP, Tapolyai M, Goormastic M, et al.: Establishing a dialysis Am Soc Artif Intern Organs J 1993, 39:778–781.
therapy/patient outcome link in intensive care unit acute dialysis for 38. Simpson K, Allison MEM: Dialysis and acute renal failure: can mor-
patients with acute renal failure. Am J Kidney Dis 1996, tality be improved? Nephrol Dial Transplant 1993, 8:946.
28(5)S3:81–90. 39. Kierdorf H: Einfuss der kontinuierlichen Hamofiltration auf
26. Wilkins RG, Faragher EB: Acute renal failure in an intensive care unit: Proteinkatabolismus, Mediatorsubstanzen und Prognose des akuten
Incidence, prediction and outcome. Anesthesiology 1983, 38:638. Nierenversagens [Habilitation-Thesis], Medical Faculty Technical
27. Firth JD: Renal replacement therapy on the intensive care unit. Q J University of Aachen, 1994.
Med 1993, 86:75–77. 40. Mehta RL, McDonald B, Pahl M, et al.: Continuous vs. intermittent
28. Bosworth C, Paganini EP, Cosentino F, et al.: Long term experience dialysis for acute renal failure (ARF) in the ICU: Results from a ran-
with continuous renal replacement therapy in intensive care unit acute domized multicenter trial. Abstract A1044. JASN 1996, 7(9):1456.
renal failure. Contrib Nephrol 1991, 93:13–16. 41. Yang VC, Fu Y, Kim JS: A potential thrombogenic hemodialysis mem-
29. Kierdorf H: Continuous versus intermittent treatment: Clinical results branes with impaired blood compatibility. ASAIO Trans 1991,
in acute renal failure. Contrib Nephrol 1991, 93:1–12. 37:M229–M232.
30. Jakob SM, Frey FJ, Uhlinger DE: Does continuous renal replacement 42. Canaud B, Leray-Moragues H, Garred LJ, et al.: Slow isolated ultra-
therapy favorably influence the outcome of patients? Nephrol Dial filtration for the treatment of congestive heart failure. Am J Kidney
Transplant 1996, 11:1250–1235. Dis 1996, 28(5)S3:67–73.
31. Mehta RL: Acute renal failure in the intensive care unit: Which out- 43. Druml W: Prophylactic use of continuous renal replacement therapies
comes should we measure? Am J Kidney Dis 1996, 28(5)S3:74–79. in patients with normal renal function. Am J Kidney Dis 1996,
32. Mauritz W, Sporn P, Schindler I, et al.: Acute renal failure in abdomi- 28(5)S3:114–120.
nal infection: comparison of hemodialysis and continuous arteriove- 44. Humes HD, Mackay SM, Funke AJ, Buffington DA: The bioartificial
nous hemofiltration. Anasth Intensivther Notfallmed 1986, renal tuble assist device to enhance CRRT in acute renal failure. Am J
21:212–217. Kidney Dis 1997, 30(Suppl. 4):S28–S30.
Normal Vascular and
Glomerular Anatomy
Arthur H. Cohen
Richard J. Glassock
T
he topic of normal vascular and glomerular anatomy is intro-
duced here to serve as a reference point for later illustrations of
disease-specific alterations in morphology.
CHAPTER
1
1.2 Glomerulonephritis and Vasculitis
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
Interlobar junction of each renal pyramid. The interlobular arteries (multiple) originate from the
artery arcuate arteries. B, The renal microcirculation. The afferent arterioles branch from the
interlobular arteries and form the glomerular capillaries (hemi-arterioles). Efferent arteri-
Arcuate oles then reform and collect to form the post-glomerular circulation (peritubular capillar-
artery Renal ies, venules and renal veins [not shown]). The efferent arterioles at the corticomedullary
artery junction dip deep into the medulla to form the vasa recta, which embrace the collecting
Pelvis
tubules and form hairpin loops. (Courtesy of Arthur Cohen, MD.)
Pyramid
Interlobular Ureter
artery
Afferent
arteriole Interlobular
artery
Glomerulus
Arcuate
artery
Efferent
arteriole
Collecting
tubule
Interlobar
artery
B
Normal Vascular and Glomerular Anatomy 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 corti-
comedullary junction, forming arcuate arteries that course between
the cortex and medulla. The arcuate arteries branch into a series of
aa ILA interlobular arteries that course at roughly right angles through the
cortex toward the capsule. Blood reaches glomeruli through affer-
ent arterioles, most of which are branches of interlobular arteries,
although some arise from arcuate arteries. ILA—interlobular
artery; aa—afferent arteriole.
FIGURE 1-3
Microscopic view of the juxtaglomerular apparatus. The juxta-
glomerular 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 (arrow-
head). 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).
FP
A B
Microscopic view of the glomeruli. Glomeruli are spherical mesangial cells (A, arrow) and the matrix (B, arrow). The free
“bags” of capillaries emanating from afferent arterioles and con- wall of glomerular capillaries, across which filtration takes place,
fined within the urinary space, which is continuous with the consists of a basement membrane (arrowheads) covered by viscer-
proximal tubule. The capillaries are partially attached to the al epithelial cells with individual foot processes (FP) and lined by
mesangium, a continuation of the arteriolar wall consisting of 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). Red—mesangial cells;
blue—mesangial matrix; black—basement membrane; green—vis-
ceral and parietal epithelial cells; yellow—endothelial cells. (From
Churg and coworkers [1]; with permission.)
FIGURE 1-7
Electron photomicrograph illustrating a portion of the ultra-
structure 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 com-
posed of Type IV collagen and negativity charged proteoglycans
(heparan sulfate). L—lumen. (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 demonstrat-
ed. 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
T
he primary glomerulopathies are those disorders that affect
glomerular structure, function, or both in the absence of a mul-
tisystem disorder. The clinical manifestations are predominate-
ly 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 progres-
sive glomerulonephritis; chronic renal failure; the nephrotic syndrome
or “asymptomatic” hematuria, proteinuria, or both.
CHAPTER
2
FIGURE 2-1
CLINICAL SYNDROMES OF GLOMERULAR DISEASE 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 hyperten-
Acute glomerulonephritis sion. Rapidly progressive glomerulonephritis is characterized by
Rapidly progressive glomerulonephritis
features of nephritis and progressive renal insufficiency. Chronic
glomerulonephritis features proteinuria and hematuria with indolent
Chronic glomerulonephritis
progressive renal failure. Nephrotic syndrome consists of massive
Nephrotic syndrome
proteinuria (>3.5 g/d in adults), hypoalbuminemia with edema,
“Asymptomatic” hematuria, proteinuria, or both
lipiduria, and hyperlipidemia. “Asymptomatic” hematuria, protein-
uria, or both is not associated initially with renal failure or edema.
Each of these syndromes may be complicated by hypertension.
FIGURE 2-2
% % %
100 Others
Age-associated prevalence of various
5 glomerular lesions in nephrotic syndrome.
4 Lupus 10.8 This schematic illustrates the age-associat-
2 90 Amyloid
5 5.9
ed prevalence of various diseases and
1 Diabetes 1.6 glomerular lesions among children and
7 80 adults undergoing renal biopsy for evalua-
Other tion of nephrotic syndrome (Guy’s
16.0
70 proliferative Hospital and the International Study of
25.8 Kidney Disease in Children) [1]. Both the
60 MCGN 9.8 systemic and primary causes of nephrotic
syndrome are included. (Diabetes mellitus
50 with nephropathy is underrepresented
because renal biopsy is seldom needed for
Membranous 19.7
76 40
diagnosis.) The bar on the left summarizes
the prevalence of various lesions in chil-
dren aged 0 to 16 years; the bar on the
30 11.8
FSGS
right summarizes the prevalence of vari-
ous lesions in adults aged 16 to 80 years.
20 Note the high prevalence of minimal
change disease in children and the increas-
10 Minimal 22 ing prevalence of membranous glomeru-
changes
lonephritis in the age group of 16 to 60
0 years. FSGS—focal segmental glomeru-
All 5 10 15 20 30 40 50 60 70 80 All osclerosis; MCGN—mesangiocapillary
children Age at onset of NS adults glomerulonephritis. (From Cameron [1];
with permission.)
FIGURE 2-3
PRIMARY GLOMERULAR LESIONS The 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
The Primary Glomerulopathies 2.3
Minimal Change Disease
A B
FIGURE 2-4
Light and electron microscopy in minimal change disease (lipoid Minimal change disease is considered to be the result of glomerular
nephrosis). A, This glomerulopathy, one of many associated with capillary wall damage by lymphokines produced by abnormal T
nephrotic syndrome, has a normal appearance on light microscopy. cells. This glomerulopathy is the most common cause of nephrotic
No evidence of antibody (immune) deposits is seen on immunoflu- syndrome in children (>70%) and also accounts for approximately
orescence. B, Effacement (loss) of foot processes of visceral epithe- 20% of adult patients with nephrotic syndrome. This glomerulopa-
lial cells is observed on electron microscopy. This last feature is the thy typically is a corticosteroid-responsive lesion, and usually has a
major morphologic lesion indicative of massive proteinuria. benign outcome with respect to renal failure.
100
100 12 weeks
8 weeks
Complete remission, cumulative %
80
Cumulative percentage sustained
80
60
remission
60
40
ISKDC children
Prednisone + Cyclophosphamide (11) 40
20
Prednisone (75)
Cyclophosphamide (25)
0 20
0 2 4 8 16 28 0 200 400 600
Weeks from starting treatment Days

Therapeutic response in minimal change disease. This graph Cyclophosphamide in minimal change disease. One of several
illustrates the cumulative complete response rate (absence of controlled trials of cyclophosphamide therapy in pediatric patients
abnormal proteinuria) in patients of varying ages in relation to that pursued a relapsing steroid-dependent course is illustrated.
type and duration of therapy [1]. Note that most children with Note the relative freedom from relapse when children were given
minimal change disease respond to treatment within 8 weeks. a 12-week course of oral cyclophosphamide. An 8-week course
Adults require prolonged therapy to reach equivalent response of chlorambucil (0.15–0.2 mg/kg/d) may be equally effective.
rates. Number of patients are indicated in parentheses. (From (From Arbeitsgemeinschaft für pediatrische nephrologie [3];
Cameron [2]; with permission.) with permission.)
FIGURE 2-7
100
Cyclosporine Cyclosporine in minimal change disease. One of several controlled
Cyclophosphamide trials of cyclosporine therapy in this disease is illustrated. Note the
80 relapses that occur after discontinuing cyclosporine therapy (arrow).
Cyclophosphamide was given for 2 months, and cyclosporine for 9
Overall probability
months. Probability—actuarial probability of remaining relapse-free.

60 (From Ponticelli and coworkers [4]; with permission.)
40
20
0
0 90 180 270 360 450 540 630 720
Time, d
Number of patients
Cyclosporine 36 36 36 31
Cyclophosphamide 30 29 28 26
Focal Segmental Glomerulosclerosis
A B
FIGURE 2-8
Light and immunofluorescent microscopy in focal segmental in the deep cortex, is affected. The abnormal glomeruli exhibit
glomerulosclerosis (FSGS). Patients with FSGS exhibit massive segmental obliteration of capillaries by increased extracellular
proteinuria (usually nonselective), hypertension, hematuria, and matrix–basement membrane material, collapsed capillary walls,
renal functional impairment. Patients with nephrotic syndrome or large insudative lesions. These lesions are called hyalinosis
often are not responsive to corticosteroid therapy. Progression to (arrow) and are composed of immunoglobulin M and comple-
chronic renal failure occurs over many years, although in some ment C3 (B, IgM immunofluorescence). The other glomeruli
patients renal failure may occur in only a few years. A, This usually are enlarged but may be of normal size. In some patients,
glomerulopathy is defined primarily by its appearance on light mesangial hypercellularity may be a feature. Focal tubular
microscopy. Only a portion of the glomerular population, initially atrophy with interstitial fibrosis invariably is present.
FIGURE 2-9
Electron microscopy of focal segmental glomerulosclerosis. The elec-
tron 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 CLASSIFICATION OF MEMBRANOUS

GLOMERULOSCLEROSIS WITH HYALINOSIS GLOMERULONEPHRITIS
Primary (Idiopathic) Primary (Idiopathic)

Classic Secondary
Tip lesion Neoplasia (carcinoma, lymphoma)
Collapsing Autoimmune disease (systemic lupus erythematosus thyroiditis)
Secondary Infectious diseases (hepatitis B, hepatitis C, schistosomiasis)
Human immunodeficiency virus–associated Drugs (gold, mercury, nonsteroidal anti-inflammatory drugs, probenecid, captopril)
Heroin abuse Other causes (kidney transplantation, sickle cell disease, sarcoidosis)
Vesicoureteric reflux nephropathy
Oligonephronia (congenital absence or hypoplasia of one kidney)
Obesity
FIGURE 2-11
Analgesic nephropathy
Hypertensive nephrosclerosis
Most adult patients (75%) have primary or idiopathic disease. Most
children have some underlying disease, especially viral infection. It
Sickle cell disease
is not uncommon for adults over the age of 60 years to have an
Transplantation rejection (chronic)
underlying carcinoma (especially lung, colon, stomach, or breast).
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 dis-
eases (eg, Immunoglobulin A nephropathy).
A B
FIGURE 2-12
Histologic variations of focal segmental glomerulosclerosis (FSGS). tubule. Some investigators have described a more favorable
Two important variants of FSGS exist. In contrast to the histologic response to steroids and a more benign clinical course.
appearance of the involved glomeruli, with the sclerotic segment in The other variant, known as collapsing glomerulopathy, most
any location in the glomerulus, the glomerular tip lesion (A) is likely represents a virulent form of FSGS. In this form of FSGS,
characterized by segmental sclerosis at an early stage of evolution, most visceral epithelial cells are enlarged and coarsely vacuolated
at the tubular pole (tip) of all affected glomeruli (arrow). and most capillary walls are wrinkled or collapsed (B). These
Capillaries contain monocytes with abundant cytoplasmic lipids features indicate a severe lesion, with a corresponding rapidly pro-
(foam cells), and the overlying visceral epithelial cells are enlarged gressing clinical course of the disease. Integral and concomitant acute
and adherent to cells of the most proximal portion of the proximal abnormalities of tubular epithelia and interstitial edema occur.
100 100
<15 y (138) 90
80 80 Without nephrotic
syndrome
Survival, %
15–59 y (68) 70
60
Survival, %
60
<15 y (62)
40 >60 y (20) 50
>15 y (60) 40
20 Minimal change disease
30
FSGS With nephrotic
0 20
syndrome
0 5 10 15 20 10
Years from onset 0
0 5 10 15 20
Years from onset
FIGURE 2-13
Evolution of focal segmental glomerulosclerosis (FSGS). This graph
compares the renal functional survival rate of patients with FSGS FIGURE 2-14
to that seen in patients with minimal change disease (in adults and The outcome of focal segmental glomerulosclerosis according to the
children). Note the poor prognosis, with about a 50% rate of renal degree of proteinuria at presentation is shown. Note the favorable
survival at 10 years. (From Cameron [2]; with permission.) 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.)
Membranous Glomerulonephritis
A B
C D
antigen(s) of the immune complexes are unknown. In the remain-
der, membranous glomerulonephritis is associated with well-
defined 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-inflam-
matory reagents. Treatment is controversial.
The changes by light and electron microscopy mirror one anoth-
er quite well and represent morphologic progression that is likely
dependent on duration of the disease. A, At all stages immuno-
fluorescence 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
E deposits (arrows) are observed in the subepithelial aspects of capillary
walls. D, In the intermediate stage the deposits are partially encircled
FIGURE 2-15 (see Color Plate) by basement membrane material. E, When viewed with periodic
Light, immunofluorescent, and electron microscopy in membra- acid-methenamine stained sections, this abnormality appears as
nous glomerulonephritis. Membranous glomerulonephritis is an spikes of basement membrane perpendicular to the basement
immune complex–mediated glomerulonephritis, with the immune membrane, with adjacent nonstaining deposits. Similar features
deposits localized to subepithelial aspects of almost all glomerular are evident on electron microscopy, with dense deposits and inter-
capillary walls. Membranous glomerulonephritis is the most com- vening basement membrane (D). Late in the disease the deposits
mon cause of nephrotic syndrome in adults in developed countries. are completely surrounded by basement membranes and are under-
In most instances (75%), the disease is idiopathic and the going resorption.
FIGURE 2-16
Evolution of deposits in membranous glomerulonephritis. This
schematic illustrates the sequence of immune deposits in red; base-
ment 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.)
A B
C D
FIGURE 2-17
100
Natural history of membranous glomerulonephritis. This schematic illustrates the clinical
Dead/ESRD
80 evolution of idiopathic membranous glomerulonephritis over time. Almost half of all patients
Nephrotic syndrome
60 undergo spontaneous or therapy-related remissions of proteinuria. Another group of patients
(25–40%), however, eventually develop chronic renal failure, usually in association with per-
%
Proteinuria
40 sistent proteinuria in the nephrotic range. (From Cameron [2]; with permission.)
20 Remission
0
0 5 10 15
Years of known disease
Membranoproliferative Glomerulonephritis
A B
at all common. The first, known as membranoproliferative
(mesangiocapillary) glomerulonephritis type I, is a primary
glomerulopathy most common in children and adolescents. The
1
same pattern of injury may be observed during the course of many
2 diseases with chronic antigenemic states; these include systemic
3 lupus erythematosus and hepatitis C virus and other infections. In
membranoproliferative glomerulonephritis type I, the glomeruli
4 are enlarged and have increased mesangial cellularity and variably
increased matrix, resulting in lobular architecture. The capillary
5 walls often are thickened with double contours, an abnormality
6 resulting from peripheral migration and interposition of
mesangium (A). Immunofluorescence discloses granular to conflu-
ent 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
C capillary walls. C, Between the basement membrane and endothe-
lial cells are, in order inwardly: (1) epithelial cell, (2) basement
FIGURE 2-18 (see Color Plate) membrane, (3) electron-dense deposits, (4) mesangial cell cyto-
Light, immunofluorescence, and electron microscopy in membra- plasm, (5) mesangial matrix, and (6) endothelial cell. Electron-
noproliferative glomerulonephritis type I. In these types of dense deposits also are in the central mesangial regions.
immune complex–mediated glomerulonephritis, patients often Subepithelial deposits may be present, albeit typically in small
exhibit nephrotic syndrome accompanied by hematuria and numbers. The electron-dense deposits may contain an organized
depressed levels of serum complement C3. The morphology is var- (fibrillar) substructure, especially in association with hepatitis C
ied, with at least three pathologic subtypes, only two of which are virus infection and cryoglobulemia.
A A
B
known as dense deposit disease, the glomeruli may be lobular
or may manifest only mild widening of mesangium. A, The capil-
lary walls are thickened, and the basement membranes are
stained intensely positive periodic acid–Schiff 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 Bowman’s capsule and the
tubular basement membranes. C, Ultrastructurally, the glomeru-
lar capillary basement membranes are thickened and darkly
stained; there may be segmental or extensive involvement of
the basement membrane. Similar findings are seen in Bowman’s
capsule and tubular basement membranes; however, in the latter,
C the dense staining is usually on the interstitial aspect of that
structure. Patients with dense deposit disease frequently show
FIGURE 2-19 (see Color Plate) isolated C3 depression and may have concomitant lipodystrophy.
Light, immunofluorescence, and electron microscopy in membra- These patients also have autoantibodies to the C3 convertase
noproliferative glomerulonephritis type II. In this disease, also enzyme C3Nef.
SERUM COMPLEMENT CONCENTRATIONS IN GLOMERULAR LESIONS
Serum Concentration
Lesion C3 C4 C’H50 Other
Minimal change disease Normal Normal Normal –
Focal sclerosis Normal Normal Normal –
Membranous glomerulonephritis (idiopathic) Normal Normal Normal –
Immunoglobulin A nephropathy Normal Normal Normal –
Membranoproliferative glomerulonephritis:
Type I Moderate decrease Mild decrease Mild decrease –
Type II Severe decrease Normal Mild decrease C3 nephritic factor+
Acute poststreptococcal glomerulonephritis Moderate decrease Normal Mild decrease Antistreptolysin 0 titer increased
Lupus nephritis:
(World Health Organization Class IV) Moderate to severe Moderate to severe Mild decrease anti–double-stranded DNA antibody+
decrease decrease
(World Health Organization Class V) Normal or mild decrease Normal or mild decrease Normal or mild decrease anti–double-stranded DNA antibody+
Cryoglobulinemia (hepatitis C) Normal or mild decrease Severe decrease Moderate decrease Cryoglobulins; hepatitis C ab
Amyloid Normal Normal Normal –
Vasculitis Normal or increased Normal or increased Normal Antineutrophil cytoplasmic antibody+
C’H50—serum hemolytic complement activity.
FIGURE 2-20
The serum complement component concentration (C3 and C4) and and secondary glomerular lesions are depicted. Note the limited
serum hemolytic complement activity (C’H50) in various primary number of disorders associated with a low C3 or C4 level.
FIGURE 2-21
CLASSIFICATION OF MEMBRANOPROLIFERATIVE Note that although there is the wide variety of underlying causes for
GLOMERULONEPHRITIS TYPE I the lesion of membranoproliferative glomerulonephritis hepatitis C,
with or without cryoglobulinemia, accounts for most cases.
Primary (Idiopathic)
Secondary
Hepatitis C (with or without cryoglobulinemia)
Hepatitis B
Systemic lupus erythematosus
Light or heavy chain nephropathy
Sickle cell disease
Sjögren’s syndrome
Sarcoidosis
Shunt nephritis
Antitrypsin deficiency
Quartan malaria
Chronic thrombotic microangiopathy
Buckley’s syndrome
Mesangial Proliferative Glomerulonephritis
A 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 erythe-
matosus). Patients with primary mesangial proliferative glomeru-
lonephritis typically exhibit the disorder in one of four ways:
asymptomatic proteinuria, massive proteinuria often in the nephrot-
ic 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
C mesangial deposits. In the most common of these disorders,
immunoglobulin M is the dominant or sole deposit. Other disorders
FIGURE 2-22 (see Color Plate) are characterized primarily or exclusively by complement C3,
Light, immunofluorescence, and electron microscopy in mesangial immunoglobulin G, or C1q deposits. C, On electron microscopy the
proliferative glomerulonephritis. This heterogeneous group of disor- major finding is of small electron-dense deposits in the mesangial
ders is characterized by increased mesangial cellularity in most of regions (arrow). Foot process effacement is variable, depending on
the glomeruli associated with granular immune deposits in the the clinical syndrome (eg, whether massive proteinuria is present).
Crescentic Glomerulonephritis
A B
C D
Crescentic glomerulonephritis. A crescent is the accumulation of trophil cytoplasmic antibodies (ANCAs). The clinical manifestations
cells and extracellular material in the urinary space of a glomerulus. are typically of rapidly progressive glomerulonephritis with moder-
The cells are parietal and visceral epithelia as well as monocytes and ate proteinuria, hematuria, oliguria, and uremia. The immunomor-
other blood cells. The extracellular material is fibrin, collagen, and phologic features depend on the basic disease process. On light
basement membrane material. In the early stages of the disease, the microscopy in both AGBM antibody–induced disease and
crescents consist of cells and fibrin. In the later stages the crescents ANCA–associated crescentic glomerulonephritis, the glomeruli with-
undergo organization, with disappearance of fibrin and replacement out crescents often have a normal appearance. It is the remaining
by collagen. Crescents represent morphologic consequences of glomeruli that are involved with crescents. D, Anti-GBM disease is
severe capillary wall damage. A, In most instances, small or large characterized by linear deposits of immunoglobulin G and often
areas of destruction of capillary walls (cells and basement mem- complement C3 in all capillary basement membranes, and in
branes) are observed (arrow), thereby allowing fibrin, other high approximately two thirds of affected patients in tubular basement
molecular weight substances, and blood cells to pass readily from membranes. The ANCA-associated lesion typically has little or no
capillary lumina into the urinary space. B, Immunofluorescence fre- immune deposits on immunofluorescence; hence the term pauci-
quently discloses fibrin in the urinary space. C, The proliferating immune crescentic glomerulonephritis is used. By electron
cells in Bowman’s space ultimately give rise to the typical crescent microscopy, as on light microscopy, defects in capillary wall conti-
shape. Whereas crescents may complicate many forms of glomeru- nuity are easily identified. Both AGBM- and ANCA-associated cres-
lonephritis, they are most commonly associated with either centic glomerulonephritis can be complicated by pulmonary hemor-
antiglomerular basement membrane (AGBM) antibodies or antineu- rhage (see Fig. 2-25).
CLASSIFICATION OF CRESCENTIC GLOMERULONEPHRITIS
Type Serologic Pattern Primary Secondary

I Anti-GBM+ ANCA- Anti-GBM antibody–mediated crescentic glomerular nephritis Goodpasture’s disease
II Anti-GBM- ANCA- Idiopathic crescentic glomerular nephritis (with or without immune Systemic lupus erythematosus, immunoglobulin A, MPGN
complex deposits) cryoimmunoglobulin (with immune complex deposits
III Anti-GBM- ANCA+ Pauci-immune crescentic glomerular nephritis (microscopic polyangiitis) Drug-induced crescentic glomerulonephritis
IV Anti-GBM+ANCA+ Anti-GBM antibody–mediated crescentic glomerular nephritis with ANCA Goodpasture’s syndrome with ANCA
ANCA—antineutrophil cytoplasmic antibody; anti-GBM—glomerular 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 mem-
brane–mediated glomerulonephritis complicated by pulmonary hemorrhage (Goodpasture’s
disease). Note the butterfly appearance of the alveolar infiltrates characteristic of intrapul-
monary (alveolar) hemorrhage. Such lesions can also occur in patients with antineutrophil
cytoplasmic autoantibody–associated vasculitis and glomerulonephritis, lupus nephritis
(SLE), cryoglobulinemia, and rarely in Henoch-Schonlein purpura (HSP).
FIGURE 2-26
↑ Serum creatinine Evaluation of rapidly progressive glomeru-
Proteinuria lonephritis. This algorithm schematically
"Nephritic" sediment
illustrates a diagnostic approach to the
various causes of rapidly progressive
Renal ultrasonography glomerulonephritis (Figure 2-24), Serologic
studies, especially measurement of circulat-
ing antiglomerular basement membrane
Normal or enlarged antibodies, antineutrophil cytoplasmic
Small kidneys Obstruction
kidneys; no obstruction antibodies, antinuclear antibodies, and
serum complement component concentra-
tions, are used for diagnosis. Serologic
Serology*
patterns (A through D)permit categoriza-
tion of probable disease entities.
Pattern type (A) (B) (C) (D)
aGBMA* + – – +
ANCA† – – + +
Goodpasture's disease Type II IC-mediated Microscopic Combined
Type I primary CrGN CGN SLE, HSP, and polyangiitis; type III form; type IV
MPGN CryoIg, type V primary crescentic primary CrGN
primary CrGN CrGN; Wegener's GN;
(idiopathic) 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 cyto-
plasmic granule antigens (mainly pro-
teinase-3). B, P-ANCA are due to antibod-
ies reacting with other antigens (mainly
myeloperoxidase).
A B
Immunoglobulin A Nephropathy
A B
C D
Light, immunofluorescence, and electron microscopy in immuno- to the term focal proliferative glomerulonephritis. In advanced
globulin A (IgA) nephropathy. IgA nephropathy is a chronic cases, segmental sclerosis often is present and associated with mas-
glomerular disease in which IgA is the dominant or sole component sive proteinuria. During acute episodes, crescents may be present.
of deposits that localize in the mesangial regions of all glomeruli. B, Large round paramesangial fuchsinophilic deposits often are
In severe or acute cases, these deposits also are observed in the identified with Masson’s trichrome or other similar stains (arrows).
capillary walls. This disorder may have a variety of clinical presenta- C, Immunofluorescence defines the disease; granular mesangial
tions. Typically, the presenting features are recurrent macroscopic deposits of IgA are seen with associated complement C3, and IgG
hematuria, often coincident with or immediately after an upper respi- or IgM, or both. IgG and IgM often are seen in lesser degrees of
ratory infection, along with persistent microscopic hematuria and intensity than is IgA. D, On electron microscopy the abnormalities
low-grade proteinuria between episodes of gross hematuria. typically are those of large rounded electron-dense deposits
Approximately 20% to 25% of patients develop end-stage renal (arrows) in paramesangial zones of most if not all lobules.
disease over the 20 years after onset. A, On light microscopy, Capillary wall deposits (subepithelial, subendothelial, or both) may
widening and often an increase in cellularity in the mesangial be present, especially in association with acute episodes. In addi-
regions are observed, a process that affects the lobules of some tion, capillary basement membranes may show segmental thinning
glomeruli to a greater degree than others. This feature gives rise and rarefaction.
FIGURE 2-29
Natural history of immunoglobulin A (IgA) nephropathy. The evolution of IgA nephropa-
thy 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 unfavor-
able outcome include elevated serum creatinine, tubulointerstitial lesions or glomeruloscle-
rosis, and moderate proteinuria (>1.0 g/d). (Modified from Cameron [2].)
Fibrillary and Immunotactoid Glomerulonephritis
A 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 protein-
uria often in the nephrotic range, with variable hematuria, hyper-
tension, 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 conflu-
ent 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 identi-
fied; in most instances, however, both light chains are equally rep-
C resented. The nature of the deposits is unknown. C, On electron
microscopy the fibrils are roughly 20-nm thick, of indefinite length,
FIGURE 2-30 (see Color Plate) and haphazardly arranged. The fibrils permeate the mesangial
Light, immunofluorescent, and electron microscopy in nonamyloid matrix and basement membranes (arrow). The fibrils have been
fibrillary glomerulonephritis. Fibrillary glomerulonephritis is an infrequently described in organs other than the kidneys.
A B
Light, immunofluorescent, and electron microscopy in immunotac-
toid 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 glomeru-
lopathy frequently is associated with lymphoplasmacytic disorders.
A, On light microscopy the glomerular capillary walls often are
thickened and the mesangial regions widened, with increased cellu-
larity. B, On immunofluorescence, granular capillary wall and
mesangial immunoglobulin G and complement C3 deposits are pre-
sent. The ultrastructural findings are of aggregates of microtubular
structures in capillary wall locations corresponding to granular
deposits by immunofluorescence. C, The microtubular structures
C are large, ranging from 30- to 50-nm thick, or more (arrows).
Collagenofibrotic Glomerulopathy
A B
Collagenofibrotic glomerulopathy (collagen III glomerulopathy). exhibit proteinuria and mild progressive renal insufficiency.
The collagens normally found in glomerular basement mem- For reasons that are not clear, hemolytic-uremic syndrome has
branes and the mesangial matrix are of types IV (which is domi- evolved in a small number of pediatric patients. A, On light
nant) and V. In collagenofibrotic glomerulopathy, accumulation microscopy the capillary walls are thickened and mesangial
of type III collagen occurs largely in capillary walls in a suben- regions widened by pale staining material. These features are in
dothelial location. It is likely that this disease is hereditary; how- sharp contrast to the normal staining of the capillary basement
ever, because it is very rare, precise information regarding trans- membranes, as evidenced by the positive period acid–Schiff reac-
mission is not known. Collagenofibrotic glomerulopathy origi- tion. With this stain, collagen type III is not stained and there-
nally was thought to be a variant of nail-patella syndrome. fore is much paler. Amyloid stains (Congo red) are negative.
Current evidence suggests little relationship exists between the B, On electron microscopy, banded collagen fibrils are evident
two disorders. Patients with collagen III glomerulopathy often in the subendothelial aspect of the capillary wall.
References
1. Cameron JS, Glassock RJ: The natural history and outcome of the 4. Ponticelli C: Cyclosporine versus cyclophosphamide for patients with
nephrotic syndrome. In The Nephrotic Syndrome. Edited by Cameron steroid-dependent and frequently relapsing idiopathic nephrotic syn-
JS and Glassock RJ. New York: Marcel Dekker, 1987. drome. A multi-center randomized trial. Nephrol Dial Transplant
2. Cameron JS: The long-term outcome of glomerular diseases. In 1993, 8:1326–1332.
Diseases of the Kidney Vol II, edn 6. Edited by Schrier RW, 5. Ponticelli C, Glassock RJ: Treatment of Segmental Glomerulonephritis.
Gottschalk CW. Boston: Little Brown; 1996. Oxford: Oxford Medical Publishers, 1996:110.
3. Arbeitsgemeinschaft für pediatrische nephrologie. Cyclophosphamide 6. Churg J, Bernstein J, Glassock RJ: Renal Disease. Classification and
treatment of steroid-dependent nephrotic syndrome: comparison of an Atlas of Glomerular Disease, edn 2. New York: Igaku-Shoin; 1995.
eight-week with a 12-week course. Arch Dis Child 1987, 62:1102–1106.
Heredofamilial
and Congenital
Glomerular Disorders
Arthur H. Cohen
Richard J. Glassock
T
he principal characteristics of some of the more common hered-
ofamilial and congenital glomerular disorders are described and
illustrated. Diabetes mellitus, the most common heredofamilial
glomerular disease, is illustrated in Volume IV, Chapter 1. These disor-
ders are inherited in a variety of patterns (X-linked, autosomal domi-
nant, 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
the eyes. The disease is inherited as an X-linked trait; in some fami-

lies, 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 Alport’s 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 pro-
gression 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 con-
sist of profound abnormalities of glomerular basement membranes.
FIGURE 3-1 These abnormalities range from extremely thin and attenuated to
Alport’s syndrome. Alport’s syndrome (hereditary nephritis) is a considerably thickened membranes. The thickened glomerular base-
hereditary disorder in which glomerular and other basement mem- ment membranes have multiple layers of alternating medium and
brane collagen is abnormal. This disorder is characterized clinically pale staining strata of basement membrane material, often with
by hematuria with progressive renal insufficiency and proteinuria. incorporated dense granules. The subepithelial contour of the base-
Many patients have neurosensory hearing loss and abnormalities of ment membrane typically is scalloped.
FIGURE 3-2
NC1 100nm Schematic of basement membrane collagen type IV. The postulated
arrangement of type IV collagen chains in a normal glomerular base-
7S ment 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
A shown). Disruption of synthesis of any of these chains may lead to
anatomic and pathologic alternations, such as those seen in Alport’s
syndrome. Arrows indicate fibrils. (From Abrahamson and coworkers
-S--S-
α1 -S--S- α1
α2 -S--S- α2
-S--S-
α1 -S--S- α1
B -S--S-
FIGURE 3-3
Neurosensory hearing defect in Alport’s syndrome. In patients with adult onset Alport’s
syndrome, classic X-linked sensorineural hearing defects occur. These defects often begin
20 with an auditory loss of high-frequency tone, as shown in this audiogram. The shaded
Hearing loss, dB
area represents normal ranges. (Modified from Gregory and Atkin [2]; with permission.)
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 abnormal-
ly 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 simi-
larities in common with the capillary basement membranes of
Alport’s syndrome, these two glomerulopathies are not directly
related. Clinically, persistent microscopic hematuria or occasional
episodic gross hematuria are important features. Nonrenal abnor-
malities 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 abnor-
mal subepithelial contours.
A 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 sphin-
golipids in the vascular tree may lead to premature coronary artery
occlusion (angina or myocardial infarction) or cerebrovascular insuf-
ficiency (stroke). Involvement of nerves leads to painful acropares-
thesias 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
C and arteriolar smooth muscle cells and tubular epithelia. At consider-
ably higher magnification, the inclusions are observed to consist of
FIGURE 3-5 (see Color Plate) multiple concentric alternating clear and dark layers, with a periodic-
Fabry’s disease. Fabry’s disease, also known as angiokeratoma cor- ity ranging from 3.9 to 9.8 nm. This fine structural appearance (best
poris diffusum or Anderson-Fabry’s disease, is the result of deficiency appreciated at the arrow) is characteristic of stored glycolipids (C).
FIGURE 3-6
Electron microscopy of nail-patella syndrome. This disorder having
skeletal and renal manifestations affects the glomeruli, with accu-
mulation of banded collagen fibrils within the substance of the cap-
illary basement membrane. This accumulation appears as empty
lacunae when the usual stains with electron microscopy (lead cit-
rate and uranyl acetate) are used. However, as here, the fibrils easi-
ly can be identified with the use of phosphotungstic acid stain in
conjunction with or instead of typical stains. Note that this disor-
der differs structurally from collagen type III glomerulopathy in
which the collagen fibrils are subendothelial and not intramembra-
nous in location. Patients with nail-patella syndrome may develop
proteinuria, sometimes in the nephrotic range, with variable pro-
gression 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 syn-
drome 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
A B
Lecithin-cholesterol acyl transferase deficiency. Lipid accumula- membranes are irregularly thickened. Some capillary lumina may
tion occurs in this hereditary metabolic disorder, especially in contain foam cells. Although quite rare, this autosomal recessive
extracellular sites throughout glomerular basement membranes disease has been described in most parts of the world; however,
and the mesangial matrix. A, On electron microscopy the lipid it occurs most commonly in Norway. Patients exhibit proteinuria,
appears as multiple small lacunae, often with small round dense often with microscopic hematuria usually noted in childhood.
granular or membranous structures (arrows). Lipid-containing Renal insufficiency may develop in the fourth or fifth decade of
monocytes may be in the capillary lumina. B, The mesangial life and may progress rapidly. Nonrenal manifestations include
regions are widened on light microscopy, usually with expansion corneal opacification, hemolytic anemia, early atherosclerosis,
of the matrix that stains less intensely than normal. Basement and sea-blue histocytes in the bone marrow and spleen.
A B
Lipoprotein glomerulopathy. Patients with this rare disease, which mesangial hypercellularity or mesangiolysis may be present. With
often is sporadic (although some cases occur in the same family), immunostaining for -lipoprotein, apolipoproteins E and B are
exhibit massive proteinuria. Lipid profiles are characterized by identified in the luminal masses. B, Electron microscopic findings
increased plasma levels of cholesterol, triglycerides, and very low indicate the thrombi consist of finely granular material with numer-
density lipoproteins. Most patients have heterozygosity for ous vacuoles (lipoprotein). Lipoprotein glomerulopathy may
apolipoprotein E2/3 or E2/4. A, The glomeruli are the sites of mas- progress to renal insufficiency over a long period of time.
sive intracapillary accumulation of lipoproteins, which appear as Recurrence of the lesions in a transplanted organ has been reported
slightly tan masses (thrombi) dilating capillaries (arrows). Segmental infrequently. Lipid-lowering agents are mostly ineffective.
A B
Nephropathic cystinosis. In older children and young adults, have occasionally enlarged and multinucleated visceral epithelial cells
compared with young children, patients with cystinosis commonly (arrow). As the disease progresses, segmental sclerosis becomes evident
exhibit glomerular involvement rather than tubulointerstitial disease. as in the photomicrograph. B, Crystalline inclusions are identified on
Proteinuria and renal insufficiency are the typical initial manifestations. electron microscopy. The crystals of cysteine are usually dissolved in
A, As the most constant abnormality on light microscopy, glomeruli processing, leaving an empty space as shown here by the arrows.
A B
Finnish type of congenital nephrotic syndrome. Several disorders the kidneys is varied. Some glomeruli are small and infantile with-
are responsible for nephrotic syndrome within the first few out other alterations, whereas others are enlarged, more mature,
months to first year of life. The most common and important of and have diffuse mesangial hypercellularity. Because of the mas-
these is known as congenital nephrotic syndrome of Finnish type sive proteinuria, some tubules are microcystically dilated, a find-
because the initial descriptions emphasized the more common ing responsible for the older term for this disorder, microcystic
occurrence in Finnish families. This nephrotic syndrome is an disease. Because this syndrome is primarily a glomerulopathy,
inherited disorder in which infants exhibit massive proteinuria the tubular abnormalities are a secondary process and should
shortly after birth; typically, the placenta is enlarged. This disorder not be used to designate the name of the disease. B, On electron
can be diagnosed in utero; increased -fetoprotein levels in amni- microscopy, complete effacement of the foot processes of visceral
otic fluid is a common feature. A, The microscopic appearance of epithelial cells is observed.
hematuria and progressive renal insufficiency. Currently, no evi-

dence exists that this disorder is an inherited process with genetic
linkage. The glomeruli characteristically are small compact mass-
es 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 syn-
drome 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 geni-
FIGURE 3-12 tal abnormalities. Thus, close observation or bilateral nephrecto-
Diffuse mesangial sclerosis. This disorder is exhibited within the my as prophylaxis against the development of Wilms’ tumor is
first few months of life with massive proteinuria, often with employed occasionally.
References
1. Abrahamson D, Van der Heurel GB, Clapp WL, et al.: Nephritogenic 2. Gregory M, Atkin C: Alport’s syndrome, Fabry disease and nail-patel-
antigens in the glomerular basement membrane. In Immunologic la syndrome. In Diseases of the Kidney, Vol. I. edn 6. Edited by
Renal Diseases. Edited by Nielson EG, Couser, WG. Philadelphia: Schrier RW, Gottschalk CW. Boston: Little Brown, 1995.
Lippincott-Raven, 1997.
Infection-Associated
Glomerulopathies
Arthur H. Cohen
Richard J. Glassock
M
any glomerular diseases may be associated with acute and
chronic infectious diseases of bacterial, viral, fungal, or
parasitic origin. In many instances, the glomerular activa-
tors 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 dis-
eases, including human immunodeficiency virus and hepatitis, are
also discussed in Volume IV.
CHAPTER
4
A 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-con-
toured, 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 pre-
dominant 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
C deposits (arrow). However, electron-dense deposits also are found
in the mesangial regions and occasionally subendothelial locations.
FIGURE 4-1 (see Color Plate) Endothelial cells often are swollen, and leukocytes are not only
Light, immunofluorescent, and electron microscopy of poststrepto- found in the capillary lumina but occasionally in direct contact
coccal (postinfectious) glomerulonephritis. Glomerulonephritis may with basement membranes in capillary walls with deposits. Similar
follow in the wake of cutaneous or pharyngeal infection with a lim- findings may be observed in glomerulonephritis after infectious
ited number of “nephritogenic” serotypes of group A -hemolytic 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.
A B
(focal segmental) glomerulosclerosis with significant tubular and
interstitial abnormalities. A, In HIVAN, many visceral epithelial
cells are enlarged, coarsely vacuolated, contain protein reabsorp-
tion droplets, and overlay capillaries with varying degrees of wrin-
kling 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 expect-
ed for the glomerulopathy as well as those common to HIV infec-
tion. 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, modifica-
tions of the cytoplasm of endothelial cells in which clusters of
microtubular arrays are in many cells (arrow). Some evidence sug-
gests that HIV or viral proteins localize in renal epithelial cells and
perhaps are directly or indirectly responsible for the cellular and
C functional damage. HIVAN often has a rapidly progressive down-
hill course, culminating in end-stage renal disease in as few as 4
FIGURE 4-3 (see Color Plate) months. HIVAN has a striking racial predilection; over 90% of
Human immunodeficiency virus (HIV) infection. Many forms of patients are black.
renal disease have been described in patients infected with HIV. The other glomerulopathy that may be an integral feature of HIV
Various immune complex–mediated glomerulonephritides associat- infection is immunoglobulin A nephropathy. In this setting, HIV
ed with complicating infections are known; however, several disor- antigen may be part of the glomerular immune complexes and cir-
ders appear to be directly or indirectly related to HIV itself. culating immune complexes. The morphology and clinical course
Perhaps the more common of these is known as HIV-associated generally are the same as in immunoglobulin A nephropathy occur-
nephropathy (HIVAN). This disease is a form of the collapsing ring in the non-HIV setting.
A B
HT
C D
Hepatitis C virus infection. The most common glomerulonephri- peripheral granular to confluent granular capillary wall deposits
tis in patients infected with the hepatitis C virus is membra- of immunoglobulin M (IgM) and complement C3; the same
noproliferative glomerulonephritis with, in some instances, immune proteins are in the luminal masses corresponding to
cryoglobulinemia and cryoglobulin precipitates in glomerular hyaline thrombi (arrow). C, Electron microscopy indicates the
capillaries. Thus, the morphology is basically the same as in luminal masses (HT). D, On electron microscopy the deposits
membranoproliferative glomerulonephritis type I (Fig. 2-18A–C). also appear to be composed of curvilinear or annular structures
A, With cryoglobulins, precipitates of protein representing cryo- (arrows). Hepatitis C viral antigen has been documented in the
globulin in the capillary lumina and appearing as hyaline throm- circulating cryoglobulins. Membranous glomerulonephritis with
bi (HT)are observed (arrows), often with numerous monocytes a mesangial component also has been infrequently described in
in most capillaries. B, Immunofluorescence microscopy discloses patients infected with the hepatitis C virus.
Infection-Associated Glomerulopathies 4.5
A B
the isolation of the hepatitis C virus and its separation from the
hepatitis B virus, membranoproliferative glomerulonephritis was
considered a common immune complex–mediated manifestation
of hepatitis B virus infection. However, more recent data indi-
cate that this form of glomerulonephritis is a feature of hepatitis
C virus infection rather than hepatitis B virus infection. In con-
trast, membranous glomerulonephritis, often with mesangial
deposits and variable mesangial hypercellularity, is the glomeru-
lopathy 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 mesan-
gial 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
C very difficult to identify mesangial deposits in this setting. C, In
addition to the expected capillary wall changes, electron micro-
FIGURE 4-5 (see Color Plate) scopy discloses deposits in mesangial regions of many lobules
Hepatitis B virus infection. Several glomerulopathies have been (the arrow indicates mesangial deposits; the arrowheads indicate
described in association with hepatitis B viral infection. Until subepithelial deposits).
Vascular Disorders
Arthur H. Cohen
Richard J. Glassock
V
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 dis-
orders are the focus: thrombotic microangiopathies, benign and
malignant nephrosclerosis, and vascular occlusive disease (atheroem-
bolism). Vasculitis and renovascular hypertension are discussed in
other chapters.
CHAPTER
5
A B
C 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 asso-
ciated 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
E capillary wall are widened (arrows). Flocculent material accumu-
lates, corresponding to mural fibrin, with associated endothelial cell
FIGURE 5-1 swelling. E, With widespread arterial thrombosis, cortical necrosis is
Light microscopy of thrombotic microangiopathies. This group a common complicating feature. The necrotic cortex consists
of disorders includes hemolytic-uremic syndrome and thrombotic of pale confluent multifocal zones throughout the cortex.
Vascular Disorders 5.3
Microangiopathic hemolytic anemia. Bizarrely shaped and Disseminated intravascular coagulation. In disseminated intravas-
fragmented erythrocytes are commonly seen in Wright’s stained cular coagulation, fibrin thrombi are typically found in many
peripheral blood smears from patients with active lesions of glomerular capillary lumina. In contrast to the thrombotic
thrombotic microangiopathy. These abnormally shaped erythro- microangiopathies, in disseminated intravascular coagulation, fib-
cytes presumably arise when the fibrin strands within small rin is not primarily in vessel walls but in the lumina. Consequently,
blood vessels shear the cell membrane, with imperfect resolution the capillary wall thickening, endothelial cell swelling, and fibrin
of the biconcave disk shape. The resultant intravascular hemoly- accumulation in subendothelial locations are not features of this
sis causes anemia, reticulocytosis, and reduced plasma haptoglo- lesion. In the glomerulus illustrated, the fibrin is in many capillary
bin level. lumina and appears as bright fuchsin positive (red) masses.
A B
FIGURE 5-4
Benign and malignant nephrosclerosis. In benign nephrosclerosis lar pole and growing as a collar around the wrinkled ischemic
the artery walls are thickened with intimal fibrosis and luminal tufts. This collagen formation ultimately is associated with tubular
narrowing. Arteriolar walls are thickened with insudative lesions, atrophy and interstitial fibrosis.
a process affecting afferent arterioles almost exclusively. Both In malignant nephrosclerosis the changes are virtually identical
of these processes, which can be quite patchy, result in chronic to those of thrombotic microangiopathies (Fig. 5-1 C). Malignant
ischemia. A, In glomeruli, chronic ischemia is manifested by grad- nephrosclerosis may be seen in essential hypertension, scleroder-
ual capillary wall wrinkling, luminal narrowing, and shrinkage ma, unilateral renovascular hypertension (with a contralateral or
and solidification of the tufts. B, As these processes progress, col- “unprotected” kidney), and as a complicating event in many
lagen forms internal to Bowman’s capsule, beginning at the vascu- chronic renal parenchymal diseases.
A 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 dispro-
portionately 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 choles-
terol 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 multinucle-
C ated foreign body giant cells. B, In this light microscopic photo-
graph, a few crystals are evident in the glomerular capillary lumi-
FIGURE 5-5 na and in an arteriole (arrows). C, In the electron micrograph the
Vascular occlusive disease and thrombosis. Atheroemboli (choles- elongated empty space represents dissolved cholesterol. Note that
terol emboli) are most commonly associated with intravascular no cellular reaction is evident.
Renal Interstitium and
Major Features of Chronic
Tubulointerstitial Nephritis
Garabed Eknoyan
Luan D. Truong
A
s a rule, diseases of the kidney primarily affect the glomeruli, vas-
culature, 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 tubulointersti-
tial 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 inter-
changeably. 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 tubulointer-
stitial 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 espe-
cially important because the magnitude of impairment in renal function
and the rate of its progression to renal failure correlate better with the CHAPTER
extent of TIN than with that of glomerular or vascular damage.
Renal insufficiency is a common feature of chronic TIN, and its diag-
6
nosis must be considered in any patient who exhibits renal insufficien-
cy. In most cases, however, chronic TIN is insidious in onset, renal insuf-
ficiency is slow to develop, and earliest manifestations of the disease are
those of tubular dysfunction. As such, it is important to maintain a high
6.2 Tubulointerstitial Disease
index of suspicion of this entity whenever any evidence of tubu- the two principal hallmarks of glomerular and vascular diseases
lar dysfunction is detected clinically. At this early stage, removal of the kidney: salt retention, manifested by edema and hyperten-
of a toxic cause of injury or correction of the underlying systemic sion; and proteinuria, which usually is modest and less than 1 to
or renal disease can result in preservation of residual renal func- 2 g/d in TIN. These clinical considerations notwithstanding, a
tion. Of special relevance in patients who exhibit renal insuffi- definite diagnosis of TIN can be established only by morphologic
ciency caused by primary TIN is the absence or modest degree of examination of kidney tissue.
Structure of the Interstitium

FIGURE 6-1
C—Cortex
Diagram of the approximate relative volume composition of tissue compartments at differ-
IS—Inner stripe of outer medulla
OS—Outer stripe of outer medulla
ent segments of the kidney in rats. The interstitium of the kidney consists of peritubular and
IZ—Inner zone of medulla periarterial spaces. The relative contribution of each of these two spaces to interstitial vol-
ume varies, reflecting in part the arbitrary boundaries used in assessing them, but increases
C 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
OS
cells are scattered and relatively inconspicuous. In fact, a loss of the normally very close
IS
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,
IZ have characteristic structural features and an organized arrangement. The ground substance
of the renal interstitium contains different types of fibrils and basementlike material embed-
ded in a glycosaminoglycan-rich substance. (From Bohman [1]; with permission.)
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 render-
ing, 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 intersti-
tial 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 corti-
cal volume in rats. The narrow interstitium occupies about one-half to two-thirds of the
A cortical peritubular capillary surface area. The remainder of the cortical interstitium con-
sists 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.)
B
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 inter-
stitium. 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 signifi-
cantly in volume, in increments that gradually become larger
toward the papillary tip.
The inner stripe of the outer medulla consists of the vascular bun-
dles 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 differ-
entiation 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
Cortex Outer medulla Inner medulla

Fibroblastic cells Fibroblastic cells Pericytes
Mononuclear cells Mononuclear cells Lipid-laden cells
Mononuclear cells
cells are important in antigen presentation. Their cytokines con-

tribute to recruitment of infiltrating cells, progression of injury,
and sustenance of fibrogenesis.
A 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,
FIGURE 6-4 some type I cells form pericytes whereas others evolve into special-
A, High-power view of the medulla showing the wide interstitium ized lipid-laden interstitial cells. These specialized cells increase
and interstitial cells, which are abundant, varied in shape, and in number toward the papillary tip and are a possible source of
arranged as are the rungs of a ladder. B, Renal interstitial cells. medullary prostaglandins and of production of matriceal glyco-
The interstitium contains two main cell types, whose numbers saminoglycans. A characteristic feature of these medullary cells is
increase from the cortex to the papilla. Type I interstitial cells are their connection to each other in a characteristic arrangement,
fibroblastic cells that are active in the deposition and degradation similar to the rungs of a ladder. These cells have a distinct close
of the interstitial matrix. Type I cells contribute to fibrosis in response and regular transverse apposition to their surrounding structures,
to chronic irritation. Type II cells are macrophage-derived mono- specifically the limbs of the loop of Henle and capillaries, but not
nuclear cells with phagocytic and immunologic properties. Type II to the collecting duct cells.
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 com-
partment, the absorbed or secreted substances must traverse the inter-
stitial space. The structure, composition, and permeability characteris-
tics of the interstitial space must, of necessity, exert an effect on any
such exchange. Although the normal structural and functional corre-
lates of the interstitial space are poorly defined, changes in its compo-
sition 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 contribut-
ing to tubular dysfunction and progressive ischemic injury.
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 inter-
spersed 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
FIGURE 6-7 periglomerular fibrosis.
Secondary chronic TIN. The arrow indicates a glomerulus with a The large blood vessels are unremarkable in the early phases of
cellular crescent. The diagnosis of TIN can be established only by the disease. Ultimately, these vessels develop intimal fibrosis, medial
morphologic examination of kidney tissue. The extent of the lesions hypertrophy, and arteriolosclerosis. These vascular changes, which
of TIN, whether focal or diffuse, correlates with the degree of also are associated with hypertension, can be present even in the
impairment in renal function. absence of elevated blood pressure in cases of chronic TIN.
CONDITIONS ASSOCIATED WITH PRIMARY CHRONIC TIN
Urinary tract
Immunologic diseases obstructions Hematologic diseases Miscellaneous Hereditary diseases Endemic diseases
Systemic lupus Vesicoureteral reflux Sickle hemoglobinopathies Vascular diseases Medullary cystic disease Balkan nephropathy
erythematosus Mechanical Multiple myeloma Nephrosclerosis Hereditary nephritis Nephropathia epidemica
Sjögren syndrome Lymphoproliferative Atheroembolic disease Medullary sponge kidney
Transplanted kidney disorders Radiation nephritis Polycystic kidney disease
Cryoglobulinemia Aplastic anemia Diabetes mellitus
Goodpasture’s syndrome Sickle hemoglobinopathies
Immunoglobulin A Vasculitis
nephropathy
Amyloidosis
Pyelonephritis
Infections Drugs Heavy metals Metabolic disorders Granulomatous disease Idiopathic TIN
Systemic Analgesics Lead Hyperuricemia- Sarcoidosis
Renal Cyclosporine Cadmium hyperuricosuria Tuberculosis
Bacterial Nitrosourea Hypercalcemia- Wegener’s granulomatosis
Viral Cisplatin hypercalciuria
Fungal Lithium Hyperoxaluria
Mycobacterial Miscellaneous Potassium depletion
Cystinosis
FIGURE 6-8
Tubulointerstitial nephropathy occurs in a motley group of diseases together because of the unifying structural changes associated with
of varied and diverse causes. These diseases are arbitrarily grouped TIN noted on morphologic examination of the kidneys.
Pathogenesis of Chronic TIN

FIGURE 6-9
Glomerular disease 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
Vascular damage Altered filtration 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
Reabsorption by the induction of an inflammatory or immunologic reaction.
Tubular ischemia of noxious Studies in experimental models and humans provide compelling
macromolecules evidence for a role of immune mechanisms. The infiltrating lympho-
cytes have been shown to be activated immunologically. It is the
inappropriate release of cytokines by the infiltrating cells and loss
Chronic tubular cell injury
of regulatory balance of normal cellular regeneration that results in
increased fibrous tissue deposition and tubular atrophy. Another
b-9
Release of cytokines, proteinases potential mechanism of injury is that of increased tubular ammonia-
↑NH3→↑C3b→↑C5
adhesion molecules, growth factors genesis by the residual functioning but hypertrophic tubules. Increased
tubular ammoniagenesis contributes to the immunologic injury by
activating the alternate complement pathway.
↑ Recruitment of Altered glomerular permeability with consequent proteinuria
Fibroblast proliferation appears to be important in the development of TIN in primary
∆Cell balance ↑Matrix deposition antigenically
activated cells 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.
Tubular Interstitial Interstitial In primary vascular diseases TIN has been attributed to ischemic
atrophy fibrosis infiltrates 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
Tubular dysfunction Eknoyan [3]; with permission.)
↓ Capillary perfusion
Progressive loss of renal function
FIGURE 6-10
ROLE OF TUBULAR EPITHELIAL CELLS The infiltrating interstitial cells contribute
to the course TIN. However, increasing
evidence exists for a primary role of the
Chemoattractant Pro-inflammatory tubular epithelial cells in the recruitment
cytokines cytokines Cell surface markers Matrix proteins of interstitial infiltrating cells and in per-
petuation of the process. Injured epithelial
Monocyte chemo- Interleukin-6 (IL-6), IL-8 Human leukocyte antigen Collagen I, III, IV cells secrete a variety of cytokines that
attractant peptide-1 class II have both chemoattractant and pro-inflam-
Platelet-derived growth Laminin, fibronectin
Osteopontin factor- Intercellular adhesion matory properties. These cells express a
molecule-1 number of cell surface markers that enable
Chemoattractant Granulocyte -macrophage
lipids colony-stimulating factor Vascular cell adhesion them to interact with infiltrating cells.
Endothelin-1 Transforming growth
molecule-1 Injured epithelial cells also participate in
factor-1 the deposition of increased interstitial
RANTES matrix and fibrous tissue. Listed are
Tumor necrosis factor-
cytokines, cell surface markers, and matrix
components secreted by the renal tubular
From Palmer [4]; with permission. cell that may play a role in the develop-
ment of tubulointerstitial disease.
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
A activated in the absence of any evidence of tubulointerstitial immune
deposits, even in classic examples of immune complex–mediated
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
B 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 hyper-
proliferative growth.
C
Mechanisms Involved in Renal Interstitial Fibrosis
Macrophage
Virus
Protein TNF4
IL 1
TGF–3
PDGF
Lymphocyte GM–CSF
l
IFN
na
IL 4
Sig
IL 2
DO
HLA– DR
Sig
DP
na
Proliferating TH-Cell
l
Proliferating B-cell
Epithelial cell
IL 1
IL1 PDGF
IL6
IL7
IL8 Proliferation ↑↑
ICAM–1 IIFNβ
GM-CSF
G-CSF Differentiation ↓
M-CSF
Factor x MF I – MF III Interstitial fibrosis
Proximal P (30/7.3) PMF IV – PMF VI
Fibroblast
tubulus
Synthesis ↑↑ and Secretion ↑
of collagen
Fibrosin
P 53/6.1
FIGURE 6-12
Expression of human leukocyte antigen class II and adhesion pathways have been proposed to operate at different stages of the
molecules released by injured tubular epithelial cells, as well disease process. Each of these individual pathways usually is part
as by infiltrating cells, modulate and magnify the process to of a recuperative process that works in concert in response to
repair the injury (Figure 6-10). When the process becomes unre- injury. However, it is the loss of their controlling feedback in
sponsive to controlling feedback mechanisms, fibroblasts prolifer- chronic TIN that seems to account for the altered balance and
ate and increase fibrotic matrix deposition. The precise mecha- results in persistent cellular infiltrates, progressive fibrosis, and
nism of TIN remains to be identified. A number of pathogenetic tubular degeneration.
Patterns of Tubular Dysfunction

The tubulointerstitial lesions are localized
either to the cortex or medulla. Cortical
PATTERNS OF TUBULAR DYSFUNCTION IN CHRONIC TIN
lesions mainly affect either the proximal or
distal tubule. Medullary lesions affect the
loop of Henle and the collecting duct. The
Site of injury Cause Tubular dysfunction change in the normal function of each of
Cortex these affected segments then determines the
Proximal tubule Heavy metals Decreased reabsorption of sodium, bicarbonate, glucose, manifestations of tubular dysfunction.
Multiple myeloma uric acid, phosphate, amino acids Essentially, the proximal nephron segment
Immunologic diseases reabsorbs the bulk of bicarbonate, glucose,
Cystinosis amino acids, phosphate, and uric acid.
Distal tubule Immunologic diseases Decreased secretion of hydrogen, potassium Changes in proximal tubular function,
Granulomatous diseases Decreased reabsorption of sodium therefore, result in bicarbonaturia (proximal
Hereditary diseases renal acidosis), 2-microglobinuria, gluco-
Hypercalcemia suria (renal glucosuria), aminoaciduria,
Urinary tract obstruction phosphaturia, and uricosuria.
Sickle hemoglobinopathy
The distal nephron segment secretes
Amyloidosis
hydrogen and potassium and regulates the
Medulla Analgesic nephropathy Decreased ability to concentrate urine final amount of sodium chloride excreted.
Sickle hemoglobinopathy Decreased reabsorption of sodium
Lesions primarily affecting this segment,
Uric acid disorders
Hypercalcemia therefore, result in the distal form of renal
Infection tubular acidosis, hyperkalemia, and salt
Hereditary disorders wasting. Lesions that primarily involve the
Granulomatous diseases medulla and papilla disproportionately
Papilla Analgesic nephropathy Decreased ability to concentrate urine affect the loops of Henle, collecting ducts,
Diabetes mellitus Decreased reabsorption of sodium and the other medullary structures essential
Infection to attaining and maintaining medullary
Urinary tract obstruction hypertonicity. Disruption of these struc-
Sickle hemoglobinopathy tures, therefore, results in different degrees
Transplanted kidney of nephrogenic diabetes insipidus and clini-
cally manifests as polyuria and nocturia.
Although this general framework is use-
ful in localizing the site of injury, consider-
FIGURE 6-13 able overlap may be encountered clinically,
The principal manifestations of TIN are those of tubular dysfunction. Because of the focal with different degrees of proximal, distal,
nature of the lesions that occur and the segmental nature of normal tubular function, the and medullary dysfunction present in the
pattern of tubular dysfunction that results varies, depending on the major site of injury. same individual. Additionally, the ultimate
The extent of damage determines the severity of tubular dysfunction. The hallmarks of development of renal failure complicates
glomerular disease (such as salt retention, edema, hypertension, proteinuria, and hema- the issue further because of the added
turia) are characteristically absent in the early phases of chronic TIN. The type of insult effect of urea-induced osmotic diuresis
determines the segmental location of injury. For example, agents secreted by the organic on tubular function in the remaining
pathway in the pars recta (heavy metals) or reabsorbed in the proximal tubule (light chain nephrons. In this later stage of TIN, the
proteins) cause predominantly proximal tubular lesions. Depositional disorders (amyloidosis absence of glomerular proteinuria and the
and hyperglobulinemic states) cause predominantly distal tubular lesions. Insulting agents more common occurrence of hypertension
that are affected by the urine concentrating mechanism (analgesics and uric acid) or in glomerular diseases can be helpful in
medullary tonicity (sickle hemoglobinopathy) cause medullary injury. the differential diagnosis.
Correlates of Tubular Dysfunction

with Severity of Chronic TIN
160 1200
Chronic GN Chronic GN
Acute GN 1100 Acute GN
PTIN PTIN
140 Nephrosclerosis Nephrosclerosis
1000
120 900
800
Maximal osmolality, mOs/kg

100
Inulin clearance, mL/min
700
80 600
500
60
400
300
40
200
20
100
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12
A Interstitial disease (total score) B Interstitial disease (total score)
FIGURE 6-14
1200
Chronic GN Relationship of inulin clearance (A), maximum urine concentration
110 Acute GN (B), and ammonium excretion in response to an acute acid load (C)
PTIN to the severity of tubulointerstitial nephritis. A close correlation
Nephrosclerosis
100 exists between the severity of chronic TIN and impaired renal
tubular and glomerular function. Repeated evaluations of kidney
90 biopsy for the extent of tubulointerstitial lesions have shown a
close correlation with renal function test results in tests performed
80 before biopsy. These tests include those for inulin clearance, maximal
Ammonium excretion, µEq/min
ability to concentrate the urine, and ability to acidify the urine. This
70 correlation has been validated in a variety of renal diseases, including
primary and secondary forms of chronic TIN. (From Shainuck and
60 coworkers [5]; with permission.)
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12
C Interstitial disease (total score)
Correlates of Chronic TIN with Progressive Renal Failure

FIGURE 6-15
100
Probability of maintaining renal function, %
Effect on long-term prognosis of the presence of cortical chronic

tubulointerstitial nephritis in patients with mesangioproliferative
80 Normal interstitium glomerulonephritis (n = 455), membranous nephropathy (n = 334),
and membranoproliferative glomerulonephritis (n = 220). The
60 extent of tubulointerstitial nephritis correlates not only with altered
glomerular and tubular dysfunction at the time of kidney biopsy
40 but also provides a prognostic index of the progression rate to end-
stage renal disease. As shown, the presence of interstitial fibrosis
Interstitial fibrosis
20 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.)
0
0 2 4 6 8 10 12 14 16
Follow-up, y
Drugs
Analgesic Nephropathy
diuresis has provided protection from anal-
Acetaminophen Metabolism gesic-induced renal injury. Relative to plasma
levels, both acetaminophen (paracetamol)
p–phenetidine Meth–hemoglobin
n–OH–p–acetophenetidine
Sulfhemoglobin and its excretory conjugate attain significant
(fourfold to fivefold) concentrations in the
medulla and papilla, depending on the state
Phenactin of hydration of the animal studied. The
p–acetophenetidine toxic effect of these drugs apparently is
related to their intrarenal oxidation to reac-
tive intermediates that, in the absence of
Glucoronide Paracetamol Cytochrome Reactive toxic reducing substances such as glutathione,
sulfate n–acetyl–p–aminophenol P–450 metabolites
become cytotoxic by virtue of their capacity
Glutathione to induce oxidative injury. Salicylates also
are significantly (sixfold to thirteenfold
Covalent binding to Glutathione above plasma levels) concentrated in the
cellular sulfhydryl conjugate
medulla and papilla, where they attain a
level sufficient to uncouple oxidative phos-
Mercapturic
phorylation and compromise the ability of
Cell death cells to generate reducing substances. Thus,
acid
both agents attain sufficient renal medullary
concentration to individually exert a detri-
FIGURE 6-16 mental and injurious effect on cell function,
Metabolism of acetaminophen and its excretion by the kidney. Prolonged exposure to drugs which is magnified when they are present
can cause chronic TIN. Although a number of drugs (eg, lithium, cyclosporine, cisplatin, together. By reducing the medullary tonici-
and nitrosoureas) have been implicated, the more commonly responsible agents are anal- ty, and therefore the medullary concentra-
gesics. As a rule, the lesions of analgesic nephropathy develop in persons who abuse anal- tion of drug attained, water diuresis pro-
gesic combinations (phenacetin, or its main metabolite acetaminophen, plus aspirin, with or tects from analgesic-induced cell injury. A
without caffeine). Experimental evidence indicates that phenacetin, or acetaminophen, plus direct role of analgesic-induced injury can
aspirin taken alone are only moderately nephrotoxic and only at massive doses, but that the be adduced from the improvement of renal
lesions can be more readily induced when these drugs are taken together. In all experimental function that can occur after cessation of
studies the extent of renal injury has been dose-dependent and, when examined, water analgesic abuse.
FIGURE 6-17
Pathogenesis of renal lesion associated Course of the renal lesions in analgesic nephropathy. The intrarenal
with analgesic abuse
distribution of analgesics provides an explanation for the medullary
location of the pathologic lesions of analgesic nephropathy. The initial
Cortex– normal 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 col-
Outer medula– patchy tubular damage
a. tubular dilatation
lecting ducts are spared. The quantities of tubular and vascular
b. increased interstitial tissue basement membrane and ground substance are increased. At this
c. casts: pigment stage the kidneys are normal in size and no abnormalities have
Stage I Papilla– possible microscopic changes 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
Cortex– normal medullary lesions increases with sclerosis and obliteration of the
Outer medula– increase in changes capillaries, atrophy and degeneration of the loops of Henle and
collecting ducts, and the beginning of calcification of the necrotic
Papilla– necrosis and atrophy foci. Ultimately, the papillae become entirely necrotic, with seques-
attached or separated tration and demarcation of the necrotic tissue. The necrotic papillae
Stage II
may then slough and are excreted into the urine or remain in situ,
Cortex– where they atrophy further and become calcified. Cortical scarring,
a. atrophy area overlying characterized by interstitial fibrosis, tubular atrophy, and periglo-
necrotic papilla
merular fibrosis, develops over the necrotic medullary segments.
b. hypertrophy
The medullary rays traversing the cortex are usually spared and
become hypertrophic, thereby imparting a characteristic cortical
Papilla– atrophic, necrotic nodularity to the now shrunken kidneys. Visual observation of these
Stage III configurational changes by computed tomography scan can be
extremely useful in the diagnosis of analgesic nephropathy.
in men and 96 mm in women. Bumpy con-

Size tours are considered to be present if at least
RV three indentations are evident (panels B and
Right kidney RA RA
C). The scan can reveal papillary calcifica-
Left kidney
tions (panels B and D). Visual observation
Spine of the configurational changes illustrated
a a in Figure 6-18 can be extremely useful in
diagnosing the scarred kidney in analgesic
nephropathy. A series of careful studies
A b b C
using CT scans without contrast material
have provided imaging criteria for the diag-
nosis of analgesic nephropathy. Validation
Appearance of these criteria currently is underway by a
Bumpy contours study at the National Institutes of Health.
From studies comparing analgesic abusers
Papillary calcifications
to persons in control groups, it has been
shown that a decrease in kidney size and
bumpy contours of both kidneys provide a
0 1–2 3–5 >5 diagnostic sensitivity of 90% and a specificity
B Number of indentations D of 95%. The additional finding of evidence of
renal papillary necrosis provides a diagnostic
sensitivity of 72% and specificity of 97%, giv-
FIGURE 6-18 ing a positive predictive value of 92%. RA—
Computed tomography (CT) imaging criteria for diagnosing analgesic nephropathy. Renal renal artery; RV— renal vein. (From DeBroe
size (A) is considered decreased if the sum of a and b (panels A and B) is less than 103 mm and Elseviers [6]; with permission.)
1 2 3
CLINICAL FEATURES
a a a
b b b
c c c
Female predominance, 60–85%
Age, >30 y
Personality disorders: introvert, dependent, anxiety, neurosis, family instability
Addictive habits: smoking, alcohol, laxatives, psychotropics, sedatives a—cortical nephron b—juxta medullary nephron c—midcortical nephron
Causes of analgesic dependency: headache, 40–60%; mood, 6–30%; musculoskeletal

pain, 20–30% FIGURE 6-20
Diagram of cortical and juxtamedullary nephrons in the normal kid-
ney (1). Papillary necrosis (2) and sloughing (3) result in loss of
juxtamedullary nephrons. Cortical nephrons are spared, thereby
FIGURE 6-19 preserving normal renal function in the early stages of the disease.
Certain personality features and clinical findings characterize patients The course of analgesic nephropathy is slowly progressive, and
prone to analgesic abuse. These patients tend to deny analgesic use deterioration of renal function is insidious. One reason for these
on direct questioning; however, their history can be revealing. In all characteristics of the disease is that lesions beginning in the papil-
cases, a relationship exists between renal function and the dura- lary tip affect only the juxtamedullary nephrons, sparing the corti-
tion, intensity, and quantity of analgesic consumed. The magnitude cal nephrons. It is only when the lesions are advanced enough to
of injury is related to the quantity of analgesic ingested chronically affect the whole medulla that the number of nephrons lost is suffi-
over years. In persons with significant renal impairment, the aver- cient to result in a reduction in filtration rate. However, renal
age dose ingested has been estimated at about 10 kg over a mean injury can be detected by testing for sterile pyuria, reduced concen-
period of 13 years. The minimum amount of drug consumption trating ability, and a distal acidifying defect. These features may be
that results in significant renal damage is unknown. It has been evident at levels of mild renal insufficiency and become more pro-
estimated that a cumulative dose of 3 kg of the index compound, nounced and prevalent as renal function deteriorates. Proximal
or a daily ingestion of 1 g/d over 3 years or more, is a minimum tubular function is preserved in patients with mild renal insufficiency
that can result in detectable renal impairment. but can be abnormal in those with more advanced renal failure.
Cyclosporine
A B
FIGURE 6-21
A, Chronic TIN caused by cyclosporine. The arrow indicates the epithelial cell injury. Whereas these early lesions tend to be
characteristic hyaline-type arteriolopathy of cyclosporine nephro- reversible with cessation of therapy, an irreversible interstitial
toxicity. B, Patchy nature of chronic TIN caused by cyclosporine. fibrosis and mononuclear cellular infiltrates develop with pro-
Note the severe TIN on the right adjacent to an otherwise intact longed use of cyclosporine, especially at high doses. The irre-
area on the left. Tubulointerstitial nephritis has emerged as the versible nature of TIN associated with the use of cyclosporine
most serious side effect of cyclosporine. Cyclosporine-mediated and its attendant reduction in renal function have raised concerns
vasoconstriction of the cortical microvasculature has been implicated regarding the long-term use of this otherwise efficient immuno-
in the development of an occlusive arteriolopathy and tubular suppressive agent.
Heavy Metals
Lead Nephropathy
exposure to lead are lead-based paints; lead leaked into food dur-
ing 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
FIGURE 6-22 changes are prominent.
Lead nephropathy. Arrows indicate the characteristic intranuclear Other heavy metals associated with TIN are cadmium, silicon,
inclusions. Exposure to a variety of heavy metals results in devel- copper, bismuth, and barium. Sufficient experimental evidence and
opment of chronic TIN. Of these metals, the more common and some weak epidemiologic evidence suggest a possible role of organic
clinically important implicated agent is lead. Major sources of 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 degener-
ation, interstitial fibrosis, and mononuclear inflammatory cell infil-
tration 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 dia-
betes, sickle cell hemoglobinopathy, cyclosporine nephrotoxicity,
and radiation nephritis.
FIGURE 6-24
Gross appearance of the kidney as a result of arteriolonephroscle-
rosis, 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) adja-
cent 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. How-
ever, 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.
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 (hyperfil-
tration) 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
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 cell–hemoglobin C disease,
or sickle cell–thalassemia disease. The predisposing factors that lead
to a propensity of renal involvement are the physicochemical prop-
erties 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 concen-
FIGURE 6-28 trating ability, depressed distal potassium and hydrogen secretion,
The kidney in sickle cell disease. Note the tubular deposition of tubular proteinuria, and decreased proximal reabsorption of phos-
hemosiderin. The principal renal lesion of hemoglobinopathy S is phate, and increased secretion of uric acid and creatinine.
Hematologic Diseases
Plasma Cell Dyscrasias
A, Myeloma cast nephropathy. The arrow indicates a multinucleated
giant cell. B, Light chain deposition disease. Note the changes indica-
tive 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 (hypercal-
cemia 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
A 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.
B 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.
C
Metabolic Disorders
Hyperuricemia
A B
FIGURE 6-30
A, Intratubular deposits of uric acid. B, Gouty tophus in the renal hyperacidity of their urine caused by an inherent abnormality in
medulla. The kidney is the major organ of urate excretion and a the ability to produce ammonia. The acidity of urine is important
primary target organ affected in disorders of its metabolism. Renal because uric acid is 17 times less soluble than is urate. Therefore,
lesions result from crystallization of urate in the urinary outflow uric acid facilitates precipitation in the distal nephron of persons
tract or the renal parenchyma. Depending on the load of urate, who do not overproduce uric acid but who have a persistently
one of three lesions result: acute urate nephropathy, uric acid acidic urine.
nephrothiasis, or chronic urate nephropathy. Whereas any of these The previous notion that chronic renal disease was common in
lesions produce tubulointerstitial lesions, it is those of chronic patients with hyperuricemia is now considered doubtful in light of
urate nephropathy that account for most cases of chronic TIN. prolonged follow-up studies of renal function in persons with
The principal lesion of chronic urate nephropathy is due to hyperuricemia. Renal dysfunction could be documented only when
deposition of microtophi of amorphous urate crystals in the inter- the serum urate concentration was more than 10 mg/dL in women
stitium, with a surrounding giant-cell reaction. An earlier change, and more than 13 mg/dL in men for prolonged periods. The deteri-
however, probably is due to the precipitation of birefringent uric oration of renal function in persons with hyperuricemia of a lower
acid crystals in the collecting tubules, with consequent tubular magnitude has been attributed to the higher than expected occur-
obstruction, dilatation, atrophy, and interstitial fibrosis. The renal rence of concurrent hypertension, diabetes mellitus, abnormal lipid
injury in persons who develop lesions has been attributed to metabolism, and nephrosclerosis.
Hyperoxaluria
A B
A, Calcium oxalate crystals (arrow) seen on light microscopy. B, Dark chronic. As a result, interstitial fibrosis, tubular atrophy, and dilation
field microscopy. When hyperoxaluria is sudden and massive (such as result in chronic TIN with progressive renal failure. The propensity
after ethylene glycol ingestion) acute renal failure develops. Other- for recurrent calcium oxalate nephrolithiasis and consequent obstruc-
wise, in most cases of hyperoxaluria the overload is insidious and tive uropathy contribute to the tubulointerstitial lesions.
Granulomatous Diseases
Malacoplakia
hallmark of certain forms of tubulointerstitial
3 5 disease. The best-known form is that of
sarcoidosis. Interstitial granulomatous reac-
tions also have been noted in renal tuberculo-
sis, xanthogranulomatous pyelonephritis,
1 2 7 renal malacoplakia, Wegener’s granulo-
matosis, renal candidiasis, heroin abuse,
hyperoxaluria after jejunoileal bypass
surgery, and an idiopathic form in associa-
tion 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
4 6 multifocal, and in one third of cases both
kidneys are involved. The lesions are nodular,
well-demarcated, and variable in size. They
FIGURE 6-32 may coalesce, developing foci of suppura-
Schematic representation of the forms and course of renal involvement by malacoplakia: tion that may become cystic or calcified.
1, normal kidney; 2, enlarged kidney resulting from interstitial nephritis without nodularity; The lesions usually are located in the cortex
3, unifocal nodular involvement; 4, multifocal nodular involvement; 5, abscess formation but may be medullary and result in papillary
with perinephric spread of malacoplakia; 6, cystic lesions; and 7, atrophic multinodular necrosis. (From Dobyan and coworkers [7];
kidney after treatment. Interstitial granulomatous reactions are a rare but characteristic with permission.)
Endemic Diseases
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 hem-
orrhagic 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 conta-
minated by rodent excreta. Antibodies to the virus are detected in
FIGURE 6-33 the serum, and viruslike structures have been demonstrated in the
Hemorrhagic TIN associated with Hantavirus infection. Two kidneys of persons infected with the virus.
endemic diseases in which tubulointerstitial lesions are a predomi- Tubulointerstitial nephropathy caused by viral infection also has
nant component are Balkan nephropathy and nephropathia epi- been reported in polyomavirus, cytomegalovirus, herpes simplex
demica. Endemic Balkan nephropathy is a progressive chronic virus, human immunodeficiency virus, infectious mononucleosis,
tubulointerstitial nephritis whose occurrence is mostly clustered and Epstein-Barr virus.
Hereditary Diseases
Hereditary Nephritis
A B
FIGURE 6-34
A, Interstitial foam cells in Alport’s syndrome. B, Late phase Alport’s associated epithelial cell proliferation account for cyst formation. It
syndrome showing chronic TIN and glomerular changes in a patient is the continuous growth of cysts and their progressive dilation that
with massive proteinuria. Tubulointerstitial lesions are a prominent cause pressure-induced ischemic injury, with consequent TIN of the
component of the renal pathology of a variety of hereditary diseases adjacent renal parenchyma.
of the kidney, such as medullary cystic disease, familial juvenile Tubulointerstitial lesions also are a salient feature of inherited
nephronophthisis, medullary sponge kidney, and polycystic kidney diseases of the glomerular basement membrane. Notable among
disease. The primary disorder of these conditions is a tubular defect them are those of hereditary nephritis or Alport’s syndrome, in
that results in the cystic dilation of the affected segment in some which a mutation in the encoding gene localized to the X chromo-
patients. Altered tubular basement membrane composition and some results in a defect in the -5 chain of type IV collagen.
Papillary Necrosis
A B
FIGURE 6-35
A, Renal papillary necrosis. The arrow points to the either one or both kidneys. The lesions are bilateral in
region of a sloughed necrotic papilla. B, Whole mount of most patients. In patients with involvement of one kid-
a necrotic papilla. Arrows delineate focal necrosis princi- ney at the time of initial presentation, RPN will devel-
pally affecting the medullary inner stripe. Renal papillary op in the other kidney within 4 years, which is not
necrosis (RPN) develops in a variety of diseases that unexpected because of the systemic nature of the dis-
cause chronic tubulointerstitial nephropathy in which the eases associated with RPN. RPN may be unilateral in
lesion is more severe in the inner medulla. The basic patients in whom predisposing factors (such as infec-
lesion affects the vasculature with consequent focal or tion and obstruction) are limited to one kidney.
diffuse ischemic necrosis of the distal segments of one or Azotemia may be absent even in bilateral papillary
more renal pyramids. In the affected papilla, the sharp necrosis, because it is the total number of papillae
demarcation of the lesion and coagulative necrosis seen involved that ultimately determines the level of renal
in the early stages of the disease closely resemble those of insufficiency that develops. Each human kidney has an
infarction. The fact that the necrosis is anatomically lim- average of eight pyramids, such that even with bilateral
ited to the papillary tips can be attributed to a variety of RPN affecting one papilla or two papillae in each kid-
features unique to this site, especially those affecting the ney, sufficient unaffected renal lobules remain to main-
vasculature. The renal papilla receives its blood supply tain an adequate level of renal function.
from the vasa recta. Measurements of medullary blood As a rule, RPN is a disease of an older age group,
flow notwithstanding, it should be noted that much of the average age of patients being 53 years. Nearly half
the blood flow in the vasa recta serves the countercur- of cases occur in persons over 60 years of age. More
rent exchange mechanism. Nutrient blood supply is pro- than 90% of cases occur in persons over 40 years of
vided by small capillary vessels that originate in each age, except for those caused by sickle cell hemoglo-
given region. The net effect is that the blood supply to binopathy. RPN is much less common in children, in
the papillary tip is less than that to the rest of the medul- whom the chronic conditions associated with papil-
la, hence its predisposition to ischemic necrosis. lary necrosis are rare. However, RPN does occur in
The necrotic lesions may be limited to only a few of children in association with hypoxia, dehydration,
the papillae or may involve several of the papillae in and septicemia.
Total Papillary Necrosis

into the pelvis and may be recovered in the
Renal Papillary Necrosis– Papillary Form urine. In most of these cases, however, the
necrotic papillae are not sloughed but are
Lesion Pyelogram
either resorbed or remain in situ, where
Normal they becomes calcified or form the nidus of
Early necrosis, mucosa Normal calyx
normal, papilla swollen. a calculus. In these patients, excretory radio-
logic examination and computed tomogra-
Progressive necrosis, Irregular or phy scanning are diagnostic. Unfortunately,
swelling, mucosal loss. fuzzy calyx these changes may not be evident until the
late stages of RPN, when the papillae
Sequestrian of necrotic Sinus or already are shrunken and sequestered. In
area. "Arc Shadow" fact, even when the papillae are sloughed
out, excretory radiography can be negative.
Sinus formation begins.
The passage of sloughed papillae is
Sinus surrounds "Ring Shadow" associated with lumbar pain, which is
sequestrum. indistinguishable from ureteral colic of
any cause and is present in about half of
Sequestrum extruded "Clubbing" patients. Oliguria occurs in less than 10%
or resorbed. "Clubbed calyx" of patients. A definitive diagnosis of RPN
"Caliectasis" can be made by finding portions of necrotic
papillae in the urine. A deliberate search
Sequestrum calcifies. "Ring Shadow" should be made for papillary fragments in
Obstruction urine collected during or after attacks of
Extruded sequestrum colicky pain of all suspected cases, by
straining the urine through filter paper or a
piece of gauze. The separation and passage
FIGURE 6-36 of papillary tissue may be associated with
Schematic of the progressive stages of the papillary form of renal papillary necrosis and hematuria, which is microscopic in some
their associated radiologic changes seen on intravenous pyelography. Papillary necrosis 40% to 45% of patients and gross in 20%.
occurs in one of two forms. In the medullary form, also termed partial papillary necrosis, The hematuria can be massive, and occa-
the inner medulla is affected; however, the papillary tip and fornices remain intact. In the sionally, instances of exsanguinating hemor-
papillary form, also termed total papillary necrosis, the calyceal fornices and entire papillary rhage requiring nephrectomy have been
tip are necrotic. In total papillary necrosis shown here, the lesion is characterized from the reported. (From Eknoyan and coworkers
outset by necrosis, demarcation, and sequestration of the papillae, which ultimately slough [8]; with permission.)
FIGURE 6-37
Renal Papillary Necrosis – Medullary Form Schematic of the progressive stages of the
medullary form of renal papillary necrosis
Normal Lesion Pyelogram
and their associated radiologic appearance
Early focal, necrosis Normal calyx seen on intravenous pyelography. In par-
of medullary inner tial papillary necrosis the lesion begins as
stripe. focal necrosis within the substance of the
medullary inner stripe. The lesion pro-
Progressive necrosis, Normal calyx gresses by coagulative necrosis to form a
coalescence of necrotic sinus to the papillary tip, with subsequent
areas. Swelling. Mucosa extrusion or resorption of the sequestered
normal. necrotic tissue. The medullary form of
papillary necrosis is commonly encoun-
Mucosal break. Sinus
tered in persons with sickle cell hemoglo-
Sequestration
binopathy. The incidence of radiographi-
and sinus formation.
cally demonstrative papillary necrosis is
Progressive sequestration, Irregular sinus as high as 33% to 65% in such persons.
extrusion, or resorption
of necrotic tissue.
Healing. Irregular Irregular

medullary cavity with medullary
communicating cavity
sinus tract.
avoided in these patients because of dye-induced nephrotoxicity.

When sought, papillary necrosis has been reported in as many as
CONDITIONS ASSOCIATED WITH
25% of cases. Analgesic nephropathy accounts for 15% to 25%
RENAL PAPILLARY NECROSIS
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 non-
Diabetes mellitus
steroidal anti-inflammatory drugs.
Urinary tract obstruction
Sickle hemoglobinopathy is another common cause of papillary
Pyelonephritis necrosis, which, when sought by intravenous pyelography, is detected
Analgesic nephropathy in well over half of cases.
Sickle hemoglobinopathy Infection is usually but not invariably a concomitant finding in
Rejection of transplanted kidney most cases of RPN. In fact, with few exceptions, most patients
Vasculitis with RPN ultimately develop a urinary tract infection, which
Miscellaneous represents a complication of papillary necrosis: that is, the infec-
tion 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
FIGURE 6-38 the symptomatology of RPN, because fever and chills are the pre-
Diabetes mellitus is the most common condition associated with senting symptoms in two thirds of patients and a positive urine
papillary necrosis. The occurrence of capillary necrosis is likely culture is obtained in 70%. However, RPN is not an extension of
more common than is generally appreciated, because pyelography severe pyelonephritis. In most patients with florid acute
(the best diagnostic tool for detection of papillary necrosis) is pyelonephritis, RPN does not occur.
FIGURE 6-39
Spectrum of Renal Papillary Necrosis
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
Obstruction areas). In most cases of RPN, more than one of the conditions associated with RPN is pre-
sent. 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 com-
bination of detrimental factors appear to operate in concert to cause RPN. As such,
Sickle whereas each of the conditions alone can cause RPN, the coexistence of more than one
Diabetes Infection
Hgb predisposing factor in any one person significantly increases the risk for RPN. The contri-
bution 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
Analgesic obstruction by sloughed papillae, it may be difficult to assign a primary role for any of
abuse
these processes in an individual patient. Furthermore, the occurrence of any of these fac-
tors (necrosis, obstruction, or infection) may itself initiate a vicious cycle that can lead to
another of these factors and culminate in RPN.
References
1. Bohman S: The ultrastructure of the renal interstitium. Contemp 5. Schainuck LI, Striker GE, Cutler RE, Benditt EP: Structural-functional
Issues Nephrol 10:1–34, 1983. correlations in renal disease II. The correlations. Hum Pathol 1970,
2. Lemley KV, Kriz W: Anatomy of the renal interstitium. Kidney Int 1:631–641.
1991, 39:370–381. 6. DeBroe ME, Elseviers MM: Analgesic nephropathy. N Engl J Med
3. Eknoyan G: Chronic tubulointerstitial nephropathies. In Diseases of 1998, 338:446–451.
the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: 7. Dobyan DC, Truong LD, Eknoyan G: Renal malacoplakia reap-
Little Brown; 1997:1983–2015. praised. Am J Kidney Dis 1993, 22:243–252.
4. Palmer BF: The renal tubule in the progression of chronic renal fail- 8. Eknoyan G, Qunibi WY, Grissom RT, et al.: Renal papillary necrosis:
ure. J Invest Med 1997, 45:346–361. an update. Medicine 1982, 61:55–73.
Selected Bibliography
Renal Interstitium Drugs
Neilson EG: Symposium on the cell biology of tubulointerstitium. Kidney Boton R, Gaviria M, Battle DC: Prevalence, pathogenesis, and treatment
Int 1991, 39:369–556. of renal dysfunction associated with chronic lithium therapy. Am J
Strutz F, Mueller GA: Symposium on Renal Fibrosis: prevention and pro- Kidney Dis 1990, 10:329–345.
gression. Kidney Int 1996, 49(suppl 54):1–90. Myer BD, Newton L: Cyclosporine induced chronic nephropathy: an obliter-
ative microvascular renal injury. J Am Soc Nephrol 1991, 2(suppl 1):4551.
Chronic Tubulointerstitial Nephritis
Eknoyan G, McDonald MA, Appel D, Truong LD: Chronic tubulointersti- Heavy Metals
tial nephritis: correlation between structural and functional findings. Batuman V: Lead nephropathy, gout, hypertension. Am J Med Sci 1993,
Kidney Int 1990, 38:736–743. 305:241–247.
Jones CL, Eddy AA: Tubulointerstitial nephritis. Ped Nephrol 1992, Batuman V, Maesaka JK, Haddad B et al.: Role of lead in gouty nephropathy.
6:572–586. N Engl J Med 1981, 304:520–523.
Nath KA: Tubulointerstitial changes as a major determinant in progression Fowler BA: Mechanisms of kidney cell injury from metals. Environ Health
of renal damage. Am J Kidney Dis 1992, 20:1–17. Perspec 1993, 100:57–63.
Hu H: A 50-year follow-up of childhood plumbism. Hypertension, renal
Pathogenesis function and hemoglobin levels among survivors. Am J Dis Child 1991,
Bohle A, Muller GA, Wehrmann M et al.: Pathogenesis of chronic renal 145:681–687.
failure in the primary glomerulopathies, renal vasculopathies and
Staessen JA, Lauwerys RR, Buchet JP et al.: Impairment of renal function
chronic interstitial nephritides. Kidney Int 1996, 49(suppl 54):2–9.
with increasing lead concentrations in the general population. N Engl J
Dodd S: The pathogenesis of tubulointerstitial disease and mechanisms of Med 1992, 327:151–156.
fibrosis. Curr Top Pathol 1995, 88:117–143.
Vedeen RP: Environmental renal disease: lead. cadmium, and Balkan
Haggerty DT, Allen DM: Processing and presentation of self and foreign endemic nephropathy. Kidney Int 34(suppl):4–8.
antigens by the renal proximal tubule. J Immunol 1992, 148:2324–2331.
Nath KA: Reshaping the interstitium by platelet-derived growth factor. Impli-
Ischemic Vascular Disease
cations for progressive renal disease. Am J Path 1996, 148:1031–1036.
Freedman BI, Ishander SS, Buckalew VM et al.: Renal biopsy findings in
Sedor JR: Cytokines and growth factors in renal injury. Semin Nephrol presumed hypertensive nephrosclerosis. Am J Nephrol 1994, 14:90–94.
1992, 12:428–440.
Meyrier A, Simon P: Nephroangiosclerosis and hypertension: things are
Wilson CB: Nephritogenic tubulointers-titial antigens. Kidney Int 1991, not as simple as you might think. Nephrol Dial Transplant 1996,
39:501–517. 11:2116–1220.
Yamato T, Noble NA, Miller DE, Border WA: Sustained expression of Schlesinger SD, Tankersley MR, Curtis JJ: Clinical documentation of end
TGF-B1 underlies development of progressive kidney fibrosis. Kidney stage renal disease due to hypertension. Am J Kidney Dis 1994,
Int 1994, 45:916–927. 23:655–660.
Correlation with Renal Failure Obstructive Nephropathy

D’Amico G, Ferrario F, Rastaldi MP: Tubulointerstitial damage in glomerular Arant BS Jr: Vesicoureteric reflux and renal injury. Am J Kidney Dis 1991,
diseases: its role in the progression of renal damage. Am J Kidney Dis 17:491–511.
1995, 26:124–132.
Diamond JR: Macrophages and progressive renal disease in experimental
Eddy AA: Experimental insights into tubulointerstitial disease accompany- hydronephrosis. Am J Kidney Dis 1995, 26:133–140.
ing primary glomerular lesions. J Am Soc Nephrol 1994, 5:1273–1287.
Klahr S: New insight into consequences and mechanisms of renal impair-
Magil AB: Tubulointerstitial lesions in human membranous glomeru-
ment in obstructive nephropathy. Am J Kidney Dis 1991, 18:689–699.
lonephritis: relationship to proteinuria. Amer J Kidney Dis 1995,
25:375–379.
Hematologic Diseases
Allon M: Renal abnormalities in sickle cell disease. Arch Intern Med 1990,
Analgesic Nephropathy 150:501–504.
Henrich WL, Agodoa LE, Barrett B, Bennett WM et al.: Analgesics and the
Kidney. Summary and Recommendations to the Scientific Advisory Falk RJ, Scheinmann JI, Phillips G et al.: Prevalence and pathologic fea-
Board of the National Kidney Foundation. Am J Kidney Dis 1996, tures of sickle cell nephropathy and response to inhibition of
27:162–165 angiotensin converting enzyme. N Engl J Med 1992, 326:910–915.
Nanra RS: Pattern of renal dysfunction in analgesic nephropathy. Comparison Ivanyi B: Frequency of light chain deposition nephropathy relative to renal
with glomerulonephritis. Nephrol Dialysis Transpl 1992, 7:384–390. amyloidosis and Bence Jones cast nephropathy in a necropsy study of
Noels LM, Elseviers NM, DeBroe ME: Impact of legislative measures of patients with myeloma. Arch Pathol Lab Med 1990, 114:986–987.
the sales of analgesics and the subsequent prevalence of analgesic Rota S, Mougenot B, Baudouin M: Multiple myeloma and severe renal
nephropathy: a comparative study in France, Sweden and Belgium. failure: a clinicopathologic study of outcome and prognosis in 34
Nephrol Dial Transplant 1995, 10:167–174. patients. Medicine 1987, 66:126–137.
Perneger TV, Whelton PK, Klag MJ: Risk of kidney failure associated with Sanders PW, Herrera GA, Kirk KA: Spectrum of glomerular and tubuloint-
the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory erstitial renal lesions associated with monotypical immunoglobulin light
drugs. N Engl J Med 1994, 331:1675–1679. chain deposition. Lab Invest 1991, 64:527–537.
Sandler DP, Burr FR, Weinberg CR: Nonsteroidal anti-inflammatory drugs
and risk of chronic renal failure. Ann Intern Med 1991, 115:165–172.
Sandler DP, Smith JC, Weinberg CR et al.: Analgesic use and chronic renal
disease. N Engl J Med 1989, 320:1238–1243.
Metabolic Disorders Viral Infections

Chaplin AJ: Histopathological occurrence and characterization of calcium Ito M, Hirabayashi N, Uno Y: Necrotizing tubulointerstitial nephritis asso-
oxalate. A review. J Clin Pathol 1977, 30:800–811. ciated with adenovirus infection. Human Pathol 1991, 22:1225–1231.
Foley RJ, Weinman EJ: Urate nephropathy. Am J Med Sci 1984, Papadimitriou M.: Hantavirus nephropathy. Kidney Int 1995, 48:887–902.
288:208–211.
Hanif M, Mobarak MR, Ronan A: Fatal renal failure caused by diethylene Hereditary Diseases
glycol in paracetamol elixir: the Bangladesh epidemic. Br Med J 1995, Fick GM, Gabow PA: Hereditary and acquired cystic disease of the kidney.
311:88–91. Kidney Int 1994, 46:951–964.
Schneider JA, Lovell H, Calhoun F: Update on nephropathic cystinosis. Gabow PA, Johnson AM, Kaehny VM: Factors affecting the progression
Ped Nephrol 1990, 4:645–653. of renal disease in autosomal-dominant polycystic kidney disease.
Kidney Int 1992, 41:1311–1319.
Zawada ET, Johnson VH, Bergstein J: Chronic interstitial nephritis. Its
Gregory MC, Atkin CL: Alports syndrome, Fabry’s disease and nail patella
occurrence with oxalosis and antitubular basement membrane antibod- syndrome. In Diseases of the Kidney, edn 6. Edited by Schrier RW,
ies after jejunal bypass. Arch Pathol Ub Med 1981, 105:379–383. Gottschalk CW. Boston: Little Brown; 1997:561–590.
Granulomatous Diseases Papillary Necrosis

Mignon F, Mery JP, Mougenot B, et al.: Granulomatous interstitial nephri- Griffin MD, Bergstralk EJ, Larson TS: Renal papillary necrosis. A sixteen
tis. Adv Nephrol 1984, 13:219–245. year clinical experience. J Am Soc Nephrol 1995, 6:248–256.
Viero RM, Cavallo T: Granulomatous interstitial nephritis. Hum Pathol Sabatini S, Eknoyan G, editors: Renal papillary necrosis. Semin Nephrol
1995, 26:1345–1353. 1984, 4:1–106.
Urinary Tract Infection
Alain Meyrier
T
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 sub-
stantial 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 patient’s 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
Diagnosis
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 colony-
forming 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 4ºC 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
A B C 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 sole-
FIGURE 7-1 ly on the basis of test strip risks failure in about 15% of simple
Urine test strips. Normal urine is sterile, but suprapubic aspira- community-acquired infections and a much larger proportion of
tion of the bladder, which is by no means a routine procedure, UTIs acquired in a hospital.
immersed in the urine, shaken, and incu-

Schematic set up of bated overnight.
a dip-slide container Interpretation after 24-hour incubation at 37°C The most specific results, however, are
provided by laboratory analysis, which
Paddle-holding Nonsignificant Significant
stopper
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 leuko-
cytes per milliliter. These classical “Kass cri-
Agar
teria,” 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 conta-
Moist sponge 103 104 105 106 107
mination has been ruled out, growth of
bacteria that are not normally urethral
saprophytes indicates infection. This is the
FIGURE 7-2 case for Pseudomonas, Klebsiella,
Culture interpretation. Urinalysis must examine bacterial and leukocyte counts Enterobacter, Serratia, and Moraxella,
(per milliliter). An approximate way of estimating bacterial counts in the urine uses among others, especially in a hospital set-
a dip-slide method: a plastic paddle covered on both sides with culture medium is ting or after urologic procedures.
Urinary Tract Infection 7.3
FIGURE 7-3
CAUSES OF ASEPTIC LEUKOCYTURIA Leukocyturia. A significant number of leukocytes (more than 10,000
per milliliter) is also required for the diagnosis of urinary tract infec-
tion, as it indicates urothelial inflammation. Abundant leukocyturia
Self-medication before urine culture can originate from the vagina and thus does not necessarily indicate
Sample contamination by cleansing solution aseptic urinary leukocyturia [1]. Bacterial growth without leukocy-
Vaginal discharge
turia indicates contamination at sampling. Significant leukocyturia
without bacterial growth (aseptic leukocyturia) can develop from
Urinary stone
various causes, among which self-medication before urinalysis is the
Urinary tract tumor
most common.
Chronic interstitial nephritis (especially due to analgesics)
Fastidious microorganisms requiring special culture medium (Ureaplasma urealyticum,
Chlamydia, Candida)
Bacteriology
FIGURE 7-4
A. MAIN MICROBIAL STRAINS RESPONSIBLE Principal pathogens of urinary tract infection (UTI). A and B, Most
FOR URINARY TRACT INFECTION pathogens responsible for UTI are enterobacteriaceae with a high pre-
dominance of Escherichia coli. This is especially true of spontaneous
UTI in females (cystitis and pyelonephritis). Other strains are less
First Episode or Relapse Due to common, including Proteus mirabilis and more rarely gram-positive
Microbial Strain Delayed Relapse Early Reinfection microbes. Among the latter, Staphylococcus saprophyticus deserves
special mention, as this gram-positive pathogen is responsible for 5%
Escherichia coli 71%–79% 60% to 15% of such primary infections, is not detected by the leukocyte
Proteus mirabilis 1.1%–9.7% 15% esterase dipstick, and is resistant to antimicrobial agents that are
Klebsiella — 20% active on gram-negative rods.
Enterobacter 1.0%–9.2% — C, Acute simple pyelonephritis is a common form of upper UTI
Enterococcus 1.0%–3.2% — in females and results from the encounter of a parasite and a host.
Staphylococcus saprophyticus 3%–7% — In the absence of urologic abnormality, this renal infection is most-
Other species 2%–6% 5% ly 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 inva-
sion is associated with a high erythrocyte sedimentation rate and
C-reactive protein level well above 2 mg/dL.
100 Minimum
Maximum
Other E. coli
5% 60%
Percent
50
P. mirabilis
15%
Klebsiella
20%
0
E. coli P. mirabilis Klebsiella Enterococcus S. saprophyticus Other
B Enterobacter C
Virulence Factors of Uropathogenic Strains
Escherichia coli
Fimbriae P S Type 1
Flagella
Hemolysin
Aerobactin
+
Fe3+ Na+ Na
Erythrocyte
FIGURE 7-6
An electron microscopic view of an Escherichia coli organism
FIGURE 7-5 showing the fimbriae (or pili) bristling from the bacterial cell.
Bacterial uropathogenicity plays a major role in host-pathogen inter-
actions 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.)
FIGURE 7-8
Proteus mirabilis Staghorn calculi.
Fimbriae MR/P PMF ATF NAF Ammonium genera-
tion alkalinizes the
urine, creating
Urease
Deaminase [Keto acid]3Fe3+ conditions favorable
Flagella for build-up of
2+
Ni Amino acid
voluminous struvite
Urea NH3+CO2 stones, which can
Na+ progressively invade
IgA protease Hemolysin
the entire pyeloca-
lyceal system, form-
ing staghorn calculi.
These stones are an
Renal epithelial cell endless source of
microbes, and the
urinary tract
obstruction per-
petuates infection.
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.
Fimbrial adhesive structures Nonfimbrial

Type P Fimbriae Type 1 Fimbriae adhesive structure
Adhesin PapG FimH
PapF FimH, FimG
Fibrillum PapE FimF, FimG
FimA
PapK ~100
FimA
Rigid fiber
PapA
Adhesins
PapH
FIGURE 7-10
Pilin
Uropathogenic strains of Escherichia coli readily adhere to epithelial
Minor subunits
Adhesin cells. This figure shows two epithelial cells incubated in urine infected
with E. coli–carrying pap adhesins. Numerous bacteria are scattered
on the epithelial cell membranes. About half of all cases of cystitis are
FIGURE 7-9 due to uropathogenic strains of E. coli–carrying adhesins. Females
Schematic representation of morphology and composition of type P with primary pyelonephritis and no urologic abnormality harbor a
and type 1 adhesive structures. Bacterial adhesins are paramount in uropathogenic strain in almost 100% of cases [5].
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 7-11
APPROPRIATE ANTIBIOTICS FOR URINARY TRACT INFECTIONS Appropriate antibiotics for urinary tract
infections (UTI). An appropriate antibiotic
for treating UTI must be bactericidal and
Antibiotics General Indications Pregnancy Prophylaxis conform to the following general specifica-
tions: 1) its pharmacology must include, in
Aminoglycosides + +* - case of oral administration, rapid absorp-
Aminopenicillins +† + - tion and attainment of peak serum concen-
Carboxypenicillins + + -
trations; 2) its excretion must be predomi-
Ureidopenicillins + + -
nantly renal; 3) it must achieve high con-
Quinolones +‡ - +
centrations in the renal or prostate tissue;
Fluoroquinolones +§ - +
4) it must cover the usual spectrum of
Cephalosporins
First generation +¶ + +‡ enterobacteria with reasonable chance of
Second generation + + - being effective on an empirical basis.
Third generation + + - Excluding special considerations for child-
Monobactams + + - hood and pregnancy, several classes of
Carbapenem + + - antibiotics fulfill these specifications and
Cotrimoxazole + - +‡ can be used alone or in combination. The
Fosfomycin trometamole +** - - choice also depends on market availability,
Nitroturantoin +†† - +
cost, patient tolerance, and potential for
inducing emergence of resistant strains.
* 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.
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 FIGURE 7-14 FIGURE 7-15

Prostatitis. Anatomically, prostatitis involves Acute prostatitis can be complicated by Pyelonephritis in females. Essentially, this is
the lower urinary tract, but invasion of ascending infection, that is, pyelonephritis. an ascending infection caused by uropatho-
prostate tissue affords easy passage of gens. From the perineum the bacteria gain
pathogens to the prostatic venous system— access to the bladder, ascending to the renal
and, usually, poor penetration by antibi- pelvocalyceal system and thence to the renal
otics. Presence of bacteria in the bladder is medulla, from which they spread toward the
also symbolized in this picture, but owing to cortex. It has been shown that “pyelitis” can-
free communication between bladder urine not be considered a pathologic entity, as renal
and prostate tissue, it can be accepted that pelvis infection is invariably associated with
pure cystitis does not exist in males. nearby contamination of the renal medulla.
CRITERIA FOR TISSUE INVASION
Clinical
Kidney or prostate infection is marked by fever over 38°C, 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 bac-
teremia, 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 else-
where, renal abscess due to enterobacteri-
aceae (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 blad-
der tumor (arrows)
infiltrates the blad-
der floor and the
initial segment of
the urethra.
FIGURE 7-18
An episode of urinary tract infection (UTI) should prompt considera-
tion 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.
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.
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, espe-
cially 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 tortu-
I II III IV V osity 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
FIGURE 7-21 tortuosity of ureter, gross dilation of renal pelvis and calyces. Papillary
The severity of vesicoureteral reflux (VUR) as graded in 1981 by impressions are no longer visible in the majority of calyces. (From
the International Reflux Study Committee. When children have International Reflux Study Committee [9]; with permission.)
A B
FIGURE 7-22
Cystogram demonstrating left ureteral reflux (A). The conse- the adjacent renal tissue. The calyceal cavities are very close to the
quences on the left kidney (B) consist of calyceal distension and a renal capsule, indicating complete cortical atrophy. This picture is
clubbed appearance due to the destruction of the papillae and of typical of chronic pyelonephritis secondary to vesicoureteral reflux.

In case of bilateral, neglected vesicoureteral reflux, chronic pyelone- When intravenous pyelography discloses two ureters, the one draining
phritis is bilateral and asymmetric. Here, the right kidney is globally the lower pyelocalyceal system crosses the upper ureter and opens
atrophic. A typical cortical scar is seen on the outer aspect of the left into the bladder less obliquely than normally, allowing reflux of urine
kidney. The lower pole, however, is fairly well-preserved with nearly and explaining repeated attacks of pyelonephritis followed by atrophy
normal parenchymal thickness. of the lower pole of the kidney. Retrograde cystography is indicated
for repeated episodes of pyelonephritis and when intravenous pyelog-
raphy or computed tomography renal examination discovers cortical
scars. In adults, retrograde cystography is obtained by direct catheter-
ization of the bladder.

(see Color Plate) In the paraplegic,
In children, isotopic and more generally
cystography allows in patients with
a diagnosis of vesi- spinal disease,
coureteral reflux neurogenic bladder
with much less radi- is responsible for
ation than if cystog- stasis, bladder
raphy were carried distension, and
out with iodinated diverticula. These
contrast medium. functional and
anatomic factors
explain the frequency
of chronic urinary
tract infection
complicated with
bladder and upper
urinary tract
infectious stones.
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 FIGURE 7-28
kidney with loss of corticomedullary differentiation, denoting renal The ultrasound procedure occasionally discloses the cavity of a small
inflammatory edema. Images corresponding to the infected zones renal abscess, a common complication of acute pyelonephritis, even
are more dense than normal renal tissue (arrows). in simple forms.
A B
FIGURE 7-29
Computed tomodensitometry. Simple pyelonephritis does not areas in an edematous, swollen kidney. The pathophysiology of
require much imaging; however, it should be remembered that there hypodense images has been elucidated by animal experiments in
is no correlation between the severity of the clinical picture and the the primates [11] which have shown that renal infection with
renal lesions. Therefore, a diagnosis of “simple” pyelonephritis at uropathogenic Escherichia coli induces intense vasoconstriction.
first contact can be questioned when response to treatment is not Computed tomodensitometric images of acute pyelonephritis can
clear after 3 or 4 days. This is an indication for uroradiologic imag- take various appearances. The most common findings consist of
ing, such as renal tomodensitometry followed by radiography of the one or several wedge-shaped or streaky zones of low attenuation
urinary tract while it is still opacified by the contrast medium. extending from papilla to cortex, A. Hypodense images can be
The typical picture of acute pyelonephritis observed after con- round, B. On this figure, the infected zone reaches the renal cortex
trast medium injection [10] consists of hypodensities of the infected and is accompanied with adjacent perirenal edema. Several such
C D
images can coexist in the same kidney, C.
Marked juxtacortical, circumscribed hypo-
dense zones, bulging under the renal cap-
sule, D, usually correspond to lesions close
to liquefaction and should be closely fol-
lowed, as they can lead to abscess forma-
tion and opening into the perinephric space,
E and F. (E and F from Talner et al. [10];
with permission.)
E F
FIGURE 7-30
100 Comparative sensitivity of four diagnostic imaging techniques for
acute pyelonephritis. Renal cortical scintigraphy using 99mTc-dimethyl
86
succinic acid (DMSA) or 99mTc-gluconoheptonate (GH) is very sensi-
75 tive 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
Percent
first-line diagnostic imaging method for renal infection in children. It is

50 42
interesting to compare its sensitivity with that of more conventional
imaging methods. (From Meyrier and Guibert [5]; with permission.)
24
0
Renal CT scan Ultrasonography IVP
scintigraphy (intravenous
pyelography)

99mTc-DMSA cortical imaging of simple pyelonephritis in a female.
The clinical signs implicated the right kidney. (Contrary to conven-
tional radiology, the right kidney appears on the right of the image.)
The false colors indicate cortical renal blood supply from red (nor-
mal) 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.
A B
FIGURE 7-32
Renal pathology in acute pyelonephritis. Renal pathology of human the diabetes patient whose kidney is shown here. A, The surgically
acute pyelonephritis is quite comparable to what is observed in removed kidney is swollen, and its surface shows whitish zones.
experimental pyelonephritis in primates [11]. However, our knowl- B, A section of the same organ shows white suppurative areas (scat-
edge of renal pathology in this condition in humans is based mainly tered with small abscesses) extending eccentrically from the medulla
on the most catastrophic cases, which required nephrectomy, like to the cortex. There also were sloughed papillae (see Fig. 7-37).
A B
FIGURE 7-33
Histologic appearance of pyelonephritic kidney. A, The renal tissue comprising a majority of polymorphonuclear leukocytes, induces
is severely edematous and interspersed with inflammatory cells and tubular destruction and is accompanied by a typical infectious cast
hemorrhagic streaks. B, On another section, severe inflammation, in a tubular lumen (arrow).
FIGURE 7-34
Clinical picture compatible A general algorithm for the investigation
with acute pyelonephritis (APN) and treatment of acute pyelonephritis.
Treatment of acute pyelonephritis is based
Urine culture and cytology on antibiotics selected from the list in
ESR CRP Figure 7-11. Preferably, initial treatment is
based on parenteral administration. It is
Renal Negative.
debatable whether common forms of sim-
Positive
scintigraphy Reconsider Initial
ple pyelonephritis initially require both an
and/or CT scan diagnosis of APN work-up aminoglycoside and another antibiotic.
Initial parenteral treatment for an average
No renal lesion. Renal lesions. Previous No previous of 4 days should be followed by about 10
Seek other Maintain history of history of days of oral therapy based on bacterial
infection diagnosis of APN upper UTI upper UTI sensitivity tests. It is strongly recommended
that urine culture be carried out some 30
to 45 days after the end of treatment, to
Abnormal. Yes Possible urinary Plain abdominal verify that bacteriuria has not recurred.
Call urologist IVP tract obstruction radiograph APN—acute pyelonephritis; ESR—erythro-
or stone? Ultrasonography cyte sedimentation rate; CRP—C-reactive
No protein; UTI—urinary tract infection;
Secondary APN Primary APN IVP—intravenous pyelography. (From
Treat Treat Normal Drug therapy only
cause infection Meyrier and Guibert [5]; with permission.)
Day
Start treatment with first-line antibiotics 1
Good clinical Atypical clinical Further Days

response and imaging
lab. Confirmation of response or 2 to
appropriate initial Wrong initial (IVP, CT) 4 or 5
antibiotic choice antibiotic choice
Continue Adapt Normal. Abnormal. Days

same antibiotic Consider drug Call 5 to 15
treatment treatment intolerance urologist
Day
End treatment 15
Recurrence Verify Between

of bacteriuria urine sterility Sterile days
30 and 45
Radiourological work-up. No further

New treatment investigations or treatment

Renal abscess. Like acute pyelonephritis, one third of cases of renal abscess occur in a nor-
mal 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 innu-
merable polymorphonuclear leukocytes within purulent material.
A B
FIGURE 7-36
Renal computed tomography (CT). In addition to ultrasound the renal parenchyma, A, or bulge outward under the renal capsule,
examination, CT is the best way of detecting and localizing a risking rupture into Gerota’s space, B.
renal abscess. The abscess cavity can be contained entirely within
A B
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 bac-
teriuria 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 papil-
la obstructs the ureter, causing retention of infected urine and severely
aggravating the pyelonephritis. C, It can lead to pyonephrosis (ie,
C complete destruction of the kidney), as shown on CT.
FIGURE 7-38
Nonpregnant Pregnant
500 Urinary tract infection (UTI) in an immunocompromised host.
IgG Pregnancy is associated with suppression of the host’s immune
response, in the form of reduced cytotoxic T-cell activity and
reduced circulating immunoglobulin G (IgG) levels. Asymptomatic
0
bacteriuria is common during pregnancy and represents a major
1000 risk of ascending infection complicated by acute pyelonephritis.
IgA
Antibody activity, % of control
500
0
1000
IgM
500
0
0 2 0 2
A Time of sampling, wks
Nonpregnant Pregnant
>250
IgG
1000 250
200
500
Levels of IL-6, units/mL

Antibody activity, Abs 405 nm
150
0 100
1000
IgA
50
500 20
20
0
0
0
0 2 0 2 Nonpregnant Pregnant Nonpregnant Pregnant
Time of sampling, wks Serum Urine
B C

Petersson and coworkers [12] recently demonstrated that the suscepti- The last may indicate that pregnant women have a generally reduced
bility of the pregnant woman to acute UTI is accompanied by reduced level of mucosal inflammation. These factors may be crucial for
serum antibody activity (IgG, IgA, IgM), reduced urine antibody activ- explaining the frequency and the severity of acute pyelonephritis
ity (IgG, IgA), and low interleukin 6 (IL-6) response, A–C, respectively. 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 inva-
sion 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) compli-
cating acute prostatitis in the right lobe (2). Acute prostatitis is
an indication for thorough radiologic imaging of the whole uri-
nary tract, giving special attention to the urethra. Urethral stric-
ture may favor prostate infection (see Fig. 7-20).
Special Forms of Renal Infection
A B
Xanthogranulomatous pyelonephritis (XPN). XPN is a special obstructive renal stone. Nephrectomy was performed. A, The
form of chronic renal inflammation caused by an abnormal obstructive renal stone is shown by an arrowhead. The renal
immune response to infected obstruction [13]. This case in a cavities are dilated. The xanthogranulomatous tissue (arrows)
middle-aged woman with a long history of renal stones is typical. consists of several round, pseudotumoral masses with a typical
For several months she complained of flank pain, fever, fatigue, yellowish color due to presence of lipids. In some instances such
anorexia and weight loss. Laboratory workup found inflammatory xanthogranulomatous tissue extends across the capsule into the
anemia and increased erythrocyte sedimentation rate and C-reactive perirenal fat and fistulizes into nearby viscera such as the colon
protein levels. Urinalysis showed pyuria and culture grew Escherichia or duodenum. B, Microscopic view of the xanthogranulomatous
coli. CT scan of the right kidney showed replacement of the renal tissue. This part of the lesion is made of lipid structures composed
tissue by several rounded, low-density areas and detected an of innumerable clear droplets.
Spectrum of renal malakoplakia
Mononuclear
cells Interstitial
Inflammation
(nonspecific) nephritis
von Hansemann Megalocytic

Persistent cells interstitial
inflammation (prediagnostic) nephritis
Ca2+
Michaelis-Gutmann
Defective
(MG) bodies Malakoplakia
cell function
(diagnostic)
B
Destuctive
granulomas Fibrosis teroid therapy for autoimmune disease. In 13% of the published cases,
xanthogranulomatous "pseudosarcoma" malakoplakia involved a transplanted kidney. The female-male ratio is
pyelonephritis 3:1. Lesions can involve the kidney, the bladder, or the ureter and form
A
pseudotumors. B, Histologically, malakoplakia is distinguished by
large, pale, periodic acid–Schiff–positive macrophages (von Hanse-
FIGURE 7-41 mann cells) containing calcific inclusions (Michaelis-Gutmann bodies).
Malakoplakia. Malakoplakia (or malacoplakia), like xanthogranulo- The larger ones are often free in the interstitium. Malakoplakia, an
matous pyelonephritis, is also a consequence of abnormal macrophage unusual form of chronic tubulointerstitial nephritis, must be recog-
response to gram-negative bacteria, A. Malakoplakia occurs in associ- nized by early renal biopsy and can resolve, provided treatment
ation with chronic UTI [14]. In more than 20% of cases, affected per- consisting of antibiotics with intracellular penetration is applied for
sons have some evidence of immunosuppression, especially corticos- several weeks. (B, Courtesy of Gary S. Hill, MD.)
References
1. Stamm WE, Hooton TM: Management of urinary tract infections in 8. Roberts JA, Marklund BI, Ilver D, et al.: The Gal( 1-4)Gal–
adults. N Engl J Med 1993, 329:1328–1334. specific tip adhesin of Escherichia coli P-fimbriae is needed for
2. Pinson AG, Philbrick JT, Lindbeck GH, Schorling JB: ED management pyelonephritis to occur in the normal urinary tract. Proc Natl Acad
of acute pyelonephritis in women: A cohort study. Am J Emerg Med Sci USA 1994, 91:11889–11893.
1994, 12:271–278. 9. International Reflux Study Committee: Medical versus surgical
3. Pappas PG: Laboratory in the diagnosis and management of urinary treatment of primary vesicoureteral reflux. J Urol 1981, 125:277.
tract infections. Med Clin North Am 1991, 75:313–325. 10. Talner LB, Davidson AJ, Lebowitz RL, et al.: Acute pyelonephritis:
4. Kunin CM, VanArsdale White L, Tong HH: A reassessment of the Can we agree on terminology? Radiology 1994, 192:297–306.
importance of “low-count” bacteriuria in young women with acute 11. Roberts JA: Etiology and pathophysiology of pyelonephritis.
urinary symptoms. Ann Intern Med 1993, 119:454–460. Am J Kidney Dis 1991, 17:1–9.
5. Meyrier A, Guibert J: Diagnosis and drug treatment of acute 12. Petersson C, Hedges S, Stenqvist K, et al.: Suppressed antibody and
pyelonephritis. Drugs 1992, 44:356–367. interleukin-6 responses to acute pyelonephritis in pregnancy. Kidney
6. Meyrier A: Diagnosis and management of renal infections. Curr Opin Int 1994, 45:571–577.
Nephrol Hypertens 1996, 5:151–157. 13. Case records of the Massachusetts General Hospital. N Engl J Med
7. Mobley HLT, Island MD, Massad G: Virulence determinants of 1995, 332:174–179.
uropathogenic Escherichia coli and Proteus mirabilis. Kidney Int 14. Dobyan DC, Truong LD, Eknoyan G: Renal malacoplakia
1994, 46(Suppl. 47):S129–S136. reappraised. Am J Kidney Dis 1993, 22:243–252.
Reflux and Obstructive
Nephropathy
James M. Gloor
Vicente E. Torres
R
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 identi-
fication 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 histocom-
patibility 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 situa-
tion is far from clear. Most children with reflux nephropathy already CHAPTER
have renal scars demonstrable at the time of the urinary tract infection
that prompts the diagnosis of VUR. Most children found to have VUR
8
do not develop further renal scarring after diagnosis, even after subse-
quent urinary tract infections. Other children may develop renal scars
in the absence of further urinary tract infections. The best treatment of
VUR has not yet been firmly established. No clear advantage has usually is accompanied by hydronephrosis, an abnormal dilation
been demonstrated for surgical correction of VUR versus medical of the renal pelvis, and calices. However, because hydronephrosis
therapy with prophylactic antibiotics after 5 years of follow-up can occur without functional obstruction, the terms obstructive
examinations. New surgical techniques such as the submucosal nephropathy and hydronephrosis are not synonymous. Hydro-
injection of bioinert substances may have a role in select cases. nephrosis is found at autopsy in 2% to 4% of cases. Obstructive
The term obstructive nephropathy is used to describe the func- nephropathy is responsible for approximately 4% of end-stage
tional and pathologic changes in the kidney that result from renal failure. Obstruction to the flow of urine can occur anywhere
obstruction to the flow of urine. Obstruction to the flow of urine in the urinary tract and has many different causes.
FIGURE 8-1
CAUSES OF OBSTRUCTIVE NEPHROPATHY Obstructive nephropathy is responsible for
end-stage renal failure in approximately 4%
of persons. Obstruction to the flow of urine
Intraluminal Extrinsic can occur anywhere in the urinary tract.
Calculus, clot, renal papilla, fungus ball Congenital (aberrant vessels): Obstruction can be caused by luminal bod-
Congenital hydrocalycosis
ies; mural defects; extrinsic compression by
Intrinsic vascular, neoplastic, inflammatory, or other
Ureteropelvic junction obstruction
Congenital: processes; or dysfunction of the autonomic
Retrocaval ureter
Calyceal infundibular obstruction nervous system or smooth muscle of the
Neoplastic tumors:
Ureteropelvic junction obstruction urinary tract. The functional and clinical
Benign tumors:
Ureteral stricture or valves consequences of urinary tract obstruction
Benign prostatic hypertrophy
Posterior urethral valves depend on the developmental stage of the
Pelvic lipomatosis kidney at the time the obstruction occurs,
Anterior urethral valves
Cysts severity of the obstruction, and whether the
Urethral stricture
Primary retroperitoneal tumors: obstruction affects one or both kidneys.
Meatal stenosis
Mesodermal origin (eg, sarcoma)
Prune-belly syndrome
neurogenic origin (eg, neurofibroma)
Neoplastic:
Embryonic remnant (eg, teratoma)
Carcinoma of the renal pelvis, ureter, or bladder
Retroperitoneal extension of pelvic or abdominal tumors:
Polyps
Uterus, cervix
Bladder, prostate
Rectum, sigmoid colon
Metastatic tumor:
Lymphoma
Inflammatory:
Retroperitoneal fibrosis
Inflammatory bowel disease
Diverticulitis
Infection or abscess
Gynecologic:
Pregnancy
Uterine prolapse
Surgical disruption or ligation
Functional
Neurogenic bladder
Drugs(anticholinergics, antidepressants, calcium channel
blockers)
Reflux and Obstructive Nephropathy 8.3
Anatomy of Vesicoureteric Reflux

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 sub-
mucosal 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 [1–3]. (From Politano [4];
Intramural with permission.)
ureter
Submucosal
ureter
FIGURE 8-3
Bladder wall
Tissue sagittal sections (upper panels) and
cystoscopic appearances (lower panels) of
the ureterovesical junction illustrating vary-
Ureter ing submucosal tunnel lengths. The length of
the submucosal segment of the distal ureter
A B C D E is an important factor in determining the
12 mm 8 mm 5 mm 2 mm 0 mm effectiveness of the ureteral valvular mecha-
nism in preventing vesicoureteral reflux
(VUR). In children without VUR, the ratio
of tunnel length to ureteral diameter is sig-
nificantly greater than in children with VUR
[5,6]. (From Kramer [7]; with permission.)
A' B' C' D' 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.
Pathogenesis of Vesicoureteric Reflux

and Reflux Nephropathy
FIGURE 8-6
Experimental vesicoureteric reflux in pigs: cystourethrogram show-
FIGURE 8-5 ing intrarenal reflux. Reflux of radiocontrast medium into the
Experimental vesicoureteric reflux in pigs. This pathology specimen renal parenchyma is seen. The pressure required to produce
demonstrates surgically induced vesicoureteric reflux in a 2-week- intrarenal reflux is lower in young children than it is in older chil-
old male piglet. Note that the submucosal canal of one of the dren or adults, which is consistent with the observation that reflux
ureters has been unroofed. scars occur more commonly in younger children [10].
A B C
FIGURE 8-7
Experimental vesicoureteric reflux in pigs. The polar location of scars. In urinary tract infections, reflux of urine from the renal
acute suppurative pyelonephritis and evolution of parenchymal pelvis into the papillary ducts of compound papillae predominantly
D E F
located in the poles (intrarenal reflux) provides bacteria access reflux nephropathy: Hemorrhagic with polymorphonuclear cell
to the renal parenchyma, resulting in suppurative pyelonephritis infiltrate (A, B); white, not retracted, with prominent mononu-
and subsequent polar scarring [11,12]. Intact (A, C, E) and coro- clear cell infiltrate (C, D), and retracted scan with prominent
nally sectioned (B, D, F) kidneys illustrating the three stages of 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 expan-
sion, mesangial hypercellularity, and the presence of large granules.
The granules test positive on periodic acid–Schiff 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 nephropa-
thy 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].
FIGURE 8-10
Integrative View of Pathogenetic Mechanisms in Reflux Nephropathy Integrative view of pathogenetic mechanisms in reflux nephropa-
thy. Abnormalities of ureteral embryogenesis may result in a defec-
Defective mesonephric mesoderm tive antireflux mechanism, permitting vesicoureteral reflux (VUR),
(ureteral bud) incomplete bladder emptying, urinary stasis, and infection.
Bacterial virulence factors modify the pathogenicity of different
Abnormal induction of bacterial strains. Bacterial surface appendages such as fimbriae may
metanephric mesoderm interact with epithelial cell receptors of the urinary tract, enhancing
High-voiding bacterial adhesion to urothelium. Endotoxin is capable of inhibit-
VUR pressures
ing ureteral peristalsis, contributing to the extension of the infec-
(In utero) +
tion into the upper urinary tract even in the absence of VUR.
IRR Inoculation of the renal parenchyma with bacteria produces an
+ acute inflammatory response, resulting in the release of inflamma-
Virulent tory mediators into the surrounding tissue. The acute inflammatory
bacterial strain response elicited by the presence of infecting bacteria is responsible
+
for the subsequent renal parenchymal injury. In addition, it is pos-
Immune sible that immune complexes, bacterial fragments, and endotoxin
Susceptible Inhibition
complexes of ureteral resulting from infection may produce a glomerulopathy.
host
Bacterial peristalsis Even in the absence of urinary tract infection, VUR associated
fragments with elevated intravesical pressure is capable of producing renal
Endotoxin
Focal exudative Toxic urine parenchymal scars. The developing kidney appears to be particular-
reaction component ly susceptible. Renal tubular distention resulting from high
Delayed intrapelvic pressure may exert an injurious effect on renal tubular
hypersensitivity epithelium. Compression of the surrounding peritubular capillary
Glomerulopathy
Pyelonephritic network by distended renal tubules may produce ischemia. During
scar micturition, elevated intravesical pressure is transmitted to the
Sterile scar
Back-pressure renal pelvis and renal tubule. This transient pressure elevation may
atrophy produce tubular disruption. Extravasation of urine into the sur-
Reduced nephron
population Diffuse interstitial rounding parenchyma results in an immune-mediated interstitial
Dysplasia fibrosis nephritis and further renal injury.
The reduction in functional renal mass produced by the interaction
Hyperfiltration High-protein diet of the pathogenetic factors listed here induces compensatory hemo-
Hypertension dynamic changes in renal blood flow and the glomerular filtration
Pregnancy rate. Over time, these compensatory changes may be maladaptive,
Glomerulosclerosis may produce hyperfiltration and glomerulosclerosis, and may even-
tuate 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].
Diagnosis of Vesicoureteric Reflux and Reflux Nephropathy

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 cystourethrogra-
phy. 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 blunt-
ing of the fornices is seen. In grade IV, moderate dilation, tortuosity,
I II III IV V 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 papil-
lary impressions are no longer visible in most calyces [18].
International Reflux Study Committee consisting of four grades of

Types of renal scarring 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 wide-
spread distortion of the calyceal anatomy, similar to changes seen in
obstructive uropathy. Grade 4 is characterized by end-stage renal dis-
ease and a shrunken kidney having very little renal function [19].
Parenchymal scarring detected by radionuclide renal scintigraphy
A Mild B Severe C "Back-pressure" D End-stage 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,
FIGURE 8-13 Grade 3 renal scarring is characterized by general damage to the
Grading of renal scarring associated with vesicoureteral reflux. entire kidney, similar to obstructive nephropathy. D, In grade 4, a
Reflux renal parenchymal scarring detected on intravenous pyelogra- contracted kidney in end-stage renal failure is seen, with less than
phy can be classified according to the system adopted by the 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 dur-
ing micturition. Contrast material is infused through a small urethral catheter under
gravity flow.
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 con-
tents 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].
A B
FIGURE 8-16
A, Intravenous pyelogram and, B, nephrotomogram demonstrating not be visible immediately after renal infection, because scars may
grade 2 reflux nephropathy. Historically, this testing modality has not be fully developed for several years [20]. The advantages of
been the one most commonly used to evaluate reflux nephropathy intravenous pyelography in evaluating reflux nephropathy include
[7]. Irregular renal contour, parenchymal thinning, small renal size, precision in delineating renal anatomic detail and providing base-
and calyceal blunting all are radiographic signs of reflux nephropa- line measurements for future follow-up evaluations, renal growth,
thy on intravenous pyelography [17]. Radiographic changes may 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 affect-
ing the lower renal poles.
A B
13
Predicted mean
12 95% predicted limits
11
10
9
Renal length, cm
8
7
6
5
4
3
2
0 2 4 6 8 10 12 5 10 15
C Months Years
A
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 ultra-
sonography examination reveals hydronephrosis [21–28]. 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 infection-
associated 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].
B
FIGURE 8-19
90 83 Male Prenatal detection of vesicoureteral reflux (VUR): gender distribution versus VUR detected
80 77 after urinary tract infection (UTI). VUR detected as part of the evaluation of prenatal
Female
70 hydronephrosis is most commonly identified in boys. In an analysis of six published stud-
60 ies of VUR diagnosed in a total of 124 infants with antenatally detected hydronephrosis,
50 83% of those affected were boys [33]. Conversely, VUR detected after a UTI most com-
%
40 monly affects girls. In the International Reflux Study in Children (IRSC) and Southwest
30 23 Pediatric Nephrology Study Group (SWPNSG) investigations of VUR detected in a total of
20 17
380 children after UTI, 77% of those affected were girls [20,36].
10
0
Prenatally Detected
detected after UTI
Clinical Course of Vesicoureteric Reflux
90
50 50
50 80 Grade 1
Grade 2
70
40 Resolved VUR, % Grade 3
60
30 50
30
%
20 21 40
20 30
20
10
10
0 0
1 2 3 4 5 0 1 2 3 4 5
Vesicoureteral reflux grade Years follow-up

Resolution of vesicoureteral reflux (VUR) detected prenatally at fol- Resolution of vesicoureteral reflux (VUR) detected postnatally
low-up examinations over 2 years. Spontaneous resolution of VUR after urinary tract infection: mild to moderate VUR. The Southwest
can occur in infants with reflux detected during the postnatal evalu- Pediatric Nephrology Study Group (SWPNSG) prospectively observed
ation of prenatal urinary tract abnormalities. In an analysis of six 113 patients aged 4 months to 5 years with grades I to III VUR
investigations of VUR detected neonatally with a follow-up period detected after urinary tract infection. The SWPNSG reported on 59
of 2 years, resolution was seen in 50% of infants with grades I and children followed up with serial excretory urograms and voiding cys-
II. High-grade reflux (grades IV to V) resolved in only 20% [33]. tourethrography 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
90 82 80 Grade 1 Resolution of vesicoureteral reflux (VUR) detected postnatally after
80 Grade 2 urinary tract infection at follow-up examinations over 5 years. Mild
70
Patients studied, %
Grade 3
to moderate VUR spontaneously resolves in a significant percentage
60 Grade 4–5 53
of children, whereas high-grade reflux resolves only rarely. The
50 43
40
40 Southwest Pediatric Nephrology Study Group (SWPNSG) found
31 that grades I and II VUR resolved in 80% of children with refluxing
30
20 17 16 18 20 ureters at follow-up examinations over 5 years. In the Birmingham
10 Reflux Study Group (BRSG), International Reflux Study in Children
0 (IRSC), and SWPNSG investigations of high-grade VUR (grades III
Resolution Improvement Unchanged 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].
FIGURE 8-23
40
Unilateral Resolution of grades III to V vesicoureteral reflux (VUR) detected
35
Bilateral postnatally after urinary tract infection: bilateral versus unilateral
30 VUR. Spontaneous resolution of high-grade VUR is much more
Resolved VUR, %
25 likely to occur in unilateral reflux. The International Reflux Study

20 in Children (IRSC) showed that grades III to V VUR resolved in
children in whom both kidneys were affected nearly five times as
15
often (39%) as in those in whom VUR was bilateral (8%). In bilat-
10 eral VUR, spontaneous resolution did not occur after 2 years of
5 observation [38].
0
0 3 9 21 33 45 57
Months follow-up
18
IRSC IRSC
60 16
BRSG SWPNSG
14
New scar formation, %

Scarred or thinned, %
50
12
40 10
30 8
6
20
4
10 2
0 0
0 I–II III IV Dilated 0 1 2 3 4 5
Vesicoureteral reflux grade Years follow-up

Frequency of parenchymal scarring at the time of diagnosis of vesi- Development of parenchymal scarring after diagnosis of
coureteral reflux (VUR). Many children in whom VUR is detected vesicoureteral reflux (VUR). Parenchymal scarring occurs after
after a urinary tract infection already have evidence of renal diagnosis and initiation of therapy as well. The Southwest
parenchymal scarring. In two large prospective studies the frequen- Pediatric Nephrology Study Group (SWPNSG) followed up 59
cy of scars seen in persons with VUR increased with VUR severity. children with mild to moderate VUR (grades I to III) diagnosed
The International Reflux Study in Children (IRSC) studied 306 after urinary tract infection [20]. None of the children studied
children under 11 years of age with grades III to V VUR [36]. The had parenchymal scarring on intravenous pyelography at the
frequency of parenchymal scarring or thinning increased from 10% time of diagnosis. Parenchymal scars were seen to develop in
in children with nonrefluxing renal units (in children with con- 10% of children over the course of 5 years of follow-up exami-
tralateral VUR) to 60% in those with severely refluxing grade V nations, including some children without documented urinary
kidneys. In another large prospective study, the Birmingham Reflux tract infections during the period of observation. In this group,
Study Group (BRSG) reported renal scarring in 54% of 161 chil- renal scarring occurred nearly three times more commonly in
dren under 14 years of age with severe VUR resulting in ureteral grade 3 VUR than it did in grades 1 and 2 VUR. In the
dilation (greater than grade 3 using the classification system adopt- International Reflux Study in Children (IRSC) (European
ed by the International Reflux Study in Children group) at the time group), a prospective study of high-grade VUR (grades III and
reflux was detected [39]. Participants in these studies were children IV), new scars developed in 16% of 236 children after 5 years’
previously diagnosed as having had urinary tract infection. 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].
Treatment of Vesicoureteric Reflux

correcting VUR in 97.5% of 231 reimplanted ureters in 151 chil-
18 dren randomized to surgical therapy. Medical therapy consisted of
Surgical
16 long-term antibiotic uroprophylaxis using nitrofurantoin, trimetho-
Medical
14 prim, or trimethoprim-sulfa. No statistically significant advantage
Renal scarring, %
12 was demonstrable for either treatment modality with respect to

10 new scar formation after 5 years of observation in either study.
8 New scars were identified in 20 of the 116 children treated surgi-
6 cally (17%) and 19 of the 155 children treated medically (16%) at
4 follow-up examinations over 5 years. Those children treated surgi-
2 cally who developed parenchymal scars generally did so within the
0 first 2 years after ureteral repeat implantation, whereas scarring
0 5 10 15 20 25 30 35 40 45 50 55 60 occurred throughout the observation period in the group that did
Months follow-up 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
FIGURE 8-27 Birmingham Reflux Study Group (BRSG) investigation of medical
Effectiveness of medical versus surgical treatment: new scar forma- versus surgical therapy for VUR in 161 children. After 2 years of
tion at follow-up examinations over 5 years in children with high- observation, progressive or new scar formation was seen in 16% of
grade vesicoureteral reflux (VUR). The International Reflux Study children with refluxing ureters in the group treated surgically and
in Children (IRSC) (European group) was designed to compare the 19% in the group treated medically. In contrast to the IRSC, how-
effectiveness of medical versus surgical therapy of VUR in children ever, new scar formation was rare after 2 years of observation in
diagnosed after urinary tract infection. Surgery was successful in both groups [37,40].
FIGURE 8-28
Effectiveness of medical versus surgical treatment: incidence of uri-
40 38 39 BRSG-Surgical nary tract infections. Vesicoureteral reflux (VUR) predisposes affected
Urinary tract infections, %
35 34 BRSG- Medical persons to urinary tract infection owing to incomplete bladder empty-
IRSC-Medical ing and urinary stasis. Medical therapy with uroprophylactic antibi-
30 28
IRSC-Surgical otics and surgical correction of VUR have as a goal the prevention of
25
21 SWPNSG
20 urinary tract infection. In three prospective studies of 400 children
15 with VUR (Southwest Pediatric Nephrology Study Group [SWPNSG],
International Reflux Study in Children [IRSC], Birmingham Reflux
10
Study Group [BRSG]) treated either medically or surgically and who
5
were observed over 5 years the rate of infection was similar, ranging
0 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
Nonpyelonephritic
Effectiveness of medical versus surgical treatment: incidence of urinary tract infection ver-
40 UTI sus pyelonephritis in severe vesicoureteral reflux (VUR). Although the incidence of uri-
UTI versus pyelonephritis, %
35 Pyelonephritis nary tract infections (UTIs) is the same in surgically and medically treated children with
30 17 VUR, the severity of infection is greater in those treated medically. The International
25 29
Reflux Study in Children (IRSC) (European group) studied 306 children with VUR and
20 observed them over 5 years; 155 were randomized to medical therapy, and 151 had surgi-
15
cal correction of their reflux. Although the incidence of UTI statistically was no different
21 between the groups (38% in the medical group, 39% in the surgical group), children
10
treated medically had an incidence of pyelonephritis twice as high (21%) as those treated
5 10
surgically (10%) [41].
0
Medical Surgical
therapy therapy
surgical correction. In children in whom

VUR resolves spontaneously, a high index
VUR detected
of suspicion for urinary tract infection
should be maintained, and urine cultures
Associated GU anomalies
expected to affect VUR? should be obtained at times of febrile illness
without ready clinical explanation.
In persons in whom mild VUR fails to
Yes No resolve after 2 to 3 years of observation,
consideration should be given to voiding pat-
Treat appropriately Severity of VUR tern. A careful voiding history and an evalu-
ation of urinary flow rate may reveal abnor-
malities in bladder function that impede res-
Mild (I-III) Severe (IV-V) olution of reflux. Correction of
dysfunctional voiding patterns may result in
Uroprophylaxis Functional study resolution of VUR. In the absence of dys-
Hygiene education (Radionuclide or ExU) functional voiding, it is controversial
Surveillance urine cultures whether older women with persistent VUR
Annual VCUG are best served by surgical correction or
Nonfunctioning Functioning close observation with uroprophylactic
Urinary tract infections? kidney kidney antibiotic therapy and surveillance urine cul-
tures, especially during pregnancy. Males
with persistent low-grade VUR may be can-
Yes No Consider didates for close observation with surveil-
nephrectomy Uroprophylaxis Surgical
correction lance urine cultures while not receiving
Consider surgery Resolution of VUR after 2 years antibiotic therapy, especially if they are over
Annual VCUG
4 years of age and circumcised. Circumcision
lowers the incidence of urinary tract infec-
Resolution of VUR after 2 years tion. In severe VUR the function of the
Yes No
affected kidney should be evaluated with a
Long term functional study (radionuclide renal scan).
Yes No
followup to Female Male High-grade VUR in nonfunctioning kidneys
detect UTI is unlikely to resolve spontaneously, and
nephrectomy may be indicated to decrease
Consider Consider Consider observation Long term Surgery the risk of urinary tract infection and avoid
surgery surgery off antibiotics followup the need for uroprophylactic antibiotic thera-
py. In patients with functioning kidneys who
have high-grade VUR, the likelihood for res-
FIGURE 8-30 olution should be considered. Severe VUR,
Proposed treatment of vesicoureteral reflux (VUR) in children. This algorithm provides an especially if bilateral, is unlikely to resolve
approach to evaluate and treat VUR in children. In VUR associated with other genitouri- spontaneously. Proceeding directly to repeat
nary anomalies, therapy for reflux should be part of a comprehensive treatment plan implantation may be indicated in some cases.
directed toward correcting the underlying urologic malformation. Children with mild VUR Medical therapy with uroprophylactic antibi-
should be treated with prophylactic antibiotics, attention to perineal hygiene and regular otics and serial VCUG may also be used,
bowel habits, surveillance urine cultures, and annual voiding cystourethrogram (VCUG). reserving surgical therapy for those in whom
Children with recurrent urinary tract infection on this regimen should be considered for resolution fails to occur.
Complications of Reflux Nephropathy

FIGURE 8-31
25
Development of hypertension in 55 normotensive subjects with reflux nephropathy at fol-
20 low-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
Hypertensive, %
15 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 percent-
10 age 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
5
Committee. Nevertheless, using this system, 78% of persons in the group could be classi-
0 fied as having reflux nephropathy severity scores between 1 and 4 [42].
0 5 10 15
Years
FIGURE 8-32
100
Frequency of hypertension versus severity of parenchymal scarring. The frequency of
80 hypertension in persons with vesicoureteral reflux–related renal scars is higher than in the
normal population. In adults with reflux nephropathy the incidence of hypertension can be
Hypertensive, %
60 correlated with the severity of renal scarring. Adding the individual grade of reflux (0–4)
for the two kidneys results in a scale ranging from 0 (no scars) to 8 (severe bilateral scar-
40 ring). 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
20
have hypertension [42,43].
0
1–4 5–8
Cumulative reflux scarring severity score
induces compensatory changes in

glomerular and vascular hemodynamics.
These changes initially maintain the
glomerular filtration rate but are mal-
adaptive over time. A–D, 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 prog-
nostic sign, indicating that renal injury
has occurred. The severity of proteinuria
A B 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. Hyper-
filtration resulting from decreased renal
mass continues and produces progressive
glomerulosclerosis and loss of renal func-
tion. Evidence exists that inhibition of the
renin-angiotensin system through the use of
angiotensin-converting enzyme inhibitors
C D decreases the compensatory hemodynamic
changes that produce hyperfiltration
FIGURE 8-33 injury. Thus, these inhibitors may be
Glomerular hypertrophy and focal segmental glomerulosclerosis (FSGS) in severe effective in slowing the progress of renal
reflux nephropathy. Reflux nephropathy resulting in reduced renal functional mass failure in reflux nephropathy.
Pathogenesis of Obstructive Nephropathy

Birth
FIGURE 8-34
Fetus Neonate Adult
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
Dysplasia disorganization of the renal parenchyma (dysplasia) and a reduction in the number of
nephrons. Partial or complete ureteral obstruction in neonates causes vasoconstriction,
Number of glomerular hypoperfusion, impaired ipsilateral renal growth, and interstitial fibrosis. The
nephrons 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
Renal growth partial or complete unilateral ureteral obstruction, is inversely related to the age of the ani-
Compensatory hypertrophy* mal at the time of obstruction. The older the animal, the less the impairment of the ipsilat-
eral kidney and the less the compensatory growth of the contralateral kidney. In addition,
Recovery of function
after relief of obstruction the recovery of renal function after relief of urinary tract obstruction also decreases with
the age of the animal [45].
*When unilateral
FIGURE 8-35
PGE2, PGI2 Renal hemodynamic response to mild partial ureteral obstruction. Renal blood flow and
Angiotensin II the glomerular filtration rate may not change in mild partial ureteral obstruction, despite a
RA RE significant reduction in glomerular capillary ultrafiltration coefficient (Kf). This is due to
PGC
the increase in glomerular capillary hydraulic pressure (PGC) caused by a prostaglandin
E2–induced reduction of afferent arteriolar resistance (RA) and an angiotensin II–induced
Kf 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].
PGE2—prostaglandin E2; PGI2—prostaglandin I2; Pt—tubule hydrostatic pressure.
Pt
vascular resistance and an increase in renal blood flow mediated by

2 h post-obstruction 24 h post-obstruction increased production of prostaglandin E2 (PGE2), prostacyclin, and
nitric oxide (NO). The increase in renal blood flow (RBF) and
PGE2, PGI2 Endothelin Angiotensin II
glomerular capillary pressure maintain the glomerular filtration rate
N0 TBX A 2
(GFR) at approximately 80% of normal, despite an increase in
RA PGC RE RA PGC RE intratubular pressure. As the ureteral obstruction persists, activation
(Macrophage of the renin-angiotensin system and increased production of throm-
infiltration)
RBF (120%) RBF (50%) boxane A2 (TBXA2) and endothelin result in progressive vasocon-
GFR (80%) (Activation of GFR (20%) striction, with reductions in renal blood flow and glomerular capil-
renin-angiotensin) lary pressure. The glomerular filtration rate decreases to approxi-
Pt Unilateral Pt mately 20% of baseline, despite normalization of the intratubular
pressures. The hemodynamic changes in the early phase (0–2 h) of
RA PGC RE RA PGC RE bilateral ureteral obstruction are similar to those observed after uni-
+ ANP lateral obstruction. As bilateral obstruction persists, however, there is
RBF (120%) RBF (50%) an accumulation of atrial natriuretic peptide (ANP) that does not
GFR (80%) GFR (20%) occur after unilateral obstruction. The increased ANP levels attenu-
ate the afferent and enhance the efferent vasoconstrictions, with
Pt Bilateral Pt maintenance of normal glomerular capillary and elevated tubular
pressures. Despite these differences in hemodynamic changes
between unilateral and bilateral ureteral obstruction, the reductions
FIGURE 8-36 in renal blood flow and glomerular filtration rate 24 hours after
Acute renal hemodynamic response to unilateral or bilateral com- obstruction are similar [47–49]. PGC—glomerular capillary hydraulic
plete ureteral obstruction. In the first 2 hours after unilateral com- pressure; PGI2—prostaglandin I2; Pt—tubule hydrostatic pressure;
plete ureteral obstruction, there is a reduction in preglomerular RA—afferent arteriolar resistance; RE—efferent arteriolar resistance.
300
FIGURE 8-37
Intrapelvic pressure Chronic renal hemodynamic response to complete unilateral ureter-
Renal blood flow al obstruction. During complete ureteral obstruction, renal blood
Change from baseline, %
200 Glomerular filtration rate 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%
100 at 8 weeks [48].
Baseline
–50
0 1 2 3 4 5 6 7 8
Weeks after obstruction
Cortex Medulla Cortex Medulla

Release of obstruction Release of obstruction
40
40
Leukocytes, 105/g
30
Leukocytes, 105/g
30
20
20
10
10
0
0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
A Control 4 h 12 h 24 h Control 4 h 12 h 24 h C Days Days
FIGURE 8-38
Cortex
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 lympho-
cytes in the cortex and medulla (A) that is accompanied by an
increase in urinary thromboxane B2 and a decrease in the glomeru-
lar filtration rate. The production of thromboxane A2 by the infil-
trating macrophages (B) contributes to the renal vasoconstriction
of chronic urinary tract obstruction. After release of the obstruc-
tion the cellular infiltration is slowly reversible, requiring several
days to revert to near normal levels (C) [50,51].
Medulla
B
obstructed kidney. Angiotensin II can

induce the synthesis of transforming growth
Tubular obstruction factor (TGF-), a cytokine that stimulates
extracellular matrix synthesis and inhibits
its degradation. Obstructive nephropathy
Pt is accompanied by downregulation of the
kallikrein-kinin system and nitric oxide
production that can be reversed by adminis-
Osteopontin Renin, angiotensinogen, EGF tration of a converting enzyme inhibitor or
PDGF Bradykinin of L-arginine. The rapid upregulation of
MCP ACE, AT1 receptor bcl2
chemotactic factors such as monocyte
chemoattractant peptide 1 (MCP-1) and
Macrophages TGF-ß Nitric oxide osteopontin in the tubular epithelial cells,
O–2 in response to increased intratubular pres-
CuZnSOD
H 2O 2 Catalase sure, contributes to the recruitment of
Fibroblasts, TIMP Apoptosis, macrophages. Macrophages produce
myofibroblasts Collagen tubular drop-out fibroblast growth factor and induce fibrob-
last proliferation and myofibroblast trans-
formation. The downregulation of epider-
Tubulointerstitial mal growth factor (EGF), Bcl 2, and antiox-
fibrosis idant enzymes and the increased production
of superoxide and hydrogen peroxide
(H2O2) contribute to an increased rate of
FIGURE 8-39 apoptosis and tubular dropout [51– 57].
Pathogenesis of tubulointerstitial fibrosis in obstructive nephropathy. This pathogenesis PDGF–platelet-derived growth factor;
has been extensively studied. Increased expression of renin, angiotensinogen, angiotensin- SOD—superoxide dismutase; TIMP—tissue
converting enzyme (ACE), and the angiotensin II type 1 (AT1) receptor occurs in the inhibitor of metalloproteinases.
FIGURE 8-40
Obstruction
Recovery of renal function after relief of complete unilateral
100 ureteral obstruction of variable duration. The recovery of the ipsi-
80 lateral glomerular filtration rate after relief of a unilateral com-
plete ureteral obstruction has been best studied in dogs and
60 depends on the duration of the obstruction. Complete recovery
occurs after 1 week of obstruction. The degree of recovery after 2
40 and 4 weeks of obstruction is only of 58% and 36%, respectively.
No recovery occurs after 6 weeks of obstruction [58]. Rare
20
reports of recovery of renal function in patients with longer peri-
0 ods of unilateral ureteral obstruction may represent high-grade
0 2 4 6 8 12 14 16 18 20 22 24 partial obstruction rather than complete obstruction or may
Weeks after obstruction reflect differences in lymphatic drainage and renal anatomy
between the human and canine kidneys [59].
Clinical Manifestations of Obstructive Nephropathy

FIGURE 8-41
Functional
Damage to Medullary Na+reabsorption ( Na+/K+ ATPase) Clinical correlates of abnormalities of tubu-
abnormalities
inner medulla blood flow Loop of Henle Collecting duct lar function in obstructive nephropathy.
in obstructed
kidneys Acute ureteral obstruction stimulates tubular
(unilteral or reabsorption, resulting in increased urine
bilateral) Corticomedullary Intraluminal
concentration gradient negative potential osmolality and reduced urine sodium con-
centration [60]. In contrast, obstructive
nephropathy is characterized by a reduced
Resistance Concentration defect Na+ wasting H+ secretion H+-ATPase
to ADH K+ secretion Na+/K+ ATPase ability to concentrate the urine, reabsorb
sodium, and secrete hydrogen ions (H+) and
Consequences potassium. In unilateral obstructive
of bilateral ECFV excess
nephropathy, these functional abnormalities
obstruction do not have a clinical correlate because of
ANP
the reduced glomerular filtration rate and
Osmotic load (urea) immaterial contribution of the obstructed
kidney to total renal function. Hyperkalemic
metabolic acidosis and, when the intake of
Clinical free water is not adequate, hypernatremia
Excessive replacement
correlates can occur in patients with partial bilateral
Hypernatremia Postobstructive diuresis after Hyperkalemic ureteral obstruction or partial ureteral
when free relief of bilateral obstruction metabolic acidosis obstruction in a solitary kidney. Similarly,
water intake is (volume contraction, in partial bilateral postobstructive diuresis can occur only after
inadequate hypomagnesemia, other ureteral obstruction relief of bilateral ureteral obstruction or
electrolyte abnormalities)
ureteral obstruction in a solitary kidney but
not after relief of unilateral obstruction
[61–67]. ADH>\#209>antidiuretic hormone;
ANP—atrial natriuretic peptide; ECFV—
extracellular fluid volume; Na-K ATPase—
sodium-potassium adenosine triphosphatase.
FIGURE 8-42
Urinary tract obstruction Clinical manifestations of obstructive nephropathy. These manifes-
tations depend on the cause of the obstruction, its anatomic loca-
tion, its severity, and its rate of development [61,68,69].
Unilateral Bilateral or solitary kidney
Partial or complete Partial Complete
• Pain (dull aching • Renin-dependent • Polyuria, polydipsia • Anuria • Bladder

renal colic) hypertension • Hypernatremia • Uremia symptoms
• Susceptibility to • Erythrocytosis • Volume contraction • Fluctuating
urinary tract (rare) • Hyperkalemic urine
infection and metabolic acidosis output
nephrolithiasis • Uremia
• Volume-dependent
hypertension
Diagnosis of Obstructive Nephropathy

1.0
Furosemide Baseline
Saline
0.8
Obstruction Saline + furosemide
Tracer activity
0.6
RI
Hydronephrosis 0.4
without obstruction
0.2
Normal
0.0
A Time B Partial obstruction 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 obstruc-
tion [70]. Diuresis renography is helpful
when the functional significance of the
dilation of the collecting system is in ques-
tion [71,72]. Renal Doppler ultrasonogra-
phy before and after administration of nor-
mal saline and furosemide also has been
used to differentiate obstructive from
nonobstructive pyelocaliectasis [73]. Other
techniques such as excretory urography,
C D computed tomography, and retrograde or
antegrade ureteropyelography are helpful
FIGURE 8-43 to determine the cause of the urinary tract
Diagnosis of obstructive nephropathy. A, Diuresis renography. B, Doppler ultrasonogra- obstruction. The utility of excretory urog-
phy. C, D, Magnetic resonance urogram utilizing a single shot fast spin echo technique raphy is limited in patients with advanced
with anterior-posterior projection (C) and left posterior oblique projection (D). Images renal insufficiency. In these cases magnetic
demonstrate a widely patent right ureteropelvic junction in a patient with abdominal pain resonance urography can provide coronal
and suspected ureteropelvic junction obstruction. Administration of gadolinium is not imaging of the renal collecting systems and
required for this technique. Note also the urine in the bladder, cerebrospinal fluid in the ureters similar to that of conventional
spinal canal, and fluid in the small bowel. urography without the use of iodinated
Ultrasonography is the procedure of choice to determine the presence or absence of a contrast. RI— resistive index. (C, D,
dilated renal pelvis or calices and to assess the degree of associated parenchymal atrophy. Courtesy of B. F. King, MD.)
FIGURE 8-44
Diagnosis of obstructive nephropathy by postnatal renal ultra-
sonography, 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.
FIGURE 8-45
Before Furosemide After Furosemide Mercaptoacetyltriglycine-3 renal scan with furosemide in a new-
born 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
1 min. 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 oth-
5 min. ers advocate withholding surgery unless renal function deteriorates
or hydronephrosis progresses.
10 min.
15 min.
Lt Rt Lt Rt
Posterior Urethral Valves

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
Type I lesion most commonly is comprised of an
oblique diaphragm with a slitlike perfora-
tion arising from the posterior urethra dis-
tal to the verumontanum and inserting at
the midline anterior urethra. (From Kaplan
and Scherz [74]; with permission.)
A
FIGURE 8-47
Excretory urogram of a patient with poste-
rior urethral valves. Bladder outlet obstruc-
tion results in bladder wall thickening, tra-
beculation, 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.
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 elon-
gation. 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.
Ureterovesical Junction Obstruction

FIGURE 8-49
Excretory urogram showing ureterovesical junction obstruction in a 2-year-old girl.
Retroperitoneal Fibrosis
A B
FIGURE 8-50
A–H, Idiopathic retroperitoneal fibrosis: computed tomography nal fibrosis, sclerosing cholangitis, Riedel’s thyroiditis, and fibrous
scans of the abdomen before (left panels, note right ureteral stent pseudotumor of the orbit. In the clinical setting, patients with idio-
and mild left ureteropyelocaliectasis) and 7 years after ureterolysis pathic retroperitoneal fibrosis exhibit systemic symptoms such as
(right panels, note omental interposition). Retroperitoneal fibrosis malaise, anorexia and weight loss, and abdominal or flank pain.
is characterized by the accumulation of inflammatory and fibrotic Renal insufficiency is often seen and is caused by bilateral ureteral
tissue around the aorta, between the renal hila and the pelvic brim. obstruction. Laboratory test results usually demonstrate anemia
Most cases are idiopathic; the remainder are associated with and an elevated sedimentation rate. The treatment is directed to the
immune-mediated connective tissue diseases, ingestion of drugs release of the ureteral obstruction, which initially can be achieved
such as methysergide, abdominal aortic aneurysms, or malignancy. by placement of ureteral stents. Administration of corticosteroids is
Idiopathic retroperitoneal fibrosis can be associated with mediasti- helpful to control the systemic manifestations of the disease and
C D
E F
G H
often to reduce the bulk of the tumor and relieve the ureteral the ureters from the fibrotic mass, lateralizing them, and wrapping
obstruction. Administration of corticosteroids, however, should be them in omentum to prevent repeat obstruction, is often necessary.
considered only when malignancy and retroperitoneal infection can Other immunosuppressive agents have been used rarely when the
be ruled out. As in other chronic renal diseases, administration of systemic manifestations of the disease cannot be controlled with
corticosteroids should be kept at the minimal level capable of con- safe doses of corticosteroids. In most cases the long-term outcome
trolling symptoms. Surgical ureterolysis, which consists of freeing of idiopathic retroperitoneal fibrosis is satisfactory [75–77].
References
1. Roshani H, Dabhoiwala NF, Verbeek FJ, Lamers WH: Functional 24. Anderson PAM, Rickwood AMK: Features of primary vesicoureteric
anatomy of the human ureterovesical junction. Anat Rec 1996, reflux detected by prenatal sonography. Br J Urol 1991, 67:267–271.
245:645–651. 25. Stocks A, Richards D, Frentzen B, Richard G: Correlation of prenatal
2. Noordzij JW, Dabhoiwala NF: A view on the anatomy of the renal pelvic anteroposterior diameter with outcome in pregnancy. J
ureterovesical junction. Scand J Urol Nephrol 1993, 27:371–380. Urol 1996, 155:1050–1052.
3. Thomson AS, Dabhoiwala NF, Verbeek FJ, Lamers WH: The func- 26. Adra AM, Mejides AA, Dennaoui MS, et al.: Fetal pyelectasis: Is it
tional anatomy of the ureterovesical junction. Br J Urol 1994, always “physiological”? [abstract]. Am J Obstet Gynecol 1995,
73:284–291. 172:359.
4. Politano VA: Vesico-ureteral reflux. In Urologic Surgery, edn 2. Edited 27. Morin L, Cendron M, Garmel SH, et al.: Minimal fetal hydronephro-
by Glenn JF. New York: Harper and Row Publishers, 1975:272–293. sis: natural history and implications for treatment. Am J Obstet
5. Paquin AJ: Ureterovesical junction: the description and evaluation of Gynecol 1995, 172:354.
a technique. J Urol 1959, 82:573. 28. Zerin JM, Ritchey MJ, Chang ACH: Incidental vesicoureteral reflux
6. Stephens FD, Lenaghan D: The anatomical basis and dynamics of in neonates with antenatally detected hydronephrosis and other
vesicoureteral reflux. J Urol 1962, 87:669. abnormalities. Radiology 1993, 187:157–160.
7. Kramer, SA: Vesicoureteral reflux. In Clinical Pediatric Urology, edn 29. Peters PC, Johnson DE, Jackson JHJ: The incidence of vesicoureteral
3. Edited by Kelalis PP, King LR, Belman AB. Philadelphia: WB reflux in the premature child. J Urol 1967, 97:259–260.
Saunders Company, 1992:441–499. 30. Lich R Jr, Howerton LW Jr, Goode LS, Davis LA: The ureterovesical
8. Ransley PG, Risdon RA: Renal papillary morphology in infants and junction of the newborn. J Urol 1964, 92:436–438.
young children. Urol Res 1975, 3:111–113. 31. Marra G, Barbieri G, Moioli C, et al.: Mild fetal hydronephrosis indi-
9. Ransley PG, Risdon RA: Renal papillary morphology and intrarenal cating vesicoureteric reflux. Arch Dis Child 1994, 70:F147–150.
reflux in the young pig. Urol Res 1975, 3:105–109. 32. Wallin L, Bajc M: The significance of vesicoureteric reflux on kidney
10. Funston MR, Cremin BJ: Intrarenal reflux-papillary morphology and development assessed by dimercaptosuccinate renal scintigraphy. Br J
pressure relationships in children’s necropsy kidneys. Br J Radiol Urol 1994, 73:607–611.
1978, 51:665–670. 33. Elder JS: Commentary: importance of antenatal diagnosis of vesi-
11. Ransley PG, Risdon RA: Reflux nephropathy: effects of antimicrobial coureteral reflux. J Urol 1992, 148:1750–1754.
therapy on the evolution of the early pyelonephritic scar. Kidney Int 34. Crabbe DCG, Thomas DFM, Gordon AC, et al.: Use of 99mtech-
1981, 20:733–742. netium-dimercaptosuccinic acid to study patterns of renal damage
12. Torres VE, Kramer SA, Holley KE, et al.: Effect of bacterial immu- associated with prenatally detected vesicoureteral reflux. J Urol 1992,
nization on experimental reflux nephropathy. J Urol 1984, 131:772. 148:1229–1231.
13. Torres VE, Kramer SA, Holley KE, et al.: Interaction of multiple risk 35. Sheridan M, Jewkes F, Gough DCS: Reflux nephropathy in the first
factors in the pathogenesis of experimental reflux nephropathy in the year of life: role of infection. Pediatr Surg Int 1991, 6:214–216.
pig. J Urol 1985, 133:131–135. 36. Weiss R, Tamminen-Mobius T, Koskimies O, et al.: Characteristics at
14. Goldraich NP, Goldraich IH, Anselmi OE, Ramos OL: Reflux entry of children with severe primary vesicoureteral reflux recruited
nephropathy: the clinical picture in South Brazilian children. Control for a multicenter international therapeutic trial comparing medical
Nephrol 1984, 39:52–67. and surgical management. J Urol 1992, 148:1644–1649.
15. Scherz HC, Downs TM, Caeser R: The selective use of dimercaptosuc- 37. Taylor CM, White RHR: Prospective trial of operative vs. non-opera-
cinic acid renal scans in children with vesicoureteral reflux. J Urol tive treatment of severe vesicoureteric reflux in children: five years’
1994, 152:628–631. observation. Br Med J 1987, 295:237–241.
16. Kramer SA: Experimental vesicoureteral reflux. Dialogues Pediatr 38. Tamminen-Mobius T, Brunier E, Ebel K-D, et al.: Cessation of vesi-
Urol 1984, 7:1. coureteral reflux for 5 years in infants and children allocated to med-
ical treatment. J Urol 1992, 148:1662–1666.
17. Hinchliffe SA, Chan Y, Jones H, et al.: Renal hypoplasia and postna-
tally acquired cortical loss in children with vesicoureteral reflux. 39. Astley R, Clark RC, Corkery JJ, et al.: Prospective trial of operative
Pediatr Nephrol1992, 6:439–444. vs. non-operative treatment of severe vesicoureteric reflux: two years’
observation in 96 children. Br Med J 1983, 287:171–174.
18. Lebowitz RL, Olbing H, Parkkulainen K, et al.: International system
of radiographic grading of vesicoureteral reflux. Pediatr Radiol 1985, 40. Olbing H, Claesson I, Ebel K-D, et al.: Renal scars and parenchymal
15:105. thinning in children with vesicoureteral reflux: a 5-year report of the
International Reflux Study in Children (European branch). J Urol
19. Smellie JM, Edwards D, Hunter N, et al.: Vesico-ureteric reflux and 1992, 148:1653–1656.
renal scarring. Kidney Int 1975, 8:s65–s72.
41. Jodal U, Koskimies O, Hanson E, et al.: Infection pattern in children
20. Arant BS: Medical management of mild and moderate vesicoureteral with vesicoureteral reflux randomly allocated to operation or long-
reflux: followup studies of infants and young children. A preliminary term antibacterial prophylaxis. J Urol 1992, 148:1650–1652.
report of the Southwest Pediatric Nephrology Study Group. J Urol
1992, 148:1683–1687. 42. Goonasekera CDA, Shah V, Wade A, et al.: 15-year follow-up of renin
and blood pressure in reflux nephropathy. Lancet 1996,
21. Steele BT, Robitaille P, DeMaria J, Grignon A: Follow-up evaluation 347:640–643.
of prenatally recognized vesicoureteric reflux. J Pediatr 1989,
115:95–96. 43. Torres V, Malek RS, Svensson JP: Vesicoureteral reflux in the adult:
nephropathy, hypertension, and stones. J Urol 1983, 130:41–44.
22. Najmaldin A, Burge DM, Atwell JD: Reflux nephropathy secondary
to intrauterine vesicoureteric reflux. J Pediatr Surg 1990, 25:387–390. 44. Torres V, Velosa J, Holley KE, et al.: The progression of vesicoureteral
reflux nephropathy. Ann Intern Med 1980, 92:776–784.
23. Marra G, Barbieri G, Dell’Agnola CA, et al.: Congenital renal damage
associated with primary vesicoureteral reflux detected prenatally in 45. Chevalier RL: Effects of ureteral obstruction on renal growth. Semin
male infants. J Pediatr 1994, 124:726–730. Nephrol 1995, 15:353–360.
46. Ichikawa I, Brenner BM: Local intrarenal vasoconstrictor-vasodilator 62. Campbell HT, Bello-Reuss E, Klahr S: Hydraulic water permeability
interactions in mild partial ureteral obstruction. Am J Physiol 1979, and transepithelial voltage in the isolated perfused rabbit cortical col-
236:F131–140. lecting tubule following acute unilateral ureteral obstruction. J Clin
47. Dal Canton A: Effects of 24-hour unilateral ureteral obstruction on Invest 1985, 75:219.
glomerular hemodynamics in rat kidney. Kidney Int 1979, 15:457. 63. Hanley MJ, Davidson K: Isolated nephron segments from rabbit mod-
48. Klahr S: Pathophysiology of obstructive nephropathy: a 1991 update. els of obstructive uropathy. J Clin Invest 1982, 69:165.
Semin Nephrol 1991, 11:156. 64. Hwang S: Transport defects of rabbit inner medullary collecting duct
49. Marin-Grez M, Fleming JT: Atrial natriuretic peptide causes pre- cells in obstructive uropathy. Am J Physiol 1993, 264:F808.
glomerular vasodilatation and post-glomerular vasoconstriction in rat 65. Hwang S: Transport defects of rabbit medullary thick ascending limb
kidney. Nature 1986, 324:473. cells in obstructive uropathy. J Clin Invest 1993, 91:21.
50. Schreiner GF, Harris KPG, Purkerson ML, Klahr S: Immunological 66. Kimura H, Mujais SK: Cortical collecting duct Na-K pump in
aspects of acute ureteral obstruction: immune cell infiltrate in the kid- obstructive uropathy. Am J Physiol 1990, 258:F1320.
ney. Kidney Int 1988, 34:487–493. 67. Muto S, Asano Y: Electrical properties of the rabbit cortical collecting
51. Diamond JR: Macrophages and progressive renal disease in experi- duct from obstructed kidneys after unilateral ureteral obstruction. J
mental hydronephrosis. Am J Kidney Dis 1995, 26:133–140. Clin Invest 1994, 94:1846.
52. Chevalier RL: Growth factors and apoptosis in neonatal ureteral 68. Davis BB, Preuss HG, Murdaugh HVJ: Hypomagnesemia following
obstruction. J Am Soc Nephrol 1996, 7:1098–1105. the diuresis of post-renal obstruction and renal transplant. Nephron
53. Ishidoya S, Morrisey J, McCracken R, Klahr S: Delayed treatment 1975, 14:275.
with enalapril halts tubulointerstitial fibrosis in rats with obstructive 69. Landsberg L: Hypernatremia complicating partial urinary tract
uropathy. Kidney Int 1996, 49:1110–1119. obstruction. N Engl J Med 1970, 283:746.
54. Morrisey J, Ishidoya S, McCracken R, Klahr S: Nitric oxide genera- 70. Whitherow RO, Whitaker RH: The predictive accuracy of antegrade
tion ameliorates the tubulointerstitial fibrosis of obstructive nephropa- pressure flow studies in equivocal upper tract obstruction. Br J Urol
thy. J Am Soc Nephrol 1996, 7:2202–2212. 1981, 53:496.
55. Ricardo SD, Ding G, Eufemio M, Diamond JR: Antioxidant expres- 71. Koff SA, Thrall JN, Keyes JW: Diuretic radionuclide urography. A
sion in experimental hydronephrosis: role of mechanical stretch and noninvasive method for evaluating nephroureteral dilatation. J Urol
growth factors. Am J Physiol 1997, 272:F789–F798. 1979, 122:451.
56. Wright EJ, McCaffrey TA, Robertson AP, et al.: Chronic unilateral ureter- 72. Whitfield HN: Furosemide intravenous urography in the diagnosis of
al obstruction is associated with interstitial fibrosis and tubular expression pelviureteric junction obstruction. Br J Urol 1979, 51:445.
of transforming growth factor-beta.Lab Invest 1996, 74:528–537. 73. Shokeir AA, Nijman RJM, El-Azab M, Provoost AP: Partial ureteral
57. Yanagisawa H: Dietary protein restriction normalized eicosanoid pro- obstruction: effect of intravenous normal saline and furosemide on the
duction in isolated glomeruli from rats with bilateral ureteral obstruc- resistive index. J Urol 1997, 157:1074–1077.
tion.Kidney Int 1994, 46:245. 74. Kaplan GW, Scherz HC: Infravesicle obstruction. In Clinical Pediatric
58. Vaughn EDJ, Gillenwater JY: Recovery following complete chronic Urology, edn 3. Edited by Kelalis PP, King LR, Belman AB.
unilateral ureteral occlusion: functional, radiographic and pathologic Philadelphia: WB Saunders Company; 1992:821–864.
alterations. J Urol 1971, 106:27–35. 75. Gilkeson GS, Allen NB: Retroperitoneal fibrosis: a true connective tis-
59. Shapiro SR: Recovery of renal function after prolonged unilateral sue disease. Rheum Dis North Am 1996, 22:23–38.
ureteral obstruction. J Urol 1976, 115:136–40. 76. Kottra JJ, Dunnick NR: Retroperitoneal fibrosis. Radiol Clin North
60. Miller TR: Urinary diagnostic studies in acute renal failure: a prospec- Am 1996, 34:1259–1275.
tive study. Ann Intern Med 1978, 89:47. 77. Massachusetts General Hospital: Case records–case 27–1996: N Engl
61. Batlle DC, Arruda JAL, Kurtzman NA: Hyperkalemic distal renal J Med 1996, 335:650–655.
tubular acidosis associated with obstructive uropathy. N Engl J Med
1981, 304:373.
Cystic Diseases
of the Kidney
Yves Pirson
Dominique Chauveau
A
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 diseases—perhaps 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 poly-
cystic). 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 gener-
ally 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-domi-
nant polycystic kidney disease), focusing on genetics, clinical manifes-
tations, 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. CHAPTER
Most of these features are illustrated in this chapter.
9
General Features
FIGURE 9-1
PRINCIPAL CYSTIC DISEASES OF THE KIDNEY Principal cystic diseases of the kidney.
Classification of the renal cystic disorders,
with the most common ones printed in bold
Nongenetic Genetic type. (Adapted from Fick and Gabow [1];
Welling and Grantham [2]; Pirson, et al. [3].)
Acquired disorders Autosomal-dominant
Simple renal cysts (solitary or multiple) Autosomal-dominant polycystic kidney disease
Cysts of the renal sinus (or peripelvic lymphangiectasis) Tuberous sclerosis complex
Acquired cystic kidney disease (in patients with von Hippel-Lindau disease
chronic renal impairment) Medullary cystic disease
Multilocular cyst (or multilocular cystic nephroma) Glomerulocystic kidney disease
Hypokalemia-related cysts Autosomal-recessive
Developmental disorders Autosomal-recessive polycystic kidney disease
Medullary sponge kidney Nephronophthisis
Multicystic dysplastic kidney X-linked
Pyelocalyceal cysts Orofaciodigital syndrome, type I
IMAGING CHARACTERISTICS OF THE MOST COMMON RENAL CYSTIC DISEASES
Disease Kidney Size Cyst Size Cyst Location Liver

Simple renal cysts Normal Variable (mm–10 cm) All Normal
Acquired renal cystic disease Most often small, sometimes large 0.5–2 cm All Normal
Medullary sponge kidney Normal or slightly enlarged mm Precalyceal Normal (most often)
ADPKD Enlarged Variable (mm–10 cm) All Cysts (most often)
ARPKD Enlarged mm increase with age All CHF
NPH Small mm–2 cm (when present) Medullary Normal
FIGURE 9-2
Characteristics of the most common renal cystic diseases detectable in the vast majority of patients. ADPKD—autosomal-dominant
by imaging techniques (ultrasonography, computed tomography, polycystic kidney disease; ARPKD—autosomal-recessive polycystic
magnetic resonance). In the context of family history and clinical kidney disease; CHF—congenital hepatic fibrosis; NPH—
findings, these allow the clinician to establish a definitive diagnosis nephronophthisis.
Cystic Diseases of the Kidney 9.3
Nongenetic Disorders
FIGURE 9-3
Solitary simple cyst. Large solitary cyst found incidentally at ultra-
sonography (longitudinal scan) in the lower pole of the right kid-
ney. 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, comput-
ed 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 M F M F M F M F
15–29 0 0 0 0 0 0 0 0
30–49 2 1 0 1 0 1 0 1
50–69 15 7 2 1 1 1 2 1
≥70 32 15 17 8 6 3 9 3
*Unilateral or bilateral. M—male; F—Female.
FIGURE 9-4
Prevalence of simple renal cysts detected by ultrasonography increases with age and is higher in males. Cyst size also increases
according to age in an Australian population of 729 persons with age. Most simple cysts are located in the cortex. (From
prospectively screened by ultrasonography. The prevalence Ravine et al. [4]; with permission.)
A B
FIGURE 9-5
A and B, Multiple simple cysts (one 7 cm in diameter in the lower Each cyst exhibits the typical features of an uncomplicated simple
pole of the left kidney and three 4 to 5 cm in diameter in the right cyst on CT: 1) homogeneous low density, unchanged by contrast
kidney) detected by contrast-enhanced computed tomography (CT). medium; 2) rounded outline; 3) very thin (most often indetectable)
Additional millimetric cysts might be suspected in both kidneys. wall; 4) distinct delineation from adjacent parenchyma.
A B
FIGURE 9-6
A, Contrast-enhanced computed tomography (CT) shows a Ultrasonographic appearance mimicked hydronephrosis. Also
simple, 3-cm wide cyst of the renal sinus (arrows) found during known as hilar lymphangiectasis or peripelvic (or parapelvic)
investigation of renal calculi. Note subcapsular hematoma cysts, this acquired disorder consists of dilated hilar lymph
(arrowheads) detected after lithotripsy. B, Contrast-enhanced channels. Its frequency is about 1% in autopsy series. Although
CT shows bilateral multiple cysts of the renal sinus, leading to usually asymptomatic, cysts of the renal sinus can cause severe
chronic compression of the pelvis and subsequent renal atrophy. urinary obstruction, B.
A B
FIGURE 9-7
A, Acquired cystic kidney disease (ACKD) detected by contrast- hemodialysis and peritoneal dialysis, respectively [5]. In the early
enhanced computed tomography (CT) in a 71-year-old man on stage, kidneys are small or even shrunken and cysts are usually
hemodialysis for 4 years. A, Note the several intrarenal calcifica- smaller than 0.5 cm. Cyst numbers and kidney volume increase
tions, which are not unusual in dialysis patients. ACKD is charac- with time, as seen on this patient’s scan (B) repeated 8 years into
terized by the development of many cysts in the setting of chronic dialysis. Advanced ACKD can mimic autosomal-dominant polycys-
uremia. It can occur at any age, including childhood, whatever the tic disease. ACKD sometimes regresses after successful transplanta-
original nephropathy. The diagnosis is based on detection of at tion; it can involve chronically rejected kidney grafts. Although
least three to five cysts in each kidney in a patient who has chronic ACKD is usually asymptomatic it may be complicated by bleed-
renal failure but not hereditary cystic disease. The prevalence of ing—confined to the cysts or extending to either the collecting sys-
ACKD averages 10% at onset of dialysis treatment and subse- tem (causing hematuria) or the perinephric spaces—and associated
quently increases, to reach 60% and 90% at 5 and 10 years into with renal cell carcinoma. (Courtesy of M. Jadoul.)
FIGURE 9-8
Age <55 and > 3 years No Screening for acquired cystic kidney disease (ACKD) and renal neoplasms in patients receiv-
on RRT and good No
screening ing renal replacement therapy (RRT). The major clinical concern with ACKD is the risk of
clinical condition?
renal cell carcinoma, often the tubulopapillary type, associated with this disorder: the inci-
Yes dence is 50-times greater than in the general population. Moreover, ACKD-associated renal
No
carcinoma is more often bilateral and multicentric; however, only a minority of them evolve
Echography: into invasive carcinomas or cause metastases [5]. There is no doubt that imaging should be
ACKD? performed when a dialysis patient has symptoms such as flank pain and hematuria, the
Yes question of periodic screening for ACKD and neoplasms in asymptomatic dialysis patients
is still being debated. Using decision analysis incorporating morbidity and mortality associ-
No
Suspicion of ated with nephrectomy in dialysis patients, Sarasin and coworkers [6] showed that only the
Biennial echo
renal neoplasm? 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,
Yes
who have been on dialysis at least 3 years and are in good general condition. Recognized
Enhanced CT: No risk factors for renal cell carcinoma in ACKD are male gender, uremia of long standing,
confirmed neoplasm? large kidneys, and analgesic nephropathy.
Yes
Nephrectomy
and annual
follow-up of
contralateral kidney
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 appear-
ance is actually indistinguishable from
those of the cystic forms of Wilms’ tumor
and renal clear cell carcinoma. (Courtesy
of A. Dardenne.)
A B
A 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 compari-
son). 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 occasional-
ly has a cystic appearance on CT and can mimic a simple cyst.
C (Courtesy of A. Dardenne.)
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 medi-
um in the papillary areas (arrows) are the typical feature of MSK. They result from congen-
ital 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 for-
mation 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 congeni-
tal and inherited disorders, including corporeal hemihypertrophy, Beckwith-Wiedemann
syndrome (macroglossia, omphalocele, visceromegaly, microcephaly, and mental retarda-
tion), polycystic kidney disease (about 3% of patients with autosomal-dominant polycystic
kidney disease have evidence of MSK), congenital hepatic fibrosis, and Caroli’s 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 com-
patible with life. Usually, the contralateral kidney is normal and
exhibits compensatory hypertrophy. In some 30% of cases, howev-
er, it is also affected by some congenital abnormalities such as dys-
plasia 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 sug-
gested the existence of polycystic kidney disease. Although usually
smaller than 1 cm in diameter, pyelocalyceal diverticula occasion-
ally are much larger, as in this case. They predispose to stone for-
mation. 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.
Genetic disorders
FIGURE 9-14
GENETICS OF ADPKD Genetics of autosomal-dominant polycystic kidney disease
(ADPKD). ADPKD is by far the most frequent inherited kidney dis-
ease. In white populations, its prevalence ranges from 1 in 400 to 1
Gene Chromosome Product Patients with ADPKD, % in 1000. ADPKD is characterized by the development of multiple
renal cysts that are variably associated with extrarenal (mainly
PKD1 16 Polycystin 1 80–90 hepatic and cardiovascular) abnormalities [1,2,3]. It is caused by
PKD2 4 Polycystin 2 10–20 mutations in at least three different genes. PKD1, the gene responsi-
PKD3 ? ? Very few ble 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 pro-
tein of 110 kD called polycystin 2. Phenotypic differences between
the two main genetic forms are detailed in Figure 9-19. The exis-
tence of (at least) a third gene is suggested by recent reports.
FIGURE 9-15
NH2 Autosomal-dominant polycystic kidney disease: predicted structure
of polycystin 1 and polycystin 2 and their interaction. Polycystin 1
Cysteine-rich domain
is a 4302-amino acid protein, which anchors itself to cell mem-
Leucine-rich domain branes by seven transmembrane domains [10]. The large extracel-
PKD1 domain lular portion includes two leucine-rich repeats usually involved in
C protein-protein interactions and a C-type lectin domain capable of
C L C-type lectin domain
L B binding carbohydrates. A part of the intracellular tail has the
B capacity to form a coiled-coil motif, enabling either self-assembling
Lipoprotein A domain or interaction with other proteins. Polycystin 2 is a 968-amino acid
R protein with six transmembrane domains, resembling a subunit of
E REJ domain
J voltage-activated calcium channel. Like polycystin 1, the C-termi-
nal end of polycystin 2 comprises a coiled-coil domain and is able
Transmembrane segment
to interact in vitro with PKD2 [11]. This C-terminal part of poly-
cystin 2 also includes a calcium-binding domain. On these grounds,
it has been hypothesized that polycystin 1 acts like a receptor and
Alpha helix coiled-coil signal transducer, communicating information from outside to
inside the cell through its interaction with polycystin 2. This coor-
R
E dinated function could be crucial during late renal embryogenesis.
J It is currently speculated that both polycystins play a role in the
Out
maturation of tubule epithelial cells. Mutation of polycystins could
Membrane
thus impair the maturation process, maintaining some tubular cells
in a state of underdevelopment. This could result in both sustained
In
cell proliferation and predominance of fluid secretion over absorp-
tion, leading to cyst formation (see Fig. 9-16 and references 12 and
NH2 13 for review). (From Hughes et al. [10] and Germino [12].)
HOOC
COOH
Polycystin 1 Polycystin 2
allele is required to trigger cyst formation

Thickened tubular (ie, a mechanism similar to that demonstrat-
basement membrane ed for tumor suppressor genes in tuberous
sclerosis complex and von Hippel-Lindau dis-
ease). The hypothesis is supported by both
the clonality of most cysts and the finding of
Fluid loss of heterozygosity in some of them [12].
Accumulation Cell immaturity resulting from mutated
polycystin would lead to uncontrolled
growth, elaboration of abnormal extracellu-
lar matrix, and accumulation of fluid.
Aberrant cell proliferation is demonstrated by
the existence of micropolyps, identification of
Normal tubule Occurrence Monoclonal Isolated cyst mitotic phases, and abnormal expression of
with germinal of somatic proliferation disconnected from proto-oncogenes. Abnormality of extracellu-
PKD1 mutation of the leading to its tubule of lar matrix is evidenced by thickening and
mutation normal PKD1 cyst formation origin lamination of the tubular basement mem-
in each cell allele in one brane; involvement of extracellular matrix
tubular cell
would explain the association of cerebral
(the "second hit")
artery aneurysms with ADPKD. As most
cysts are disconnected from their tubule of
FIGURE 9-16 origin, they can expand only through net
Hypothetical model for cyst formation in autosomal-dominant polycystic kidney disease transepithelial fluid secretion, just the reverse
(ADPKD), relying on the “two-hit” mechanism as the primary event. The observation that of the physiologic tubular cell function [13].
only a minority of nephrons develop cysts, despite the fact that every tubular cell harbors ger- Figure 9-17 summarizes our current knowl-
minal PKD1 mutation, is best accounted for by the two-hit model. This model implies that, in edge of the mechanisms that may be involved
addition to the germinal mutation, a somatic (acquired) mutation involving the normal PKD1 in intracystic fluid accumulation.
FIGURE 9-17
Autosomal-dominant polycystic kidney disease (ADPKD): mecha-
nisms of intracystic fluid accumulation [13,14]. The primary mech-
Basolateral Aden
ylate Apical anism of intracystic fluid accumulation seems to be a net transfer
cycla
se of chloride into the lumen. This secretion is mediated by a
(CFTR) bumetanide-sensitive Na+-K+-2Cl- cotransporter on the basolateral
Na+ cAMP ATP
K+ Cl– side and cystic fibrosis transmembrane regulator (CFTR) chloride
2Cl– channel on the apical side. The activity of the two transporters is
PKA regulated by protein kinase A (PKA) under the control of cyclic
Bumetanide DPC
2K + adenosine monophosphate (AMP). The chloride secretion drives
+ + ATP movement of sodium and water into the cyst lumen through elec-
(Na -K -ATPase) Lumen trical and osmotic coupling, respectively. The pathway for transep-
3Na+ ADP + Pi
ithelial Na+ movement has been debated. In some experimental
H 2O conditions, part of the Na+ could be secreted into the lumen via a
Ouabain
(A P)
Q mispolarized apical Na+-K+-ATPase (“sodium pump”); however, it
H 2O
Na+ is currently admitted that most of the Na+ movement is paracellu-
lar and that the Na+-K+-ATPase is located at the basolateral side.
( AQP)
The movement of water is probably transcellular in the cells that
express aquaporins on both sides and paracellular in others [13,
14]. AQP—aquaporine; DPC—diphenylamine carboxylic acid.
0.46
ADPKD: CLINICAL MANIFESTATIONS 1.0 (0.22-0.98)
Odds ratio (95% Cl) PKD2 vs. PKD1

0.47
(0.28-0.81)
0.8
Manifestation Prevalence, % Reference
Renal 0.6 0.28 0.18
Hypertension Increased with age [15] (0.16-0.48) (0.07-0.47)
(80 at ESRD)
Pain (acute and chronic) 60 [3,16] 0.4
Gross hematuria 50 [3,16]
Urinary tract infection Men 20; women 60 [3]
[17] 0.2
Calculi 20
Renal failure 50 at 60 y [18]
Hepatobiliary (see Fig. 9–23) 0.0
Cardiovascular Hypertension Renal infection Subarachnoid Abdominal
Cardiac valvular abnormality 20 [16] history hemorrhage hernia
Intracranial arteries
Aneurysm 8 [3] 80
PKD2 74 75
Dolichoectasia 2 [19]
Rare PKD1 70
? Ascending aorta dissection 70
? Coronary arteries aneurysm Rare
61 60
Other 60
Pancreatic cysts 9 [20]
Arachnoid cysts 8 [21] 50
Hernia Age, y
Inguinal 13 [22]
7 [22] 40
Umbilical 35
Spinal Meningeal Diverticula 0.2 [23]
30
20
FIGURE 9-18
10
Main clinical manifestations of autosomal-dominant polycystic kid-
ney disease (ADPKD). Renal involvement may be totally asympto- 0
matic at early stages. Arterial hypertension is the presenting clinical Clinical End-stage Death
finding in about 20% of patients. Its frequency increases with age. presentation renal failure
Flank or abdominal pain is the presenting symptom in another Median age
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 FIGURE 9-19
for hospital admission, can involve the upper collecting system, Autosomal-dominant polycystic kidney disease (ADPKD): pheno-
renal parenchyma or renal cyst. Diagnostic data are obtained by type PKD2 versus PKD1. Families with a PKD2 mutation have a
ultrasonography, excretory urography and CT: use of CT in cyst milder phenotype than those with a PKD1 mutation. In this study
infection is described in Figure 9-21. Frequently, stones are radiolu- comparing 306 PKD2 patients (from 32 families) with 288 PKD1
cent or faintly opaque, because of their uric acid content. The main patients (17 families), PKD2 patients were, for example, less likely
determinants of progression of renal failure are the genetic form of to be hypertensive, to have a history of renal infection, to suffer a
the disease (see Fig. 9-19) and gender (more rapid progression in subarachnoid hemorrhage, and to develop an abdominal hernia. As
males). Hepatobiliary and intracranial manifestations are detailed a consequence of the slower development of clinical manifestations,
in Figures 9-23 to 9-26. Pancreatic and arachnoid cysts are most PKD2 patients were, on average, 26 years older at clinical presen-
usually asymptomatic. Spinal meningeal diverticula can cause pos- tation, 14 years older when they started dialysis, and 5 years older
tural headache. ESRD—end-stage renal disease. when they died. Early-onset ADPKD leading to renal failure in
childhood has been reported only in the PKD1 variety. (Data from
Hateboer [24].)
A B
C D
FIGURE 9-20
Autosomal-dominant polycystic kidney disease (ADPKD): kidney kidneys may be observed, as in this 36-year-old woman. In the early
involvement. Examples of various cystic involvements of kidneys in stage of the disease, making the diagnosis may be more difficult (see
ADPKD. Degree of involvement depends on age at presentation and Fig. 9-28 for the minimal sonographic criteria to make a diagnosis
disease severity. A, With advanced disease as in this 54-year-old of ADPKD in PKD1 families). C, D, Contrast-enhanced CT is more
woman, renal parenchyma is almost completely replaced by innu- sensitive than ultrasonography in the detection of small cysts. The
merable cysts. Note also the cystic involvement of the liver. B, presence of liver cysts helps to establish the diagnosis, as in this 38-
Marked asymmetry in the number and size of cysts between the two year-old man with PKD2 disease and mild kidney involvement.
A B
FIGURE 9-21
Autosomal-dominant polycystic kidney disease (ADPKD): kidney antibiotherapy (fluoroquinolone). B, CT repeated 17 days later
cyst infection. Course of severe cyst infection in the right kidney of showed considerable enlargement of the infected cysts (arrows).
a patient with ADPKD who was admitted for fever and acute right Percutaneous drainage failed to control infection, and nephrectomy
flank pain. Blood culture was positive for Escherichia coli. A, CT was necessary. This case illustrates the potential severity of cyst
performed on admission showed several heterogeneous cysts in the infection and the contribution of sequential CT in the diagnosis
right kidney (arrows). Infection did not respond to appropriate and management of complicated cysts.
FIGURE 9-22
ADPKD: SPECIFIC CAUSES OF Autosomal-dominant polycystic kidney disease (ADPKD): specific
ACUTE ABDOMINAL PAIN 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
Cause Frequency Fever or may not cause gross hematuria. Cyst hemorrhage is responsible for
most high-density cysts and cyst calcifications demonstrated by CT.
Renal Spontaneous resolution is the rule. Excretory urography or enhanced
Cyst Bleeding ++++ Mild (<38°C, maximum 2 days) or none CT is needed mostly to locate obstructive, faintly opaque stones.
Stone ++ With pyonephrosis Stones may be treated by percutaneous or extracorporal lithotripsy.
Infection + High; prolonged with cyst involved Renal infection may involve the upper collecting system,
Liver Cyst renal parenchyma, or cyst. Parenchymal infection is evidenced
Infection Rare High, prolonged by positive urine culture and prompt response to antibiotherapy;
Bleeding Very Rare Mild (<38°C, maximum 2 days) or none 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 het-
erogeneous 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.
ADPKD: HEPATOBILIARY MANIFESTATIONS
Finding Frequency
Asymptomatic liver cysts Very common; increased prevalence with
age (up to 80% at age 60)
Symptomatic polycystic liver disease Uncommon (male/female ratio: 1/10)
Complicated cysts (hemorrhage,
infection)
Massive hepatomegaly
Chronic pain/discomfort
Early satiety
Supine dyspnea
Abdominal hernia
Obstructive jaundice
Hepatic venous outflow obstruction
Congenital hepatic fibrosis Rare (not dominantly transmitted)
Idiopathic dilatation of intrahepatic or Very rare
extrahepatic biliary tract
Cholangiocarcinoma Very rare
FIGURE 9-24
Autosomal-dominant polycystic kidney disease (ADPKD): polycys-
tic liver disease. Contrast-enhanced CT in a 32-year-old woman
FIGURE 9-23 with ADPKD, showing massive polycystic liver disease contrasting
Autosomal-dominant polycystic kidney disease (ADPKD): hepato- with mild kidney involvement.
biliary manifestations. Liver cysts are the most frequent extrarenal Massive polycystic liver disease can cause chronic pain, early
manifestation of ADPKD. Their prevalence increases dramatically satiety, supine dyspnea, abdominal hernia, and, rarely, obstructive
from the third to the sixth decade of life, reaching a plateau of 80% jaundice, or hepatic venous outflow obstruction. Therapeutic
thereafter [25, 26]. They are observed earlier and are more numer- options include cyst sclerosis and fenestration, hepatic resection,
ous and extensive in women than in men. Though usually mild and and, ultimately, liver transplantation [25, 26].
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 B
FIGURE 9-25
Autosomal-dominant polycystic kidney disease (ADPKD): ICA rupture in ADPKD is ill-defined. ICA rupture entails 30% to
intracranial aneurysm detection. Magnetic resonance angiogra- 50% mortality. It is generally manifested by subarachnoid hemor-
phy (MRA), A, and spiral computed tomography (CT) angiogra- rhage, which usually presents as an excruciating headache. In this
phy, B, in two different patients, both with ADPKD, show an setting, the first-line diagnostic procedure is CT. Management
asymptomatic intracranial aneurysm (ICA) on the posterior com- should proceed under neurosurgical guidance [27].
municating artery (arrow), A, and the anterior communicating Given the severe prognosis of ICA rupture and the possibility
artery (arrow), B, respectively. of prophylactic treatment, screening ADPKD patients for ICA has
The prevalence of asymptomatic ICA in ADPKD is 8%, as been considered. Screening can be achieved by either MRA or spi-
compared with 1.2% in the general population. It reaches 16% ral CT angiography. Current indications for screening are present-
in ADPKD patients with a family history of ICA [27]. The risk of ed in Figure 9-26. (Courtesy of T. Duprez and F. Hammer.)
FIGURE 9-26
Age 18–40 years No Autosomal-dominant polycystic kidney disease (ADPKD): intracranial aneurysm (ICA)
and family history No
screening. On the basis of decision analyses (taking into account ICA prevalence, annual
of ICA? screening
risk of rupture, life expectancy, and risk of prophylactic treatment), it is currently pro-
Yes posed 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
Brain MR angiography No
or spiral CT scan: Repeat every who want reassurance. Guidelines for prophylactic treatment are the same ones used in
ICA? 5 years 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.
Yes
Conventional
angiography
Discuss management
with neurosurgeon
ADPKD: PRESYMPTOMATIC DIAGNOSIS ADPKD: ULTRASONOGRAPHIC

DIAGNOSTIC CRITERIA
Presymptomatic diagnosis
Is advisable in families when early management of affected patients would be altered Age Cysts
(eg, because of history of intracranial aneurysm)
15–29 2, uni- or bilateral
Should be made available to persons at risk who are 18 years or older who request
the test 30–59 2 in each kidney
Should be preceded by information about the possibility of inconclusive results and ≥60 4 in each kidney
the consequences of the diagnosis:
If negative, reassurance Minimal number of cysts to establish a diagnosis of ADPKD in PKD1 families at risk.
If positive, regular medical follow-up, possible psychological burden,
risk of disqualification from employment and insurances
FIGURE 9-28
Autosomal-dominant polycystic kidney disease (ADPKD): ultra-
sonographic diagnostic criteria. Ultrasound diagnostic criteria for
FIGURE 9-27 the PKD1 form of ADPKD, as established by Ravine’s group on the
Autosomal-dominant polycystic kidney disease (ADPKD): presymp- basis of both a sensitivity and specificity study [4, 28]. Note that
tomatic diagnosis. Presymptomatic diagnosis is aimed at both detect- the absence of cyst before age 30 years does not rule out the diag-
ing affected persons (to provide follow-up and genetic counseling) nosis, the false-negative rate being inversely related to age. When
and reassuring unaffected ones. Until a specific treatment for ADPKD ultrasound diagnosis remains equivocal, the next step should be
is available, presymptomatic diagnosis in children is not advised either contrast-enhanced CT (more sensitive than ultrasonography
except in rare families where early-onset disease is typical. Presymp- in the detection of small cysts) or gene linkage (see Figure 9-29). A
tomatic diagnosis is recommended when a family is planned and similar assessment is not yet available for the PKD2 form. (From
when early management of affected patients would be altered. The Ravine et al. [28]; with permission.)
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.
FIGURE 9-29
Deceased Example of the use of gene linkage to identify ADPKD gene carriers
I ? ? Unaffected among generation IV of a PKD1 family. Two markers flanking the
1 2 Affected PKD1 gene were used. The first one (3’ HVR) has six possible alle-
? Unknown status les (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,
II IV3) have a 99% chance of being disease free.
1 2 3 4 5
Until direct gene testing for PKD1 and PKD2 is readily available,
1 1 genetic diagnosis will rest on gene linkage. Such analysis requires
b b that other affected and unaffected family members (preferably from
III
1 2 3 two generations) be available for study. Use of markers on both
sides of the tested gene is required to limit potential errors due to
2 3 2 5 4 2
a b b a a a recombination events. Linkage to PKD1 is to be tested first, as it
accounts for about 85% of cases.
IV ? ? ? ?
1 2 3 4
2 3 3 2 3 5 2 5
b b b b b a a a
FIGURE 9-30
Life expectancy <5 yrs Autosomal-dominant polycystic kidney disease (ADPKD): renal
or contraindication to surgery Yes replacement therapy. Transplantation nowadays is considered in any
or to immunosuppressants? ADPKD patient with a life expectancy of more than 5 years and
No with no contraindications to surgery or immunosuppression.
Pretransplant workup should include abdominal CT, echocardiogra-
Pretransplant workup: phy, myocardial stress scintigraphy, and, if needed (see Figure 9-26),
Yes Eligibility for transplantation? screening for intracranial aneurysm. Pretransplant nephrectomy is
advised for patients with a history of renal cyst infection, particularly
No if the infections were recent, recurrent, or severe. Patients not eligible
History of No
cyst infection? for transplantation may opt for hemodialysis or peritoneal dialysis.
Very large kidneys Yes Although kidney size is rarely an impediment to peritoneal dialysis,
Yes or abdominal hernia?
this option is less desirable for patients with very large kidneys,
No because their volume may reduce the exchangeable surface area and
Remove the tolerance for abdominal distension. Outcome for ADPKD
kidney(s)? or
patients following renal replacement therapy is similar to that of
matched patients with another primary renal disease [29, 30].
Transplantation Peritoneal dialysis Hemodialysis
FIGURE 9-31
CLINICAL FEATURES Tuberous sclerosis complex (TSC): clinical features. TSC is an auto-
somal-dominant multisystem disorder with a minimal prevalence of
1 in 10,000 [30, 31]. It is characterized by the development of mul-
Finding Frequency, % Age at onset, y tiple hamartomas (benign tumors composed of abnormally arranged
and differentiated tissues) in various organs. The most common
Skin manifestations are dermatologic (see Fig. 9-32) and neurologic (see
Hypomelanotic macules 90 Childhood Fig. 9-33). Renal involvement occurs in 60% of cases and includes
Facial angiofibromas 80 5–15
Forehead fibrous plaques 30 ≥5
cysts (see Fig. 9-34). Retinal involvement, occurring in 50% of
“Shagreen patches” (lower back) 30 ≥10 cases, is almost always asymptomatic. Liver involvement, occurring
Periungual fibromas 30 ≥15 in 40% of cases, includes angiomyolipomas and cysts. Involvement
Central nervous system of other organs is much rarer [31, 32].
Cortical tubers 90 Birth
Subependymal tumors 90 Birth
(may be calcified)
focal or generalized seizures 80 0–1
Mental retardation/ 50 0–5
behavioral disorder
Kidney
Angiomyolipomas 60 Childhood
Cysts 30 Childhood
Renal cell carcinoma 2 Adulthood
Eye
Retinal hamartoma 50 Childhood
Retinal pigmentary abnormality 10 Childhood
Liver (angiomyolipomas, cysts) 40 Childhood
Heart (rhabdomyoma) 2 Childhood
Lung (lymphangiomyomatosis; 1 ≥20
affects females)
B
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 patch-
es 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
A patches of brown or pink skin). (Courtesy of A. Bourloud and C. van Ypersele.)
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) occur-
ring in 80% of infants, and varying degrees of intellectual disability or behavioral disorder,
reported in 50% of children [32].
A B
FIGURE 9-34
Tuberous sclerosis complex (TSC): kidney involvement. Contrast- of fat into the tumor, but it is not always possible to distinguish
enhanced CT, A, and gadolinium-enhanced T1 weighted magnetic between AML and renal cell carcinoma. The main complication of
resonance images, B, of a 15-year-old woman with TSC, show AML is bleeding with subsequent gross hematuria or potentially life-
both a large, hypodense, heterogeneous tumor in the right kidney threatening retroperitoneal hemorrhage.
(arrows) characteristic of angiomyolipoma (AML) and multiple Cysts seem to be restricted to the TSC2 variety (see Fig. 9-35)
bilateral kidney cysts. Kidney cysts had been detected at birth. [33]. Their extent varies widely from case to case. Occasionally,
AML is a benign tumor composed of atypical blood vessels, polycystic kidneys are the presenting manifestation of TSC2 in early
smooth muscle cells, and fat tissue. While single AML is the most childhood: in the absence of renal AML, the imaging appearance is
frequent kidney tumor in the general population, multiple and bilat- indistinguishable from ADPKD. Polycystic kidney involvement leads
eral AMLs are characteristic of TSC. In TSC, AMLs develop at a to hypertension and renal failure that reaches end stage before age
younger age in females; frequency and size of the tumors increase 20 years. Though the frequency of renal cell carcinoma in TSC is
with age. Diagnosis of AML by imaging techniques (ultrasonography small, the incidence is increased as compared with that of the gener-
[US], CT, magnetic resonance imagine [MRI]) relies on identification al population. (Courtesy of J. F. De Plaen and B. Van Beers.)
VHL: ORGAN INVOLVEMENT
Mean age (range)

HG loci PKD1 TSC2 16 pter
Death Findings Frequency, % at diagnosis, y
Chromosome 16 Central nervous system 30 (9–71)
Hemangioblastoma
Cerebellar 60
FIGURE 9-35 Spinal cord 20
Tuberous sclerosis complex (TSC): genetics. Representative examples Endolymphatic sac tumor Rare
of various contiguous deletions of the PKD1 and TSC2 genes in Eye/Retinal hemangioblastoma 60 25 (8–70)
five patients with TSC and prominent renal cystic involvement (the Kidney
size of the deletion in each patient is indicated). Clear cell carcinoma 40 40 (18–70)
TSC is genetically heterogeneous. Two genes have been identified. Cysts 30 35 (15–60)
The TSC1 gene is on chromosome 9, and TSC2 lies on chromosome Adrenal glands/ 15 20 (5–60)
16 immediately adjacent and distal to the PKD1 gene. Half of affect- Pheochromocytoma
ed families show linkage to TSC1 and half to TSC2. Nonetheless, Pancreas 30 (13–70)
60% of TSC cases are apparently sporadic, likely representing new Cysts 40
mutations (most are found in the TSC2 gene) [34]. The proteins Microcystic adenoma 4
encoded by the TSC1 and TSC2 genes are called hamartin and Islet cell tumor 2
tuberin, respectively. They likely act as tumor suppressors; their pre- Carcinoma 1
cise cellular role remains largely unknown. The diseases caused by
Liver (cysts) Rare ?
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].)
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 relat-
ed to central nervous system hemangioblastoma and renal cell carci-
noma. 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 involve-
ment. 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.)

Von Hippel-Lindau disease (VHL): retinal
involvement. Ocular fundus, A, and corre-
sponding fluorescein angiography, B, in a
patient with VHL, shows two typical reti-
nal 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 asympto-
matic, whereas large central tumors can
impair vision. (Courtesy of B. Snyers.)
FIGURE 9-40
Von Hippel-Lindau disease (VHL): adrenal gland involvement.
FIGURE 9-39 Gadolinium-enhanced abdominal magnetic resonance image of a
Von Hippel-Lindau disease (VHL): kidney involvement. Contrast- patient with VHL shows bilateral pheochromocytoma (arrows).
enhanced CT of a patient with VHL, showing the polycystic aspect Renal lesions include cysts and solid carcinomas (arrow heads).
of the kidneys. Renal involvement of VHL includes cysts (simple, Pheochromocytoma may be the first manifestation of VHL. It
atypical, and cystic carcinoma) and renal cell carcinoma [36, 37]. tends to cluster within certain VHL families [36]. (Courtesy of
The latter is the leading cause of death from VHL. Occasionally, H. Neumann.)
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 9-41
Von Hippel-Lindau disease (VHL): pancreas involvement. Contrast-
enhanced abdominal CT in a patient with VHL shows multiple cysts
in both pancreas (especially the tail, arrows) and kidneys. The major-
ity 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.
FIGURE 9-42
VHL: SCREENING PROTOCOL 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
Study Affected persons Relatives at risk for presymptomatic identification of affected persons, it must be
remembered that a mutation in the VHL gene currently is detected
Physical examination Annual Annual in only 70% of families. For persons at risk in the remaining families,
24-h Urine collection for Annual Annual a screening program is also proposed.
metadrenaline and
normetadrenaline
Funduscopy Annual Annual (age 5 to 60)
Gadolinium MRI brain scan Every 3 y (from age 10) Every 3 y (age 15 to 60)
Abdomen Annual gadolinium MRI Annual echography or
gadolinium MRI
(age 15 to 60)
FIGURE 9-43
Medullary cystic disease (MCD). Contrast-enhanced CT in a 35-
year-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 end-
stage disease between 20 and 40 years of age. Dominant inheri-
tance 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.
THERE IS A WHITE
BOX PLACED OVER
HANDWRITTEN
TYPE.
A
B
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 Masson’s trichrome stain.
C, Cysts consisted of a dilatation of Bowman’s space surrounding
a primitive-looking glomerulus.
C GCKD may be sporadic or genetically dominant. Among the
familial cases, some patients are infants who have early-onset auto-
FIGURE 9-44 somal-dominant polycystic disease. In others (children or adults) the
Glomerulocystic kidney disease (GCKD). Contrast-enhanced CT, A, disease is unrelated to PKD1 and PKD2 and may or not progress to
in a 23-year-old woman with the sporadic form of GCKD shows end-stage renal failure [38]. (Courtesy of D. Droz.)
FIGURE 9-45
ARPKD: CLINICAL MANIFESTATIONS Autosomal-recessive polycystic kidney disease (ARPKD): clinical man-
ifestations. ARPKD is characterized by the development of cysts origi-
nating from collecting tubules and ducts, invariably associated with
Renal congenital hepatic fibrosis. Its prevalence is about 1 in 40,000 [39].
Antenatal (ultrasonographic changes) In the most severe cases, with marked oligohydramnios and an empty
Oligohydramnios with empty bladder
bladder, the diagnosis may be suspected as early as the 12th week of
Increased renal volume and echogenicity
gestation. Some neonates die from either respiratory distress or renal
failure. In most survivors, the disease is recognized during the first
Neonatal period
year of life. The ultrasonographic (US) kidney appearance is depicted
Dystocia and oligohydramnios
in Figure 9-46. Excretory urography shows medullary striations
Enlarged kidneys
owing to tubular ectasia. Kidney enlargement may regress with time.
Renal failure
End-stage renal failure develops before age 25 in 70% of patients.
Respiratory distress with pulmonary hypoplasia (possibly fatal)
Liver involvement consists of portal fibrosis (see Fig. 9-47) and
Infancy of childhood
intrahepatic bilary ectasia, frequently resulting in portal hypertension
Nephromegaly (may regress with time)
(leading to hypersplenism and esophageal varices) and less often in
Hypertension (often severe in the first year of life) cholangitis, respectively. US may show dilatation of the biliary ducts,
Chronic renal failure (slowly progressive, with a 60% probability of renal survival at and even cysts. The respective severity of kidney and liver involve-
15 years of age and 30% at 25 years of age)
ment vary widely between families and even in a single kindred.
Hepatic
A comparison of the diagnostic features of autosomal-dominant
Portal fibrosis
polycystic kidney disease (ADPKD) and ARPKD is summarized in
Intrahepatic biliary tract ectasia
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].
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.)
A B

Autosomal-recessive polycystic kidney disease (ARPKD): liver his- Nephronophthisis (NPH): renal involvement. Kidney biopsy specimen
tology. Liver biopsy specimen from a child with ARPKD shows visualized by light microscopy with periodic acid–Schiff stain, in a
typical congenital hepatic fibrosis (hematoxylin eosin safran [HES] patient with juvenile NPH of an early stage. Note the typical thicken-
stain). This portal space is enlarged by fibrosis, and the number of ing and disruption of the tubular basement membrane (appearing
biliary channels is increased, many of them being enlarged and all in red); the histiolymphocytic infiltration present at this stage is pro-
being irregular in outline. (Courtesy of S. Gosseye.) gressively 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 corti-
comedullary 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 dele-
tion is detected in this gene [43]. (Courtesy of P. Niaudet.)
FIGURE 9-49
NPH: EXTRARENAL INVOLVEMENT Nephronophthisis (NPH): extrarenal involvement. Extrarenal involve-
ment occurs in 20% of NPH cases. The most frequent finding is
tapetoretinal degeneration (known as Senior-Loken syndrome), which
Retinitis pigmentosa (Senior-Loken syndrome) often results in early blindness or progressive visual impairment.
Multiple organ involvement, including Other rare manifestations include liver (hepatomegaly, hepatic fibro-
Liver fibrosis
sis), bone (cone-shaped epiphysis), and central nervous system (mental
retardation, cerebellar ataxia) abnormalities, quite often in association.
Other rare features
Skeletal changes (cone-shaped epiphyses)
Cerebellar ataxia
Mental retardation
A B
FIGURE 9-50
Orofaciodigital syndrome (OFD). Contrast-enhanced CT, Characteristic dysmorphic features include oral (hyperplastic
A, and the hands, B, of a 26-year-old woman with OFD type 1 frenulum, cleft tongue, cleft palate or lip, malposed teeth), facial
(OFD1) [43]. Multiple cysts involve both kidneys. Note that (asymmetry, broad nasal root), and digit (syn-brachy-polydacty-
they are smaller and more uniform than in ADPKD and that ly) abnormalities. Mental retardation is present in about half the
renal contours are preserved. Some cysts were also detected in cases. Kidneys may be involved by multiple (usually small) cysts,
liver and pancreas (arrow). Syndactyly was surgically corrected, mostly of glomerular origin; renal failure occurs between the
and the digits of the hands are shortened (brachydactyly). second and the seventh decade of life. Recognition of the dys-
OFD1 is a rare X-linked, dominant disorder, diagnosed morphic features is the key to the diagnosis [44, 45]. (Courtesy
almost exclusively in females, as affected males die in utero. of F. Scolari.)
References
1. Fick GM, Gabow PA: Hereditary and acquired cystic disease of the 6. Sarasin FP, Wong JB, Levey AS, Meyer KB: Screening for acquired
kidney. Kidney Int 1994, 46:951–964. cystic kidney disease: A decision analytic perspective. Kidney Int
2. Welling LW, Grantham JJ: Cystic and developmental diseases of the 1995, 48:207–219.
kidney. In The Kidney. Edited by Brenner M. Philadelphia:WB 7. Hildebrandt F, Jungers P, Grünfeld JP: Medullary cystic and medullary
Saunders Company; 1996:1828–1863. sponge renal disorders. In Diseases of the Kidney. Edited by Schrier
RW, Gottschalk CW. Boston: Little Brown; 1997:499–520.
3. Pirson Y, Chauveau D, Grünfeld JP: Autosomal dominant polycystic
kidney disease. In Oxford Textbook of Clinical Nephrology. Edited 8. The European Polycystic Kidney Disease Consortium: The polycystic
kidney disease 1 gene encodes a 14 kb transcript and lies within a
by Davison AM, Cameron JS, Grünfeld JP, et al. Oxford:Oxford duplicated region on chromosome 16. Cell 1994, 77:881–894.
University Press; 1998:2393–2415.
9. Mochizuki T, Wu G, Hayashi T, et al.: PKD2, a gene for polycystic
4. Ravine D, Gibson RN, Donlan J, Sheffield LJ: An ultrasound renal kidney disease that encodes an integral membrane protein. Science
cyst prevalence survey: Specificity data for inherited renal cystic dis- 1996, 272:1339–1342.
eases. Am J Kidney Dis 1993, 22:803–807. 10. Hughes J, Ward CJ, Peral B, et al.: The polycystic kidney disease 1
5. Levine E: Acquired cystic kidney disease. Radiol Clin North Am (PKD1) gene encodes a novel protein with multiple cell recognition
1996, 34:947–964. domains. Nature Genet 1995, 10:151–160.
11. Qian F, Germino FJ, Cai Y, et al.: PKD1 interacts with PKD2 through 30. Culleton B, Parfrey PS: Management of end-stage renal failure and
a probable coiled-coil domain. Nature Genet 1997, 16:179–183. problems of transplantation in autosomal dominant polycystic kidney
12. Germino GG: Autosomal dominant polycystic kidney disease: a two- disease. In Polycystic Kidney Disease. Edited by Watson ML, Torres
hit model. Hospital Pract 1997, 81–102. VE. Oxford:Oxford University Press; 1996:450–461.
13. Grantham JJ: The etiology, pathogenesis, and treatment of autosomal 31. Torres VE: Tuberous sclerosis complex. In Polycystic Kidney Disease.
dominant polycystic kidney disease: Recent advances. Am J Kidney Edited by Watson ML, Torres VE. Oxford:Oxford University Press;
Dis 1996, 28:788–803. 1996:283–308.
14. Devuyst O, Beauwens R: Ion transport and cystogenesis: The para- 32. Huson SM, Rosser EM: The Phakomatoses. In Principles and Practice
digm of autosomal dominant polycystic kidney disease. Adv Nephrol of Medical Genetics. Edited by Rimoin DL, Connor JM, Pyeritz RE.
1998, (in press). New York:Churchill Livingstone; 1997: 2269–2302.
15. Parfrey PS, Barrett BJ: Hypertension in autosomal dominant polycys- 33. Sampson JR, Maheshwar MM, Aspinwall R, et al.: Renal cystic dis-
tic kidney disease. Curr Opin Nephrol Hypertens 1995, 4:460–464. ease in tuberous sclerosis: Role of the polycystic kidney disease 1
gene. Am J Human Genet 1997, 61:843–851.
16. Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J
Med 1993, 329:332–342. 34. Jones AC, Daniells CE, Snell RG, et al.: Molecular genetic and pheno-
typic analysis reveals differences between TSC1 and TSC2 associated
17. Torres WE, Wilson DM, Hattery RR, Segura JW: Renal stone disease
familial and sporadic tuberous sclerosis. Hum Molec Genet 1997,
in autosomal dominant polycystic kidney disease. Am J Kidney Dis
6:2155–2161.
1993, 22:513–519.
35. Michels V: Von Hippel-Lindau disease. In Polycystic Kidney Disease.
18. Choukroun G, Itakura Y, Albouze G, et al.: Factors influencing pro-
Edited by Watson ML, Torres VE. Oxford:Oxford University Press;
gression of renal failure in autosomal dominant polycystic kidney dis-
1996:309–330.
ease. J Am Soc Nephrol 1995, 6:1634–1642.
36. Neumann HPH, Zbar B: Renal cysts, renal cancer and von Hippel-
19. Schievink WI, Torres VE, Wiebers DO, Huston J III: Intracranial arterial
Lindau disease. Kidney Int 1997, 51:16–26.
dolichoectasia in autosomal dominant polycystic kidney disease. J Am
Soc Nephrol 1997, 8:1298–1303. 37. Chauveau D, Duvic C, Chretien Y, et al.: Renal involvement in von
Hippel-Lindau disease. Kidney Int 1996, 50:944–951.
20. Torra R, Nicolau C, Badenas C, et al.: Ultrasonographic study of pan-
creatic cysts in autosomal dominant polycystic kidney disease. Clin 38. Sharp CK, Bergman SM, Stockwin JM, et al.: Dominantly transmitted
Nephrol 1997, 47:19–22. glomerulocystic kidney disease: A distinct genetic entity. J Am Soc
Nephrol 1997, 8:77–84.
21. Schievink WI, Huston J III, Torres VA, Marsh WR: Intracranial cysts
in autosomal dominant polycystic kidney disease. J Neurosurg 1995, 39. Gagnadoux MF, Broyer M: Polycystic kidney disease in children. In
83:1004–1007. Oxford Textbook of Clinical Nephrology. Edited by Davison AM,
Cameron JS, Grünfeld JP, et al. Oxford:Oxford University Press;
22. Gabow PA: Autosomal dominant polycystic kidney disease—more
1998:2385–2393.
than a renal disease. Am J Kidney Dis 1990, 16:403–413.
40. Zerres K, Mücher G, Bachner L, et al.: Mapping of the gene for auto-
23. Schievink WI, Torres VE: Spinal meningeal diverticula in autosomal
somal recessive polycystic kidney disease (ARPKD) to chromosome
dominant polycystic kidney disease. Lancet 1997, 349:1223–1224.
6p21-cen. Nature Genet 1994, 7:429–432.
24. Hateboer N, Dijk M, Torra R, et al.: Phenotype PKD2 vs. PKD1;
41. Antignac C, Arduy CH, Beckmann JS, et al.: A gene for familial juve-
results from the European concerted action. J Am Soc Nephrol 1997,
nile nephronophthisis (recessive medullary cystic kidney disease) maps
8:373A.
to chromosome 2p. Nature Genet 1993, 3:342–345.
25. Chauveau D, Pirson Y, Le Moine A, et al.: Extrarenal manifestations
42. Hildebrandt F, Otto E, Rensing C, et al.: A novel gene encoding an
in autosomal dominant polycystic kidney disease. Adv Nephrol 1997,
SH3 domain protein is mutated in nephronophthisis type 1. Nature
26:265–289.
Genet 1997, 17:149–153.
26. Torres VE: Polycystic liver disease. In Polycystic Kidney Disease.
43. Konrad M, Saunier S, Heidet L, et al.: Large homozygous deletions of
Edited by Watson ML, Torres VE. Oxford: Oxford University Press;
the 2q13 region are a major cause of juvenile nephronophthisis. Hum
1996:500–529.
Molec Genet 1996, 5: 367–371.
27. Pirson Y, Chauveau D: Intracranial aneurysms in autosomal dominant
44. Scolari F, Valzorio B, Carli O, et al.: Oral-facial-digital syndrome type
polycystic kidney disease. In Polycystic Kidney Disease. Edited by
I: An unusual cause of hereditary cystic kidney disease. Nephrol Dial
Watson ML, Torres VE. Oxford:Oxford University Press;
Transplant 1997, 12:1247–1250.
1996:530–547.
45. Feather SA, Winyard PJD, Dodd S, Woolf AS: Oral-facial-digital syn-
28. Ravine D, Gibson RN, Walker RG, et al.: Evaluation of ultrasono-
drome type 1 is another dominant polycystic kidney disease: Clinical,
graphic diagnostic criteria for autosomal dominant polycystic kidney
radiological and histopathological features of a new kindred. Nephrol
disease 1. Lancet 1994, 343:824–827.
Dial Transplant 1997, 12:1354–1361.
29. Pirson Y, Christophe JL, Goffin E: Outcome of renal replacement
therapy in autosomal dominant polycystic kidney diseases. Nephrol
Dial Transplant 1996, 11 (suppl. 6):24–28.
Toxic Nephropathies
Jean-Louis Vanherweghem
T
ubular interstitial structures of the kidney are particularly vul-
nerable 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 nephrotoxici-
ty 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 pre-
vention of renal diseases. The diagnosis of “chronic interstitial nephri-
tis of unknown origin” should, therefore, no longer be used.
CHAPTER
10
Exposure to Nephrotoxins
FIGURE 10-1
TOXIC CAUSES OF CHRONIC Chronic exposure to drugs, occupational hazards, or environmental
TUBULOINTERSTITIAL RENAL DISEASES toxins can lead to chronic interstitial renal diseases. The following
are the major causes of chronic interstitial renal diseases: occupation-
al exposure to heavy metals; abuse of over-the-counter analgesics;
Metals (Environmental or Occupational Exposure) misuse of germanium; chronic intake of mesalazine for intestinal dis-
Lead orders, lithium for depression, and cyclosporine in renal and nonre-
Cadmium
nal diseases; and environmental or iatrogenic exposure to fungus or
plant nephrotoxins (ochratoxins, aristolochic acids).
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
30
Occupational exposure to metals and risks for chronic renal fail-
25 ure. Comparison of the occupational histories of 272 patients with
(95% confidence intervals)
chronic renal failure with those of a matched control group having

20
normal renal function has shown an increased risk of chronic renal
Odds ratio
15 failure after exposure to mercury, tin, chromium, copper, and lead.

In this study the increased risk with exposure to cadmium was not
10 statistically significant. Squares indicate odds ratios; circles indicate
5 CIs. (Adapted from Nuyts and coworkers [1]; with permission.)
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
Environmental Gout
Eating paint from lead-painted furniture, woodwork, and toys in children Arterial hypertension
Lead-contaminated flour Renal failure (interstitial type)
Home lead-contaminated drinking water from lead pipes
Drinking of moonshine whiskey
Occupational
Lead-producing plants: lead smelters, battery plants 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
FIGURE 10-3 and gout nephropathy. Lead urinary excretion after ethylenedi-
Lead nephropathy associated with environmental and occupational amine tetraacetic acid (EDTA)–lead mobilization testing may help
exposure. Epidemiologic observations have established the relation- with the correct diagnosis [3].
ship between lead exposure and renal failure in association with
children eating lead paint in their homes, chronic ingestion of lead-
contaminated flour, lead-loaded drinking water in homes, and
drinking of illegal moonshine whiskey [2,3]. Occupational expo-
sure in lead-producing industries also has been associated with a
higher incidence of renal dysfunction.
FIGURE 10-5
Days 1 2 3 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
8 AM 8 PM 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,
EDTA 1 g 1g the cumulative total remains less than 0.6 mg over 3 days (From Batuman and coworkers
IM IM
Urinary Lead,
collection mg
Excessive lead exposure:

No < 0.6
Yes >0.6
FIGURE 10-6
120 I II 1500 Ethylenediamine tetraacetic acid (EDTA)–
Creatinine clearance, mL/min
IV lead mobilization test in chronic renal

100
failure of uncertain origin (A–C). In a
80 study of 296 patients without history of
1000
Lead, mg/72 h
60 V lead exposure, the results of this test were

III
IV III abnormal in 15.4% (II) of patients with
40
II hypertension and normal renal function
20 500 and in 56.1% of patients with renal fail-
I V
0 ure of uncertain origin (in 44.1% of the
Blood pressure N patients without associated gout (III) and
A Gout + B 0 in 68.7% of the patients with associated
gout (IV), respectively).

The EDTA–lead mobilization test was normal in normotensive subjects with normal renal
IV function and in patients with chronic renal failure (I) of well-known origin (V). (Adapted
Patients with abnormal test
from Sanchez-Fructuoso and coworkers [4].)

results, %
50 III
II
C 0
Cadmium nephropathy
FIGURE 10-7
110 Decrease in renal function after 25-year exposure to cadmium (Cd). In workers exposed to
Glomerular filtration rate,
105 cadmium for an average time of 25 years, a progressive decrease in renal function occurs
mL/min/1.73 m2
100 during a 5-year follow-up period, despite removal from cadmium exposure 10 years earlier.
95 On average, the glomerular filtration rate was shown to be decreased to 31 mL/min/1.73
90 m2 after 5 years instead of the expected age-related value of 5 mL/min/1.73 m2. (Adapted
85 from Roels and coworkers [5].)
80
Expected values
75 Cd exposure
70
5 6 7 8 9 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
ß2-m 73 112 102 834
FIGURE 10-8
* Tubular markers in cadmium workers. Impairment of renal proximal
NEP 834
800 CC16
tubular epithelium induced by cadmium can be documented by an
RBP
increase in urinary excretion of urinary neutral endopeptidase 24.11
Creatinine, µg/g
ß2–m *
594
(NEP), an enzyme of the proximal tubule brush borders, as well as
600 by an increase in microproteinuria: Clara cell protein (CC16),
*P < 0.05
200 retinol-binding protein (RBP) and 2-microglobulin (2-m). The data
*
were obtained from 106 healthy persons working in cadmium smelt-
* ing plants. These markers could be used for the screening of cadmi-
um workers. (Adapted from Nortier and coworkers [6].)
0
I II III IV
I II III IV
Creatinine
103 103 90* 79*
clearance, mL/min
Urinary Cd,
0.55 1.34 3.28* 8.45*
µg/g/creatinine
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 hor-
mone–induced 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 FIGURE 10-10 (see Color Plate)
lithium has been discontinued [7]. Lithium also induces an impair- Lithium nephropathy. A 22-year-old female patient was on mainte-
ment of distal urinary acidification. Chronic renal failure secondary nance lithium therapy (lithium carbonate 750 mg/d) for 5 years.
to chronic interstitial fibrosis may appear in up to 21% of patients She presented with polyuria (6500 mL/d) and moderate renal fail-
on maintenance lithium therapy for more than 15 years [8]. ure (creatinine clearance, 60 mL/min). Proteinuria was not present,
However, these observations are still a matter of debate [7]. and the urinary sediment was unremarkable. A renal biopsy
showed focal interstitial fibrosis with scarce inflammatory cell infil-
trate, tubular atrophy, and characteristic dilated tubule (microcyst
formation). Half of the glomeruli (not shown) were sclerotic.
(Magnification 125, periodic acid–Schiff reaction.)
Germanium nephropathy
FIGURE 10-11
CIRCUMSTANCES OF CHRONIC RENAL FAILURE Germanium (atomic number, 32; atomic weight, 72.59) is con-
SECONDARY TO GERMANIUM SUPPLEMENTS tained 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 pro-
Ge-dioxyde elixir, food additives, or capsules (used to improve health tect, improve, or restore the health has lead regular supplementa-
in normal persons [Japan]) tion with germanium salts either through food addition or by the
Ge-lactate-citrate (used to rebuild the immune system) in patients means of elixirs and capsules. The chronic supplementation by
with HIV infection (Switzerland) germanium salts was at the origin of the development of chronic
Ge-lactate-citrate (used to improve health) in patients with cancer renal failure secondary to a tubulointerstitial nephritis [9–12].
(the Netherlands)
Ge-dioxyde elixir (used to restore health) in patients with chronic
hepatitis (Japan)
A B
FIGURE 10-12
Light microscopy of renal tissue in a patient with chronic renal Renal tubular epithelial cells show numerous dark small inclu-
failure secondary to the chronic intake of germanium, showing sions. B, Periodic acid–Schiff reaction. (Magnification, 350).
focal tubular atrophy and focal interstitial lymphocyte infiltra- (From Hess and coworkers [12]; with permission).
tion. A, Hematoxylin and eosin stain. (Magnification 162.)
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 ero-
sion, detachment, and calcification of necrotic papillae.
FIGURE 10-14
Pathology of analgesic nephropathy. Nephrectomy showing a kid-
ney reduced in size with necrosed and calcified papillae.
CLINICAL FEATURES OF ANALGESIC NEPHROPATHY
Daily consumption of analgesic mixtures 100%

Women 80%
Headache 80%
Gastrointestinal disturbances 35–40%
Urinary tract infection 30–48%
Papillary necrosis (clinical) 20%
Papillary calcifications (computed tomography scan) 65%
FIGURE 10-16
Classic analgesic nephropathy is a slowly progressive disease
resulting from the daily consumption over several years of mix-
tures containing analgesics usually combined with caffeine,
codeine, or both. Caffeine and codeine create psychological depen-
dence. Most cases of analgesic nephropathy occur in women. In
80% of the cases, analgesics were taken for persistent headache.
FIGURE 10-15 Gastrointestinal complaints are also frequent, as are urinary tract
Radiologic appearance of papillary necrosis in analgesic nephropa- infections. Evidence of clinical papillary necrosis (fever and pain)
thy. The pyelogram was obtained by pyelostomy. It shows a swollen is present in 20% of cases. Calcifications of papillae (detected by
papilla (upper calyx), forniceal erosions (middle calyx), and detach- computed tomography scan) are present in 65% of persons who
ment of papilla, or filling defect (lower calyx). abuse analgesics [13].
FIGURE 10-17
EPIDEMIOLOGY OF ANALGESIC NEPHROPATHY Worldwide epidemiology of analgesic nephropathy. The frequency
AMONG ESRD PATIENTS of analgesic nephropathy in patients with end-stage renal diseases
(ESRD) varies greatly within and among countries [14–16]. The
highest prevalence rates of end-stage renal disease from analgesic
Australia 20% nephropathy occur in South Africa (22%), Switzerland and Australia
Belgium 18% (20%), Belgium (18%), and Germany (15%). In Belgium, the preva-
Canada 6%
lence 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,
Germany 15%
the rate is 5% nationwide, 13% in North Carolina, and 3% in
South Africa 22%
Washington, DC. In Canada, the rate is 6% nationwide.
Switzerland 20%
United Kingdom 1%
United States 5%
FIGURE 10-18
25 Prevalence of analgesic nephropathy versus
Prevalence (EDTA, 1989)
Analgesic nephropathy nephropathy with unknown cause. Cross-
20
Unknown cause national comparisons in Europe indicate
15 that the proportion of cases of end-stage
renal disease attributed to analgesics varies
%
10 considerably; however, it is inversely pro-

portional to unknown causes. These find-
5 ings suggest an underestimation of the
prevalence of analgesic nephropathy in sev-
0
eral countries, probably owing to the lack
any
in
a
m
nce
ds
y
d
al
of well-defined criteria for diagnosis

stri
Ital
rlan
Spa
tug
giu
rlan
rm
Fra
Au
Bel
[13,15]. EDTA—European Dialysis and

Por
itze
the
Ge
Sw
Ne
.
Transplant Association. (From Elseviers and

F.R
coworkers [13]; with permission).

has been replaced with acetaminophen

3000 in analgesia mixtures without signifi-
Belgium
1983 sales of mixtures containing two

Pills taken in lifetime cant changes in the cause of analgesic
< 5000 Rs = 0.86
P< 0.001 nephropathy in some countries [15].
≥ 5000
analgesic components
A, The risk factor for end-stage renal
2000
disease of unknown cause is increased in
relationship to the cumulative intake of
10.0
95% confidence intervals
acetaminophen as well as nonsteroidal

1000 anti-inflammatory drugs but not to
Odds ratio,
5.0 aspirin. Moreover, mixtures containing

several analgesic compounds were
shown to be more nephrotoxic than are
0 simple drugs. B, In Belgium, the preva-
1.0 0 10 20 30 40 50
0 Acetaminiophen Aspirin 1991 prevalence of analgesic lence of analgesic nephropathy in 1991
A B nephropathy, % was strongly correlated with sales of
analgesic mixtures in 1983. Rs—coeffi-
cient of correlation. (A, Adapted from
FIGURE 10-19 Perneger and coworkers [17]; B, adapt-
Risk of analgesic nephropathy associated with specific types of analgesics. The initial ed from Elseviers and De Broe [18];
reports of analgesic nephropathy chiefly concerned phenacetin mixtures. Phenacetin with permission).
Renal volume Indentations Papillary calcifications

RA RV RA
Right kidney Left kidney
A SP A
B B 0 1–2 3–5 >5

Decreased: A + B < 103 mm (males)
A < 96 mm (females) B Bumpy contours C
FIGURE 10-20
D. PERCENTAGES OF SENSITIVITY AND SPECIFICITY High performance of computed tomography (CT) scan for diagnos-
ing analgesic nephropathy. Three criteria may be used to diagnose
analgesic nephropathy by CT scan: decrease in renal size, measured
Criteria Sensitivity, % Specificity, % 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
Decrease in renal size 95 10 at which most indentations are present (more than three are quali-
Bumpy contours 50 90 fied of bumpy contours) (B); and papillary calcifications (C).
Papillary calcifications 87 97 Percentages of sensitivity and specificity are given for the three cri-
teria (D). Example of papillary calcifications on CT scan (E). RA—
renal artery; RV—renal vein; SP—spine. (Adapted from Elseviers
and De Broe [19]; with permission).
E
FIGURE 10-21
HONCOCH3 NCOCH3 O OH
Malignancies of the urinary tract and their association with anal-
gesic 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
OC2H5 O O OH substances in the major pathways of the metabolism of phenacetin.
N-hydroxy- Probable carcinogenic substances are indicated by a plus sign.
p-ocetophenetidine
HNCOCH3 HNCOCH3 NH2 HNOH NO
OH
[OH]
OC2H5 OC2H5 OC2H5 OC2H5 OC2H5

Phenacetin N-hydroxy- p-nitroso-
(p-ocetophenetidine) p-phenetidine phenetidine
HNCOCH3 NH2 H 2N O OH
OH
H NH2
OH OC2H5 OC2H5 OC2H5

N-acetyl-p-amino- 2-hydroxy- Arene oxide NIH shift
phenol (NAPA) phenetidine
FIGURE 10-22
Malignant uroepithelial tumors of the
upper urinary tract in patients with anal-
gesic 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.)
B
Exposure to Cyclosporine
Cyclosporine toxicity Cyclosporine induced hypertension

Cyclosporine
Cyclosporine
Intestinal
absorption
25–30% Acute effects Chronic effects
Inactive
metabolites Sympathetic Endothelium Cytosol
Liver
cytochrome nervous Thromboxane calcium
P450 system Endothelin
Chronic
Renal vasoconstruction renal failure
Inhibition
Ketoconazole
Verapamil Sodium chloride
Diltiazem retention
Erythromycin
Hypertension
FIGURE 10-23
Toxicity of cyclosporine. Cyclosporine is a neutral fungal FIGURE 10-24
hydrophobic 11-amino acid cyclic polypeptide. Cyclosporine is
Cyclosporine and hypertension. Hypertension can develop in 10%
metabolized by hepatic cytochrome P450 to multiple less active
to 80% of patients treated with cyclosporine, depending on dosage
and less toxic metabolites. Drugs that inhibit cytochrome P450
and length of the exposure. Cyclosporine increases cytosol calcium
enzymes such as ketoconazole, verapamil, diltiazem, and ery-
and, thus, enhances arteriolar smooth muscle responsiveness to
thromycin increase the concentration of cyclosporine and may
vasoconstrictive stimuli. Vasoconstrictive effects of cyclosporine
thus precipitate renal side effects [20,21].
also are mediated by enhanced thromboxane action, sympathetic
nerve stimulation, and release of endothelin. Renal vasoconstric-
tion 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
Mechanisms of cyclosporine renal injury Pathogenesis of cyclosporine nephropathy. Chronic administration of cyclosporine may
induce sustained renal vasoconstriction. Impairment of renal blood flow leads to tubuloin-
Cyclosporine terstitial 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 inter-
Sustained Renin stitial fibrosis [20].
vasoconstriction
Angiotensin II
Renal ischemia TGF-ß
Interstitial
fibrosis
100 CyA, 7.5 mg/kg 100 CyA, 9.3 mg/kg 100 CyA, 10 to 6 mg/kg

80 80 80
% of normal values
% of normal values
% of normal values
60 60 60
40 40 40
20 20 20
0 0 0
0 8 Weeks 0 13 Months 0 36 Months
A Psoriasis B Autoimmune diseases C Cardiac transplantations
FIGURE 10-26
100 CyA, 5 mg/kg 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
80 values in the glomerular filtration rate after 8 weeks of therapy. B, Of patients treated with
% of normal values
60
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
40 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.
20 Patients treated with azathioprine did not show any reduction in renal function. D,
0
Patients receiving cyclosporine (5 mg/kg) for uveitis for 2 years showed a decrease in
0 24 Months glomerular filtration rate to 65% of the initial values. (Panel A adapted from Ellis and
D Uveitis 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 B
FIGURE 10-27
Morphology of cyclosporine nephropathy on renal biopsy of a periodic acid–Schiff reaction). B, A striped form of interstitial
patient with cardiac transplantation. Two different types of lesions fibrosis characterized by irregularly distributed areas of stripes of
are seen in cyclosporine nephropathy. A, Arteriolopathy: Hyalin, interstitial fibrosis and tubular atrophy in the renal cortex. Tubules
paucicellular thickening of the intima with focal wall necrosis in other areas were normal (magnification x 100 periodic
results in narrowing of the vascular lumen (magnification 300 acid–Schiff reaction).
Exposure to Aminosalicylic Acid
10.6
10
C.P. man born
Seerum creatinine, mg/dL
8 January 19, 1971
6
4.9
4.2 4.0 3.9
4 IBD diagnosis
32 mg/d
2 1.1 Renal biopsy Renal biopsy
Methyl- 16 mg/d
Oral Pentasa® 500 mg/d, 3 x per day Hemodialysis prednisolone
0
De , 1994
1, 4
Jan 1994
1
96
994
4
995
96
De , 1994
De 2, 199
199
199
199
, 19
, 19
2, 1
6, 1
t 3,
rch
23,
y1
c1
c2
v2
c2
c3
rch
Oc
Ma
Ma
Feb
De
No
Ma
B C
FIGURE 10-28
Aminosalicylic acid and chronic tubulointerstitial nephritis. A, A of the interstitium tubular atrophy, and fibrosis. Several atrophic
36-year-old man suffering from Crohn’s disease exhibited severe tubules are surrounded by one or more layers of -smooth mus-
renal failure after 23 months of treatment with 5-aminosalicylic cle actin positive cells. The patient had normal renal function on
acid (5-ASA, or Pentasa, Hoechst Marion Roussel, Kansas City, beginning treatment with 5-ASA. After 5 years of 5-ASA therapy,
MO). B, The first renal biopsy showing widening and massive the patient demonstrated severe impaired renal function. The
cellular infiltration of the interstitium, tubular atrophy, and rela- association between the use of 5-ASA and development of chron-
tive spacing of glomeruli. C, The second renal biopsy 8 months, ic tubulointerstitial nephritis in patients with inflammatory bowel
after discontinuation of the drug and moderate improvement of disease (IBD) has gained recognition in recent years [27,28].
the renal function, again showing important cellular infiltration (Courtesy of ME De Broe, MD.)
Exposure to Ochratoxins
FIGURE 10-29
Ochratoxin A
Ochratoxin nephropathy. Ochratoxin A is a mycotoxin produced by various species of
COOH OH O Aspergillus and Penicillium. Ochratoxins contaminate foods (mainly cereals) for humans as
well as for cattle. Ochratoxins are mutagenic, oncogenic, and nephrotoxic. Ochratoxins are
– CH2- CH-NH-CO- responsible for chronic nephropathy in pigs and also may be the cause of endemic Balkan
CH3 nephropathy and some chronic interstitial nephropathies seen in North Africa and France [29].
CI
Contamination of cereals
Chronic nephropathy in pigs
Endemic Balkan nephropathy
Chronic interstitial nephritis in Tunisia
Chronic interstitial nephritis in France (?)
R. Danube
Austria
Hungary CLINICAL FEATURES OF BALKAN NEPHROPATHY
Slovenia
R. Sava
Croatia
R. S Romania Residence in an endemic area
ava Slavonski
Brod Occupational history of farming
Bneljina Oravita Progressive renal failure
Belgrade Turn Severin
Bosnia and Microproteinuria of tubular type
Herezgovina Lazarevac be
Paracin anu Unremarkable urinary sediment
R. D
Sarajevo Mikhaylovgrad Small and shrunken kidneys
Nis
Yugoslavia Vratsa Associated urothelial tumors
Italy Sofia Bulgaria
Macedonia
FIGURE 10-31
Albania Clinical features in Balkan nephropathy. Balkan nephropathy is
characterized by progressive renal failure in residents (generally
Greece 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].
FIGURE 10-30
Endemic Balkan nephropathy. Endemic nephropathy is encoun-
tered 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.)
A B
FIGURE 10-32
Pathology of Balkan nephropathy. Balkan nephropathy is characterized hyperplasia of the myocythial cells with narrowing of the lumen of the
by pure interstitial fibrosis with marked tubular atrophy (A) and by vessel (B) (From Stefanovic and M. Polenakovic [30]; with permission).
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 patient’s blood and urine.
(From Godin and coworkers [29].)
80 74.2
12.8
Cereal samples contaminated
Number of urothelial cancers
70
per million inhabitants
60
by ochratoxin, %
10
50
40
30
20
1.6
10 3.2
0 0
Endemic Nonendemic Endemic Nonendemic
Areas of Balkan nephropathy Areas of Balkan nephropathy

Balkan nephropathy and ochratoxin A in food. A survey of home- Balkan nephropathy and urothelial cancers. Urothelial cancers
produced foodstuffs in the Balkans has revealed that contamination appear as a frequent complication of Balkan nephropathy. An
with ochratoxin A is more frequent in areas in which endemic increased prevalence of upper tract urothelial tumors is described
nephropathy is prevalent (endemic areas) than in areas in which in inhabitants of areas in which Balkan nephropathy is endemic.
nephropathy is absent. (Adapted from Krogh and coworkers [31].) (Adapted from Godin and coworkers [29].)
Exposure to Chinese Herbs

FIGURE 10-36
Release of Chinese herb Epidemiology of Chinese herbs nephropathy. Chinese herbs
(so-called Stephania tetrandra)
on Belgian market nephropathy was described for the first time in Belgium in 1993
40 [32]. A peak incidence of new cases of women with rapidly pro-
Chinese herb nephropathy
90 92 gressive interstitial nephritis in Brussels during 1992 lead to suspi-

(number of new cases)
31 32
30 cion of a new cause of renal disease. The relationship between this
24 new renal disease and the recent introduction of Chinese herbs
(namely, Stephania tetrandra) in a slimming regimen was estab-
20
15 lished [32]. The withdrawal from the market of this herb has
decreased the incidence of interstitial nephritis in Brussels, Belgium.
10 7
5
1 1
0
1989 1990 1991 1992 1993 1994 1995 1996
Year
FIGURE 10-37
A. CHINESE HERBAL MEDICINE Role of Aristolochia in Chinese herbs nephropathy. Stephania tetran-
dra was the Chinese herb chronologically associated with the develop-
ment of Chinese herbs nephropathy. However, tetrandrine, the alka-
Chinese Name Western name Chemical Marker loid characterizing Stephania tetrandra was not found in the capsules
taken by the patients. In fact, confusion between Stephania tetrandra
Han fang-ji Stephania tetrandra Tetrandrine and Aristolochia fang chi was done in the delivery of Chinese herbs in
Guang fang-ji Aristolochia fang chi Aristolochic acid 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
30
30 not tetrandrine (From Vanhaelen and coworkers [33] and P Daenens,
Katholiek Universiteit Leuven, Belgium, report of expertise 1996.)
(Number of batches)
Chinese herbs
20
10
7
5
4
0
+A, +T +A, –T –A, +T –A, –T
+A, aristolochic acid present
–A, aristolochic acid absent
+T, tetrandrine present
B –T, tetrandine absent
FIGURE 10-38
DNA ADDUCTS FORMED BY DNA aristolochic acid adducts in kidney tissues of patients with
ARISTOLOCHIC ACID IN RENAL TISSUE Chinese herbs nephropathy. The role of Aristolochia in the pathogen-
esis of Chinese herbs nephropathy was confirmed by the demonstra-
tion of DNA aristolochic acid adducts (a biomarker of aristolochic
Chinese Herb Nephropathy (n = 5) Controls (n = 6) acids exposure) in renal tissue of patients with Chinese herbs
nephropathy, whereas these adducts were absent in the renal tissue
0.7–5.3 per 107 nucleotides 0 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

The clinical features of Chinese herbs nephropathy are character- Photographic image of the pathology of Chinese herbs nephropa-
ized by rapidly progressive renal failure without both urinary sedi- thy. Chinese herbs nephropathy is characterized by a large reduc-
ment abnormalities and proteinuria except for a microproteinuria tion in kidney volume. Moreover, an associated tumor of the lower
of tubular type. The kidneys are small and shrunken. Vascular ureter is shown.
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].
A B
Pathology of Chinese herb nephropathy. The major pathologic extensive interstitial fibrosis with relative sparing of glomeruli.
lesion consists of extensive interstitial fibrosis with atrophy (Masson trichrome stain, magnification 50.) B, A normal
and loss of the tubules, predominantly located in superficial glomerulus surrounded by a paucicellular interstitial fibrosis
cortex [38,39]. A, A low-power view of transition between and atrophic tubules. (Masson’s trichrome stain, magnification
superficial cortex (left) and deep cortex (right) shows an 300.)
50 NEP CC16 B2–m

40 5
40 4
30
log ug/24 h
log ug/24 h
ug/24 h
30 3
20
20 2
10 10 1
0 0 0
Controls Normal Renal End-stage Controls Normal Renal End-stage Controls Normal Renal End-stage
renal function failure renal disease renal function failure renal disease renal function failure renal disease
A After exposure to Chinese herbs B After exposure to Chinese herbs C After exposure to Chinese herbs
FIGURE 10-42
5
RBP A–D, Microproteinuria and neutral endopeptidase enzymuria in Chinese herbs nephropathy.
Proximal tubular injury in Chinese herbs nephropathy is demonstrated by a significant
4 increase in urinary excretion of microproteins (Clara cell protein, CC16; 2-microglobulin
log ug/24 h
3 [2-m] and retinol binding protein [RBP]) as well as a decrease in urinary excretion of neu-
tral endopeptidase (NEP) a marker of the brush border tubular mass. (Adapted from Nortier
2
1
0
Controls Normal Renal End-stage
renal function failure renal disease
D After exposure to Chinese herbs
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).
A B
FIGURE 10-44
Pathology of urothelial tumors associated with Chinese herbs is shown in Fig. 10-40). A, Part of the urothelial proliferation.
nephropathy. Microscopic pattern is shown of a lower urothe- Plurifocal thickening of the urothelium is present. (Hematoxylin
lial tumor obtained by ureteronephrectomy of a native kidney and eosin stain x 50.) B, In situ transitional cell carcinoma
in a patients with transplantation who has Chinese herbs with high mitotic rate. (Magnification x 400 periodic acid–
nephropathy (the macroscopic appearance of the nephrectomy Schiff reaction.)
0.7
Controls, n = 23 TOXIC CHRONIC INTERSTITIAL NEPHROPATHIES
0.6 Steroids, n = 12 WITH UROTHELIAL CANCERS
1/P creatinine ratio
0.5
0.4
Analgesic nephropathy (phenetidin compounds)
0.3 Balkan nephropathy (ochratoxins)
0.2 Chinese herbs nephropathy (aristolochic acids)
0.1
–6 –3 0 3 6 9 12
Months
FIGURE 10-46
Of interest is the association between chronic renal interstitial
FIGURE 10-45
fibrosis and urothelial cancers. This association appears, at least,
Effects of steroids on the evolution of renal failure in Chinese herbs in three chronic toxic nephropathies: analgesic nephropathy,
nephropathy. Steroid therapy was shown to decrease the evolution Balkan nephropathy, and Chinese herbs nephropathy. This associ-
of renal failure in a subgroup of patients with Chinese herbs ation indicates that nephrotoxins promoting interstitial fibrosis
nephropathy [41]. The evolution is shown of the 1/P creatinine (analgesics, ochratoxins, and aristolochic acids) also may be
ratio of patients with Chinese herbs nephropathy, 12 of whom oncogenic substances.
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.)
References
1. Nuyts GD, Van Vlem E, Thys J, et al.: New occupational risk factors 22. Luke RG: Mechanism of cyclosporine-induced hypertension. Am J
for chronic renal failure. Lancet 1995, 346:7–11. Hypertens 1991, 4:468-471.
2. Nuyts GD, Daelemans RA, Jorens PG, et al.: Does lead play a role in 23. Ellis CN, Fradin MS, Messana JM, et al.: Cyclosporine for plaque-
the development of chronic renal disease? Nephrol Dial Transplant type psoriasis. N Engl J Med 1991, 324:277–284.
1991, 6:307–315. 24. Feutren G, Mihatsch MJ: Risk factors for cyclosporine-induced
3. Batuman V, Maesaka JK, Haddad B, et al.: The role of lead in gout nephropathy in patients with autoimmune diseases. N Engl J Med
nephropathy. N Engl J Med 1981, 304:520–523. 1992, 326: 1654–1660.
4. Sanchez-Fructuoso AI, Torralbo A, Arroyo M, et al.: Occult lead 25. Myers BD, Newton L: Cyclosporin induced chronic nephropathy: an
intoxication as a cause of hypertension and renal failure. Nephrol obliterative renal injury. J Am Soc Nephrol 1991, 2:S45–S52.
Dial Transplant 1996, 11:1775–1780. 26. Deray G, Benhmida M, Le Hoang P, et al. Renal function and blood
5. Roels HA, Lauwerys RR, Buchet JP, et al.: Health significance of cad- pressure in patients receiving long-term, low-dose cyclosporine therapy
mium induced renal dysfunction: a five year follow up. Br J Ind Med for idiopathic autoimmune uveitis. Ann Intern Med 1992, 117:578–583.
1989, 46:755–764. 27. World MJ, Stevens PE, Ashton MA, Rainford DJ: Mesalazine-associ-
6. Nortier J, Bernard A, Roels H, et al.: Urinary neutral endopeptidase ated interstitial nephritis. Nephrol Dial Transplant 1996, 11:614–621.
in workers exposed to cadmium: interaction with cigarette smoking. 28. De Broe ME, Stolear JC, Nouwen EJ, Elseviers MM: 5-Aminosalicylic
Occup Environ Med 1997, 54:432–436. acid (5-ASA) and chronic tubulointerstitial nephritis in patients with
7. Walker RG: Lithium nephrotoxicity. Kidney Int 1993, 44(suppl chronic inflammatory bowel disease: Is there a link? Nephrol Dial
42):S93–S98. Transplant 1997; 12:1839–1841.
8. Bendz H, Aurell M, Balldin J, et al.: Kidney damage in long-term lithi- 29. Godin M, Fillastre JP, Simon P, et al.: L’ochratoxine est-elle néphro-
um patients: a cross-sectional study of patients with 15 years or more toxique chez l’homme ? In Actualités Néphrologiques. Edited by
on lithium. Nephrol Dial Transplant 1994, 9:1250–1254. Brentano JL, Bach JF, Kreis H, Grunfeld JP. Paris:
9. Sanai T, Okuda S, Onoyama K, et al.: Germanium dioxide-induced Flammarion–Medecine Sciences; 1996:225–250.
nephropathy: a new type of renal disease. Nephron 1990, 54:53–60. 30. Stefanovic V, Polenakovic MH: Balkan nephropathy: kidney disease
10. Van Der Spoel JI, Stricker BH, Esseveld MR, Schipper MEI: Dangers beyond the Balkans? Am J Nephrol 1991, 11:1–11.
of dietary germanium supplements. Lancet 1990, 336:117. 31. Krogh P, Hald B, Plestina R, Ceovic S: Balkan (endemic) nephropathy
11. Takeuchi A, Yoshizawa N, Oshima S, et al.: Nephrotoxicity of germa- and foodborn ochratoxin A: preliminary results of a survey of food-
nium compounds: report of a case and review of the literature. stuffs. Acta Path Microbiol Scand Sect B 1977, 85:238–240.
Nephron 1992, 60:436–442. 32. Vanherweghem JL, Depierreux M, Tielemans C, et al.: Rapidly pro-
12. Hess B, Raisin J, Zimmermann A, et al.: Tubulointerstitial nephropa- gressive interstitial renal fibrosis in young women: association with
thy persisting 20 months after discontinuation of chronic intake of slimming regimen including Chinese herbs. Lancet 1993,
germanium lactate citrate. Am J Kidney Dis 1993, 21:548–552. 341:387–391.
13. Elseviers MM, Bosteels V, Cambier P, et al.: Diagnostic criteria of 33. Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL:
analgesic nephropathy in patients with end-stage renal failure: Identification of aristolochic acid in Chinese herbs. Lancet 1994,
results of the Belgian study. Nephrol Dial Transplant 1992, 343:174.
7:479–486. 34. Schmeiser HH, Bieler CA, Wiessler M, et al.: Detection of DNA-
14. Drukker W, Schwarz A, Vanherweghem JL: Analgesic nephropathy: adducts formed by aristolochic acid in renal tissue from patients with
an underestimated cause of end-stage renal disease. Int J Artif Organs Chinese herbs nephropathy. Cancer Res 1996, 56:2025–2028.
1986, 9:216–243. 35. Vanherweghem JL: Association of valvular heart disease with Chinese
15. Klag MJ, Whelton PK, Perneger TV: Analgesics and chronic renal dis- herbs nephropathy. Lancet 1997, 350:1858.
ease. Curr Opinion Nephrol Hypertens 1996, 5:236–241. 36. Cosijns JP, Jadoul M, Squifflet JP: Urothelial malignancy in nephropa-
16. Vanherweghem JL, Even-Adin D: Epidemiology of analgesic thy due to Chinese herbs. Lancet 1994, 344:118.
nephropathy in Belgium. Clin Nephrol 1982, 17:129–133. 37. Vanherweghem JL, Tielemans C, Simon J, Depierreux M: Chinese
17. Perneger TV, Whelton PK, Klag MJ: Risk of kidney failure associated herbs nephropathy and renal pelvic carcinoma. Nephrol Dial
with the use of acetaminophen, aspirin, and nonsteroidal anti-inflam- Transplant 1995, 10:270–273.
matory drugs. N Engl J Med 1994, 331:1675–1679. 38. Depierreux M, Van Damme B, Vanden Houte K, Vanherweghem JL:
18. Elseviers MM, De Broe ME: Analgesic nephropathy in Belgium is Pathologic aspects of a newly described nephropathy related to the
related to the sales of particular analgesic mixtures. Nephrol Dial prolonged use of Chinese herbs. Am J Kidney Dis 1994, 24:172–180.
Transplant 1994, 9:41–46. 39. Cosijns JP, Jadoul M, Squifflet JP et al.: Chinese herbs nephropathy: a
19. Elseviers MM, De Schepper A, Corthouts R, et al.: High diagnostic clue to Balkan endemic nephropathy? Kidney Int 1994,
performance of CT scan for analgesic nephropathy in patients with 45:1680–1688.
incipient to severe renal failure. Kidney Int 1995, 48:1316–1323. 40. Nortier JL, Deschodt-Lankman MM, Simon S, et al. Proximal tubular
20. Shihab FS: Cyclosporine nephropathy: pathophysiology and clinical injury in Chinese herbs nephropathy: monitoring by neutral endopep-
impact. Sem Nephrol 1996, 16:536–547. tidase enzymuria. Kidney Int 1997, 51:288–293.
21. Bennett WM, De Mattos A, Meyer MM, et al.: Chronic cyclosporine 41. Vanherweghem JL, Abramowicz D, Tielemans C, Depierreux M:
nephropathy: The Achilles’ heel of immunosuppressive therapy. Effects of steroids on the progression of renal failure in chronic inter-
Kidney Int 1996, 50:1089–1100. stitial renal fibrosis: a pilot study in Chinese herbs nephropathy. Am J
Kidney Dis 1996, 27:209–215.
Metabolic Causes of
Tubulointerstitial Disease
Steven J. Scheinman
A
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 con-
fines 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 hyperox-
aluria, hypokalemia, and hyperuricemia.
CHAPTER
11
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 distur-
bances in renal tubular function [1]. In the
parathyroid gland the calcium-sensing recep-
tor allows the cell to sense extracellular levels
of calcium and transduce that signal to regu-
late parathyroid hormone production and
release. In the nephron, expression of the
calcium receptor can be detected on the api-
cal surface of cells of the papillary collecting
Hypercalcemia duct, where calcium inhibits antidiuretic
inhibits reabsorption hormone action. Thus, hypercalcemia impairs
of NaCl, Ca, and Mg 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
inhibits hypercalcemia causes hypercalciuria through
reabsorption an increased filtered calcium load and
of water suppression of parathyroid hormone release
with a consequent reduction in calcium
reabsorption. Ca—calcium; Mg—magne-
sium; NaCl—sodium chloride.
FIGURE 11-2
RENAL EFFECTS OF CALCIUM Hypercalcemia leads to renal vasoconstriction and a reduction in
the glomerular filtration rate. However, no expression of the calci-
um-sensing receptor has been reported so far in renal vascular or
Hypercalcemia glomerular tissue. Calcium receptor expression is present in the
Collecting duct proximal convoluted tubule, on the basolateral side of cells of the
Resistance to vasopressin, leading to isotonic polyuria
distal convoluted tubule, and on the basolateral side of macula
densa cells. Functional correlates of calcium receptor expression
Thick ascending limb of the loop of Henle
at these sites are not yet clear [3].
Impaired sodium chloride reabsorption, leading to modest salt wasting
Hypercalciuria leads to microscopic hematuria and, in fact, is
Inhibition of calcium transport, leading to hypercalciuria
the most common cause of microscopic hematuria in children. The
Inhibition of magnesium transport, leading to hypomagnesemia
mechanism is presumed to involve microcrystallization of calcium
Renal vasculature
salts in the tubular lumen. Conflicting effects of calcium on urinary
Arteriolar vasoconstriction acidification have been reported in clinical settings in which other
Reduction in ultrafiltration coefficient factors, such as parathyroid hormone levels, may explain the obser-
Hypercalciuria vations. whether or not it is the result of renal tubular acidosis,
Microscopic hematuria Nephrocalcinosis often is associated with impaired urinary acidifica-
Nephrocalcinosis tion, whether or not it is the result of renal tubular acidosis.
Impaired urinary acidification
Metabolic Causes of Tubulointerstitial Disease 11.3
FIGURE 11-3
CAUSES OF NEPHROCALCINOSIS 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. Nephro-
Medullary (total) 97.6 calcinosis can be seen in association with chronic or severe hypercal-
Primary hyperparathyroidism 32.4 cemia or in a variety of hypercalciuric states. The spectrum of causes
Distal renal tubular acidosis 19.5
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
Medullary sponge kidney 11.3
is affected to some extent by Wrong’s interests in, eg, renal tubular
Idiopathic hypercalciuria 5.9
acidosis (RTA) and Dent’s disease, but this is by far the largest pub-
Dent’s disease 4.3
lished series. As in other studies, the most important causes of
Milk-alkali syndrome 3.2
nephrocalcinosis are primary hyperparathyroidism, distal RTA, and
Oxalosis 3.2
medullary sponge kidney. The primary factor predisposing patients
Hypomagnesemia-hypercalciuria 1.6 to renal calcification in many of these conditions is hypercalciuria,
Sarcoidosis 1.6 as occurs in idiopathic hypercalciuria, Dent’s disease, milk-alkali
Renal papillary necrosis 1.6 syndrome, sarcoidosis, hypervitaminosis D, and often in distal RTA.
Hypervitaminosis D 1.6 In distal RTA and milk-alkali syndrome, relative or absolute urinary
Other* 4.0 alkalinity promote precipitation of calcium phosphate crystals in the
Undiscovered causes 6.7 tubular lumena, and hypocitraturia is an important contributing
Cortical (total) 2.4 factor in distal RTA. Causes of cortical nephrocalcinosis in this study
included acute cortical necrosis, chronic glomerulonephritis, and
chronic pyelonephritis.
Adapted from Wrong [3]; with permission.
* Other causes include Bartter syndrome, idiopathic Fanconi syndrome, hypothy-
roidism, and severe acute tubular necrosis.
both systemic acidosis and hypokalemia.

Impaired urinary acidification Alkaline urine The high urine pH favors precipitation of
calcium phosphate (CaPO4). Thus, RTA-1
should be suspected in any patient with
Systemic acidosis
Hypercalciuria pure calcium phosphate stones [4].
Systemic acidosis also promotes hypercal-
ciuria, although not all patients with
RTA-1 have excessive urinary calcium
Hypokalemia Decreased urinary Resorption of excretion [5]. Hypercalciuria results from
citrate excretion bone mineral resorption of bone mineral and the conse-
quent increased filtered load of calcium as
Reduced renal
tubular calcium Hypercalciuria
acidosis leads to consumption of bone
reabsorption buffers. Acidosis also has a direct effect of
inhibiting renal tubular calcium reabsorp-
CaPO4 precipitation tion. Conversely, nephrocalcinosis from
other causes can impair urinary acidifica-
tion and lead to RTA in some patients.
FIGURE 11-4 The mainstay of therapy for RTA-1 is
Nephrocalcinosis in type I (distal) renal tubular acidosis. Nephrocalcinosis and potassium citrate, which corrects acidosis,
nephrolithiasis are common complications in distal renal tubular acidosis (RTA-1). replaces potassium, restores urinary cit-
Several factors contribute to the pathogenesis. The most important of these factors rate excretion, and reduces urinary loss of
are a reduction in urinary excretion of citrate and a persistently alkaline urine. Citrate calcium [5]. (From Buckalew [5]; with
inhibits the growth of calcium stones; its excretion is reduced in RTA-1 as a result of permission.)
involved in the coordinated transport of salt in the thick ascending

Epithelial cell of the thick ascending limb of the loop of Henle. In this nephron segment, sodium chloride
limb of the loop of Henle is transported into the cell together with potassium by the bumet-
Lumen Blood
amide-inhibitible sodium-potassium-2 chloride cotransporter
(NKCC2). Recycling of potassium back to the lumen through an
Na+ ClC-Kb
apical potassium channel (ROMK) allows an adequate supply of
NKCC2 2Cl– potassium for optimal activity of the NKCC2. Chloride exits the
K+ basolateral side of the cell through a voltage-gated chloride channel
(ClC-Kb), and sodium is expelled separately by the sodium-potassi-
Na+ um adenosine triphosphatase cotransporter. Inactivating mutations
ROMK K+
ATP in NKCC2, ROMK, and ClC-Kb have been identified in patients
K+ with Bartter syndrome [6–8].
Approximately 20% of filtered calcium is reabsorbed in the
thick ascending limb, and inactivation of any of these three trans-
port proteins can lead to hypercalciuria. Nephrocalcinosis occurs
in almost all patients with mutations in NKCC2 or ROMK, but it
FIGURE 11-5 is less common in patients with a mutation in the basolateral chlo-
Bartter syndrome. Bartter syndrome is a hereditary renal functional ride channel ClC-Kb, even though patients with chloride-channel
disorder characterized by hypokalemic metabolic alkalosis, renal mutations currently make up the largest reported group [8]. This
salt wasting with normal or low blood pressure, polyuria, and interesting observation is unexplained at present. In addition, a sig-
hypercalciuria. Other features include juxtaglomerular hyperplasia, nificant number of patients with Bartter syndrome have been found
secondary hyperreninemia and hyperaldosteronism, and excessive to have normal coding sequences for all three of these genes, indi-
urinary excretion of prostaglandin E. It often has been noted that cating that mutations in other gene(s) may explain Bartter
patients with Bartter syndrome appear as if they were chronically syndrome in some patients.
exposed to loop diuretics; in fact, the major differential diagnosis is In contrast, the Gitelman variant of Bartter syndrome is associated
with diuretic abuse. Bartter syndrome often presents with growth with hypocalciuria. In this respect these patients resemble people
retardation in children, and nephrocalcinosis is common. Bartter treated with thiazide diuretics. In fact, mutations have been found
syndrome is inherited as an autosomal recessive trait. in the thiazide-sensitive sodium chloride cotransporter of the distal
The speculation that this syndrome could be explained by tubule [9]. Hypomagnesemia is common and often severe, and
impaired reabsorption in the loop of Henle has now been confirmed patients with Gitelman syndrome do not develop nephrocalcinosis.
by molecular studies. R.P. Lifton’s group [6–8] identified loss-of- ATP—adenosine triphosphate. (From Simon and coworkers [8];
function mutations in three genes encoding different proteins, each with permission.)
FIGURE 11-7
Noncontrast
abdominal
radiograph in a
24-year-old man
with X-linked
nephrolithiasis
(Dent’s disease).
The patient had
recurrent calcium
nephrolithiasis
beginning in child-
hood 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 (DENT’S DISEASE)
Males who are affected Females who are carriers

Low molecular weight proteinuria Extreme Absent, mild, or moderate
Other defects in proximal tubular function Variable Uncommon
Hypercalciuria Occurs early in most Present in half
Nephrocalcinosis Nearly all have it Rare
Calcium stones Common but not universal Uncommon
Renal failure Common but not universal Rare
Rickets Present in some Not reported
FIGURE 11-8
Syndromes of X-linked nephrolithiasis have been Rickets occurs early in childhood in some patients but
reported under various names, including Dent’s disease is absent in most patients with X-linked nephrolithiasis
in the United Kingdom, X-linked recessive hypophos- (Dent’s disease). In a few families, all affected males have
phatemic rickets in Italy and France, and a syndrome of had rickets. In other families, rickets is present in only
low molecular weight (LMW) proteinuria with hyper- one of several males sharing the same mutation. At pre-
calciuria and nephrocalcinosis in Japanese schoolchild- sent, the variability of this feature and other features of
ren. Mutations in a gene encoding a voltage-gated chlo- the disease is unexplained and may reflect dietary or envi-
ride channel (ClC-5) are present in all of these syn- ronmental factors or the participation of other genes in
dromes, establishing that they represent variants of one the expression of the phenotype.
disease [10]. The disease occurs most often in boys, Females who are carriers often have mild to moder-
with microscopic hematuria, proteinuria, and hypercal- ate LMW proteinuria. This abnormality can be used
ciuria. Many but not all have recurrent nephrolithiasis clinically as a screening test, but LMW protein excre-
from an early age. Affected males excrete extremely tion will not be abnormal in all heterozygous females.
large quantities of LMW proteins, particularly 2- Approximately half of women who are carriers have
microglobulin and retinol-binding protein. Other defects hypercalciuria, but other biochemical abnormalities are
of proximal tubular function, including hypophos- rare. Although symptomatic nephrolithiasis and even
phatemia, aminoaciduria, glycosuria, or hypokalemia, renal insufficiency have been reported in female carri-
occur variably and often intermittently. Many affected ers, they are very uncommon.
males have mild to moderate polyuria and nocturia, and The gene for ClC-5 that is mutated in X-linked nephro-
they often exhibit this symptom on presentation. lithiasis (Dent’s disease) is expressed in the endosomal
Urinary acidification is usually normal, and patients do vacuoles of the proximal tubule; it appears to be impor-
not have acidosis in the absence of advanced renal tant in acidification of the endosome. Thus, defective
insufficiency. Nephrocalcinosis is common by the endosomal function would explain the LMW proteinuria.
teenage years, and often earlier. Renal failure is common The mechanism of hypercalcinuria remains unexplained
and often progresses to end-stage renal disease by the at present. This gene belongs to the family of voltage-
fourth or fifth decade, although some patients escape it. gated chloride channels that includes ClC-Kb, one of the
Renal biopsy documents a nonspecific pattern of inter- gene mutations in some patients with Bartter syndrome.
stitial fibrosis and tubular atrophy, with glomerular scle- To date, 32 mutations have been reported in 40 families,
rosis that is probably secondary [11]. and nearly all are unique [11].
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)
PH2 Functional deficiency of DGDH Nephrolithiasis
Secondary:
Dietary Sources include for example spinach, rhubarb, beets, peanuts, Increased risk of nephrolithiasis
chocolate, and tea
Enteric Enhanced oxalate absorption because of increased oxalate solu- Nephrolithiasis
bility, bile salt malabsorption, and altered gut flora (eg, inflam- Nephrocalcinosis
matory bowel disease and bowel resection) Systemic oxalosis (rarely)
Metabolism from excess of precursors Ascorbate Nephrolithiasis
Ethylene glycol, glycine, glycerol, xylitol, methoxyflurane Tubular obstruction by crystals leading to acute renal failure
Pyridoxine deficiency Cofactor for AGT Nephrolithiasis
FIGURE 11-9
Oxalate is a metabolic end-product of limited solubility in physiologic from either exposure to metabolic precursors of oxalate or pyri-
solution. Thus, the organism is highly dependent on urinary excretion, doxine deficiency. Normally, dietary sources of oxalate account for
which involves net secretion. Normal urine is supersaturated with only approximately 10% of urinary oxalate. Restriction of dietary
respect to calcium oxalate. Crystallization is prevented by a number of oxalate can be effective in some patients with kidney stones who
endogenous inhibitors, including citrate. A mild excess of oxalate load, are hyperoxaluric, but even conscientious adherence to dietary
as occurs with excessive dietary intake, contributes to nephrolithiasis. restriction is disappointing in many patients who may have mild
A more severe oxalate overload, as in type 1 primary hyperoxaluria, metabolic hyperoxaluria, an entity that probably exists but is poorly
can lead to organ damage through tissue deposition of calcium oxalate understood. Intestinal absorption of oxalate can be enhanced
and possibly through the toxic effects of glyoxalate [12]. markedly in patients with bowel disease, particularly inflammatory
Two types of primary hyperoxaluria (PH) have been identified bowel disease or after extensive bowel resection or jejunoileal bypass.
(Fig. 11-10), of which type 1 (PH1) is much more common. PH1 In this setting, several mechanisms have been described including a)
results from absolute or functional deficiency of the liver-specific enhanced oxalate solubility as a consequence of binding of calcium
enzyme alanine:glyoxalate aminotransferase (AGT). This deficiency to fatty acids in patients with fat malabsorption; b) a direct effect
leads to calcium oxalate nephrolithiasis in childhood, with nephro- of malabsorbed bile salts to enhance absorption of oxalate by
calcinosis and progressive renal failure. Because the kidney is the intestinal mucosa, and c) altered gut flora with reduction in the
main excretory route for oxalate, in the face of excessive oxalate population of oxalate-metabolizing bacteria [4,12]. Because of
production even mild degrees of renal insufficiency can lead to the important role of the colon in absorbing oxalate, ileostomy
systemic deposition of oxalate in a wide variety of tissues. It is inter- abolishes enteric hyperoxaluria [4].
esting that the liver itself is spared from calcium oxalate deposition. Excessive endogenous production of oxalate occurs in patients
Clinical consequences include heart block and cardiomyopathy, ingesting large quantities of ascorbic acid, which may increase the
severe peripheral vascular insufficiency and calcinosis cutis, and bone risk of nephrolithiasis. In the setting of acute exposure to large
pain and fractures. Many of these conditions are exacerbated by the quantities of metabolic precursors, such as ingestion of ethylene
effects of end-stage renal disease. In contrast, PH2 is much more rare glycol or administration of glycine or methoxyflurane, tubular
than is PH1. Patients with PH2 have recurrent nephrolithiasis. obstruction by calcium oxalate crystals can lead to acute renal
Nephrocalcinosis, renal failure, and systemic oxalosis have not been failure. Pyridoxine deficiency is associated with increased oxalate
reported in PH2. The metabolic defect in PH2 appears to be a func- excretion clinically in humans and experimentally in animals; it
tional deficiency of D-glycerate dehydrogenase (DGDH) [12]. can contribute to mild hyperoxaluria. In all patients with primary
Secondary causes of hyperoxaluria include dietary excess, enteric hyperoxaluria, a trial of pyridoxine therapy should be given,
hyperabsorption, and enhanced endogenous production resulting because some patients will have a beneficial response.
consequences of these defects. Both diseases are inherited as autoso-

mal recessive traits.
Primary hyproxaluria metabolism
In PH1, much clinical, biochemical, and molecular heterogeneity
exists. Liver AGT catalytic activity is absent in approximately two
Peroxisome Cytosol
thirds of patients with PH1. It is detectable in the remaining third,
Glycolate Glycolate however, in whom the enzyme is targeted to the mitochondria
rather than peroxisomes. Absence of peroxisomal AGT activity
DGDH leads to impaired transamination of glyoxalate to glycine, with
Block in PH2
excessive production of oxalate and, usually, glycolate. In PH2,
Glycine Glyoxylate Glycine deficiency of cytosolic DGDH results in overproduction of oxalate
AGT
and glycine. Mild cases of PH1, without nephrocalcinosis or systemic
oxalosis, resemble PH2 clinically, but the two usually can be distin-
Block in PH1 guished by measurement of urinary glycolate and glycine. Assay of
Oxalate Oxalate 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
FIGURE 11-10 have been identified in patients with absent enzymatic activity,
Metabolic events in the primary hyperoxalurias. Primary hyper- abnormal enzyme targeting to mitochondria, aggregation of AGT
oxaluria type 1 (PH1) results from functional deficiency of the within peroxisomes, and absence of both enzymatic activity and
peroxisomal enzyme alanine:glyoxalate aminotransferase (AGT). immunoreactivity. However, mutations have not been identified in
PH2 results from a deficiency of the cytosolic enzyme d-glycerate all patients with PH1 who have been studied, and molecular
dehydrogenase (DGDH), which also functions as glyoxalate reduc- diagnosis is not yet routinely available [12]. (Adapted from
tase. This figure presents a simplified illustration of the metabolic Danpure and Purdue [12].)
A B
FIGURE 11-11
Sequential biopsies of a transplanted kidney documenting progressive and eosin. Panels A–C show specimens viewed by polarization
recurrence of renal oxalosis. This patient with primary hyperoxaluria microscopy, all at the same low-power magnification, from biop-
type I received renal transplantation, without liver transplantation, at sies taken after transplantation within the first year (A), third
24 years of age. Panels A–D show tissue stained with hematoxylin year (B),
C D
radial array of oxalate crystals and phagocytosis of small crystals by
multinucleated giant cells (E).
Conservative treatment of PH1 is of limited efficacy. Dietary
Multinucleated restriction has little effect on the course of the disease. High-dose
giant cells pyridoxine should be tried in all patients, but many patients do not
Ox Oxalate crystals respond. Strategies to prevent calcium oxalate stone formation
Ox include a high fluid intake (recommended in all patients), magnesium
oxide (because magnesium increases the solubility of calcium oxalate
Ox Ox salts), and inorganic phosphate. Lithotripsy or surgery may be neces-
Ox sary but do not alter the progression of nephrocalcinosis [12,13].
Ox 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
Ox
patients with PH1. Once end-stage renal disease develops, hemo-
dialysis does not prevent the progression of systemic oxalosis. In
some patients, renal transplantation accompanied by an aggressive
E program of management has been followed by a good outcome for
years [14]. However, oxalosis often recurs in the transplanted kid-
ney, particularly if any degree of renal insufficiency develops for
FIGURE 11-11 (Continued) any reason. In recent years, liver transplantation has been used
and fifth year (C), following renal transplantation. Deposition of with success, with or without renal transplantation, and offers the
oxalate crystals became progressively more severe with time, and the prospect of definitive cure. Results of liver transplantation are best
kidney failed after 5 years. Panel D illustrates a higher-power magni- in patients who have not yet developed significant renal insufficien-
fication, without polarization, of the biopsy at 5 years, showing a cy [12]. (Courtesy of Paul Shanley, MD.)
URIC ACID AND RENAL DISEASE
Disease Clinical setting Features Therapeutic issues

Uric acid nephrolithiasis Hyperuricosuria Uric acid nephrolithiasis Allopurinol; alkalinize urine
Calcium nephrolithiasis Allopurinol
Acute uric acid nephropathy Cytotoxic chemotherapy for leukemia or Intratubular obstruction by uric acid crystals Prevention with allopurinol, fluids,
lymphoma; occasionally spontaneous in acidic urine and alkalinization
Acute dialysis as indicated
Chronic gouty nephropathy Gout or hyperuricemia in the setting of Intrarenal tophi; sodium urate crystals in Hemodialysis for renal failure
hypertension, preexisting renal disease, interstitium with accompanying destructive
advanced age, vascular disease, inflam- inflammatory reaction
matory reaction, and chronic exposure
to lead
Familial hyperuricemic nephropathy Autosomal dominant inheritance Interstitial fibrosis, chronic inflammation; No consensus regarding allopurinol
crystals are rare
FIGURE 11-12
Uric acid contributes to the risk of kidney stones in several ways. Pure dialysis because of the higher clearance rates for uric acid. Frequent
uric acid stones occur in patients with hyperuricosuria, particularly hemodialysis, even multiple times per day, may be necessary to pre-
when the urine is acidic. Thus, therapy involves both allopurinol and vent extreme hyperuricemia and facilitate recovery of renal func-
alkalinization with potassium alkali salts. Hyperuricosuria also pro- tion. A modification of continuous arteriovenous hemodialysis has
motes calcium oxalate stone formation. In these patients, calcium recently been reported to be effective in management of these
nephrolithiasis can be prevented by therapy with allopurinol. The patients [16].
mechanism may involve heterogenous nucleation of calcium oxalate Chronic gouty nephropathy is a term referring to deposition of
by uric acid microcrystals, binding of endogenous inhibitors of calci- sodium urate crystals in the renal interstitium, with an accompanying
um crystallization, or “salting out” of calcium oxalate by urate [4]. destructive inflammatory reaction. As a specific entity with intrarenal
Acute uric acid nephropathy occurs most often in the setting of tophi, gouty nephropathy appears to have become uncommon. It
brisk cell lysis from cytotoxic therapy or radiation for myeloprolif- appears clear that long-standing hyperuricemia alone is not sufficient
erative or lymphoproliferative disorders or other tumors highly to cause this condition in most patients, and that renal failure in
responsive to therapy. Uric acid nephropathy can uncommonly patients with hyperuricemia or gout is almost always accompanied
occur spontaneously in malignancies or other states of high uric by other predisposing conditions, particularly hypertension or expo-
acid production. Examples are infants with the Lesch-Nyhan syn- sure to lead [17].
drome who have excessive uric acid production resulting from defi- Familial hyperuricemic nephropathy is an entity that now has been
ciency of hypoxanthine-guanine phosphoribosyltransferase deficiency reported in over 40 kindreds. It is characterized by recurrent gout,
and, rarely, adults with gout who become volume-contracted and often occurring in youth and even childhood; hyperuricemia; and
whose urine is concentrated and acidic. The mechanism involves renal failure. Histopathology reveals interstitial inflammation and
intratubular obstruction by crystals of uric acid in the setting of an fibrosis, almost always without evidence of urate crystal deposition,
acute overwhelming load of uric acid, particularly in acidic urine. In although this has been found in two patients. In contrast to gouty
recent years, the widespread use of an effective prophylactic regimen nephropathy, hypertension usually is absent until renal failure is
for chemotherapy has made acute uric acid nephropathy much less advanced. The hyperuricemia appears to reflect decreased renal
common [15]. This regimen includes preparation of the patient with excretion of urate rather than overproduction of urate. Although
high-dose allopurinol, volume-expanding the patient to maintain a hyperuricemia precedes and is disproportionate to any degree of
dilute urine, and alkaline diuresis. In patients whose tumor lysis renal failure, the role, if any, that uric acid plays in the pathogenesis
leads to hyperphosphatemia, however, it is important to discontinue of the renal failure remains unclear. These is no consensus among
urinary alkalinization or else calcium phosphate precipitation may authors regarding the potential value of allopurinol in this disease.
occur. Occasionally, patients will develop renal failure despite these The inheritance follows an autosomal dominant pattern, but, beyond
measures. In such patients, hemodialysis is preferable to peritoneal this, the genetics of the disease are not understood [18,19].
References
1. Hebert SC: Extracellular calcium-sensing receptor: implications for 11. Scheinman SJ: X-linked hypercalciuric nephrolithiasis: clinical syn-
calcium and magnesium handling in the kidney. Kidney Int 1996, dromes and chloride channel mutations. Kidney Int 1998, 53:3–17.
50:2129–2139. 12. Danpure CJ, Purdue PE: Primay hyperoxaluria. In The Metabolic and
2. Riccardi D, Hall A, Xu J, et al.: Localization of the extracellular Ca2+ Molecular Bases of Inherited Disease, edn 6. Edited by Scriver CR, et
(polyvalent) cation-sensing receptor in kidney. Am J Physiol (Renal al. New York: McGraw-Hill; 1995:2385–2424.
Fluid Electrolyte Physiol), 1998, in press. 13. Scheinman JI: Primary hyperoxaluria. Miner Electrolyte Metab 1994,
3. Wrong OM: Nephrocalcinosis. In The Oxford Textbook of Clinical 20:340–351.
Nephrology. Edited by Davison AM, et al. London: Oxford 14. Katz A, Freese D, Danpure CJ, et al.: Success of kidney transplanta-
University Press; 1997:1378–1396. tion in oxalosis is unrelated to residual hepatic enzyme activity.
4. Coe FL, Parks JH, Asplin JR: The pathogenesis and treatment of Kidney Int 1992, 42:1408–1411.
kidney stones. N Engl J Med 1992, 327:1141–1152. 15. Razis E, Arlin ZA, Ahmed T, et al.: Incidence and treatment of tumor
5. Buckalew VM: Nephrolithiasis in renal tubular acidosis. J Urol 1989, lysis syndrome in patients with acute leukemia. Acta Haematol 1994,
141:731–737. 91:171–174.
6. Simon DB, Karet FE, Hamdan JM, et al.: Bartter’s syndrome, 16. Pichette V, Leblanc M, Bonnardeaux A, et al.: High dialysate flow
hypokalaemic alkalosis with hypercalciuria, is caused by mutations in rate continuous arteriovenous hemodialysis: a new approach for the
the Na-K-2Cl cotransporter NKCC2. Nature Genet 1996, 13:183–188. treatment of acute renal failure and tumor lysis syndrome. Am J
7. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogene- Kidney Dis 1994, 23:591–596.
ity of Bartter’s syndrome revealed by mutations in the K+ channel, 17. Beck LH: Requiem for gouty nephropathy. Kidney Int 1986,
ROMK. Nature Genet 1996, 14:152–156. 30:280–287.
8. Simon DB, Bindra RS, Mansfield TA, et al.: Mutations in the chloride 18. Puig JG, Miranda ME, Mateos FA, et al. Hereditary nephropathy
channel gene, CLCNKB, cause Bartter’s syndrome type III. Nature associated with hyperuricemia and gout. Arch Intern Med 1993,
Genet 1997, 17:171–178. 153:357–365.
9. Simon DB, Nelson-Williams C, Bia MJ, et al.: Gitelman’s variant of 19. Reiter L, Brown MA, Edmonds J: Familial hyperuricemic nephropathy.
Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by Am J Kidney Dis 1995, 25:235–241.
mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet
1996, 12:24–30.
10. Lloyd SE, Pearce SHS, Fisher SE, et al.: A common molecular basis
for three inherited kidney stone diseases. Nature 1996, 379:445–449.
Renal Tubular Disorders
Lisa M. Guay-Woodford
I
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 under-
lying pathogenesis.
CHAPTER
12
Overview of Renal Tubular Disorders

FIGURE 12-1
OVERVIEW OF RENAL TUBULAR DISORDERS Inherited renal tubular disorders generally
INHERITED AS MENDELIAN TRAITS are transmitted as autosomal dominant,
autosomal recessive, X-linked dominant,
or X-linked recessive traits. For many of
Inherited disorder Transmission mode Defective protein these disorders, the identification of the
disease-susceptibility gene and its associated
Renal glucosuria ?AR, AD Sodium-glucose transporter 2 defective protein product has begun to pro-
Glucose-galactose malabsorption syndrome AR Sodium-glucose transporter 1 vide insight into the molecular pathogenesis
Acidic aminoaciduria AR Sodium-potassium–dependent of the disorder.
glutamate transporter
Cystinuria AR Apical cystine-dibasic amino acid
transporter
Lysinuric protein intolerance AR Basolateral dibasic amino acid
transporter
Hartnup disease ? ?
Blue diaper syndrome AR Kidney-specific tryptophan transporter
Neutral aminoacidurias: AR ?
Methioninuria
Iminoglycinuria
Glycinuria
Hereditary hypophosphatemic rickets AR ? Sodium-phosphate cotransporter
with hypercalciuria
X-linked hypophosphatemic rickets X-linked dominant Phosphate-regulating with endopepti-
dase features on the X chromosome
Inherited Fanconi’s syndrome isolated disorder AR and AD ?
Inherited Fanconi’s syndrome associated with AR –
inborn errors of metabolism
Carbonic anhydrase II deficiency AR Carbonic anhydrase type II
Distal renal tubular acidosis AR ?
AD Basolateral anion exchanger (AE1)
Bartter-like syndromes:
Antenatal Bartter variant AR NKCC2, ROMK, ClC-K2
Classic Bartter variant AR ClC-K2b
Gitelman’s syndrome AR NCCT
Pseudohypoparathyroidism:
Type Ia AD Guanine nucleotide–binding protein
Type Ib ?
Low-renin hypertension:
Glucocorticoid-remedial aldosteronism AD Chimeric gene (11-hydroxylase and
aldosterone synthase)
Liddle’s syndrome AD and subunits of the sodium channel
Apparent mineralocorticoid excess AR 11--hydroxysteroid dehydrogenase
Pseudohypoaldosteronism:
Type 1 AR and AD and subunits of the sodium channel
Type 2 (Gordon’s syndrome) AD ?
Nephrogenic diabetes insipidus:
X-linked X-linked recessive Arginine vasopressin 2 receptor
Autosomal AR and AD Aquaporin 2 water channel
Urolithiases:
Cystinuria AR Apical cystine–dibasic amino
acid transporter
Dent’s disease X-linked Renal chloride channel (ClC-5)
X-linked recessive nephrolithiasis X-linked Renal chloride channel (ClC-5)
X-linked recessive hypophosphatemic rickets X-linked Renal chloride channel (ClC-5)
Hereditary renal hypouricemia AR ? Urate transporter
AD—autosomal dominant; AR—autosomal recessive; ClC-K2—renal chloride channel; NCCT—thiazide-sensitive

cotransporter; NKCC2—bumetanide-sensitive cotransporter; ROMK—inwardly rectified.
Renal Tubular Disorders 12.3
Renal Glucosuria
FIGURE 12-2
400 Physiology and pathophysiology of glucose titration curves. Under
Tmax
normal physiologic conditions, filtered glucose is almost entirely
Observed curve reabsorbed in the proximal tubule by way of two distinct sodium-
coupled glucose transport systems. In the S1 and S2 segments, bulk
Threshold
reabsorption of glucose load occurs by way of a kidney-specific
200 high-capacity transporter, the sodium-glucose transporter-2 (SGLT2)
[1]. The residual glucose is removed from the filtrate in the S3 seg-
ment by way of the high-affinity sodium-glucose transporter-1
Glucose reabsorption, mg/min 1.73m2
(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 concen-
0 tration in the tubular fluid accelerates the transport rate of the
0 200 400 600 glucose transporters until a maximal rate is achieved. The term
400 threshold applies to the point that glucose first appears in the
urine. The maximal overall rate of glucose transport by the proxi-
Normal mal tubule SGLT1 and SGLT2 is termed the Tmax. Glucose is
detected in urine either when the filtered load is increased (as in
Type B renal glucosuria diabetes mellitus) or, as shown in the bottom panel, when a defect
occurs in tubular reabsorption (as in renal glucosuria). Kinetic
200
studies have demonstrated two types of glucosuria caused by either
reduced maximal transport velocity (type A) or reduced affinity of
Type A renal glucosuria 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
0 mild renal glucosuria (type B). Defects in SGLT2 result in a com-
0 200 400 600 paratively more severe renal glucosuria (type A). However, this dis-
Filtered glucose load, mg/min 1.73m2 order is clinically benign. Among members of the basolateral glu-
cose transporter (GLUT) family, only GLUT1 and GLUT2 are rele-
vant 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.)
Aminoacidurias
CLASSIFICATION OF INHERITED AMINOACIDURIAS
Major categories Forms OMIM number* Amino acids involved

Acidic amino acids Acidic aminoaciduria 222730 Glutamate, aspartate
Basic amino acids and cystine Cystinuria 220100, 600918, 104614 Cystine, lysine, arginine, ornithine
Lysinuric protein intolerance 222690, 222700, 601872 Lysine, arginine, ornithine
Isolated cystinuria 238200 Cystine
Lysinuria – Lysine
Neutral amino acids Hartnup disease 234500, 260650 Alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine,
serine, threonine, tryptophan, tyrosine, valine
Blue diaper syndrome 211000 Tryptophan
Iminoglycinuria 242600 Glycine, proline, hydroxyproline
Glycinuria 138500 Glycine
Methioninuria – Methionine
*OMIM—Online 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 Cystine actually is a neutral amino acid that shares a common
the proximal tubule. The term aminoaciduria is applied when more carrier with the dibasic amino acids lysine, arginine, and ornithine.
than 5% of the filtered load is detected in the urine. Aminoaciduria The transport of all four amino acids is disrupted in cystinuria. The
can occur in the context of metabolic defects, which elevate plasma rarer disorder, lysinuric protein intolerance, results from defects in
amino acid concentrations and thus increase the glomerular filtered the basolateral transport of dibasic amino acids but not cystine.
load. Aminoaciduria can be a feature of generalized proximal tubu- Increased intracelluar concentrations of lysine, arginine, and
lar dysfunction caused by toxic nephropathies or Fanconi’s syn- ornithine are associated with disturbances in the urea cycle and
drome. In addition, aminoaciduria can arise from genetic defects in consequent hyperammonemia [7].
one of the several amino acid transport systems in the proximal Disorders involving the transport of neutral amino acids include
tubule. Three distinct groups of inherited aminoacidurias are distin- Hartnup disease, blue diaper syndrome, methioninuria, iminogly-
guished based on the net charge of the target amino acids at neutral cinuria, and glycinuria. Several neutral amino acid transporters
pH: acidic (negative charge), basic (positive charge), and neutral have been cloned and characterized. Clinical data suggest that
(no charge) [5]. Hartnup disease involves a neutral amino acid transport system
Acidic aminoaciduria involves the transport of glutamate and in both the kidney and intestine, whereas blue diaper syndrome
aspartate and results from a defect in the high-affinity sodium- involves a kidney-specific tryptophan transporter [5]. Methioninuria
potassium–dependent glutamate transporter [6]. It is a clinically appears to involve a separate methionine transport system in the
benign disorder. proximal tubule. Case reports describe seizures, mental retardation,
Four syndromes caused by defects in the transport of basic and episodic hyperventilation in affected patients [8]. The patho-
amino acids or cystine have been described: cystinuria, lysinuric physiologic basis for this phenotype is unclear. Iminoglycinuria
protein intolerance, isolated cystinuria, and isolated lysinuria. and glycinuria are clinically benign disorders.
FIGURE 12-4
ROSENBERG CLASSIFICATION OF CYSTINURIAS In this autosomal recessive disorder the apical
transport of cystine and the dibasic amino
acids is defective. Differences in the urinary
Category Phenotype Intestinal transport defect excretion of cystine in obligate heterozygotes
and intestinal amino acid transport studies in
I homozygotes have provided the basis for
Heterozygote No abnormality defining three distinct phenotypes of cystin-
Homozygote Cystinuria, basic aminoaciduria, cystine stones Cystinine, basic amino acids
uria [9]. Genetic studies have identified
II
mutations in the gene (SCL3A1) encoding a
Heterozygote Excess excretion of cystine and basic amino acids
Homozygote Cystinuria, basic aminoaciduria, cystine stones Basic amino acids only high-affinity transporter for cystine and the
III dibasic amino acids in patients with type I
Heterozygote Excess excretion of cystine and basic amino acids cystinuria [10,11]. In patients with type III
Homozygote Cystinuria, basic aminoaciduria, cystine stones None cystinuria, SCL3A1 was excluded as the
disease-causing gene [12]. A second cystin-
uria-susceptibility gene recently has been
From Morris and Ives [5]; with permission.
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 characteris-
tic 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].
Renal Hypophosphatemic Rickets
INHERITED FORMS OF HYPOPHOSPHATEMIC RICKETS
Disorder Vitamin D Parathyroid hormone Serum calcium Urinary calcium Treatment

X-linked hypophosphatemic rickets Low, low normal Normal, high normal Low, normal Elevated Calciferol, phosphate supplementation
Hereditary hypophosphatemic rickets Elevated Low, low normal Normal Elevated Phosphate supplementation
with hypercalciuria
Vitamin D—1,25-dihydroxy-vitamin D3
FIGURE 12-6
Several inherited disorders have been described that result in isolated Pi); and associated metabolic bone disease, eg, rickets in children or
renal phosphate wasting. These disorders include X-linked hypo- osteomalacia in adults [5]. These disorders can be distinguished on
phosphatemic rickets (HYP), hereditary hypophosphatemic rickets the basis of the renal hormonal response to hypophosphatemia, the
with hypercalciuria (HHRH), hypophosphatemic bone disease (HBD), biochemical profile, and responsiveness to therapy. In addition, the
autosomal dominant hypophosphatemic rickets (ADHR), autosomal rare disorder XLRH is associated with nephrolithiasis. The clinical
recessive hypophosphatemic rickets (ARHR), and X-linked recessive features of the two most common disorders HYP and HHRH are
hypophosphatemic rickets (XLRH). These inherited disorders share contrasted here. Whereas both disorders have defects in renal Pi
two common features: persistent hypophosphatemia caused by reabsorption, the renal hormonal response to hypophosphatemia is
decreased renal tubular phosphate (Pi) reabsorption (expressed as impaired in HYP but not in HHRH. Indeed, in children with
decreased ratio of plasma concentration at which maximal phosphate HHRH, phosphate supplementation alone can improve growth rates,
reabsorption occurs [TmP] to glomerular filtration rate [GFR], resolve the radiologic evidence of rickets, and correct all biochemical
[TmP/GFR], a normogram derivative of the fractional excretion of abnormalities except the reduced TmP GFR [5].
ized by growth impairment in children, metabolic bone disease, phos-

PEX (endopeptidase)
phaturia, and abnormal bioactivation of vitamin D [16]. Cell culture,
parabiosis, and transplantation experiments have demonstrated that
Phosphatonin Degradation the defect in HYP is not intrinsic to the kidney but involves a circulat-
ing 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
ATP transporter is regulated by multiple hormones. Among these is a puta-
Na + 3Na+ tive phosphaturic factor that has been designated phosphatonin [18].
It is postulated that phosphatonin inhibits Pi reabsorption by way of
Pi 2K+ the sodium-coupled phosphate cotransporter, and it depresses serum
1α-hydroxylase ADP 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
25-Vitamin D 1,25-Vitamin D (phosphate-regulating gene with homologies to endopeptidases on the
X chromosome), that is mutated in patients with X-linked hypophos-
phatemia [19]. PEX, a neutral endopeptidase, presumably inactivates
Lumen Interstitium phosphatonin. Defective PEX activity would lead to decreased
phosphatonin degradation, with excessive phosphaturia and deranged
vitamin D metabolism. A similar scenario associated with increased
FIGURE 12-7 phosphatonin production has been proposed as the basis for
Proposed pathogenesis of X-linked hypophosphatemic rickets (HYP). oncogenic hypophosphatemic osteomalacia, an acquired disorder
HYP, the most common defect in renal phosphate (Pi) transport, is manifested in patients with tumors of mesenchymal origin [17].
transmitted as an X-linked dominant trait. The disorder is character- Na+—sodium ion; K+—potassium ion.
Fanconi’s Syndrome
FIGURE 12-8
INHERITED FANCONI’S SYNDROME Fanconi’s syndrome is characterized by two components: general-
ized dysfunction of the proximal tubule, leading to impaired net
reabsorption of bicarbonate, phosphate, urate, glucose, and amino
Disorder OMIM number* acids; and vitamin D–resistant metabolic bone disease [20]. The
clinical manifestations in patients with either the hereditary or
Idiopathic 227700, 227800 acquired form of Fanconi’s syndrome include polyuria, dehydra-
Cystinosis 219800, 219900, 219750 tion, hypokalemia, acidosis, and osteomalacia (in adults) or
Hepatorenal tyrosinemia (tyrosinemia type I) 276700 impaired growth and rickets (in children). Inherited Fanconi’s syn-
Hereditary fructose intolerance 229600 drome occurs either as an idiopathic disorder or in association with
Galactosemia 230400 various inborn errors of metabolism.
Glycogen storage disease type I 232200
Wilson’s disease 277900
Oculocerebrorenal (Lowe’s) syndrome 309000
Vitamin-D–dependent rickets 264700
*OMIM—Online Mendelian Inheritance in Man (accessible at

http://www3.ncbi.nlm.nih.gov/omin/).
From Morris and Ives [5]; with permission.
with Fanconi’s syndrome cause a global disruption in sodium-

coupled transport systems rather than a disturbance in specific
Na Na+ transporters. Bergeron and coworkers [20] have proposed a patho-
ATP (2) physiologic model that involves the intracellular gradients of sodium,
(1)
3Na+
adenosine triphosphate (ATP), and adenosine diphosphate (ADP).
Na+
(4) A transepithelial sodium gradient is established in the proximal
S 2K+ tubule cell by sodium (Na) entry through Na-solute cotransport
ADP systems (Na-S) (1) and Na exit through the sodium-potassium
adenosine triphosphatase (Na-K ATPase) (2). This Na gradient
(3) ADP drives the net uptake of cotransported solutes. A small decrease in
ATP
H+ the activity of the Na-K ATPase cotransporter may translate into
a proportionally larger increment in the Na concentration close
ATP 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
Lumen Interstitium 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
FIGURE 12-9 pump activities. Therefore, a relatively small mitochondrial defect
Proposed pathogenic model for Fanconi’s syndrome. The underly- may be amplified by the effects on the intracellular sodium gradi-
ing pathogenesis of Fanconi’s syndrome has yet to be determined. ents and ADP-ATP gradients and may lead to a global inhibition
It is likely, however, that the various Mendelian diseases associated of Na-coupled transport. H+—hydrogen ion.
Renal Tubular Acidoses

FIGURE 12-10
INHERITED RENAL TUBULAR ACIDOSES 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
Disorder Transmission mode excretion of ammonium (NH4+). RTA can result from a number of
disease processes involving either inherited or acquired defects. In
Isolated proximal RTA Autosomal recessive addition, RTA may develop from an isolated defect in tubular trans-
Carbonic anhydrase II deficiency Autosomal recessive port; may involve multiple tubular transport abnormalities, eg,
Isolated distal RTA Autosomal dominant Fanconi’s syndrome; or may be associated with a systemic disease
Distal RTA with sensorineural deafness Autosomal recessive process. Isolated proximal RTA (type II) is rare, and most cases of
proximal RTA occur in the context of Fanconi’s syndrome. Inherited
forms of classic distal RTA (type I) are transmitted as both autoso-
RTA—renal tubular acidosis. mal dominant and autosomal recessive traits. Inherited disorders in
which RTA is the major clinical manifestation are summarized.
and water to hydrogen ions (H+) and bicar-

bonate (HCO-3) [21]. A least two isoenzymes
Proximal tubule Distal tubule: α intercalated cell of carbonic anhydrase are expressed in the
Cl– kidney and play critical roles in urinary
Interstitium acidification. In the proximal tubule, bicar-
bonate reabsorption is accomplished by the
combined action of both luminal carbonic
Na+ HCO3– K+ Cl– HCO3
– anhydrase type IV (CA4) and cytosolic car-
bonic anhydrase type II (CA2), the luminal
sodium-hydrogen exchanger, and the baso-
–
HCO3
CO2 + H2O
CA2 lateral sodium-bicarbonate exchanger.

–
CA2
H2CO3
OH– Impaired bicarbonate reabsorption in the

CO2
proximal tubule is the underlying defect in
H+
type II or proximal RTA. In the distal

nephron, carbonic anhydrase type II is
H+ K+ expressed in the intercalated cells of the
cortical collecting duct. There carbonic
anhydrase type II plays a critical role in
CA4 catalyzing the condensation of hydroxy ions,
Na+ Lumen
Na+ + H2CO3
–
CO2 H+ K+ H+ generated by the proton-translocating H+-
H adenosine triphosphatase (H+ ATPase), with
HCO3
–
– carbon dioxide to form bicarbonate. In
HCO3
carbonic anhydrase type II deficiency, the
increase in intracellular pH impairs the
activity of the proton-translocating H-ATPase.
FIGURE 12-11 Carbonic anhydrase inhibitors (eg, acetazo-
Carbonic anhydrase II deficiency. Carbonic anhydrase II deficiency is an autosomal recessive lamide) act as weak diuretics by blocking
disorder characterized by renal tubular acidosis (RTA), with both proximal and distal compo- bicarbonate reabsorption. Cl-—chloride ion;
nents, osteopetrosis, and cerebral calcification. Carbonic anhydrase catalyzes the reversible H2CO3—carbonic acid; K+—potassium ion;
hydration of carbon dioxide (CO2), and thereby accelerates the conversion of carbon dioxide Na+—sodium ion.
and the hydrogen ions (H+) generated from

Cl– dietary protein catabolism are secreted. The
distal nephron is composed of several distinct
segments, eg, the connecting tubule, cortical
Cortical collecting duct, and medullary collecting duct.
K+ Cl– HCO3
–
α intercalated The tubular epithelia within these segments
collecting Principal cell
duct cell are composed of two cell types: principal cells
that transport sodium, potassium, and water;
CA2
and intercalated cells that secrete hydrogen
CO2 OH– ions and bicarbonate (HCO-3) [22].
Urinary acidification in the distal nephron
K+
depends on several factors: an impermeant
luminal membrane capable of sustaining
large pH gradients; a lumen-negative poten-
Lumen – Na+ K+ tial difference in the cortical collecting duct
H+ K+ H+
that supports both hydrogen and potassium
Cl–
ion (K+) secretion; and secretion of hydrogen
ions by the intercalated cells of the cortical
and medullary collecting ducts at a rate suffi-
Outer K+
cient to regenerate the bicarbonate consumed
Cl– HCO3
–
α intercalated
medullary Principal cell by metabolic protons [22]. Abnormalities in
collecting cell
any of these processes could result in a distal
duct acidification defect.
Recent studies in families with isolated
autosomal dominant distal RTA have
K+ identified defects in the basolateral chloride-
bicarbonate exchanger, AE1 [23,24]. Defects
in various components of the H+-adenosine
triphosphatase (H+ ATPase) and subunits of
Lumen + H 2O H+ K+ H+ the H+-K+ ATPase (H+\K+ ATPase) also have
been proposed as the basis for other heredi-
tary forms of distal RTA. CA2—cytosolic
FIGURE 12-12 carbonic anhydrase type II; Cl-—chloride
Distal renal tubular acidosis (RTA). The collecting duct is the principal site of distal tubule ion; CO2—carbon dioxide; Na+—sodium
acidification, where the final 5% to 10% of the filtered bicarbonate load is reabsorbed ion; OH-—hydroxy ions.
Bartter-like Syndromes
FIGURE 12-13
CLINICAL FEATURES DISTINGUISHING BARTTER-LIKE SYNDROMES Familial hypokalemic, hypochloremic meta-
bolic alkalosis, or Bartter’s syndrome, is not
a single disorder but rather a set of closely
Classic Bartter’s Gitelman’s Antenatal Bartter’s related disorders. These Bartter-like syn-
Feature syndrome syndrome syndrome dromes share many of the same physiologic
derangements but differ with regard to the
Age at presentation Infancy, early childhood Childhood, adolescence In utero, infancy age of onset, presenting symptoms, magni-
Prematurity, polyhydramnios +/- - ++ tude of urinary potassium and prostaglandin
Delayed growth ++ - +++
excretion, and extent of urinary calcium
Delayed cognitive development +/- - +
excretion. At least three clinical phenotypes
Polyuria, polydipsia ++ + +++
have been distinguished: classic Bartter’s
Tetany Rare ++ -
syndrome, the antenatal hypercalciuric
Serum magnesium Low in 20% Low in about 100% Low-normal to normal
Urinary calcium excretion Normal to high Low Very high
variant (also called hyperprostaglandin E
Nephrocalcinosis +/- - ++ syndrome), and hypocalciuric-hypomagne-
Urine prostaglandin excretion High Normal Very high semic Gitelman’s syndrome [25].
Clinical response to +/- - Often life-saving
indomethacin
From Guay-Woodford [25]; with permission.

FIGURE 12-14
Lumen Interstitium Transport systems involved in transepithelial sodium-chloride trans-
port in the thick ascending limb (TAL). Clinical data suggest that
Ca2+ the primary defect in the antenatal and classic Bartter syndrome
AA sensing
receptor variants involves impaired sodium chloride transport in the TAL.
Na+ 3Na+ Under normal physiologic conditions, sodium chloride is transported
K+ across the apical membrane by way of the bumetanide-sensitive
2Cl– 2K+
sodium-potassium-2chloride (Na-K-2Cl) cotransporter (NKCC2).
K+
This electroneutral transporter is driven by the low intracellular sodi-
20 HETE
Cl– um and chloride concentrations generated by the sodium-potassium
K+
Ca2+ pump and the basolateral chloride channels and potassium-chloride
Cl– cotransporter. In addition, apical potassium recycling by way of the
ATP
low-conductance potassium channel (ROMK) ensures the efficient
functioning of the Na-K-2Cl cotransporter. The activity of the ROMK
ATP cAMP V2R
Stimulatory channel, in turn, is regulated by a number of cell messengers, eg,
EP3 calcium (Ca2+) and adenosine triphosphate (ATP), as well as by the
Inhibitory
PGE2 calcium-sensing receptor (CaR), prostaglandin EP3 receptor, and vaso-
pressin receptor (V2R) by way of cAMP-dependent pathways and
arachidonic acid (AA) metabolites, eg, 20-hydroxy-eicosatetraenoic
Vte + Ca2+
Mg2+ acid (20-HETE). The positive transluminal voltage (Vte) drives the
paracellular reabsorption of calcium ions and magnesium ions
(Mg2+) [25]. cAMP—cyclic adenosine monophosphate; PGE2—
prostaglandin E2; PKA—protein kinase A.
FIGURE 12-15
Defective Defective Defective Proposed pathogenic model for the antenatal
NKCC2 ROMK CIC-Kb and classic variants of Bartter’s syndrome.
Gene defect
Genetic studies have identified mutations in
Pathophysiology
the genes encoding the bumetanide-sensitive
Defective NaCl ↓ Voltage-driven sodium-potassium-2chloride cotransporter
transport in TAL paracellular (NKCC2), luminal ATP–regulated potas-
reabsorption of
Ca2+ and Mg2+
sium channel (ROMK), and kidney-specific
Volume ↑ NaCl delivery to chloride channel (ClC-K2). These findings
contraction the distal nephron support the theory of a primary defect in
thick ascending limb (TAL) sodium-chloride
(Na-Cl) reabsorption in, at least, subsets of
↑ Renin
patients with the antenatal or classic variants
of Bartter’s syndrome. In the proposed model
↑ Angiotensin II (AII) the potential interrelationships of the com-
plex set of pathophysiologic phenomena are
Hypercalciuria illustrated. The resulting clinical manifesta-
↑ Kallikrein ↑ Aldosterone ↑ H+ and K+ Hypermagnesuria tions are highlighted in boxes [25]. Ca2+—
secretion calcium ion; H+—hydrogen ion; K+—potas-
sium ion; Mg2+—magnesium ion; PGE2—
Normotension prostaglandin E2.
Blunted vascular
response to AII and Metabolic alkalosis Impaired
norepinephrine Hypokalemia vasopressin-
stimulated
urinary
↑ PGE2 concentration
Hyposthenuria
Fever
↑ Urinary ↑ Bone
prostaglandins reabsorption
FIGURE 12-16
Defective NCCT Proposed pathogenic model for Gitelman’s
Gene defect
syndrome. The electrolyte disturbances
Pathophysiologic model
evident in Gitelman’s syndrome also are
DefectiveHypercalciuria
NaCl transport in DCT observed with administration of thiazide
? diuretics, which inhibit the sodium-chloride
(Na-Cl) cotransporter in the distal convoluted
tubule (DCT). In families with Gitelman’s
Volume ↑ NaCl delivery to Cl– efflux mediates ↓ Na+-dependent
contraction Mg2+ reabsorption syndrome, genetic studies have identified
the distal nephron cell hyperpolarization defects in the gene encoding the thiazide-
in DCT
sensitive cotransporter (NCCT) protein.
↑ Renin
The proposed pathogenic model is predicated
on loss of function of the NCCT protein
↑ Angiotensin II (AII) and, thus, most closely applies to those
patients who inherit Gitelman’s syndrome
↑ Aldosterone ↑ H+ and K+ secretion ↑ Ca2+ reabsorption as an autosomal recessive trait. Given that
the physiologic features of this syndrome
Metabolic alkalosis are virtually indistinguishable in familial
Hypocalciuria Hypermagnesuria and sporadic cases, it may be reasonable
hypokalemia
to propose the same pathogenesis for all
patients with Gitelman’s syndrome. How-
ever, it is important to caution that evidence
for NCCT mutations in sporadic cases has
not yet been established [25]. Ca2+—calci-
um ion; Cl-—chloride ion; H+—hydrogen ion;
K+—potassium ion; Mg2+—magnesium ion;
Na+—sodium ion.
Pseudohypoparathyroidism
CLINICAL SUBTYPES OF PSEUDOHYPOPARATHYROIDISM
Disorder Pathophysiology Skeletal anomalies Associated endocrinopathies

Pseudohypoparathyroidism type Ia Defect in guanine nucleotide—binding protein Yes Yes
Pseudohypoparathyroidism type Ib Resistance to parathyroid hormone, normal guanine No No
nucleotide—binding protein activity
? Defect in parathyroid hormone receptor
FIGURE 12-17
Pseudohypoparathyroidism applies to a heterogeneous group of hered- Pseudohypoparathyroidism type Ia (Albright’s hereditary osteo-
itary disorders whose common feature is resistance to parathyroid dystrophy) is associated with a myriad of physical abnormalities
hormone (PTH). Affected patients are hypocalcemic and hyperphos- and resistance to multiple adenylate cyclase–coupled hormones,
phatemic, despite elevated plasma PTH levels. Hypocalcemia and most notably thyrotropin and gonadotropin [27]. The molecular
hyperphophatemia result from the combined effects of defective PTH- defect in a guanine nucleotide–binding protein (Gs) blocks the
mediated calcium reabsorption in the distal convoluted tubule and coupling of PTH and other hormone receptors to adenylate cyclase.
reduced formation of 1,25-dihydroxy-vitamin D3. The latter leads to The molecular defect has not been identified in type Ib, although
defects in renal phosphate excretion, calcium mobilization from bone, specific resistance to PTH suggests a defect in the PTH receptor.
and gastrointestinal calcium reabsorption. Differences in clinical fea- Oral supplementation with 1,25 dihydroxy-vitamin D3 and, if
tures and urinary cyclic adenosine monophosphate response to infused necessary, oral calcium, is used to correct the hypocalcemia and
PTH provide the basis for distinguishing three distinct subtypes of minimize PTH-induced bone disease [26]. Pseudohypoparathroid-
pseudohypoparathyroidism (type Ia, type Ib, and type II) [26]. ism type II may be an acquired disease.
Disorders of Aldosterone-Regulated Transport

and the basolateral sodium-potassium adenosine triphosphatase
(A) GRA chimeric gene (Na-K ATPase). Sodium moves from the lumen into the cell and
down its electrochemical gradient, thus generating a lumen-negative
Aldosterone synthetase 11-OHase transepithelial voltage that drives potassium secretion from the
principal cells and hydrogen secretion from the intercalated cells.
Unequal crossover 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
Aldosterone synthetase Chimeric gene 11-OHase intracellular cortisol to its metabolite cortisone.
Three hypertensive syndromes, glucocorticoid-remedial aldostero-
(B) nism (GRA), Liddle’s syndrome, and apparent mineralocorticoid
Amiloride-sensitive excess (AME), share a common clinical phenotype that is charac-
Na+ channel terized by normal physical examinations, hypokalemia, and very
Na+ Na+ low plasma renin activity. The molecular defect in GRA derives
from an unequal crossover event between two adjacent genes
K+
encoding 11--hydroxylase and aldosterone synthase (A). The
resulting chimeric gene duplication fuses the regulatory elements
Aldosterone MR of 11--hydroxylase and the coding sequence of aldosterone synthase.
(A) Consequently, aldosterone is ectopically synthesized in the adrenal
zona fasciculata and its synthesis regulated by adrenocorticotropic
hormone rather than its physiologically normal secretagogue, angio-
K+ channel Cortisol Degradation tensin II [28]. Activating mutations in the and regulatory sub-
(A) GRA (C) units of the epithelial sodium channel (B) are responsible for
(B) Liddle's Liddle’s syndrome [29]. Deficiency of the kidney type 2 isozyme
(C) AME of 11--hydroxysteroid dehydrogenase (C) can render type I MR
responsive to cortisol and produce the syndrome of apparent mineral-
ocorticoid excess [30]. Inhibitors of this enzyme (eg, licorice) also can
FIGURE 12-18 produce an acquired form of apparent mineralocorticoid excess.
Aldosterone-regulated transport in the cortical collecting duct and Medical management of these disorders focuses on dietary sodium
defects causing low-renin hypertension. The mineralocorticoid aldos- restriction, blocking the sodium channel with the potassium-sparing
terone regulates electrolyte excretion and intravascular volume by diuretics triamterene and amiloride, downregulating the ectopic
way of its action in the principal cells of the cortical collecting duct. aldosterone synthesis with glucocorticoids (GRA), or blocking
The binding of aldosterone to its nuclear receptor (MR) leads directly the MR using the competitive antagonist spironolactone (GRA
or indirectly to increased activity of the apical sodium (Na) channel and AME).
FIGURE 12-19
Low-renin hypertension Algorithm for evaluating patients with low-
renin hypertension. Glucocorticoid-remedial
aldosteronism (GRA), Liddle’s syndrome,
and apparent mineralocorticoid excess (AME)
+ Family history – Family history can be distinguished from one another by
characteristic urinary steroid profiles [31].
K+—potassium ion; PE—physical examina-
tion; TH18oxoF/THAD—ratio of urinary
Abnormal PE Normal PE 18-oxotetrahydrocortisol (TH18oxoF) to
Serum K+ urinary tetrahydroaldosterone (normal:
0–0.4; GRA patients: >1); THF + allo-
THF/THE—ratio of the combined urinary
Virilization Hypogonadism
tetrahydrocortisol and allotetrahydrocortisol
Low
High-normal Low-normal to urinary tetrahydrocortisone (normal:
serum K+
11β-hydroxylase 17α-hydroxylase <1.3; AME patients: 5–10-fold higher).
Gordon's deficiency deficiency
syndrome
TH180x0F Negligible urinary THF + alloTHF
Urinary THAD aldosterone THE
steroid profile:
Diagnosis: GRA Liddle's syndrome AME
and metabolic acidosis. The diagnosis is sup-

CLINICAL SUBTYPES OF PSEUDOHYPOALDOSTERONISM ported by elevated plasma renin and plasma
aldosterone concentrations. Life-saving inter-
ventions include aggressive sodium chloride
supplementation and treatment with ion-bind-
Disorder Clinical features Treatment
ing resins or dialysis to reduce the hyper-
Pseudohypoaldosteronism type I kalemia. This autosomal recessive form of
Autosomal recessive Dehydration, severe neonatal salt wasting, Sodium chloride PHA1 results from inactivating mutations in
hyperkalemia, metabolic acidosis supplementation the or subunits of the epithelial sodium
Elevated plasma renin activity Ion-binding resin; dialysis channel [32]. A milder form of PHA1 with
Severity of electrolyte abnormalities may autosomal dominant inheritance also has
diminish after infancy been described; however, the molecular defect
Autosomal dominant Mild salt wasting remains unexplained [33]. Adolescents or
Pseudohypoaldosteronism type II Hypertension, hyperkalemia, mild hyper- Thiazide diuretics adults with hyperkalemic, hyperchloremic
(Gordon’s syndrome) chloremic metabolic acidosis metabolic acidosis, low-normal renin and
Undetectable plasma renin activity aldosterone levels, and hypertension have
been recently described and classified as
having pseudohypoaldosteronism type II
(PHA2) or Gordon’s syndrome [34]. Pheno-
FIGURE 12-20 typically, this disorder is the mirror image of
Mineralocorticoid resistance with hyperkalemia (pseudohypoaldosteronism) includes at Gitelman’s syndrome; however, the thiazide-
least three clinical subtypes, two of which are hereditary disorders. Pseudohypoaldo- sensitive cotransporter (NCCT) has been
steronism type I (PHA1) is characterized by severe neonatal salt wasting, hyperkalemia, excluded as a candidate gene [35].
Nephrogenic Diabetes Insipidus

FIGURE 12-21
The relationship between urine osmolality and plasma arginine
Primary polydipsia vasopressin (AVP). Nephrogenic diabetes insipidus (NDI) is charac-
1200 Pituitary diabetes insipidus
terized by renal tubular unresponsiveness to the antidiuretic hor-
mone AVP or its antidiuretic analogue 1-desamino-8-D-arginine
1000 vasopressin (DDAVP). In both the congenital and acquired forms
of this disorder the clinical picture is dominated by polyuria, poly-
Urine osmolality, mOsm/kg
800 dipsia, and hyposthenuria despite often elevated AVP levels [17].
(From Robertson et al. [36]; with permission.)
600
400
200 NDI
0 1 2 3 4 5 10 15
Plasma AVP, pg/mL
volume occurs. As shown, the binding of

Physiologic Pathophysiologic
arginine vasopressin (AVP) to the vaso-
pressin V2 receptor (V2R) stimulates a
AQP3 AQP2 X-linked AQP3 AQP2 series of cyclic adenosine monophosphate–
–ADH
H 2O NDI H 2O (cAMP) mediated events that results in the
fusion of cytoplasmic vesicles carrying
V2R V2R water channel proteins (aquaporin-2
[AQP2]), with the apical membrane,
thereby increasing the water permeability
AQP4 AQP4
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
AQP2 Autosomal AQP2 vesicles and the water permeability of the
recessive apical membrane returns to its baseline
+ADH AQP3 AQP3
NDI
H 2O low rate [37].
ATP ATP
Genetic studies have identified mutations
V2R H 2O V2R
in two proteins involved in this water trans-
cAMP cAMP port process, the V2 receptor and AQP2
water channels. Most patients (>90%)
AQP4 AQP4
inherit NDI as an X-linked recessive trait.
In these patients, defects in the V2 receptor
Interstitium Lumen Interstitium Lumen have been identified. In the remaining
patients, the disease is transmitted as either
an autosomal recessive or autosomal domi-
FIGURE 12-22 nant trait involving mutations in the AQP2
Pathogenic model for nephrogenic diabetes insipidus (NDI). The principle cell of the inner gene [38,39]. ADH— antidiuretic hormone;
medullary collecting duct is the site where fine tuning of the final urinary composition and ATP—adenosine triphosphate.
Urolithiases
amino acid transport in the proximal tubule.
Cystinuria is the leading single gene cause of
INHERITED CAUSES OF UROLITHIASES
inheritable urolithiasis in both children and
adults [41,42]. Three Mendelian disorders,
Dent’s disease, X-linked recessive nephrolithi-
Disorder Stone characteristics Treatment asis, and X-linked recessive hypophospha-
Cystinuria Cystine High fluid intake, urinary alkalization temic rickets cause hypercalciuric urolithiasis.
Sulfhydryl-containing drugs These disorders involve a functional loss of
Dent’s disease Calcium-containing High fluid intake, urinary alkalization the renal chloride channel ClC-5 [43]. The
X-linked recessive nephrolithiasis Calcium-containing High fluid intake, urinary alkalization common molecular basis for these three
X-linked recessive hypophos- Calcium-containing High fluid intake, urinary alkalization inherited kidney stone diseases has led to
phatemic rickets speculation that ClC-5 also may be involved
Hereditary renal hypouricemia Uric acid, calcium oxalate High fluid intake, urinary alkalization in other renal tubular disorders associated
Allopurinol with kidney stones. Hereditary renal hypour-
Hypoxanthine-guanine phospho- Uric acid High fluid intake, urinary alkalization icemia is an inborn error of renal tubular
ribosyltransferase deficiency Allopurinol transport that appears to involve urate reab-
Xanthinuria Xanthine High fluid intake, dietary purine restriction sorption in the proximal tubule [16].
Primary hyperoxaluria Calcium oxalate High fluid intake, dietary oxalate restriction In addition to renal transport deficiencies,
Magnesium oxide, inorganic phosphates defects in metabolic enzymes also can cause
urolithiases. Inherited defects in the purine
salvage enzymes hypoxanthine-guanine phos-
phoribosyltransferase (HPRT) and adenine
FIGURE 12-23 phosphoribosyltransferase (APRT) or in the
Urolithiases are a common urinary tract abnormality, afflicting 12% of men and 5% of women catabolic enzyme xanthine dehydrogenase
in North America and Europe [40]. Renal stone formation is most commonly associated with (XDH) all can lead to stone formation [44].
hypercalciuria. Perhaps in as many as 45% of these patients, there seems to be a familial Finally, defective enzymes in the oxalate
predisposition. In comparison, a group of relatively rare disorders exists, each of which is metabolic pathway result in hyperoxaluria,
transmitted as a Mendelian trait and causes a variety of different crystal nephropathies. The oxalate stone formation, and consequent
most common of these disorders is cystinuria, which involves defective cystine and dibasic loss of renal function [45].
Acknowledgment
The author thanks Dr. David G. Warnock for critically reviewing this manuscript.
References
1. Wells R, Kanai Y, Pajor A, et al.: The cloning of a human cDNA with 7. Oynagi K, Sogawa H, Minawi R,et al.: The mechanism of hyperam-
similarity to the sodium/glucose cotransporter. Am J Physiol 1992, monemia in congenital lysinuria. J Pediatr 1979, 94:255.
263:F459–F465. 8. Smith A, Strang L: An inborn error of metabolism with the urinary
2. Hediger M, Coady M, Ikeda T, Wright E: Expression cloning and excretion of -hydroxybutric acid and phenyl-pyruvic acid. Arch Dis
cDNA sequencing of the Na/glucose co-transporter. Nature 1987, Child 1958, 33:109.
330:379–381. 9. Rosenberg LE, Downing S, Durant JL, Segal S: Cystinuria: biochemi-
3. Woolf L, Goodwin B, Phelps C: Tm-limited renal tubular reabsorption cal evidence for three genetically distinct diseases. J Clin Invest 1966,
and the genetics of renal glycosuria. J Theor Biol 1966, 11:10–21. 45:365–371.
4. Meuckler M: Facilitative glucose transporters. Euro J Biochem 1994, 10. Pras E, Arber N, Aksentijevich I, et al.: Localization of a gene causing
219:713–725. cystinuria to chromosome 2p. Nature Genet 1994, 6:415–419.
5. Morris JR, Ives HE: Inherited disorders of the renal tubule. In The 11. Calonge MJ, Gasparini P, Chillaron J, et al.: Cystinuria caused by
Kidney. Edited by Brenner B, Rector F. Philadelphia: WB Saunders, mutations in rBAT, a gene involved in the transport of cystine. Nature
1996:1764–1827. Genet 1994, 6:420–425.
6. Kanai Y, Hediger M: Primary structure and functional characteriza- 12. Calonge M, Volpini V, Bisceglia L, et al.: Genetic heterogeneity in
tion of a high affinity glutamate transporter. Nature 1992, cystinuria: the SLC3A1 gene is linked to type I but not to type III
360:467–471. cystinuria. Proc Am Acad Sci USA 1995, 92:9667–9671.
13. Wartenfeld R, Golomb E, Katz G, Bale S, et al.: Molecular analysis of 30. White P, Mune T, Rogerson F, et al.: 11--hydroxysteroid dehydroge-
cystinuria in Libyan Jews: exclusion of the SLC3A1 gene and mapping nase and its role in the syndrome of apparent mineralocorticoid
a new locus on 19q. Am J Med Genet 1997, 60:617–624. excess. Pediatr Res 1997, 41:25–29.
14. Stephens AD: Cystinuria and its treatment: 25 years’ experience at St. 31. Yiu V, Dluhy R, Lifton R, Guay-Woodford L: Low peripheral plasma
Bartholomew’s Hospital. J Inherited Metab Dis 1989, 12:197–209. renin activity as a critical marker in pediatric hypertension. Pediatr
15. Perazella M, Buller G: Successful treatment of cystinuria with captopril. Nephrol 1997, 11:343–346.
Am J Kidney Dis 1993, 21:504–507. 32. Chang S, Grunder S, Hanukoglu A, et al.: Mutations in subunits of
16. Grieff M: New insights into X-linked hypophosphatemia. Curr Opin the epithelial sodium channel cause salt wasting with hyperkalemic
Nephrol Hypertens 1997, 6:15–19. acidosis, pseudohypoaldosteronism type 1. Nature Genet 1996,
17. Robertson GL: Vasopressin in osmotic regulation in man. Annu Rev 12:248–253.
Med 1974, 25:315. 33. Kuhle U: Pseudohypoaldosteronism: mutation found, problem solved?
18. Econs M, Drezner M: Tumor-induced osteomalacia: unveiling a new Mol Cell Endocrinol 1997, 133:77–80.
hormone. N Engl J Med 1994, 330:1679–1681. 34. Gordon R: Syndrome of hypertension and hyperkalemia with normal
19. The HYP Consortium: A gene (PEX) with homologies to endopepti- glomerular filtration rate. Hypertension 1986, 8:93–102.
dases is mutated in patients with X-linked hypophosphatemic rickets. 35. Mansfield T, Simon D, Farfel Z, et al.: Multilocus linkage of familial
Nature Genet 1995, 11:130–136. hyperkalaemia and hypertension, pseudohypoaldosteronism type II,
20. Bergeron M, Gougoux A, Vinay P: The renal Fanconi syndrome. In to chromosomes 1q31-42 and 17p11-q2. Nature Genet 1997,
The Metabolic and Molecular Bases of Inherited Diseases. Edited by 16:202–205.
Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill, 36. Robertson GL, et al: Development and clinical application of a new
1995:3691–3704. method for the radioimmunoassay of arginine vasopressin in human
21. Sly W, Hu P: The carbonic anhydrase II deficiency syndrome: osteo- plasma. J Clin Invest 1973, 52:2340–2352.
petrosis with renal tubular acidosis and cerebral calcification. In The 37. Bichet D, Osche A, Rosenthal W: Congenital nephrogenic diabetes
Metabolic and Molecular Bases of Inherited Diseases. Edited by insipidus. JASN 1997, 12:1951–1958.
Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 38. van Lieburg A, Verdijk M, Knoers N, et al.: Patients with autosomal
1965:3581–3602. recessive nephrogenic diabetes insipidus homozygous for mutations
22. Bastani B, Gluck S: New insights into the pathogenesis of distal renal in the aquaporin 2 water channel gene. Am J Hum Genet 1994,
tubular acidosis. Miner Electrolyte Metab 1996, 22:396–409. 55:648–652.
23. Bruce L, Cope D, Jones G, et al.: Familial distal renal tubular acidosis 39. Bichet D, Arthus M-F, Lonergan M, et al.: Autosomal dominant and
is associated with mutations in the red cell anion exchanger (band 3, autosomal recessive nephrogenic diabetes insipidus: novel mutations
AE1) gene. J Clin Invest 1997, 100:1693–1707. in the AQP2 gene. J Am Soc Nephrol 1995, 6:717A.
24. Jarolim P, Shayakul C, Prabakaran D, et al.: Autosomal dominant dis- 40. Coe F, Parks J, Asplin J: The pathogenesis and treatment of kidney
tal renal tubular acidosis is associated in three families with heterozy- stones. N Engl J Med 1992, 327:1141–1152.
gosity for the R589H mutation in the AE1 (band 3) Cl-/HCO-3
41. Segal S, Thier S: Cystinuria. In The Metabolic and Molecular Bases of
exchanger. J Biol Chem, 1998, 273:6380–6388.
Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle
25. Guay-Woodford L: Bartter syndrome: unraveling the pathophysiologic D. York: McGraw-Hill; 1995:3581–3602.
enigma. Am J Med, 1998, 105:151–161.
42. Polinsky MS, Kaiser BA, Baluarte HJ: Urolithiasis in childhood.
26. Spiegel A, Weinstein L: Pseudohypoparathyroidism. In The Metabolic Pediatr Clin North Am 1987, 34:683–710.
and Molecular Bases of Inherited Diseases. Edited by Scriver CH,
Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 43. Lloyd S, Pearce S, Fisher S, et al.: A common molecular basis for three
1995:3073–3085. inherited kidney stone diseases. Nature 1996, 379:445–449.
27. Van Dop C: Pseudohypoparathyroidism: clinical and molecular 44. Cameron J, Moro F, Simmonds H: Gout, uric acid and purine metab-
aspects. Semin Nephrol 1989, 9:168–178. olism in paediatric nephrology. Pediatr Nephrol 1993, 7:105–118.
28. Lifton RP, Dluhy RG, Powers M., et al.: A chimaeric 11--hydroxy- 45. Danpure C, Purdue P: Primary Hyperoxaluria. In The Metabolic and
lase aldosterone synthase gene causes glucocorticoid-remediable aldos- Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet
teronism and human hypertension. Nature 1992, 355:262–265. AL, Sly WS, Valle D. New York: McGraw-Hill; 1995:2385–2424.
29. Shimkets RA, Warnock DG, Bositis CM, et al.: Liddle’s syndrome:
heritable human hypertension caused by mutations in the subunit
of the epithelial sodium channel. Cell 1994, 79:407–414.
The Kidney in Blood
Pressure Regulation
L. Gabriel Navar
L. Lee Hamm
D
espite extensive animal and clinical experimentation, the
mechanisms responsible for the normal regulation of arterial
pressure and development of essential or primary hyperten-
sion remain unclear. One basic concept was championed by Guyton
and other authors [1–4]: 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 gener-
alized 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, pos-
itive 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 CHAPTER
intake lead to chronic increases in extracellular fluid volume and
blood volume. These increases can result in hypertension. When the
1
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
1.2 Hypertension and the Kidney
the capacitance, often referred to as the effective blood volume. extrinsic influences and intrarenal derangements can lead to
Through the mechanism of pressure natriuresis, however, the reduced sodium excretory capability. Many factors also exist
increases in arterial pressure increase renal sodium excretion, that alter cardiac output, total peripheral resistance, and cardio-
allowing restoration of sodium balance but at the expense of vascular capacitance. Accordingly, hypertension is a multifactorial
persistent elevations in arterial pressure [9]. In support of this dysfunctional process that can be caused by a myriad of different
overall concept, various studies have demonstrated strong conditions. These conditions range from stimulatory influences
relationships between kidney disease and the incidence of that inappropriately enhance tubular sodium reabsorption to
hypertension. In addition, transplantation studies have shown overt renal pathology, involving severe reductions in filtering
that normotensive recipients from genetically hypertensive capacity by the renal glomeruli and associated marked reduc-
donors have a higher likelihood of developing hypertension tions in sodium excretory capability. An understanding of the
after transplantation [10]. normal mechanisms regulating sodium balance and how
This unifying concept has helped delineate the cardinal role derangements lead to altered sodium homeostasis and hyperten-
of the kidneys in the normal regulation of arterial pressure as sion provides the basis for a rational approach to the treatment
well as in the pathophysiology of hypertension. Many different of hypertension.
200 C A
B
HEMODYNAMIC DETERMINANTS
160 Isolated systolic hypertension 180
(61 y)
Arterial pressure, mm Hg
Aortic pressure,
160
140
mm Hg
120 PP = 72 mm Hg For any vascular bed:

120
100 PP = 40 mm Hg Arterial pressure gradient
Blood flow =
80 80 Vascular resistance
PP = 30 mm Hg
60 For total circulation averaged over time:
Normotensive 40 Blood flow = cardiac output
Aortic blood
flow, mL/s
400 (56 y)
20
Therefore,
Arterial pressure - right atrial pressure
0 500 600 700 800 900 Cardiac output =
A B Arterial volume, mL Total peripheral resistance
and:
Mean arterial pressure =
FIGURE 1-1 Cardiac output total peripheral resistance
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 FIGURE 1-2
a specific stroke volume. The normal relationship is shown in curve A, and arrows designate Hemodynamic determinants of arterial
the PP. A highly distensible arterial tree, as depicted in curve B, can accommodate the stroke pressure. During the diastolic phase of the
volume with a smaller PP. Pathophysiologic processes and aging lead to decreases in aortic dis- cardiac cycle, the elastic recoil characteris-
tensibility. These decreases lead to marked increases in PP and overall mean arterial pressure tics of the arterial tree provide the kinetic
for any given arterial volume, as shown in curve C. Decreased distensibility is partly responsi- energy that allows a continuous delivery of
ble for the isolated systolic hypertension often found in elderly persons. Recordings of actual blood flow to the tissues. Blood flow is
aortic pressure and flow profiles in persons with normotension and systolic hypertension are dependent on the arterial pressure gradient
shown in panel A [11,12]. (Panel B Adapted from Vari and Navar [4] and Panel A from and total peripheral resistance. Under nor-
Nichols et al. [12].) mal 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 time-
integrated 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).
The Kidney in Blood Pressure Regulation 1.3
FIGURE 1-3
Dietary Insensible losses Urinary Volume determinants of arterial pressure.
intake (skin, respiration, fecal) excretion The two major determinants of arterial
+ – – Arterial baroreflexes pressure, cardiac output and total peripheral
Atrial reflexes
Renin-angiotensin-aldosterone
resistance, are regulated by a combination
Adrenal catecholamines of short- and long-term mechanisms. Rapidly
Vasopressin Neurohumoral adjusting mechanisms regulate peripheral
Net sodium and Natriuretic peptides systems vascular resistance, cardiovascular capacitance,
fluid balance Endothelial factors: and cardiac performance. These mechanisms
nitric oxide, endothelin
kallikrein-kinin system include the neural and humoral mechanisms
Prostaglandins and other eicosanoids listed. On a long-term basis, cardiac output
ECF volume
is determined by venous return, which is
Arterial Total peripheral regulated primarily by the mean circulatory
(Autoregulation)
pressure resistance pressure. The mean circulatory pressure
Blood Interstitial depends on blood volume and overall cardio-
volume fluid volume vascular capacitance. Blood volume is closely
linked to extracellular fluid (ECF) volume
and sodium balance, which are dependent
Mean circulatory Venous Cardiac Heart rate and on the integration of net intake and net
pressure return output contractility
losses [13]. (Adapted from Navar [3].)
Cardiovascular
capacitance
Antidiuretic hormone Concentrated urine: Increased Edema

NaCl release free water reabsorption 6
intake Thirst:
If increased 5
Increased water intake
Blood volume, L
+
Na+ and Cl– 4
Quantity of Extracellular concentrations
÷ =
NaCl in ECF fluid volume in ECF volume
– 3
If decreased Decreased water intake

Increased salt intake 2
NaCl losses
(urine Antidiuretic hormone inhibition 0
insensible) Dilute urine:
Increased solute-free 10 15 20
A water excretion B Extracellular fluid volume, L
FIGURE 1-4
A, Relationship between net sodium balance and extracellular fluid B, Relationship between the ECF volume and blood volume. Under
(ECF) volume. Sodium balance is intimately linked to volume balance normal conditions a consistent relationship exists between the total
because of powerful mechanisms that tightly regulate plasma and ECF volume and blood volume. This relationship is consistent as
ECF osmolality. Sodium and its accompanying anions constitute the long as the plasma protein concentration and, thus, the colloid
major contributors to ECF osmolality. The integration of sodium osmotic pressure are regulated appropriately and the microvasculature
intake and losses establishes the net amount of sodium in the body, maintains its integrity in limiting protein leak into the interstitial
which is compartmentalized primarily in the ECF volume. The quotient compartment. The shaded area represents the normal operating
of these two parameters (sodium and volume) determines the sodium range [13]. A chronic increase in the total quantity of sodium chloride
concentration and, thus, the osmolality. Osmolality is subject to very in the body leads to a chronic increase in ECF volume, part of
tight regulation by vasopressin and other mechanisms. In particular, which is proportionately distributed to the blood volume compartment.
vasopressin is a very powerful regulator of plasma osmolality; how- When accumulation is excessive, disproportionate distribution to
ever, it achieves this regulation primarily by regulating the relative the interstitium may lead to edema. Chronic increases in blood
solute-free water retention or excretion by the kidney [13–15]. The volume increase mean circulatory pressure (see Fig. 1-3) and lead
important point is that the osmolality is rapidly regulated by adjusting to an increase in arterial pressure. Therefore, the mechanisms
the ECF volume to the total solute present. Corrections of excesses regulating sodium balance are primarily responsible for the
in extracellular fluid volume involve more complex interactions that chronic regulation of arterial pressure. (Panel B adapted from
regulate the sodium excretion rate. Guyton and Hall [13].)
Intrarenal Mechanisms Regulating Sodium Balance

reductions in arterial pressure cause antinatriuresis [9]. This phenome-
6
High sodium intake B
non of pressure natriuresis serves a critical role linking arterial
Normal sodium intake pressure to sodium balance. Representative relationships between
5
Sodium excretion, normal
Low sodium intake arterial pressure and sodium excretion under conditions of normal,
4 A high, and low sodium intake are shown. When renal function is
2 4 normal and responsive to sodium regulatory mechanisms, steady
Elevated
3 sodium intake state sodium excretion rates are adjusted to match the intakes.
2
These adjustments occur with minimal alterations in arterial pressure,
C
5 as exemplified by going from point 1 on curve A to point 2 on
Normal 1
1 curve B. Similarly, reductions in sodium intake stimulate sodium-
sodium intake
Reduced 3 retaining mechanisms that prevent serious losses, as exemplified by
0 point 3 on curve C. When the regulatory mechanisms are operating
60 80 100 120 140 160 180 200 appropriately, the kidneys have a large capability to rapidly adjust
Renal arterial pressure, mm Hg
the slope of the pressure natriuresis relationship. In doing so, the
kidneys readily handle sodium challenges with minimal long-term
FIGURE 1-5 changes in extracellular fluid (ECF) volume or arterial pressure. In
Arterial pressure and sodium excretion. In principle, sodium balance contrast, when the kidney cannot readjust its pressure natriuresis
can be regulated by altering sodium intake or excretion by the kidney. curve or when it inadequately resets the relationship, the results are
However, intake is dependent on dietary preferences and usually is sodium retention, expansion of ECF volume, and increased arterial
excessive because of the abundant salt content of most foods. There- pressure. Failure to appropriately reset the pressure natriuresis is
fore, regulation of sodium balance is achieved primarily by altering illustrated by point 4 on curve A and point 5 on curve C. When
urinary sodium excretion. It is therefore of major significance that, this occurs the increased arterial pressure directly influences sodium
for any given set of conditions and neurohumoral environment, excretion, allowing balance between intake and excretion to be
acute elevations in arterial pressure produce natriuresis, whereas reestablished but at higher arterial pressures. (Adapted from Navar [3].)
FIGURE 1-6
150 Intrarenal responses to changes in arterial pressure at different levels of sodium intake.
Filtered sodium load,
The renal autoregulation mechanism maintains the glomerular filtration rate (GFR) during
µmol/min/g
100
Low changes in arterial pressure, GFR, and filtered sodium load. These values do not change
50 Normal significantly during changes in arterial pressure or sodium intake [3,16]. Therefore, the
High changes in sodium excretion in response to arterial pressure alterations are due primarily
0 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
100
intake to effect the large increases in the sodium excretion rate. These responses demon-
Fractional sodium
strate the importance of tubular reabsorptive mechanisms in modulating the slope of the
reabsorption, %
98
pressure natriuresis relationship. (Adapted from Navar and Majid [9].)
96
94
92
8
Fractional sodium
6
excretion, %
0
75 100 125 150 175
of the glomerular capillaries as protein-free

fluid is filtered such that filtration is greatest in
the early segments of the glomerular capillar-
RA
ies, as designated by the large arrow. The
glomerular forces, EFP, and blood flow are
regulated by mechanisms that control the vas-
cular smooth muscle tone of the afferent and
πga=25 πB<1 efferent arterioles and of the intraglomerular
mesangial cells. The filtration coefficient also
PB=20 is subject to regulation by neural, humoral,
and paracrine influences [17]. Changes in
Pg=60 EFP=9 GFR=Kf• EFP tubular reabsorption can result from alter-
ations of various processes governing both
πge=37 active and passive transport along the
πi=8 nephron segments. Peritubular capillary
Tubular reabsorption
uptake (PCU) of the tubular reabsorbate is
Pi=6
mediated by the net colloid osmotic pressure
gradient (πc - πi). As a result of the filtration
of protein-free filtrate, the plasma colloid
Pc=20 15
osmotic pressure entering the peritubular capil-
laries is markedly increased. Thus, the colloid
RE πc=37 25
RV osmotic gradient exceeds the outwardly
PCU=Kr• ERP directed hydrostatic pressure gradient (Pc - Pi).
Appropriate responses of one or more of
these modulating mechanisms allow the kid-
FIGURE 1-7 neys to respond rapidly and efficiently to
Hemodynamic mechanisms regulating sodium excretion. Many different neurohumoral changes in sodium chloride intake [3,17].
mechanisms, paracrine factors, and drugs exist that can influence sodium excretion and the πB—colloid osmotic pressure in Bowman’s
pressure natriuresis relationship. These modulators may influence sodium excretion by alter- space; πga—colloid osmotic pressure in initial
ing changes in filtered load or changes in tubular reabsorption. Filtered load depends primar- parts of glomerular cappillaries; πge—colloid
ily on hemodynamic mechanisms that regulate the forces operating at the glomerulus. As osmotic pressure in terminal segments of
shown, the glomerular filtration rate (GFR) is determined by the filtration coefficient (Kf) glomerular capillaries; RA—resistance of
and the effective filtration pressure (EFP). The EFP is a distributed force determined by the preglomerular arterioles; RE—efferent
glomerular pressure (Pg), the pressure in Bowman’s space (PB), and the plasma colloid osmot- resistance; RV—venous resistance.
ic pressure within the glomerular capillaries (πg). The πg increases progressively along the length (Adapted from Navar [3].)
FIGURE 1-8
Renal autoregulatory mechanism. Because the glomerular filtration rate (GFR) is so
0.6
responsive to changes in the glomerular forces, highly efficient mechanisms have been
developed to maintain a stable intrarenal hemodynamic environment [16]. These powerful
mL/min•g
0.4
mechanisms adjust vascular smooth muscle tone in response to various extrinsic disturbances.
0.2 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
0 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
20 RA
load, and the intrarenal pressures are maintained stable in the face of various extrarenal
Vascular resistance,
mm Hg•min•g/mL
15 disturbances by the autoregulatory mechanism. (Adapted from Navar [3].)

RE
10
0
5
Renal blood flow,
4
mL/min•g
3
2
1
0
0 50 100 150 200
Arterial Plasma colloid Proximal tubular Collection

pressure osmotic pressure and loop of Henle pipette
reabsorption
Wax blocking
pipette
Macula
densa
Perfusion
Glomerulotubular pipette
balance
Glomerular Glomerular Proximal to Early distal tubule: Proximal
pressure and filtration distal tubule flow-related changes Distal tubule
plasma flow rate flow in fluid composition tubule
Macula densa:
Preglomerular Vascular effector
Sensor mechanism
resistance (afferent arteriole)
Transmitter
A B
vasoconstriction, whereas decreases in flow cause afferent vasodilation

40 [16,18,19]. Blocking flow to the distal tubule or interrupting the feed-
back 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,
30 while collections are made or pressure measured in an early tubular
segment. C, When the tubule is perfused at increased flows, the
Single nephron GFR, nL/min
High sodium intake, glomerular pressure and GFR of that nephron decrease. The shaded
ECF volume expansion area in the normal relationship represents the normal operating
level of the TGF mechanism. This mechanism helps stabilize the
20 filtered load and the solute and sodium load to the distal nephron
segment. The responsiveness of the TGF mechanism is modulated
Normal by changes in sodium intake and in extracellular fluid (ECF) volume
status. At high sodium intake and ECF volume expansion the sensi-
tivity of the TGF mechanism is low, thus allowing greater spillover
10
Low sodium intake of salt to the distal nephron. During low sodium intake and other
Decreased ECF volume 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 hor-
0 monal and paracrine mechanisms responsible for regulating TGF
0 10 20 30 40 sensitivity are discussed subsequently.
C Late proximal perfusion rate, nL/min 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
FIGURE 1-9 efferent arterioles exhibit myogenic responses to changes in wall
Tubuloglomerular feedback (TGF) and myogenic mechanisms. Two tension [16,20]. The residual autoregulatory capacity that exists
mechanisms are responsible for efficient renal autoregulation: the during blockade of the tubuloglomerular feedback mechanism
TGF and myogenic mechanisms. The TGF mechanism is explained indicates that the myogenic mechanism contributes about half to
here. A, Increases in distal tubular flow past the macula densa generate the autoregulatory efficiency of the renal vasculature. (Figure
signals from the macula densa cells to the afferent arterioles to elicit adapted from Navar [3].)
Agents that increase cytosolic calcium:

Angiotensin II, vasopressin, epinephrine (α),
TXA2, leukotrienes, adenosine (A1),
ATP, norepinephrine, endothelin Chloride Calcium-activated Agents that increase cAMP (or cGMP):
Voltage- Epinephrine (β), PTH, PGI2,
Receptor- operated channel_ potassium channel
PGE2, ANP, dopamine, nitric oxide,
operated channel 2+ Cl K+ adenosine (A2)
channel 2+ Ca +
Ca Ca2+
Ca2+
–
R
cAMP R
Gq Na+
PLC Gi Gs
Phosphoinositides
Ad Cy
Ca2+ Phosphorylated MLCK cAMP
(inactive)
DAG + IP3
PKA
Ca2+
SR
Ca2+-Cal Active MLCK Phosphorylated Tension
PKC MLC development
Calmodulin MLCK MLC Actin
Smooth muscle cell
FIGURE 1-10
Cellular mechanisms of vascular smooth muscle contrac- tone are identified. Ad Cy—adenylate cyclase;
tion. The vascular resistances of different arteriolar ANP—atrial natriuretic protein; Cal—calmodulin;
segments are ultimately regulated by the contractile cGMP—cyclic GMP; DAG—1,2-diacylglycerol; Gq,
tone of the corresponding vascular smooth muscle Gi, Gs—G proteins; IP3—inositol 1,4,5-triphosphate;
cells. Shown are the various membrane activation MLC—myosin light chain; MLCK—myosin light chain
mechanisms and signal transduction events leading to kinase; PGE2—prostaglandin E2; PGI2—prostaglandin
a change in cytosolic calcium ions (Ca2+), cyclic AMP I2; PKA—protein kinase A; PKC—protein kinase C;
(cAMP), and phosphorylation of myosin light chain PLC—phospholipase C; PTH—parathyroid hormone;
kinase. Many of the circulating hormones and paracrine R—receptor; SR—sarcoplasmic reticulum; TXA2 —
factors that increase or decrease vascular smooth muscle 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]. AA—afferent arteriole;
ArA—arcuate artery; PC—peritubular capillaries; V—vein;
VR—vasa recta.
A

30
Afferent arteriole Efferent arteriole 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
25 angiotensin II. In contrast, Ca2+ channel blockers do not signifi-
cantly vasodilate efferent arterioles and do not block the vasocon-
Diameter, µ
strictor effects of angiotensin II. Thus, afferent and efferent arteri-

20
oles can be differentially regulated by various hormones and
paracrine agents. (Panel A from Casellas and Navar [21]; panel B
Control from Navar et al. [23].)
15 Ca2+ channel blockers
0.1 nM 10 nM 0.1 nM 10 nM
10
B Control Angiotensin II Control Angiotensin II
paracrine agents that alter vascular smooth

muscle tone and influence tubular transport
Smooth muscle cell function. (Examples are shown.) Angiotensin-
Vasodilation Vasoconstriction converting 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
TXA2 EDCF from the endothelial cells to activate soluble
EDHF NO PGI PGF2α
2 Endothelin guanylate cyclase and increases cyclic
Relaxing factors Constricting factors GMP (cGMP) levels in vascular smooth
Angiotensin II muscle cells, thus causing vasodilation.
Agents that can stimulate nitric oxide
ACE
are shown. The relative amounts of the
Endothelial cell various factors released by endothelial
Angiotensin I cells depend on the physiologic circum-
Thrombin Insulin stances and pathophysiologic status.
Shear Bradykinin Thus, endothelial cells can exert vasodilator
Platelet Histamine
stress activating ATP-ADP Serotonin or vasoconstrictor effects. At least one
Leukotrienes factor Acetylcholine major influence participating in the normal
regulation of vascular tone is nitric oxide.
EDCF—endothelial derived constrictor
factor; EDHF—endothelial derived hyper-
FIGURE 1-12 polarizing factor; PGF2—prostaglandin
Endothelial-derived factors. In addition to serving as a diffusion barrier, the endothelial F2; PGI2—prostaglandin I2; TXA2—
cells lining the vasculature participate actively in the regulation of vascular function. They thromboxane A2. (Adapted from Navar
do so by responding to various circulating hormones and physical stimuli and releasing et al. [16].)
FIGURE 1-13
Renal Shear Endothelial Vascular dilation Nitric oxide in mediation of pressure natriuresis. Several recent studies
arterial stress nitric oxide but counteracted have demonstrated that nitric oxide also directly affects tubular sodi-
pressure release by autoregulation um transport and may be an important mediator of the changes
induced by arterial pressure in sodium excretion, as described in Figure
Sodium excretion, normal
Diffusion to 1-5 [9,24]. Increases in arteriolar shear stress caused by increases in

3 tubules arterial pressure stimulate production of nitric oxide. Nitric oxide may
2 exert direct effects to inhibit tubule sodium reabsorptive mechanisms
Control Epithelial and may elicit vasodilatory actions. Nitric oxide increases intracellular
1
NOS inhibition cGMP cyclic GMP (cGMP) in tubular cells, which leads to a reduced reab-
sorption rate through cGMP-sensitive sodium entry pathways [24,25].
When formation of nitric oxide is blocked by agents that prevent nitric
50 75 100 125 150 Decreased sodium Sodium
reabsorption excretion 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].)
FIGURE 1-14
DCT
Tubular transport processes. Sodium excretion is the difference
PCT
between the very high filtered load and net tubular reabsorption
60% rate such that, under normal conditions less than 1% of the filtered
sodium load is excreted. The percentage of reabsorption of the filtered
7%
load occurring in each nephron segment is shown. The end result is
CCD that normally less than 1% of the filtered load is excreted; however,
PST the exact excretion rate can be changed by many mechanisms. Despite
the lesser absolute sodium reabsorption in the distal nephron seg-
ments, the latter segments are critical for final regulation of sodium
2% –3% excretion. Therefore, any factor that changes the delicate balance
TALH OMCD
30%
existing between the hemodynamically determined filtered load and
the tubular reabsorption rate can lead to marked alterations in
sodium excretion. ALH—thin ascending limb of the loop of Henle;
DLH IMCD
CCD—cortical collecting duct; DCT—distal convoluted tubule;
ALH DLH—thin descending limb of the loop of Henle; IMCD—inner
medullary collecting duct; OMCD—outer medullary collecting
duct; PCT—proximal convoluted tubule; PST—proximal straight
< 1% tubule; TALH—thick ascending limb of the loop of Henle.
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%
FIGURE 1-15
Peritubular capillary Proximal tubule reabsorptive mechanisms. The proximal tubule is
Lateral responsible for reabsorption of 60% to 70% of the filtered load of
intercellular ∆P
space ∆π Na K 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
Na compartment. The major driving force for this reabsorption is the
basolateral sodium-potassium ATPase (Na+-K+ ATPase) that transports
Active [K ] +
Na
K
Na+ out of the proximal tubule cells in exchange for K+. As in most
transcellular
K
cells, this maintains a low intracellular Na+ concentration and a
Na+ high intracellular K+ concentration. The low intracellular Na+
Cells (–) concentration, along with the negative intracellular electrical
potential, creates the electrochemical gradient that drives most of
Paracellular
[Na+] the apical transport mechanisms. In the late proximal tubule, a lumen
(passive) to interstitial chloride concentration gradient drives additional net
Tubule lumen
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.
P—transcapillary hydrostatic pressure gradient; π—transcapillary
colloid osmotic pressure gradient.
pathways across the apical membrane may

Proximal tubule cells include a coupled sodium chloride entry
Lumen step or chloride anion exchange that is
Regulation of reabsorption coupled with sodium-hydrogen exchange.
_ Stimulation Major transport pathways at the basolateral
ATP Angiotensin II
Na+ 3Na+ membrane include the ubiquitous and
Adrenergic agents or increased
Glucose 2 K+ renal nerve activity preeminent sodium-potassium ATPase
ADP Increased luminal flow or (Na+-K+ ATPase) that creates the major
Na+ _ solute delivery
HCO3 Increased filtration fraction driving force. The other major pathway
Na+ CO3 is a sodium-bicarbonate transport system
Inhibition
H+ Volume expansion (via that transports the equivalent of one sodium
_ Ca2+ increased backleak) ion coupled with the equivalent of three
Anion
_ _ 3Na+ Atrial natriuretic peptide bicarbonate ions (HCO-3). Because this
Cl Dopamine
Increased interstitial pressure 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
FIGURE 1-16 calcium. Not shown are several other
Major transport pathways across proximal tubule cells. At the apical membrane, sodium is pathways that predominantly transport
transported in conjunction with organic solutes (such as glucose, amino acids, and citrate) protons or other ions and organic sub-
and inorganic anions (such as phosphate and sulfate). The major mechanism for sodium strates. Several major regulatory factors
entry into the cells is sodium-hydrogen exchange (the isoform NHE3). Chloride transport are listed.
FIGURE 1-17
Lumen Thick ascending
limb cells Sodium transport mechanisms in the thick ascending limb of the
Furosemide Cell Regulation of reabsorbtion loop of Henle. The major sodium chloride reabsorptive mechanism
_ Stimulation in the thick ascending limb at the apical membrane is the sodium-
ATP Antidiuretic hormone
potassium-chloride cotransporter. This electroneutral transporter is
Na 3Na+ β-adrenergic agents
2Cl-
inhibited by furosemide and other loop diuretics and is stimulated
2 K+ Mineralocorticoids
K+ Inhibition
by a variety of factors. Potassium is recycled across the apical
or ADP
NH4+ Hypertonicity membrane into the lumen, creating a positive voltage in the lumen.
+10mv _
Prostaglandin E2 An apical sodium-hydrogen exchanger also exists that may function
K+ CI Acidosis to reabsorb some sodium bicarbonate. The sodium-potassium
Calcium ATPase (Na+-K+ ATPase) at the basolateral membrane again is the
driving force. The basolateral chloride channel and possibly other
Na+
chloride cotransporters are important in mediating chloride efflux
H+ across the basolateral membrane. Sodium and chloride are reab-
sorbed 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.
FIGURE 1-18
Distal tubule and Mechanisms of sodium chloride reabsorption in the distal tubule. The distal convoluted
connecting tubule cells
Thiazides 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
Na ATP exchange mechanism also are present. Amiloride inhibits sodium channel activity. Again
_
Cl 3Na+ the sodium-potassium ATPase (Na+-K+ ATPase) on the basolateral membrane provides
2 K+ most of the driving force for sodium reabsorption.
Na+ ADP
Amiloride
Na+
H+
FIGURE 1-19
Collecting duct principal cell
Mechanism of sodium chloride reabsorption in collecting duct cells.
Lumen Cell Sodium transport in the collecting duct is mainly via amiloride-
Regulation of reabsorbtion
Stimulation sensitive sodium channels in the apical membrane. Some evidence for
ATP Aldosterone other mechanisms such as an electroneutral sodium-chloride cotrans-
Na+ 3Na+ Antidiuretic hormone port mechanism and a different sodium channel also has been
2 K+ Inhibition reported. Again, the basolateral sodium-potassium ATPase (Na+-K+
ADP Prostaglandins ATPase) creates the driving force for overall sodium transport.
_ Nitric oxide
Atrial natriuretic peptide There are some differences between the cortical collecting duct and
Bradykinin the deeper inner medullary collecting duct (IMCD). In the cortical
Amiloride collecting duct, sodium transport occurs in the predominant principal
K+ Na+_ cell type interspersed between acid-base transporting intercalated
2CI cells. The principal cell also is an important site of potassium
K+
(IMCD) 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.
Systemic Factors Regulating Arterial

Pressure and Sodium Excretion
Medulla
NTS
Normal Glossopharyngeal
firing rate, impulses/s
nerve
∆I
Baroreceptor
Afferents
Resetting NA
Carotid DN –
sinus
∆P
Efferents Bulbospinal
Vagus pathway epinephrine
Arterial nerve
100 pressure
Arterial pressure, mm Hg
Atrial
receptors Aortic
arch
Preganglionic
Heart sympathetics
rate (acetylcholine)
Postganglionic
Sympathetics Adrenal
medulla
Vascular smooth Norepinephrine
muscle
Kidney
↓ RBF
TPR ↓ GFR Epinephrine
↑Reabsorption
↓Na+ excretion
FIGURE 1-20
Neural and sympathetic influences. The neural reflexes serve as the so by enhancing cardiac performance and stimulating vascular
principal mechanisms for the rapid regulation of arterial pressure. smooth muscle tone, leading to increased total peripheral resis-
The neural reflexes also exert a long-term role by influencing sodium tance and decreased capacitance. The direct effects of the sympa-
excretion. The pathways and effectors of the arterial baroreflex thetic nervous system on kidney function lead to decreased sodium
and atrial pressure-volume reflex are depicted. The arrows indicate excretion caused by decreases in filtered load and increases in
increased or decreased activity in response to an acute reduction in tubular reabsorption [26].
arterial pressure which is sensed by the baroreceptors in the aortic The decreases in the glomerular filtration rate (GFR) and
arch and carotid sinus. filtered sodium load are due to increases in both afferent and
The insert depicts the relationship between the arterial blood efferent arteriolar resistances and to decreases in the filtration
pressure and baroreflex primary afferent firing rate. At the normal coefficient (see Fig. 1-7). Sympathetic activation also enhances
level of mean arterial pressure of approximately 100 mm Hg, the proximal sodium reabsorption by stimulating the sodium-hydrogen
sensitivity (I/P) is set at the maximum level. After chronic resetting (Na+-H+) exchanger mechanism (see Fig. 1-16) and by increasing
of the baroreceptors, the peak sensitivity and threshold of activation the net chloride reabsorption by the thick ascending limb of the
are shifted to a higher level of arterial pressure. loop of Henle. The indirect effects include stimulation of renin
The cardiovascular reflexes involve high-pressure arterial recep- secretion and angiotensin II formation, which, as discussed next,
tors in the aortic arch and carotid sinus and low-pressure atrial also stimulates tubular reabsorption. I—change in impulse firing;
receptors. In response to decreases in arterial pressure or vascular P—change in pressure; DN—dorsal motor nucleus; NA—nucleus
volume, increased sympathetic stimulation participates in short- ambiguous; NTS—nucleus tractus solitarii; RBF—renal blood flow;
term control of arterial pressure. This increased stimulation does TPR—total peripheral resistance. (Adapted from Vari and Navar [4].)
FIGURE 1-21
Angiotensinogen Renin-angiotensin system. The renin-angio-
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Val-Tyr-Ser-R tensin system serves as one of the most
powerful regulators of arterial pressure
Renin
and sodium balance. In response to various
stimuli that compromise blood volume,
Angiotensin I extracellular fluid (ECF) volume, or arterial
NaCl Arterial ECF Stress
intake pressure volume trauma Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu pressure—or those associated with stress
and trauma—three major mechanisms are
Angiotensin-
converting activated. These mechanisms stimulate renin
Macula densa mechanism enzyme, release by the cells of the juxtaglomerular
Baroreceptor mechanism chymase (heart) apparatus that act on angiotensinogen to
Sympathetic nervous system
form angiotensin I. Angiotensinogen is an
Angiotensin II
2 globulin formed primarily in the liver
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe and to a lesser extent by the kidney. Angio-
Juxtaglomerular apparatus Renin
Cytosolic Ca2+ Angiotensinases tensin I is a decapeptide that is rapidly
cAMP release converted by angiotensin-converting
enzyme (ACE) and to a lesser extent by
Metabolites AT1, AT2, AT? chymase (in the heart) to angiotensin II, an
Receptor binding and octapeptide. Recent studies have indicated
Angiotensin (1–7) Biologic actions that other angiotensin metabolites such as
Angiotensin (2–8)
Angiotensin (3–8) angiotensin (2–8), angiotensin (1–7), and
Inactive fragments angiotensin (3–8) have biologic actions.
Angiotensin II and/or active metabolites
Adrenal Kidney Intestine Central nervous Peripheral nervous Vascular smooth Heart Growth
cortex system system muscle factors
Adrenergic
Aldosterone Vasoconstriction facilitation Contractility
transport effects Sympathetic
discharge Proliferation
Distal
nephron Proximal and Thirst, salt appetite Vasoconstriction
reabsorption distal sodium + water
Reabsorption by Vasopressin release
intestine
Water reabsorption
Maintain or increase Total peripheral Cardiac
extracellular fluid volume resistance output Hypertrophy
FIGURE 1-22
Multiple actions of angiotensin. Angiotensin II and interacts with the sympathetic nervous system by
some of the other angiotensin II metabolites have a facilitating adrenergic transmission and has long-term
myriad of actions on many different vascular beds actions on vascular smooth muscle proliferation by
and organ systems. Angiotensin II exerts short- and interacting with growth factors. Angiotensin II exerts
long-term actions, including vasoconstriction and several important effects on the kidney that contribute
stimulation of aldosterone release. Angiotensin II also to sodium conservation. (Adapted from Navar [3].)
FIGURE 1-23
Enhance proximal
tubular reabsorption Angiotensin II actions on renal hemodynamics. Systemic and
intrarenal angiotensin II exert powerful vasoconstrictive actions on
PT 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
BS
Decrease Kf 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]. BS—Bowman’s
GC space; GC—glomerular capillaries; PC—peritubular capillaries;
PT—proximal tubule; TAL—thick ascending limb; TGF—tubu-
loglomerular feedback mechanism. (Adapted from Arendshorst and
Navar [17].)
EA Inhibit renin release
Afferent arteriolar
PC vasoconstriction
Efferent Increased
arteriolar TAL
sensitivity
vasoconstriction of TGF
mechanism
AA
FIGURE 1-24
Angiotensin II actions on tubular transport. Angiotensin II receptors
are located on both the luminal and basolateral membranes of the
Angiotensin proximal and distal nephron segments. The proximal effect has
Angiotensin
been studied most extensively. Activation of angiotensin II-AT1
receptors leads to increased activities of the sodium-hydrogen
G (Na+-H+) exchanger and the sodium-bicarbonate (Na+-HCO-3)
PLA _ _ + cotransporter. These increased activities lead to augmented volume
_
H+ + HCO3 reabsorption. Higher angiotensin II concentrations can inhibit the
cAMP
Tubule Na+ Na+ tubular sodium reabsorption rate; however, the main physiologic
lumen role of angiotensin II is to enhance the reabsorption rate [28].
cAMP—cyclic AMP; G—G protein; PLA—phospholipase A.
(Adapted from Mitchell and Navar [28].)
K+
Na+
Reabsorption 60
A. SYNERGISTIC RENAL ACTIONS OF ANGIOTENSIN II Proximal
55
Glomerular pressure, mm Hg
SNGFR
Enhancement of proximal reabsorption rate
50
Stimulation of apical amiloride-sensitive Na-H exchanger
Stimulation of basolateral Na-HCO3 cotransporter
Distal 45
Sustained changes
in distal volume delivery
and sodium delivery 40
Increased sensitivity of afferent arteriole to signals from macula densa cells
35
30
0 10 20 30 40
B End proximal fluid flow, nL/min
Proximal reabsorption 60
55 FIGURE 1-25
SNGFR
A–C, Synergistic effects of angiotensin II on proximal reabsorption
50 and tubuloglomerular feedback mechanisms. The actions of
angiotensin II on proximal nephron reabsorption and the ability
Distal 45 of angiotensin II to enhance the sensitivity of the tubuloglomerular
delivery feedback (TGF) mechanism prevent a compensatory increase in
40 glomerular filtration rate caused by the reduced distal tubular flow.
These actions allow elevated angiotensin II levels to exert a
35 sustained reduction in sodium delivery to the distal nephron
segment. This effect is shown here by the shift of operating levels
30 to a lower proximal fluid flow under the influence of elevated
0 10 20 30 40 angiotensin II [27]. The effects of angiotensin II to enhance TGF
C End proximal fluid flow, nL/min
sensitivity allow the glomerular pressure (GP) and nephron filtra-
tion rate to be maintained at a reduced distal volume delivery rate
that would occur as a consequence of the angiotensin II effects on
reabsorption. SNGFR—single nephron glomerular filtration rate.
(Panels B and C adapted from Mitchell et al. [27].)
FIGURE 1-26
Lumen Principal cell 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
Mitochondria
ATP gland. The increased aldosterone levels synergize with the direct
3Na+
Na+ effects of angiotensin II to enhance distal tubule sodium reabsorp-
Proteins 2 K+ tion. Aldosterone increases sodium reabsorption and potassium
ADP
secretion in the distal segments of the nephron by binding to the
mRNA 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
K+ mRNAs encode for proteins that stimulate sodium reabsorption
Nucleus Aldosterone by increasing sodium-potassium ATPase (Na+-K+ ATPase) protein
MR _ Spironolactone 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
A nongenomic actions of aldosterone to activate sodium entry
pathways such as the amiloride-sensitive sodium channel [30].

14
B, The net effect of aldosterone is to stimulate sodium reabsorption
12
along the distal nephron segment, decreasing the remaining sodium
to only 2% or 3% of the filtered load. The direct action of aldosterone
Filtered sodium remaining, %
10 Aldosterone blockade can be blocked by drugs such as spironolactone that bind directly
to the mineralocorticoid receptor.
8
4 Normal
0
0 20 40 60 80 100
B Distal nephron length, %
FIGURE 1-27
Lumen Principal cell Syndrome of apparent mineralocorticoid excess and hypertension.
Aldosterone increases sodium reabsorption and potassium secretion
Mitochondria
in the distal segments of the nephron by binding to the cytoplasmic
ATP mineralocorticoid receptor (MR). Cortisol, the glucocorticoid that
3Na+
Na+ circulates in plasma at much higher concentrations than does aldos-
Proteins 2 K+ terone, also binds to MR. However, cortisol normally is prevented
ADP
from this by the action of 11--hydroxysteroid dehydrogenase (11-
mRNA -OHSD), which metabolizes cortisol to cortisone in mineralocorti-
coid-sensitive cells. A deficiency or defect in this enzyme has been
MR Aldosterone found to be responsible for a rare form of hypertension in persons
K+ with the hereditary syndrome of apparent mineralocorticoid excess.
Nucleus
Cortisone Cortisol In these persons, cortisol binds to the MR receptor, causing sodium
retention and hypertension [31]. This enzyme also is blocked by gly-
II-β_OHSD defect or cyrrhizic acid (in some forms of licorice) and carbenoxolone. The
glycyrrhizic acid or diuretic spironolactone acting by way of inhibition of MR is able to
carbenoxolone
block this excessive action of cortisol on the MR receptor.
FIGURE 1-28
Lumen Principal cell Hyperaldosteronism and glucocorticoid-remediable aldosteronism.
Hypertension can result from increased aldosterone or from
Mitochondria ATP
increases in other closely related steroids derived from abnormal
3Na+
adrenal metabolism (11--hydroxylase deficiency and 17--
Na+ hydroxylase deficiency). The most common cause is an aldos-
Proteins 2K+
ADP terone-producing adenoma; bilateral hyperplasia of the adrenal
Primary
hyperaldosteronism zona glomerulosa is the next most common cause. In glucocorti-
mRNA Adrenal enzymatic coid-remediable aldosteronism, a DNA crossover mutation results
disorder
Adenoma in a chimeric gene in which aldosterone production is regulated by
Glucorticoid-remediable adrenocorticotropic hormone (ACTH). Increases in aldosterone
K+ aldosteronism
also can result secondarily from any state of increased renin such
MR
Nucleus as renal artery stenosis, which leads to increased circulating con-
Aldosterone centrations of angiotensin II and stimulation of aldosterone release
[31]. MR—mineralocorticoid receptor; mRNA—messenger RNA.
FIGURE 1-29
Excess epithelial sodium channel activity in Liddle’s syndrome. The
epithelial sodium channel responsible for sodium reabsorption in
Lumen Cell much of the distal portions of the nephron is a complex of three
Liddle's homologous subunits, , , and each with two membrane-span-
syndrome ning domains. Liddle’s syndrome, an autosomal dominant disorder
Na+ ATP
δ pp 3Na+ causing low renin-aldosterone hypertension often with hypokalemia,
δ pp 2 K+ results from mutated or subunits. These mutations increase the
β
β ADP sodium reabsorptive rate by way of these channels by keeping them
α pp Liddle's
α syndrome open longer, increasing sodium channel density on the membranes,
K+ 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 Intrathoracic Atrial stretch

Blood volume blood volume receptors
Na Cl
Gitleman's
syndrome Aldosterone
Sodium Renin Atrial
excretion Tubular sodium natriuretic peptide
Na+ reabsorption
L Vascular
B Na+- Vasodilation
_ 2Cl Pseudohypoaldosteronism resistance
Cl K+ K+
Bartter's FIGURE 1-31

syndrome
Atrial natriuretic peptide (ANP). In response to increased intravas-
cular volume, atrial distention stimulates the release of ANP from
FIGURE 1-30 the atrial granules where the precursor is stored. Extracellular fluid
volume expansion is associated with increased ANP levels, whereas
Syndromes of diminished sodium reabsorption and hypotension.
reductions in vascular volume and dehydration elicit decreases in
Recently, a variety of syndromes associated with salt wasting, and
plasma ANP levels. ANP participates in arterial pressure regulation
usually hypotension, have been attributed to specific molecular
by sensing the degree of vascular volume expansion and exerting
defects in the distal nephron. Bartter’s syndrome, which usually is
direct vasodilator actions and natriuretic effects. ANP has been
accompanied by metabolic alkalosis and hypokalemia, has been
shown to markedly increase the slope of the pressure natriuresis
found to be associated with at least three separate defects (the three
relationship (see Figs. 1-5 and 1-6). The vasorelaxant and transport
transporters shown) in the thick ascending limb. These defects are
actions are mediated by stimulation of membrane-bound guanylate
at the level of the sodium-potassium-2chloride (Na+-K+-2Cl-)
cyclase, leading to increased cyclic GMP levels. ANP also inhibits
cotransporter, apical potassium channel, and basolateral chloride
renin release, which reduces circulating angiotensin II levels
channel (see Fig. 1-17). Malfunction in any of these three proteins
[33–35]. Related peptides, such as brain natriuretic peptides, have
results in diminished sodium chloride reabsorption similar to that
similar effects on sodium excretion and renin release [36].
occurring with administration of loop diuretics. Gitelman’s syndrome,
which was originally described as a variant of Bartter’s 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
Bartter’s and Gitelman’s syndromes, hyperkalemia may be present.
These rare disorders illustrate that defects in sodium chloride reab-
sorptive 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]. B—basolateral side; L—lumen of tubule.
States of volume depletion and hypoperfu-

Membrane phospholipids sion stimulate prostaglandin synthesis
[16,17,38].
The vasodilator prostaglandins attenuate
Phospholipase A2 the influence of vasoconstrictor substances
during activation of the renin-angiotensin
COOH system, sympathetic nervous system, or both
[33]. These prostaglandins also have trans-
Arachidonic acid port effects on renal tubules through activa-
tion of distinct prostaglandin receptors
[40]. In some pathophysiologic conditions,
Cytochrome P450 enhanced production of TXA2 and other
Cyclooxygenase Lipoxygenases
monooxygenases
vasoconstrictor prostanoids may occur. The
vasoconstriction induced by TXA2 appears
Endoperoxides HPETEs
EETs HETEs to be mediated primarily by calcium influx
(vasodilation ) (vasoconstriction) [17,40].
Leukotrienes HETEs Leukotrienes are hydroperoxy fatty acid
TXA2/PGH2
PGI2/PGE2 (vasoconstriction) (vasoconstriction) products of 5-hydroperoxyeicosatetraenoic
(vasodilation, acid (HPETE) that are synthesized by way of
natriuresis) Lipoxins the lipoxygenase pathway. Leukotrienes are
released in inflammatory and immunologic
reactions and have been shown to stimulate
FIGURE 1-32 renin release. The cytochrome P450 mono-
Arachidonic acid metabolites. Several eicosanoids (arachidonic acid metabolites) are oxygenases produce several vasoactive
released locally and exert both vasoconstrictor and vasodilator effects as well as effects on agents [16,37,41,42] usually referred to as
tubular transport [16,37]. Phospholipase A2 catalyzes formation of arachidonic acid (an EETs and hydroxy-eicosatetraenoic acids
unsaturated 20-carbon fatty acid) from membrane phospholipids. The cyclooxygenase path- (HETEs). These substances exert actions
way and various prostaglandin synthetases are responsible for the formation of endoperox- on vascular smooth muscle and epithelial
ides (PGH2), prostaglandins E2 (PGE2) and I2 (PGI2), and thromboxane (TXA2) [38,39]. tissues [16,41,42]. (Adapted from Navar [3].)
FIGURE 1-33
Kallikrein-kinin system
Kallikrein-kinin system. Plasma and tissue kallikreins are function-
Low molecular weight kininogen High molecular weight kininogen ally different serine protease enzymes that act on kininogens (inac-
tive 2 glycoproteins) to form the biologically active kinins
Tissue kallikrein Plasma kallikrein (bradykinin and lysyl-bradykinin [kallidin]). Kidney kallikrein and
kininogen are localized in the distal convoluted and cortical collect-
Bradykinin
ing tubules. Release of kallikrein into the tubular fluid and intersti-
Kininase I Kininase II (ACE)
NEP tium can be stimulated by prostaglandins, mineralocorticoids,
angiotensin II, and diuretics. B1 and B2 are the two major
Des Arg-bradykinin Kinin degradation products bradykinin receptors that exert most of the vascular actions.
B2-receptor Although glomerulus and distal nephron segments contain both B1
Endothelium-dependent and B2 receptors, most of the renal vascular and tubular effects
B1-receptor Nitric oxide appear to be mediated by B2-receptor activation [16,17,43,44].
PGE2 Bradykinin and kallidin elicit vasodilation and stimulate nitric
oxide, prostaglandin E2 (PGE2) and I2 (PGI2), and renin release
Vasodilation natriuresis [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 deple-
tion, indicating it serves as a mechanism to dampen or offset the
effects of enhanced angiotensin II levels [47,48]. Des Arg—
bradykinin; NEP—neutral endopeptidase.
FIGURE 1-34
10
Decreased Normal Vasopressin. Vasopressin is synthesized by the paraventricular and supraoptic nuclei of
Plasma vasopressin, pg/mL
8 ECF ECF the hypothalamus. Vasopressin is stored in the posterior pituitary gland and released in
volume volume
response to osmotic or volume-dependent baroreceptor stimuli, or both. Atrial filling
6 inhibits vasopressin release. Increases in plasma osmolality increase vasopressin release;
4
Increased however, the relationship is shifted by the status of extracellular fluid (ECF) volume, with
ECF
volume decreases in the ECF volume increasing the sensitivity of the relationship. Stress and trauma
2 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.
0
(Adapted from Navar [8].)
260 280 300 320 340
Plasma osmolality, mOsm/kg
FIGURE 1-35
Collecting duct Plasma membrane Tubule Vasopressin receptors. Vasopressin exerts its cellular actions through
principal cell lumen
two major receptors. Activation of V1 receptors leads to vascular
ATP smooth muscle constriction and increases peripheral resistance.
Adenylate
cyclase Vasopressin stimulates inositol 1,4,5-triphosphate and calcium ion
cAMP + PPi
(Ca2+) mobilization from cytosolic stores and also increases Ca2+
GTP entry from extracellular stores as shown in Figure 1-10. The vaso-
Gα Protein kinase A constrictive action of vasopressin helps increase total peripheral
G
resistance and reduces medullary blood flow, which enhances the
GTP H 2O concentrating ability of the kidney. V2 receptors are located pri-
Aquaporin 2 marily on the basolateral side of the principal cells in the collecting
Gα water
Circulating channels duct segment. Vasopressin activates heterotrimeric G proteins that
vasopressin G GDP
activate adenylate cyclase, thus increasing cyclic AMP levels. Cyclic
V2 Aquaporin 2 AMP (cAMP) activates protein kinase A, which increases the density
of water channels in the luminal membrane. Water channels (aqua-
porin 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 conflu-
ence of homeostatic mechanisms regulating sodium balance
with those regulating extracellular fluid volume. G and
G—proteins; PPi— inorganic pyrophosphate. (Adapted from
Vari and Navar [4].)
Hypertensinogenic Process
either one or more of the physiologic mechanisms described in
Initial increase in Initial increase this chapter fails to respond appropriately to intravascular expan-
vascular resistance in volume sion or some pathophysiologic process causes excess production of
one or more sodium-retaining factors such as mineralocorticoids or
Neurogenic or Volume angiotensin II [51,52]. Through mechanisms delineated earlier,
humoral stimuli overexpansion leads to increased cardiac output that results in over-
perfusion of tissues; the resultant autoregulatory-induced increases
Vasoconstrictor Renal volume Effective blood in peripheral resistance contribute further to an increase in total
Cardiac output
effects retention volume peripheral resistance and elevated arterial pressure [2,53,54].
Hypertension also can be initiated by excess vasoconstrictor
Tissue blood flow
influences that directly increase peripheral resistance, decrease
cardiovascular capacitance, or both. Examples of this type of
Capacitance
Autoregulatory hypertension are enhanced activation of the sympathetic nervous
resistance system and overproduction of catecholamines such as that occurring
adjustments
with a pheochromocytoma [45,54,55]. When hypertension caused
Increased vascular resistance by a vasoconstrictor influence persists, however, it must also exert
significant renal vasoconstrictor and sodium-retaining actions.
Increased arterial Without a renal effect the elevated arterial pressure would cause
blood pressure pressure natriuresis, leading to a compensatory reduction in extra-
cellular fluid volume and intravascular volume. Thus, the elevated
systemic arterial pressure would not be sustained [2,8,54]. Derange-
FIGURE 1-36 ments that activate both a vasoconstrictor system and produce
Overview of mechanisms mediating hypertension. From a patho- sodium-retaining effects, such as inappropriate elevations in the
physiologic perspective, the development of hypertension requires activity of the renin-angiotensin-aldosterone system, lead to an
either a sustained absolute or relative overexpansion of the blood even more powerful hypertensinogenic mechanism that is not easily
volume, reduction of the capacitance of the cardiovascular system, counteracted [27]. These dual mechanisms are why the renin-
or both [4,49,50]. One type of hypertension is due primarily to angiotensin system has such a critical role in the cause of many
overexpansion of either the actual or the effective blood volume forms of hypertension, leaving only the option to increase arterial
compartment. In such a condition of volume-dependent hypertension, pressure and elicit a pressure natriuresis. (Adapted from Navar [3].)
FIGURE 1-37
180
Angiotensin II + Predominance of the renin-angiotensin-aldosterone mechanisms. Collectively, the various
Mean arterial pressure,
160 Aldosterone mechanisms discussed provide overlapping influences responsible for the highly efficient
regulation of sodium balance, extracellular fluid (ECF) volume, blood volume, and arterial
140
mm Hg
pressure. Nevertheless, the synergistic actions of the renin-angiotensin-aldosterone system

120 Aldosterone on both vasoconstrictor as well as sodium-retaining mechanisms exert a particularly pow-
100 Renal perfusion pressure
erful influence that is not easily counteracted. In a recent study by Seeliger and coworkers
Reduce renal perfusion pressure [56], renal perfusion pressure was lowered to 90 to 95 mm Hg. The angiotensin II and
80 aldosterone levels were not allowed to decrease and were fixed at normal levels by contin-
14 uous infusions. The results demonstrated that all compensatory mechanisms (such as
Cumulative sodium balance,
12
Angiotensin II + increased release of atrial natriuretic peptide and reduced activity of the sympathetic sys-
10 Aldosterone tem) could not overcome the hypertensinogenic influence of maintained aldosterone or
mmol/kg BW
8
6 aldosterone plus angiotensin II as long as renal perfusion pressure was not allowed to
4 Aldosterone increase. Thus, under conditions of increased activity of the renin-angiotensin system, an
2 increased renal arterial pressure seems essential to reestablish sodium balance.
0 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
0 1 2 3 4 5 normotensive arterial pressures that cannot be completely compensated by other neural,
Reduced renal pressure, d humoral, or paracrine mechanisms, leaving only the option to increase arterial pressure
and elicit a pressure natriuresis. (Adapted from Seeliger et al. [56].)
References
1. Guyton AC: Blood pressure control: special role of the kidneys and 24. Stoos BA, Garcia NH, Garvin JL: Nitric oxide inhibits sodium reab-
body fluids. Science 1991, 252:1813–1816. sorption in the isolated perfused cortical collecting duct. J Am Soc
2. Cowley AW Jr: Long-term control of arterial blood pressure. Physiol Nephrol 1995, 6:89–94.
Rev 1992, 72:231–300. 25. Stoos BA, Carretero OA, Garvin JL: Endothelial-derived nitric oxide
3. Navar LG: The kidney in blood pressure regulation and development inhibits sodium transport by affecting apical membrane channels in
of hypertension. Med Clin North Am 1997, 81:1165–1198. cultured collecting duct cells.J Am Soc Nephrol 1994, 4:1855–1860.
4. Vari RC, Navar LG: Normal regulation of arterial pressure. In 26. DiBona GF, Kopp UC: Neural control of renal function.Physiol Rev
Principles and Practice of Nephrology, edn 2. Edited by Jacobson HR, 1997, 77:75–197.
Striker GE, Klahr GE. St. Louis: Mosby-Yearbook; 1995:354–361. 27. Mitchell KD, Braam B: Navar LG: Hypertensinogenic mechanisms
5. Luke RG: Essential hypertension: a renal disease? A review and mediated by renal actions of renin-angiotensin system. Hypertension
update of the evidence. Hypertension 1993, 21:380–390. 1992, 19(suppl I):I-18–I-27.
6. Freedman BI, Iskandar SS, Appel RG: The link between hypertension 28. Mitchell KD, Navar LG: Intrarenal actions of angiotensin II in the
and nephrosclerosis. Am J Kidney Dis 1995, 25:207–221. pathogenesis of experimental hypertension. In Hypertension:
Pathophysiology, Diagnosis, and Management, edn 2. Edited by
7. Tepel M, Zidek W: Hypertensive crisis: pathophysiology, treatment
Laragh JH, Brenner BM. New York: Raven Press; 1995:1437–1450.
and handling of complications. Kidney Int 1998, 53(suppl 64):S-2–S-5.
29. O’Neil RG: Aldosterone regulation of sodium and potassium trans-
8. Navar LG: Regulation of body fluid balance. In Edema. Edited by
port in the cortical collecting duct. Sem Nephrol 1990, 10:365–374.
Staub NC, Taylor AE. New York: Raven Press; 1984:319–352.
30. Wehling M, Eisen C, Christ M: Membrane receptors for aldosterone:
9. Navar LG, Majid DSA: Interactions between arterial pressure and
a new concept of nongenomic mineralocorticoid action. NIPS 1993,
sodium excretion. Curr Opin Nephrol Hypertens 1996, 5:64–71.
8:241–244.
10. Rettig R, Schmitt B, Pelzl B, Speck T: The kidney and primary hyper-
31. Lifton RP: Molecular genetics of human blood pressure variation.
tension: contributions from renal transplantation studies in animals
Science 1996, 272:676–680.
and humans. J Hypertens 1993, 11:883–891.
32. Warnock DG: Liddle syndrome: an autosomal dominant form of
11. Folkow B: Pathophysiology of hypertension: differences between
human hypertension. Kidney Int 1998, 53:18–24.
young and elderly. J Hypertens 1993, 11(suppl 4):S21–S24.
33. Jamison RL, Canaan-Kuhl S, Pratt R: The natriuretic peptides and
12. Nichols WW, Nicolini FA, Pepine CJ: Determinants of isolated systolic
their receptors. Am J Kidney Dis 1992, 20:519–530.
hypertension in the elderly. J Hypertens 1992, 10(suppl 6):S73–S77.
34. Paul RV, Kirk KA, Navar LG: Renal autoregulation and pressure natri-
13. Guyton AC, Hall JE: Integration of renal mechanisms for control of
uresis during ANF-induced diuresis. Am J Physiol 1987, 253:F424–F431.
blood volume and extracellular fluid volume. In Textbook of Medical
Physiology, edn 9. Philadelphia: WB Saunders; 1994:367–383. 35. Knepper MA, Lankford SP, Terada Y: Renal tubular actions of ANF.
Can J Physiol Pharmacol 1991, 69:1537–1545.
14. Bankir L, Bouby N, Trinh-Trang-Tan M-M: The role of the kidney in
the maintenance of water balance. In Bailliere’s Clinical Endocrinology 36. Jensen KT, Carstens J, Pedersen EB: Effect of BNP on renal hemody-
and Metabolism. Water and Salt Homeostasis in Health and Disease. namics, tubular function and vasoactive hormones in humans. Am J
Edited by Baylis PH. London: Bailliere; 1989:249–311. Physiol (Renal Fluid Electrolyte Physiol 43) 1998, 274:F63–F72.
15. Baylis PH: Regulation of vasopressin secretion. In Bailliere’s Clinical 37. Capdevila JH, Falck JR, Estabrook RW: Cytochrome P450 and the
Endocrinology and Metabolism: International Practice and Research. arachidonate cascade. FASEB J 1992, 6:731–736.
Edited by Baylis PH. London: Bailliere Tindall; 1989:313–330. 38. Smith WL: Prostanoid biosynthesis and mechanisms of action. Am J
16. Navar LG, Inscho EW, Majid DSA, et al.: Paracrine regulation of the Physiol (Renal Fluid Electrolyte Physiol 32) 1992, 263:F181–F191.
renal microcirculation. Physiol Rev 1996, 76:425–536. 39. Frazier LW, Yorio T: Eicosanoids: their function in renal epithelia ion
17. Arendshorst WJ, Navar LG: Renal circulation and glomerular hemo- transport. Proceedings of the Society for Experimental Biology and
dynamics. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Medicine 1992, 201:229–243.
Gottschalk CW. Boston: Little-Brown; 1997:59–106. 40. Breyer MD, Jacobson HR, Breyer RM: Functional and molecular aspects
18. Braam B, Mitchell KD, Koomans HA: Navar LG: Relevance of the of renal prostaglandin receptors. J Am Soc Nephrol 1996, 7:8–17.
tubuloglomerular feedback mechanism in pathophysiology. J Am Soc 41. McGiff JC: Cytochrome P-450 metabolism of arachidonic acid. Ann
Nephrol 1993, 4:1257–1274. Rev Pharmacol Toxicol 1991, 31:339–369.
19. Briggs JP, Schnermann J: Control of renin release and glomerular 42. Imig JD, Zou A-P, Stec DE, et al.: Formation and actions of 20-
vascular tone by the juxtaglomerular apparatus. InHypertension: hydroxyeicosatetraenoic acid in rat renal arterioles. Am J Physiol
Pathophysiology, Diagnosis, and Management, edn 2. Edited by (Regulat Integrative Comp Physiol 39) 1996, 270:R217–R227.
Laragh JH, Brenner BM. New York: Raven Press, 1995:1359–1385. 43. Bhoola KD, Figueroa CD, Worthy K: Bioregulation of kinins:
20. Carmines PK, Inscho EW, Gensure RC: Arterial pressure effects on kallikreins, kininogens, and kininases. Pharmacol Rev 1992, 44:1–80.
preglomerular microvasculature of juxtamedullary nephrons. Am J 44. El-Dahr SS: Development biology of the renal kallikrein-kinin system.
Physiol (Renal Fluid Electrolyte Physiol 27) 1990, 258:F94–F102. Pediatr Nephrol 1994, 8:624–631.
21. Casellas D, Navar LG: In vitro perfusion of juxtamedullary nephrons 45. Carretero OA, Scicli AG: Local hormonal factors (intracrine,
in rats. Am J Physiol (Renal Fluid Electrolyte Physiol 15) 1984, autocrine, and paracrine) in hypertension. Hypertension 1991, 18
246:F349–F358. (suppl I):I-58–I-69.
22. Carmines PK, Navar LG: Disparate effects of Ca channel blockade on 46. Siragy HM, Jaffa AA, Margolius HS: Bradykinin B2 receptor modulates
afferent and efferent arteriolar responses to ANG II. Am J Physiol renal prostaglandin E2 and nitric oxide. Hypertension 1997, 29:757–762.
(Renal Fluid Electrolyte Physiol 25) 1989, 256:F1015–F1020.
47. Margolius HS: Kallikreins and kinins: molecular characteristics and
23. Navar LG, Inscho EW, Imig JD, Mitchell KD: Heterogenous activa- cellular and tissue responses. Diabetes 1996, 45:S14–S19.
tion mechanisms in the renal microvasculature. Kidney Int 1998,
54(suppl 67):S17–S21.
48. Siragy HM: Evidence that intrarenal bradykinin plays a role in regula- 53. Coleman TG, Guyton AC: Hypertension caused by salt loading in the
tion of renal function. Am J Physiol (Endocrinol Metab28) 1993, dog. Circ Res 1969, XXV:153–160.
265:E648–E654. 54. Guyton AC, Hall JE, Coleman TG, et al.: The dominant role of the
49. Ploth DW, Navar LG: Physiologic control of arterial blood pressure kidneys in long-term arterial pressure regulation in normal and hyper-
and mechanisms of hypertension. In Clinical Approaches to High tensive states. In Hypertension: Pathophysiology, Diagnosis, and
Blood Pressure in the Young. Edited by Kotchen TA, Kotchen JM. Management, edn 2. Edited by Laragh JH, Brenner BM. New York:
Boston: John Wright, PSG; 1983:23–78. Raven Press; 1995, 78:1311–1326.
50. Guyton AC, Manning RA, Normon RA, et al.: Current concepts and 55. Julius S, Nesbitt S: Sympathetic overactivity in hypertension: a moving
perspectives of renal volume regulation in relationship to hyperten- target. Am J Hypertens 1996, 9:113S–120S.
sion. J Hypertens 1986, 4(suppl 4):S49–S56. 56. Seeliger E, Boemke W, Corea M, et al.: Mechanisms compensating Na
51. DeWardener HE: The primary role of the kidney and salt intake in the and water retention induced by long-term reduction of renal perfusion
aetiology of essential hypertension: part II. Clin Sci 1990, 79:289–297. pressure. Am J Physiol (Regulat Integrative Comp Physiol 42) 1997,
52. Hamlyn JM, Blaustein MP: Sodium chloride, extracellular fluid vol- 273:R646–R654.
ume, and blood pressure regulation. Am J Physiol (Renal Fluid
Electrolyte Physiol 20) 1986, 251:F563–F575.
Renal Parenchymal Disease
and Hypertension
Stephen C. Textor
H
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 inter-
stitial 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 mor-
tality 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
FIGURE 2-1
FORMS OF UNILATERAL RENAL Forms of unilateral renal parenchymal diseases related to hypertension. Many unilateral
PARENCHYMAL DISEASE RELATED abnormalities, such as congenital malformations, renal agenesis, reflux nephropathy, and
TO HYPERTENSION 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
Renal artery stenosis should be emphasized that unilateral renal disease does not reduce the overall glomerular
Atherosclerosis and fibromuscular lesions (Chapter X) filtration rate beyond that expected in patients with a solitary kidney. It follows that addi-
Small vessel disease tional reductions in the glomerular filtration rate must reflect bilateral renal injury.
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 2-2
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.
80
Most forms of renal disease are associated with hypertension. This
70 association is most evident with glomerular diseases, including diabetic
Prevalence of hypertension, %
60
nephropathy (DN) and membranoproliferative glomerulonephritis
(MPGN), in which 70% to 80% of patients are affected. Minimal
50 change nephropathy (MCN) is a notable exception. Tubulointerstitial
40 disorders such as analgesic nephropathy, medullary cystic diseases,
and chronic reflux nephropathies are less commonly affected.
30 APKD—adult-onset polycystic kidney disease; CIN—chronic intersti-
20 tial nephritis; FSGN—focal segmental glomerulonephritis; MGN—
membranous glomerulonephritis. (Data from Smith and Dunn [1].)
10
0
CIN APKD MCN IgA MGN DN MPGN FSGN
Renal Parenchymal Disease and Hypertension 2.3
FIGURE 2-4
100 Prevalence of hypertension requiring therapy as a function of the degree of chronic renal
*n=255 patients
90 failure in the Modification of Diet in Renal Disease (MDRD) trial on progressive renal
Mean GFR=18.5 mL/min/1.73 m2
80 failure. The mean age of these patients was 52 years, with glomerular disease (25%) and
70 Mean GFR=39 mL/min/1.73 m2 polycystic disease (24%) being the most common renal diagnoses in this trial. In Study B,
60 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
50
severe the level of renal dysfunction, the more antihypertensive therapy is required to
%
40 NHANES estimates
achieve acceptable blood pressures. Patients with glomerular filtration rates (GRFs) below
30 10 mL/min were hypertensive in 95% of cases. NHANES—National Health and Nutrition
20 Examination Survey. (Data from Klahr and coworkers [2].)
10
0
MDRD: MDRD: US
Study B* Study A Population
FIGURE 2-5
Early
Hypertension in acute renal disease. Acute renal failure is defined as transient increases in
80
Late serum creatinine above 5.0 mg/dL. During the course of acute renal failure, worsening of
70 preexisting levels or newly detected hypertension (>140/90 mm Hg) is common and almost
Prevalence of hypertension, %
60
universally observed in patients with acute glomerulonephritis (GN). Many of these
patients have lower pressures as the course of acute renal injury subsides, although resid-
50 ual abnormalities in renal function and sediment may remain. Blood pressure returns to
40 normal in some but not all of these patients. Overall, 39% of patients with acute renal
failure develop new hypertension. IN—interstitial nephritis. (Adapted from Rodriguez-
30 Iturbe and coworkers [3]; with permission.)
20
10
0
Acute GN Acute IN

Micrograph of an onion skin lesion from a patient with malignant
hypertension.
Pathophysiology of Hypertension in Renal Disease

FIGURE 2-7
Pathophysiologic mechanisms related to
hypertension in parenchymal renal disease:
Blood pressure = Cardiac output x Systemic vascular resistance
schematic view of candidate mechanisms. The
balance between cardiac output and systemic
Increased extracellular fluid volume Increased Increased vasoconstriction Decreased vasodilation vascular resistance determines blood pressure.
Decreased glomerular filtration rate contraction Increased adrenergic stimuli Decreased prostacyclin Numerous studies suggest that cardiac output
Impaired sodium excretion Increased Inappropriate Decreased nitric oxide is normal or elevated, whereas overall extra-
Increased renal nerve activity adrenergic renin-endothelin release
cellular fluid volume is expanded in most
Ineffective natriuresis, eg, atrial activation Increased endothelin-derived
natriuretic peptide resistance contracting factor patients with chronic renal failure. Systemic
Increased thromboxane 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 renin-
angiotensin system, endothelin, and vasoac-
tive prostaglandins. An additional feature in
some disorders appears to depend on reduced
vasodilation, such as in impaired production
of nitric oxide.
7 7
6 6
Intake and output of water and salt
Intake and output of water and salt
t
blat
G o ld
5 5 Normal
ys
ne
(x normal)
(x normal)
kid
4 D 4
ted
High intake
ula
tim
3 3
n
e-s
F
nsio
High intake
Normal
ron
hyp tial
ass G
erte
ste
E
n
2 2 lm
E s se
do
ena
Al
r
of
Normal intake A B Normal intake A B ss D
1 1 Lo
C
Low intake Low intake H
C
0 0
0 50 100 150 200 0 50 100 150 200
A Arterial pressure, mm Hg B Arterial pressure, mm Hg
FIGURE 2-8
A, The relationship between renal artery perfusion pressure and as “loss of renal mass.” Similar effects are observed in conditions
sodium excretion (which defines “pressure natriuresis”) has been with disturbed hormonal effects on sodium excretion (aldos-
the subject of extensive research. Essential hypertension is charac- terone-stimulated kidneys) or reduced renal blood flow as a
terized by higher renal perfusion pressures required to achieve result of an arterial stenosis (“Goldblatt” kidneys). In all of these
daily sodium balance. B, Distortion of this relationship routinely instances, higher arterial pressures are required to maintain
occurs in patients with parenchymal renal disease, illustrated here sodium balance.
200
Hemodialysis Cumulative daily
130 40
Percentage of body weight, kg
sodium intake
Total blood volume, mL/cm

0
126 35 Cumulative urinary sodium loss
–400
Sodium, mEq
122 30
–800
Sodium losses during
hemodialysis or ultrafiltration
118
–1200
Net sodium loss
F S S M T W TH F S S M
Days –1600
Total net loss of
10.0 sodium=1741 mEq
activity, mg/mL/h
Uremic
Plasma renin
control F S S M T W TH F S S M T
5.0 subjects B Days
activity, and blood pressure (before and after administration of an

ACE inhibitor) over 11 days of vigorous fluid ultrafiltration.
180
Blood pressure, mm Hg
Captopril, 25 mg
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
140
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
100 renin activity gradually increased during sodium removal, and blood
A
pressure became dependent on the renin-angiotensin system, as
defined by a reduction in blood pressure after administration of the
FIGURE 2-9 angiotensin-converting enzyme inhibitor captopril. Achieving adequate
Sodium expansion in chronic renal failure. The degree of sodium reduction of both extracellular fluid volume and sodium is essential
expansion in patients with chronic renal failure can be difficult to to satisfactory control of blood pressure in patients with renal failure.
ascertain. A, Shown are data regarding body weight, plasma renin B, Daily and cumulative sodium balance.
FIGURE 2-10
Angiotensin II inhibitor, µg/kg/min
5 10 50 100 10 10
Interaction between sodium balance and angiotensin-dependence in malignant hypertension.
Studies in a patient with renal dysfunction and accelerated hypertension during blockade
pressure, mm Hg
Saline infusion L40

200 of the renin-angiotensin system using Sar-1-ala-8-angiotensin II demonstrate the interaction
Blood
between angiotensin and sodium. Reduction of blood pressure induced by the angiotensin
150
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],
100
40 mg intravenously) induced net sodium losses, restimulated plasma renin activity, and
restored sensitivity to the angiotensin II antagonist. Such observations further establish the
Plasma renin Cumulative sodium
reciprocal relationship between the sodium status and activation of the renin-angiotensin
balance, mEq
200 system [5]. (From Brunner and coworkers [5]; with permission.)
100
0
activity, ng/mL/hr
100
50
0
0 1 11 35 38 41 65 67
Hours
FIGURE 2-11
15 s A, Sympathetic neural activation in chronic
Normal
renal disease. Adrenergic activity is dis-
person turbed in chronic renal failure and may par-
ticipate in the development of hypertension.
Microneurographic studies in patients
undergoing hemodialysis demonstrate
enhanced neural traffic (panel A) that
Hemodialysis,
relates closely to peripheral vascular tone [6].
bilateral
nephrectomy 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
Hemodialysis, no
central adrenergic outflow. B, Delayed onset
nephrectomy
hypertension in denervated rats. Panel B
shows evidence from experimental studies in
denervated animals subjected to deoxycortico-
sterone–salt hypertension. The role of the
renal nerves in modifying the development
of hypertension is supported by studies of
Neurogram
renal denervation that show a delayed onset
of hypertension, although no alteration in
Electrocardiogram the final level of blood pressure was achieved.
NS—not significant. (Panel A from
A 3s Converse and coworkers [6]; with permis-
sion. Panel B from Katholi and coworkers
200 Sham
Renal denervated
Systolic blood pressure, mm Hg
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
0 5 10 15 20 25 30 35
B Deoxycorticosterone acetate–salt administration, d
FIGURE 2-12
MAJOR CANDIDATE MECHANISMS THAT MAY Major candidate mechanisms that may elevate peripheral vascular
ELEVATE PERIPHERAL VASCULAR RESISTANCE resistance in renal parenchymal disease. Some data support each of
IN RENAL PARENCHYMAL DISEASE 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,
Increased vasoconstrictors Impaired or relatively inadequate vasodilators rarely is the effect major [8,9]. Most levels of vasodilators, including
nitric oxide, prostacyclin, and atrial natriuretic peptide, are normal
Renin-angiotensin system Nitric oxide: inadequate compensation or elevated in patients with renal disease. The vasodilators appear
Endothelin Vasodilator prostaglandins: prostacyclin 2 to buffer the vasoconstrictive actions of angiotensin II, which may
Prostanoids: thromboxane Natriuretic peptides: atrial natriuretic peptide be increased abruptly if the vasodilator is removed, as occurs with
Arginine vasopressin Kallikrein-kinin system inhibition of cyclo-oxygenase with the use of nonsteroidal anti-
Endogenous digitalis-like inflammatory drugs.
substance: ouabain (?)
Sham-operated rats Rats with renal mass reduction
Mean ±SEM
200 Horizontal bars=mean values
Urinary endothelin excretion, pg/d

80 *P<0.01 vs pretransplantation P<0.01 vs basal
†P<0.01 vs normal subjects
Urinary endothelin, ng/d
160
60 *† *† 120
40 80 *
†
20 Normal
40
0 0
A Pretransplantation 12 mo 24 mo B Basal Day 45 Basal Day 45
FIGURE 2-13
Urinary endothelin in renal disease. A, Urinary endothelin levels in diminished glomerular filtration rate. With time, however, these
patients with cyclosporine-induced renal dysfunction and hypertension changes lose the feature of reversibility [11]. B, Renal ablation.
before and after liver transplantation. These patients had near-normal Urinary endothelin levels in rats exposed to reduced renal mass
kidney function before liver transplantation, after which their glomeru- achieved by 5/6 nephrectomy. As in humans, plasma levels of
lar filtration rates decreased from 85 to 55 mL/min, on average. These endothelin were dissociated from urinary levels, and injected
data underscore the observation that the kidney itself is a rich source endothelin was not excreted. These results suggest that urinary levels
of vasoactive materials and that renal excretion of substances such as were of renal origin. These studies further support the concept that the
endothelin is independent of circulating blood levels [10]. Endothelin has diminished nephron number elicits production of potent vasoactive
properties that both facilitate vasoconstriction and enhance mitogenic and inflammatory materials that may accelerate irreversible parenchy-
and fibrogenic responses, perhaps accelerating interstitial fibrosis in mal injury. (Panel A from Textor and coworkers [10]; with permis-
the kidney. Early withdrawal of cyclosporine leads to reversal of a sion. Data in panel B from Benigni and coworkers [12].)
Renal parenchymal disease PHARMACOLOGIC AGENTS THAT COMMONLY

AGGRAVATE OR INDUCE HYPERTENSION IN
PARENCHYMAL RENAL DISEASE
Decreased afferent
Increased angiotensin Increased cytokine
resistance
Increased norepinephrine Increased growth Other agents
Decreased efferent
Increased endothelin factors
resistance
Corticosteroids Over-the-counter sympathomimetic
Cyclosporine agents, eg, phenylpropanolamine
Impaired Systemic Cellular Supplements containing ephedrine
Erythropoietin
autoregulation hypertension proliferation
Nonsteroidal anti-inflammatory drugs Oral contraceptives
(less common with low-dose forms)
Amphetamines and stimulants,
eg, methylphenidate hydrochloride
Increased glomerular Increased glomerular and cocaine
pressure volume
Increased glomerular
pressure FIGURE 2-15
Many pharmacologic agents affect blood pressure levels or the
effectiveness of antihypertensive therapy. Shown here are several
FIGURE 2-14 agents that commonly lead to worsening hypertension and are like-
Mechanisms of glomerular injury in hypertension and progressive ly to be administered to patients with renal disease.
renal failure. This schematic diagram summarizes the general mech-
anisms 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].)
160 Control
*
pressure, mL/min
10 µg L–NAME
pressure, mm Hg
120 *
Mean arterial
150 * 50 µg L–NAME
Blood
90 140 *
*
60 130
30 120
1 min
Heart rate, bpm
280
110
240
flow, mL/min
Results=means±standard error
Renal plasma
4.0 *P<0.05 compared with controls

200 *
L-NAME L-Arginine 3.0
*
100 mg kg-1 300 mg kg-1 *
A 2.0 * * *
1.0
Glomerular filtration
FIGURE 2-16
rate, mL/min
1.2
*
Increase in arterial pressure induced by inhibition of nitric oxide. *
1.0 *
A, Intra-arterial pressure in rabbits during N-nitro-L-arginine * *
methyl ester (L-NAME) infusion. B, Decrease in renal plasma flow 0.8
and glomerular filtration rate in the blood pressures of rats during
nitric oxide inhibition.
B Control 60' 120' 180'

Control
C, Urine flow rate and urinary sodium excretion over time. Inhibition
21 of nitric oxide synthesis from L-arginine by a competitive substrate
10 µg/kg/min L– NAME *
50 µg/kg/min L– NAME such as L-NAME produces dose-dependent and widespread vaso-
excretion, µEq/min
19
Urinary sodium
constriction, leading to an increase in blood pressure [13]. Within

17 specific regional beds such as the kidney, inhibition of nitric oxide
produces a decrease in renal plasma flow, diminished glomerular
15
filtration, and sodium retention [14]. The magnitude of these changes
13 * in normal animals and humans suggests that tonic nitric oxide produc-
* tion is a major endothelial buffering mechanism preserving vascular
11
tone. The degree to which renal parenchymal disease alters the pro-
9 duction of nitric oxide is not known precisely. In some situations,
140 Results=means±standard error such as nephrotoxicity associated with cyclosporine administration,
*P<0.05 compared with controls endothelial production of nitric oxide appears to be substantially
*
impaired [15]. (Panel A from Rees and coworkers [13]; with per-
rate, mL/min
120
Urinary flow
mission. Panel B from Lahera and coworkers [14]; with permission.)

100
80
*
60
C Control 60' 120' 180'
Clinical Features of Hypertension in Renal Disease
A. HYPERTENSION IN PARENCHYMAL RENAL DISEASE: 100 Cardiac

CLINICAL MANIFESTATIONS OF HYPERTENSIVE DISEASE 90 Vascular
Infection
80 Other
70
Percentage of total
Cardiovascular disease Central nervous system Progressive renal injury

60
Myocardial infarction Stroke End-stage renal disease 50
Congestive heart failure Intracerebral hemorrhage Increased proteinuria
40
Atherosclerotic vascular disease
30
Claudication and limb ischemia
Aneurysm 20
10
0
B Transplantation Dialysis
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.)
Left ventricular Congestive 40

Blood pressure
hypertrophy heart failure
35
30
Percentage of total
25
Death: Congestive heart failure 20
Blood pressure
Overall mortality
15
A
10
5
FIGURE 2-18
Based on average blood pressure values, a strong direct relationship 0
was found between arterial pressure and left ventricular hypertrophy, B Left ventricular Systolic Left ventricular
chamber dilation dysfunction 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 rela-
tionship 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].)
FIGURE 2-19
250 Around-the-clock ambulatory blood pressure
Awake: 156/101 mm Hg Nocturnal: 167/100 mm Hg
monitoring in a patient with renal disease.
Loss of diurnal blood pressure patterns
200 Blood pressure values

Heart rate have been implicated in increased rates of
target organ injury in patients with hyper-
150 tension. In normal persons with essential
140 hypertension, nocturnal pressures decreased
by at least 10% and were associated with a
100 decrease in heart rate. Several conditions have
90
been associated with a loss of the nocturnal
decrease in pressure, particularly chronic
50
steroid administration and chronic renal
MMMM Rx F d Fd ZZZZZ Rx RxZZZ ZZZZZZZZZZZZZZZZZZ MMMM failure. Such a loss in normal circadian
MMMM
rhythm, in particular loss of the nocturnal
0
decrease in blood pressure is more commonly
0.0 10a 12n 2p 4p 6p 8p 10p 12m 2a 4a 6a 8a
associated with left ventricular hypertrophy
Real time data
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.
1.0
0.9
0.8
0.7
1/Creatinine
0.6
0.5
0.4
0.3
0.2
0.1
0.0
May Feb Nov Aug May Jan Oct Jul
1979 1982 1984 1987 1990 1993 1995 1998
B Date
A
Hypertension accelerates the rate of progressive renal failure in blood pressure level at approximately 240/130 mm Hg. The biopsy
patients with parenchymal renal disease. A, Photomicrograph of specimen shows the following features of malignant nephrosclerosis:
malignant phase hypertension. Regardless of the cause of renal disease, these patients develop vascular and glomerular injury, which can
untreated hypertension leads to more rapid loss of remaining nephrons progress to irreversible renal failure. Before the introduction of antihy-
and decline in glomerular filtration rates. A striking example of pertensive drug therapy, patients with malignant phase hypertension
pressure-related injury may be observed in patients with malignant routinely proceeded to uremia. Effective antihypertensive therapy can
phase hypertension. This image is an open biopsy specimen obtained slow or reverse this trend in some but not all patients. B, Progressive
from a patient with papilledema, an expanding aortic aneurysm, and renal failure in malignant hypertension over 8 years.
100
0.12 n=11,912 men White=300,645
SBP>180
P<0.001 Black=20,222 83.1
0.10 N=332,544 men
80
Incidence per 100,000 person-years, %
Proportion with ESRD
0.08
60
0.06
165<SBP≤180 40 37.21
32.37
0.04 27.34 26.18
20 15.83
0.02 14.22
SBP≤165 9.1
5.43 5.41
0.00 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 <117 117–123 124–130 131–140 >140
A Years from beginning therapy to ESRD B Systolic blood pressure, mm Hg
FIGURE 2-21
Blood pressure levels and rates of end-stage renal disease (ESRD). A, follow-up period [18]. Similarly, follow-up studies after 16 years of
Line graph showing Kaplan-Meier estimates of ESRD rates; 15-year more than 300,000 men in MRFIT demonstrated a progressive increase
follow-up. B, Age-adjusted 16-year incidence of all-cause ESRD in in the risk for ESRD, most pronounced in blacks [19]. These data
men in the Multiple Risk Factor Intervention Trial (MRFIT). Large- suggest that blood pressure levels predict future renal disease. However,
scale epidemiologic studies indicate a progressive increase in the risk it remains uncertain whether benign essential hypertension itself
for developing ESRD as a function of systolic blood pressure levels. induces a primary renal lesion (hypertensive renal disease nephroscle-
Follow-up of nearly 12,000 male veterans in the United States rosis) or acts as a catalyst in patients with other primary renal disease,
established that systolic blood pressure above 165 mm Hg at the initial otherwise not detected at initial screening. SBP—systolic blood
visit was predictive of progressively higher risk of ESRD over a 15-year pressure. (Panel A from Perry and coworkers [18]; with permission.)
50
0 0
40
Ccr, mL/min
–3 –3
filtration rate, mL/min/y

Decrease in glomerular
30
–6 –6
Chronic glomerulonephritis:
20 Rates of progression over time decrease
after reduction of BP from 149/102 mm Hg –9 –9
Protein excretion, g/d
to treated level, 136/90 mm Hg. 0–0.25 1.0–3.0
4 –12 0.25–1 ≥3.0 –12
mL/mmol-1
3 –15 –15
Study A: mean GFR: 39 mL/min/1.73 m2
N=585: range: 25–55 mL/min
2 –18 –18
Cr-1/s,
86 92 98 107
1 Mean follow-up MAP, mm Hg
–400 –200 0 +200 +400
Days
FIGURE 2-23
Blood pressure, proteinuria, and the rate of renal disease progression:
FIGURE 2-22 results from the Modification of Diet in Renal Disease (MDRD)
Rates of progression in glomeruloneophritis. The decrease in glomeru- trial. Shown are rates of decrease of glomerular filtration rate
lar filtration rate is illustrated. The rates of decline decreased con- (GFR) for patients enrolled in the MDRD trial, depending on level
siderably with administration of antihypertensive drug therapy. of achieved treated blood pressure during the trial [21]. A component
Among other mechanisms, the decrease in arterial pressure lowers of this trial included strict versus conventional blood pressure control.
transcapillary filtration pressures at the level of the glomerulus [20]. The term strict was defined as target mean arterial pressure (MAP)
This effect is correlated with a reduction in proteinuria and slower of under 92 mm Hg. The term conventional was defined as MAP
development of both glomerulosclerosis and interstitial fibrosis. A of under 107 mm Hg. The rate of decline in GFR increased at higher
distinctive feature of many glomerular diseases is the massive pro- levels of achieved MAP in patients with significant proteinuria
teinuria and nephron loss associated with high single-nephron (>3.0 g/d). No such relationship was evident over the duration of
glomerular filtration, partially attributable to afferent arteriolar this trial (mean, 2.2 years) for patients with less severe proteinuria.
vasodilation. The appearance of worsening proteinuria (>3 g/d) is These data emphasize the importance of blood pressure in deter-
related to progressive renal injury and development of renal failure. mining disease progression in patients with proteinuric nondiabetic
Reduction of arterial pressure can decrease urinary protein excre- renal disease. No distinction was made in this study regarding the
tion and slow the progression of renal injury. Ccr—creatinine clear- relative benefits of specific antihypertensive agents. (From Peterson
ance rate; Cr-1/s—reciprocal creatinine, expressed as 1/creatinine. and coworkers [21]; with permission.)
(From Bergstrom and coworkers [20]; with permission.)
Effects of Antihypertensive Therapy

on Renal Disease Progression
FIGURE 2-24
Blood pressure and rate of progressive renal failure. Rates of disease
Slope of 1/creatinine vs time, dL/mg mo
progression (defined as the slope of 1/creatinine) were determined in

–0.006 86 patients who reached end-stage renal disease and dialytic therapy.
The rates of progression were defined between mean creatinine levels
–0.008 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
–0.010
achieved diastolic blood pressure during this interval. Hence, these
authors argue that more intensive antihypertensive therapy may
–0.012 delay the need for replacement therapy in patients with end-stage
renal disease. As noted in the Modification of Diet in Renal Disease
0 trial, such benefits are most apparent in patients with proteinuria
70–85 85–90 90–96 96–113 over a shorter follow-up period. (From Brazy and coworkers [22];
Range of diastolic blood pressure (mm Hg) for with permission.)
each quartile of the population
FIGURE 2-25
CLASSES OF ANTIHYPERTENSIVE AGENTS USED The current classification of agents applied for chronic treatment
IN TREATMENT OF CHRONIC RENAL DISEASE 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 accu-
Diuretics: mulation and limitations of individual drug efficacy as glomerular
Thiazide class filtration rates decrease in chronic renal disease. Potassium levels
Loop diuretics
may increase during administration of potassium-sparing agents
and medications that inhibit the renin-angiotensin system, especial-
Potassium-sparing agents
ly in patients with impaired renal function [24].
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
4
60 Conventional Mean
Strict ±SEM
n=87 patients 3
Rate of change in GFR, mL/min/1.73 m2/y
55 Bars=95% confidence
intervals for GFR
estimates 2
GFR, mL/min/1.73 m2/y
50
45 1
40 0
35 –1
30 –2
25 –3
–6 0 6 12 18 24 30 36 42 48 Strict Conventional
A Time, mo B Blood pressure control group
FIGURE 2-26
Strict blood pressure control and progression of hypertensive these patients were low. It should be emphasized that entry criteria
nephrosclerosis. Whether vigorous blood pressure reduction reduces excluded patients with diabetes and massive proteinuria. Initial
progression of early parenchymal renal disease in blacks with studies from the African American Study of Kidney Disease trial
nephrosclerosis is not yet certain. A and B, A randomized prospective confirm that biopsy findings in most patients with clinical features of
trial comparing strict (panel A) blood pressure control (defined as hypertension were considered consistent with primary hypertensive
diastolic blood pressure [DBP] <80 mm Hg) with conventional (panel disease [26]. Whether lower than normal levels of blood pressure in
B) levels of diastolic control between 85 and 95 mm Hg for more these patients will prevent progression to end-stage renal disease over
than 3 years could not identify a reduction in rates of disease progres- longer time periods remains to be determined. GFR—glomerular
sion [25]. Of patients, 68 of 87 were black. Rates of progression in filtration rate. (From Toto and coworkers [25]; with permission.)
FIGURE 2-27
100
Angiotensin-converting enzyme (ACE)
90 inhibitors and chronic renal disease.
Progression of type I diabetic nephropathy
80 to renal failure was reduced in the ACE
inhibitor arm of a trial comparing conven-
dialysis or transplantation, %
Patients who died or needed
70
tional antihypertensive therapy with a
60 regimen containing the ACE inhibitor
captopril. All patients in this trial had
50
significant proteinuria (>500 mg/d). The
P=0.002 most striking effect of the ACE inhibitor
40
regimen was seen in patients with higher
30 serum creatinine levels (>1.5 mg/dL) as
shown in the top two lines. It should be
20
noted that calcium channel blocking drugs
10 were excluded from this trial and the ACE
inhibitor arm had somewhat lower arterial
0 P=0.14
pressures during treatment. These data offer
support to the concept that ACE inhibition
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
lowers intraglomerular pressures, reduces
Years of follow-up
Creatinine ≥1.5 mg/dL proteinuria, and delays the progression of
Placebo 49 48 44 40 33 23 16 7 1 diabetic nephropathy by more mechanisms
Captopril 53 53 52 51 48 36 25 17 8 than can be explained by pressure reduction
Creatinine <1.5 mg/dL alone. (Data from Lewis and coworkers [27].)
Placebo 153 150 148 146 138 98 84 52 25
Captopril 154 154 152 150 147 104 78 47 29
2.6 2.6
Benazepril: n=583 patients; creatinine=1.5–4.0 Benazepril: n=583 patients; creatinine=1.5–4.0 117
Placebo Placebo
2.4 239 2.4

137
262
2.2 2.2
2.0 2.0
0 1 2 3 0 1 2 3
A Years B Years
FIGURE 2-28
Angiotensin-converting enzyme (ACE) inhibition in nondiabetic renal data support a role for ACE inhibition, the results are considerably
disease. A and B, Shown here are serum creatinine levels from the less convincing than are those for diabetic nephropathy. These results
12-month (panel A) and 36-month (panel B) cohorts followed in the argue that some groups may not experience major benefit from ACE
benazepril trial. In this trial, 583 patients were randomized to therapy inhibition over the short term. Preliminary reports from recent studies
with or without benazepril [28]. Slight reductions in the rates of limited to patients with proteinuria suggest that rates of progression
increase in creatinine and of stop points in the ACE inhibitor group were substantially reduced by treatment with ramipril [29]. (From
occurred; however, these reductions were modest. Whereas these Maschio and coworkers [28]; with permission.)
FIGURE 2-29
CONCLUSIONS AND RECOMMENDATIONS OF THE SIXTH REPORT OF Conclusions and Recommendations of the
THE JOINT NATIONAL COMMITTEE ON PREVENTION, DETECTION, Sixth Report of the Joint National
EVALUATION AND TREATMENT OF HIGH BLOOD PRESSURE, 1997 Committee (JNC) on Prevention, Detection,
Evaluation and Treatment of High Blood,
1997 [23]. The JNC Committee has empha-
1. Hypertension may result from renal disease that reduces functioning nephrons. sized the importance of vigorous blood
2. Evidence shows a clear relationship between high blood pressure and end-stage renal disease. pressure control with any agents needed,
3. Blood pressure should be controlled to ≤130/85 mm Hg (<125/75 mm Hg) in patients with proteinuria
rather than specific classes of medication.
in excess of 1 g/24 h. Angiotensin-converting enzyme inhibitors
4. Angiotensin-converting enzyme inhibitors work well to lower blood pressure and slow progression of renal failure. in proteinuric disease are the exception.
References
1. Smith MC, Dunn MJ: Hypertension in renal parenchymal disease. In 16. Whitworth JA: Renal parenchymal disease and hypertension. In
Hypertension: Pathophysiology, Diagnosis and Management. Edited by Clinical Hypertension. Edited by Robertson JIS. Amsterdam: Elsevier,
Laragh JH, Brenner BM. New York: Raven Press; 1995:2081–2102. 1992:326–350.
2. Klahr S, Levey AS, Beck GJ, et al.: The effects of dietary protein 17. Foley RN, Parfrey PS, Harnett JD, et al.: Impact of hypertension on
restriction and blood-pressure control on the progression of chronic cardiomyopathy, morbidity and mortality in end-stage renal disease.
renal disease. N Engl J Med 1994, 330:877–884. Kidney Int 1996, 49:1379–1385.
3 Rodriguez-Iturbe B, Baggio B, Colina-Chouriao J, et al.: Studies on the 18. Perry HM, Miller JP, Fornoff JR, et al.: Early predictors of 15-year
renin-aldosterone system in the acute nephritic syndrome. Kidnet Int end-stage renal disease in hypertensive patients. Hypertension 1995,
1981, 445–453 25(part 1):587–594.
4. Curtiss JJ, Luke RG, Dustan HP, et al.: Remission of essential hyperten- 19. Klag MJ, Whelton PK, Randall BL, et al.: End-stage renal disease in
sion after renal transplantation. N Engl J Med 1983, 309:1009–1015. African-American and White men. JAMA 1997, 277:1293–1298.
5. Brunner HR, Gavras H, Laragh JH: Specific inhibition of the renin- 20. Bergstrom J, Alvestrand A, Bucht H, Guttierrez A: Progression of chronic
angiotensin system: a key to understanding blood pressure regulation. renal failure in man is retarded with more frequent clinical follow-ups
Prog Cardiovasc Dis 1974; 17:87–98. and better blood pressure control. Clin Nephrol 1986, 25:1–6.
6. Converse RL, Jacobsen TN, Toto RD, et al.: Sympathetic overactivity in 21. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control, pro-
patients with chronic renal failure. N Engl J Med1992, 327:1912–1918. teinuria and the progression of renal disease. Ann Intern Med 1995;
123:754–762.
7. Katholi RE, Nafilan AJ, Oparil S: Importance of renal sympathetic
tone in the development of DOCA-salt hypertension in the rat. 22. Brazy PC, Stead WW, Fitzwilliam JF: Progression of renal insufficiency:
Hypertension 1980, 2:266–273. role of blood pressure. Kidney Int 1989, 35:670–674.
23. JNC Committee: Sixth Report of the Joint National Committee on
8. Benigni A, Zoja C, Cornay D, et al.: A specific endothelin subtype A
Prevention, Detection, Evaluation and Treatment of High Blood Pressure.
receptor antagonist protects against injury in renal disease progression.
Bethesda, MD: National Institutes of Health Publication; 1997.
Kidney Int 1993, 44:440–444.
24. Textor SC: Renal failure related to ACE inhibitors. Semin Nephrol
9. Levin ER: Mechanisms of disease: endothelins. N Engl J Med 1995,
1997, 17:67–76.
333:356–363.
25. Toto RD, Mitchell HC, Smith RD, et al.: “Strict” blood pressure control
10. Textor SC, Burnett JC, Romero JC, et al.: Urinary endothelin and renal and progression of renal disease in hypertensive nephrosclerosis.
vasoconstriction with cyclosporine or FK506 after liver transplantation. Kidney Int 1995, 48:851–859.
Kidney Int 1995, 47:1426–1433.
26. Fogo A, Breyer JA, Smith MC, et al.: Accuracy of the diagnosis of
11. Sandborn WJ, Hay JE, Porayko MK, et al.: Cyclosporine withdrawal for hypertensive nephrosclerosis in African-Americans: a report from the
nephrotoxicity in liver transplant recipients does not result in sustained African American Study of Kidney Disease (ASSK) trial. Kidney Int
improvement in kidney function and causes cellular and ductopenic 1997; 51:244–252.
rejection. Hepatology 1994, 19:925–932.
27. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-
12. Benigni A, Perico N, Gaspari F, et al.: Increased renal endothelin pro- converting-enzyme inhibition on diabetic nephropathy. N Engl J Med
duction in rats with renal mass reduction. Am J Physiol 1991, 1993, 329:1456–1462.
260:F331–F339.
28. Maschio G, Alberti D, Janin G, et al.: Effect of the angiotensin-converting
13. Rees DD, Palmer RMJ, Moncada S: Role of endothelium-derived nitric enzyme inhibitor benazepril on the progression of chronic renal insuf-
oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A ficiency. N Engl J Med 1996, 334:939–945.
1989, 86:3375–3378.
29. Ruggenenti P, Perna A, Mosconi M, et al.: The angiotensin converting
14. Lahera V, Salom MG, Miranda-Guardiola F, et al.: Effects of N-nitro- enzyme inhibitor ramipril slows the rate of GFR decline and the pro-
L-arginine methyl ester on renal function and blood pressure. Am J gression to end-stage renal failure in proteinuric, non-diabetic chronic
Physiol 1991, 261:F1033–F1037. renal diseases [abstract]. J Am Soc Nephrol 1997, 8:147A.
15. Gaston RS, Schlessinger SD, Sanders PW, et al.: Cyclosporine inhibits 30. Giatras I, Lau J, Levey AS: Effect of angiotensin-converting enzyme
the renal response to L-arginine in human kidney transplant recipients. inhibitors on the progression of non-diabetic renal disease: a meta-
J Am Soc Nephrol 1995, 5:1426–1433. analysis of randomized trials. Ann Intern Med 1997, 127:345.
Renovascular Hypertension
and Ischemic Nephropathy
Marc A. Pohl
T
he major issues in approaching patients with renal artery steno-
sis 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 hyper-
tension, the renin angiotensin system, diagnostic tests to detect pre-
sumed renovascular hypertension, and the relative merits of surgical
renal revascularization (SR), percutaneous transluminal renal angio-
plasty (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 func-
tioning 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 condi-
tion and has attracted the fascination of nephrologists, vascular sur-
geons, and interventional cardiologists and radiologists.
The detection of renal artery stenosis in a patient with hyperten-
sion usually evokes the assumption that the hypertension is due to the
renal artery stenosis. However, renal artery stenosis is not synony-
mous with “renovascular hypertension.” On the basis of autopsy
studies and clinical angiographic correlations, high-grade atheroscle- CHAPTER
rotic renal artery stenosis (ASO-RAS) in patients with mild blood
pressure elevation or in patients with normal arterial pressure is well
3
recognized. The vast majority of patients with ASO-RAS who have
hypertension have essential hypertension, not renovascular hyperten-
sion. These hypertensive patients with ASO-RAS are rarely cured of
their hypertension by interventive procedures that either bypass or
dilate the stenotic lesion. Thus, it is critical to distinguish chronic subcapsular hematoma, and unilateral ureteral obstruction
between the anatomic presence of renal artery stenosis, in may also be associated with hypertension that is relieved when
which a stenotic lesion is present but not necessarily causing the affected kidney is removed. These clinical analogues of the
hypertension, and the syndrome of renovascular hypertension experimental Page kidney reflect the syndrome of renovascular
in which significant arterial stenosis is present and sufficient to hypertension (RVHT), but without main renal artery stenosis.
produce renal tissue ischemia and initiate a pathophysiologic Takayasu’s arteritis and atheroembolic renal disease are additional
sequence of events leading to elevated arterial pressure. In the examples of RVHT without main renal artery stenosis.
final analysis, proof that a patient has the entity of “renovas- Accordingly, the anatomic presence of renal artery stenosis
cular hypertension” rests with the demonstration that the should not be equated with renovascular hypertension and the
hypertension, presumed to be “renovascular,” can be eliminat- syndrome of RVHT need not reflect renal artery stenosis.
ed or substantially ameliorated following removal of the steno- This chapter reviews the types of renal arterial disease asso-
sis by surgical or endovascular intervention, or by removing ciated with RVHT, the pathophysiology of RVHT, clinical
the kidney distal to the stenosis. features and diagnostic approaches to renal artery stenosis and
Although the great majority of patients diagnosed as having RVHT, evolving concepts regarding ischemic nephropathy, and
renovascular hypertension have this syndrome because of main renal management considerations in patients with renal artery stenosis,
artery stenosis, hypertension following unilateral renal trauma, presumed RVHT, and ischemic renal disease.
FIGURE 3-1
CLASSIFICATION OF RENAL Classification of renal artery disease. Two main types of renal arterial lesions form the
ARTERY DISEASE 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,
Disease Incidence, %* 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.
Atherosclerosis 60–80
Fibrous dysplasia 20–40
Medial (30%)
Perimedial (5%)
Intimal (5%)
*Percent of renal artery lesions.
Atherosclerotic renal artery disease is typi-

cally associated with atherosclerotic changes
of the abdominal aorta (see panel B). ASO-
RAD 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 invad-
ing the renal artery ostium (ostial lesion).
Twenty to 30 percent of patients with ASO-
RAD demonstrate atherosclerotic narrowing
1 to 3 cm beyond the takeoff of the renal
artery (nonostial lesion). Nonostial lesions
are technically more amenable to percuta-
neous transluminal renal angioplasty (PTRA)
than ostial ASO-RAD lesions, which are
technically difficult to dilate and have a high
A B restenosis rate after PTRA. Renal artery
stenting has gained wide acceptance for ostial
FIGURE 3-2 lesions. Endovascular intervention for nonos-
Angiographic examples of atherosclerotic renal artery disease (ASO-RAD). A, Aortogram tial lesions includes both PTRA and stents.
demonstrating severe nonostial atherosclerotic renal artery disease of the left main renal artery. Surgical renal revascularization is used for
B, Intra-arterial digital subtraction aortogram showing severe proximal right renal artery stenosis both ostial and nonostial ASO-RAD lesions.
(ostial lesion) and moderately severe narrowing of the left renal artery due to atherosclerosis. (From Pohl [1]; with permission.)
Renovascular Hypertension and Ischemic Nephropathy 3.3
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 1968 12/88 30 21 (70) NA
Meaney 1968 6/120 39 14 (36) 3 (8)
Dean 1981 6/102 35 10 (29) 4 (11)
Schreiber 1984 12/60 85 37 (44) 14 (I6)
Tollefson 1991 15/180 48 34 (71) 7 (15)
Total 237 116 (49) 28 (14)
FIGURE 3-3
Natural history of atherosclerotic renovascular disease. cumulative incidence of progession of lesions with less than
Retrospective studies, based on serial renal angiograms, suggest 60% reduction in lumen diameter progressing to more than 60%
that atherosclerotic renal artery disease (ASO-RAD) is a progres- reduction in lumen diameter was 30% at 1 year, 44% at 2 years,
sive disorder. This figure summarizes retrospective series on the and 48% at 3 years. Progression to total occlusion occurred only
natural history of ASO-RAD. A large series from the Cleveland in arteries with a baseline reduction in lumen diameter of more
Clinic in nonoperated patients indicated progression of renal artery than 60%. The cumulative incidence of progression to total
obstruction in 44%; progression to total occlusion occurred in occlusion in patients with baseline stenosis of 60% or greater
16% of these patients. Reduction in ipsilateral renal size is associ- was 4% at 1 year, 4% at 2 years, and 7% at 3 years. Blood
ated with angiographic evidence of progression in contrast to pressure control and serum creatinine were not predictors of
patients with nonprogressive (angiographically) ASO-RAD. progression. The risk of renal parenchymal atrophy over time in
Zierler and coworkers have prospectively studied the progres- kidneys with ASO-RAD has also been described. (Table adapted
sion of ASO-RAD by sequential duplex ultrasonography. The from Rimmer and Gennari [2]; with permission.)
the second most common type of fibrous

dysplasia, accounting for 10% to 25% of
FREQUENCY AND NATURAL HISTORY OF FIBROUS RENAL ARTERY DISEASES
fibrous renal artery lesions. This lesion also
occurs predominantly in women, is diagnosed
between the ages of 15 and 30, is frequently
Lesion Frequency, %* Risk of progression Threat to renal function bilateral and highly stenotic, and may progress
Intimal fibroplasia and 10 ++++ ++++ to total arterial occlusion. These patients
medial hyperplasia should undergo surgical renal revascularization
Perimedial fibroplasia 10–25 ++++ ++++ to relieve hypertension and to avoid loss of
Medial fibroplasia 70–85 ++ — renal function. Intimal fibroplasia and medial
hyperplasia (usually indistinguishable angio-
*Frequency relates to frequency of only the fibrous renal artery diseases. graphically) are not common, accounting for
only 5% to 10% of fibrous renal artery
lesions. Intimal fibroplasia occurs primarily in
FIGURE 3-4 children and adolescents. Medial hyperplasia
Frequency and natural history of fibrous renal artery diseases. There are four types of fibrous is found predominantly in adolescents; angio-
renal artery disease (fibrous dysplasias): medial fibroplasia, perimedial fibroplasia, intimal graphically it appears as a smooth linear
fibroplasia, and medial hyperplasia. Although the true incidence of these specific types of stenosis that may extend into the primary
fibrous renal artery disease is not clearly defined, medial fibroplasia is the most common, renal artery branches. Medial hyperplasia, like
estimated to account for 70% to 85% of fibrous renal artery disease. The majority of patients intimal fibroplasia, is a progressive lesion and
with medial fibroplasia are almost exclusively women who are diagnosed between the ages of is associated with ipsilateral renal atrophy.
25 to 50 years. Although medial fibroplasia progresses to higher degrees of stenosis in about Surgical renal revascularization is recommended
one third of cases, complete arterial occlusion or ischemic atrophy of the involved kidney is for patients with either intimal fibroplasia or
rare. Intervention on this type of fibrosis dysplasia is for relief of hypertension because the medial hyperplasia to avoid lifelong antihyper-
threat of progressive medial fibroplasia to renal function is negligible. Perimedial fibroplasia is tensive therapy and to avert renal atrophy.
FIGURE 3-5
Arteriogram and schematic diagrams of
medial fibroplasia. A, Right renal arteri-
ogram 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 characteris-
tically 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
B 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 aneurys-
mal dilatation is wider than the nonaffected
proximal renal artery, an angiographic clue
to medial fibroplasia. (Panel A from Pohl [1];
A with permission.)
FIGURE 3-6
Arteriogram and schematic diagram of peri-
medial 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 peri-
medial fibroplasia. B, Schematic diagram of
perimedial fibroplasia.
Perimedial fibroplasia, accounting for
10% to 25% of the fibrous renal artery dis-
eases, is also observed almost exclusively in
women. The stenotic lesion occurs in the
mid and distal main renal artery or branches
B and may be bilateral. Angiographically, serial
A 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 occlu-
sion; collateral blood vessels and renal atro-
phy 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 dis-
section and/or thrombosis are common.
(Panel A from Pohl [1]; with permission.)
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 angiographi-
cally gives the appearance of a localized,
highly stenotic, smooth lesion, with post-
stenotic dilatation. It may occur in the prox-
imal portion of the renal artery as well as
B in the mid and distal portions of the renal
A artery, is progressive, and is occasionally
associated with dissection or renal infarc-
tion. Pathologically, idiopathic intimal fibro-
plasia 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
ATHEROSCLEROTIC RENAL ARTERY DISEASE VERSUS MEDIAL FIBROPLASIA
atrophy of the kidney ipsilateral to the medial
fibroplasia lesion is rare. Surgical intervention
or pecutaneous transluminal renal angioplasty
Atherosclerotic Medial fibroplasia (PTRA) typically produce good cure rates for
Men and women Women the hypertension in medial fibroplasia and
Age >50–55 y Age 20–40 y these lesions are technically quite amenable to
Total occlusion common Total occlusion rare
PTRA. In contrast, ASO-RAD is, technically,
Ischemic atrophy common Ischemic atrophy rare
much less amenable to PTRA (particularly
ostial lesions), and surgical intervention or
Surgical intervention or angioplasty: Surgical intervention or angioplasty: PTRA produce mediocre-to-poor cure rates
Mediocre cure rates of the hypertension Good cure rates of the hypertension of the hypertension. ASO-RAD and medial
Less amenable to PTRA More amenable to PTRA fibroplasia may cause hypertension and
when the hypertension is cured or markedly
improved following intervention, the patient
may be viewed as having “renovascular
FIGURE 3-8 hypertension.” This sequence of events is
A comparison of atherosclerotic renal artery disease and medial fibroplasia. The most far more likely to occur in patients with
common types of renal artery disease (atherosclerotic renal artery disease [ASO-RAD] and medial fibroplasia than in patients with
medial fibroplasia) are compared here. In general, ASO-RAD is observed in men and ASO-RAD. ASO-RAD and medial fibroplasia
women older than 50 to 55 years of age, whereas medial fibroplasia is observed primarily involve both main renal arteries in approxi-
in younger white women. Total occlusion of the renal artery and, hence, atrophy of the mately 30% to 40% of patients.
Pathophysiology of Renovascular Hypertension

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
Stenotic presence of hemodynamically sufficient unilateral renal artery
kidney 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 II–mediated vasoconstriction
Contralateral Ischemia and hypertension in the early phase of this experimental model.
kidney In addition, the high levels of angiotensin II stimulate the adren-
Renin al cortex to elaborate larger amounts of aldosterone such that
• Supressed renin the “stenotic kidney” demonstrates sodium retention. This sec-
• Pressure natriuresis Angiotensin II ondary aldosteronism also produces hypokalemia. The degree
of renal artery stenosis necessary to produce hemodynamically
Vasoconstriction Aldosterone significant reductions in perfusion, triggering renal ischemia
and activation of the renin angiotensin system, generally does
• Intrarenal hemodynamics not occur until a reduction of 80% or more in both lumen diameter
• Sodium retention 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
FIGURE 3-9 the contralateral (nonaffected) kidney is present, and that its
Schematic representation of renovascular hypertension. Renovascular renal artery is not hemodynamically significantly narrowed.
hypertension may be defined as the secondary elevation of blood As illustrated, the “contralateral kidney” demonstrates sup-
pressure produced by any of a variety of conditions that interfere pressed renin production and undergoes a pressure natriuresis,
with the arterial circulation to kidney tissue and cause renal ischemia. presumably because of angiotensin II–initiated vasoconstriction
Almost always, renovascular hypertension is caused by obstruction and sodium retention, leading to systemic elevation of blood
of the renal artery or its branches, and demonstration of causality pressure that then results in suppression of renin release and
between the renal artery lesion and the hypertension is essential enhanced excretion of sodium (pressure natriuresis) by the
to this definition. “contralateral kidney.”
augmented proximal tubular reabsorption of sodium and water

and angiotensin II–induced stimulation of aldosterone secretion
Phase
I II contribute to this sodium and water retention. In addition, the high
Clip III
levels of angiotensin II stimulate thirst, which further augments
Blood pressure expansion of the extracellular fluid volume. The expanded extra-
cellular fluid volume results in a progressive suppression of peripheral
renin activity. During this transition phase, the hypertension is still
Renin responsive to removal of the unilateral renal artery stenosis, to
angiotensin II blockade, or unilateral nephrectomy, although these
Change in blood pressure maneuvers do not normalize the blood pressure as promptly and
on removing clip 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
FIGURE 3-10 widespread arteriolar damage to the “contralateral kidney,” conse-
Sequential phases in two-kidney, one-clip (2K,1C) experimental reno- quent to prolonged exposure to high blood pressure and high levels
vascular hypertension. The schematic representation of renovascular of angiotensin II. In this chronic phase of 2K,1C renovascular hyper-
hypertension depicted in Figure 3-9 is an oversimplification. In tension, extracellular fluid volume expansion and systemic vasocon-
fact, the course of experimental 2K,1C hypertension may be divided striction are the main pathophysiologic abnormalities. The pressure
into three sequential phases. In phase I, renal ischemia and activation natriuresis of the “contralateral kidney” blunts the extracellular
of the renin angiotensin system are of fundamental importance, fluid volume expansion caused by the “stenotic kidney;” but as the
and in this early phase of experimental hypertension, the blood contralateral kidney suffers vascular damage from extended exposure
pressure elevation is renin- or angiotensin II–dependent. Acute to elevated arterial pressure, its excretory function diminishes and
administration of angiotensin II antagonists, administration of extracellular fluid volume expansion persists. In this third phase of
angiotensin-converting enzyme (ACE) inhibitors, removal of the experimental 2K,1C hypertension, acute blockade of the renin
renal artery stenosis (ie, removal of the clip in the experimental angiotensin system fails to lower blood pressure. Sodium depletion
animal or removal of the “stenotic kidney”) promptly normalizes may ameliorate the hypertension but does not normalize it. The
blood pressure. Several days after renal artery clamping, renin levels clinical surrogate of phase III experimental 2K,1C hypertension is
fall, but blood pressure remains elevated. This second phase of duration of hypertension. Widespread clinical experience indicates
experimental 2K,1C hypertension may be viewed as a pathophysio- that major improvements in blood pressure control or cure of the
logic transition phase that, depending on the experimental model hypertension following renal revascularization or even removal of
and species, may last from a few days to several weeks. During this the kidney ipsilateral to the renal artery stenosis are rarely observed
transition phase (phase II), salt and water retention are observed as in patients with a long duration (ie, >5 years) of hypertension.
a consequence of the effect of hypoperfusion of the stenotic kidney; (Adapted from Brown and coworkers [3]; with permission.)
FIGURE 3-11
Two-kidney hypertension One-kidney hypertension 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 “reno-
Blood Renin Volume Blood Renin Volume vascular hypertension” known as “one-kidney” hypertension,
pressure pressure wherein in the experimental model, one renal artery is constricted
High Normal Normal High 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.
FIGURE 3-12
A. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR Lesions producing the syndrome of reno-
HYPERTENSION (“TWO-KIDNEY HYPERTENSION”)* vascular hypertension. A, Two-kidney
hypertension. The most common clinical
counterpart to “two-kidney” hypertension
Unilateral atherosclerotic renal arterial disease is unilateral renal artery stenosis due to either
Unilateral fibrous renal artery disease atherosclerotic or fibrous renal artery disease.
Renal artery aneurysm
Unilateral renal trauma, with development
of a calcified fibrous capsule surrounding
Arterial embolus
the injured kidney causing compression of
Arteriovenous fistula (congenital and traumatic)
the renal parenchyma, may produce reno-
Segmental arterial occlusion (traumatic)
vascular hypertension; this clinical situation is
Pheochromocytoma compressing renal artery
analogous to the experimental Page kidney,
Unilateral perirenal hematoma or subcapsular hematoma (compressing renal parenchyma)
wherein cellophane wrapping of one of two
kidneys causes hypertension, which is
*Implies contralateral (nonaffected) kidney present. relieved by removal of the wrapped kidney.
B, One-kidney hypertension. Clinical
counterparts of experimental one-kidney,
one-clip (“one kidney”) hypertension
B. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR include renal artery stenosis to a solitary
HYPERTENSION (“ONE-KIDNEY HYPERTENSION”)* functioning kidney, bilateral renal arterial
stenosis, aortic coarctation, Takayasu’s
arteritis, fulminant polyarteritis nodosa,
Stenosis to a solitary functioning kidney atheroembolic renal disease, and renal
Bilateral renal arterial stenosis artery stenosis in a transplanted kidney.
Aortic coarctation In some parts of the world, eg, China and
Vasculitis (polyarteritis nodosa and Takayasu’s arteritis) India, Takayasu’s arteritis is a frequent
Atheroembolic disease
cause of renovascular hypertension.
*Implies total renal mass ischemic.
Although elderly atherosclerotic hypertensive individuals often have

atherosclerotic renal artery disease, their hypertension is usually
STEPS IN MAKING THE DIAGNOSIS
essential hypertension, not RVHT. On balance, the prevalence of
OF RENOVASCULAR HYPERTENSION
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
1. Demonstration of renal arterial stenosis by angiography surgical revascularization, percutaneous transluminal renal angio-
2. Determination of pathophysiologic significance of the stenotic lesion plasty (PTRA), or renal artery stenting. Whether or not to use these
3. Cure of the hypertension by intervention, ie, revascularization, percutaneous trans- interventions for the goal of improving blood pressure depends on
luminal angioplasty, nephrectomy
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
FIGURE 3-13 stenosis by one of several imaging procedures and, eventually, by
Steps in making the diagnosis of renovascular hypertension (RVHT). angiography. The second step in establishing the probability that
With the exception of oral contraceptive use and alcohol ingestion, the renal artery stenosis is instrumental in promoting hypertension
RVHT is the most common cause of potentially remediable secondary is to determine the pathophysiologic significance of the stenotic
hypertension. RVHT is estimated to occur with a prevalence of 1% lesion. Finally, the hypertension, presumed to be renovascular in
to 15%. Some hypertension referral clinics have estimated a preva- origin, is proven to be RVHT when the elevated blood pressure is
lence of RVHT as high as 15%, whereas other prevalence data suggest cured or markedly ameliorated by an interventive maneuver such as
that less than 1% to 2% of the hypertensive population has RVHT. surgical revascularization, PTRA, renal artery stent, or nephrectomy.
longstanding essential hypertension. Grade III

hypertensive retinopathy, malignant hyper-
DIAGNOSIS OF RENAL ARTERIAL STENOSIS
tension, and flash pulmonary edema all
suggest renal artery stenosis with or without
renovascular hypertension. The observation
Clinical clues Diagnostic tests of a diastolic bruit in the abdomen of a young
Age of onset of hypertension <30 y or >55 y Duplex ultrasonography white women suggests fibrous renal artery
Abrupt onset of hypertension Radionuclide renography disease and, further, is a reliable clinical clue
Acceleration of previously well-controlled hypertension Captopril renography that the hypertension will be helped substan-
Hypertension refractory to an appropriate Captopril provocation test tially by surgical renal revascularization or
three-drug regimen Intravenous digital subtraction angiography percutaneous transluminal renal angioplasty.
Accelerated retinopathy Rapid sequence IVP The diagnostic tests listed along the right
Systolic-diastolic abdominal bruit Magnetic resonance angiography side are used mainly to detect renal artery
Evidence of generalized atherosclerosis obliterans Spiral CT angiography stenosis (ie, the anatomic presence of dis-
Malignant hypertension CO2 angiography ease). Captopril renography is also used
Flash pulmonary edema Conventional (contrast) angiography to predict physiologic significance of the
Acute renal failure with use of angiotensin-converting stenotic lesion. The popularity of these
enzyme inhibitors or angiotensin II receptor-blockers diagnostic tests in detecting renal artery
stenosis varies from institution to institu-
tion; correlations with percent stenosis by
comparative angiography are widely vari-
FIGURE 3-14 able. A substantial fall in blood pressure
Diagnosis of renal artery stenosis. Clinical clues suggesting renal artery stenosis, some of following initiation of an angiotensin-con-
which suggest that the stenosis is the cause of the hypertension, are listed on the left. The verting enzyme inhibitor or angiotensin II
well-documented age of onset of hypertension in an individual under the age of 30 or over receptor blocker suggests RVHT. With the
age 55 years, particularly if the hypertension is severe and requiring three antihypertensive exception of a diastolic abdominal bruit
drugs, is a strong clinical clue to renal artery stenosis and predicts that the stenosis is causing and accelerated retinopathy, no clear-cut
the hypertension. The patient with a long history of mild hypertension, easily controlled with physical findings definitely discriminate
one or two drugs, who, particularly in older age, develops severe and refractory hypertension, patients with RVHT from the larger pool
is likely to have developed atherosclerotic renal artery stenosis as a contributor to underlying 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 dis-
continue 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 renal-
aortic ratio was 5.3, consistent with a 60% to 99% left renal artery stenosis. (From Hoffman
and coworkers [4]; with permission.)
FIGURE 3-16
COMPARISON OF DUPLEX ULTRASOUND Comparison of duplex ultrasound with arteriography. A total of
WITH ARTERIOGRAPHY 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,
Percent stenosis by arteriogram unexplained azotemia, or associated peripheral vascular disease,
Percent stenosis giving them a high pretest likelihood of renovascular hypertension.
by ultrasound 0–59 60–79 80–99 100 Total Sixty-two of 63 arteries that showed less than 60% stenosis by formal
0–59 62 0 1 1 64 arteriography, were identified by duplex ultrasound scanning.
60–99 1 31 67 0 99 Twenty-two of 23 arteries with total occlusion on arteriography
100 0 1 1 22 24 were correctly identified by duplex ultrasound. Thirty-one of 32
Total 63 32 69 23 187 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
Sensitivity, 0.98.
to have 60% to 99% stenosis on ultrasound. A current limitation
Specificity, 0.98.
of duplex ultrasound is the inability to consistently distinguish
Positive predictive value, 0.99. between more than and less than 80% stenosis (considered to be
Negative predictive value, 0.97. 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 ultra-
sound and remain a limitation of this test. (Adapted from Olin
and coworkers [5]; with permission.)
renogram not only suggest the anatomic presence of renal artery

stenosis but also imply that the stenosis is instrumental in pro-
DETERMINATION OF PATHOPHYSIOLOGIC
ducing the hypertension. Reductions of lumen diameter of less
SIGNIFICANCE OF THE STENOTIC LESION
than 70% to 80% generally do not initiate renal ischemia or acti-
vation of the renin angiotensin system; thus, before recommend-
ing a renal revascularization procedure, severe renal artery steno-
Duration of hypertension <3–5 y sis (>75% reduction in lumen diameter) should be observed on
Appearance of lesion on angiogram (>75% stenosis) the renal angiogram. A lateralizing renal vein renin ratio (a com-
Systolic-diastolic bruit in abdomen parison of renin harvested from the renal vein ipsilateral to the
Renal vein renin ratio >1.5 renal artery stenosis with the renin level from renal vein of the
Positive captopril provocation test or captopril renogram contralateral kidney), particularly when renin production from
Abnormal rapid sequence IVP the contralateral kidney is suppressed, suggests that an interven-
Hypokalemia tion 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 revascu-
larization has been reported in nearly 50% of cases in the
FIGURE 3-17 absence of lateralizing renal vein renins. Hypokalemia, in the
Determination of pathophysiologic significance of the stenotic absence of diuretic therapy, strongly suggests that the hyperten-
lesion. The second step in making the diagnosis of renovascular sion is renovascular in origin, consequent to secondary aldostero-
hypertension (RVHT) is to determine the pathophysiologic signif- nism. The sensitivity of an IVP in detecting unilateral RVHT is
icance of the stenotic lesion demonstrated by angiography. The relatively poor (about 75%) and the overall sensitivity in detect-
likelihood of cure of the hypertension by an interventive maneu- ing patients with bilateral renal artery disease is only about 60%.
ver is greatly enhanced when one or more of the items listed here Because RVHT has a low prevalence in the general population, a
are present. A positive captopril provocation test, abnormal rapid negative IVP provides strong evidence (98% to 99% certainty)
sequence intravenous pyelogram (IVP), or positive captopril against RVHT.
value as a diagnostic screening test for renovascular hypertension

RENIN CRITERIA FOR CAPTOPRIL TEST THAT (RVHT). The notion that patients with high PRA, even in the
DISTINGUISH PATIENTS WITH RVHT FROM face of high urinary sodium excretion, might turn out to have
THOSE WITH ESSENTIAL HYPERTENSION 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.
Stimulated PRA of 12 ng/mL/h or more
Preparation of patients for this test is vital; ideally patients
Absolute increase in PRA of 10 ng/mL/h or more
should discontinue their antihypertensive medications, maintain
Percent increase in PRA a diet adequate in salt, and have good renal function. A baseline
Increase in PRA of 150% if baseline PRA >3 ng/mL/h blood pressure and PRA are obtained after which captopril is
Increase in PRA of 400% if baseline PRA <3 ng/mL/h administered; 60 minutes after captopril administration, a “post-
captopril” PRA is obtained along with repeat measurements of
blood pressure. Early reports with this test indicated a high sensi-
tivity and specificity (95% to 100%) in identifying RVHT if all
FIGURE 3-18 three of the renin criteria listed here were met. Subsequent
The captopril test: renin criteria that distinguish patients with reports have not been as encouraging such that the overall sensi-
renovascular hypertension from those with essential hypertension. tivity of this captopril test is only about 70%, with a specificity
The captopril provocation test evolved because the casual measure- of approximately 85%. (Adapted from Muller and coworkers [6];
ment of peripheral plasma renin activity (PRA) has been of little with permission.)
1.0
1.0
0.8
0.8
Relative acidity
Relative acidity
0.6
0.6
0.4 0.4
0.2 0.2
Bladder Bladder
Right kidney Right kidney
Left kidney Left kidney
0 0
0 8 16 24 32 40 48 0 8 16 24 32 40 48
A Time, min B Time, min
FIGURE 3-19
Captopril renography. A, TcDPTA time-activity curves during asymmetry of renal size and function and on specific, captopril-
baseline. B, TcDPTA time-activity curves after captopril adminis- induced changes in the renogram, including delayed time to maximal
tration. These curves represent a captopril renogram in a patient activity (≥11 minutes), significant asymmetry of the peak of each
with unilateral left renal artery stenosis. This diagnostic test has been kidney, marked cortical retention of the radionuclide, and marked
used to screen for renal artery stenosis and to predict renovascular reduction in the calculated glomerular filtration rate of the kidney
hypertension. Captopril renography appears to be highly sensitive ipsilateral to the stenosis. One must interpret the clinical and reno-
and specific for detecting physiologically significant renal artery graphic data with caution, as protocols are complex and diagnostic
stenosis. Scintigrams and time-activity curves should both be analyzed criteria are not well standardized. Nevertheless, captopril renogra-
to assess renal perfusion, function, and size. If the renogram following phy appears to be an improvement over the captopril provocation
captopril administration is abnormal (panel B, demonstrating delayed test, with many reports indicating sensitivity and specificity from
time to maximal activity and retention of the radionuclide in the right 80% to 95% in predicting an improvement in blood pressure
kidney), another renogram may be obtained without captopril for following intervention. (Adapted from Nally and coworkers [7];
comparison. The diagnosis of renal artery stenosis is based on with permission.)
now available to detect renal artery stenosis

Suggested work-up for renovascular hypertension and several tests designed to predict the
physiologic significance of the stenotic lesion,
the index of clinical suspicion for RVHT
Index of clinical suspicion
remains the focal point of the work-up for
RVHT. A brief duration of moderately severe
hypertension is the most important clue
Low (<1%) PRA Moderate (≈5%–15%) High (>25%)
directing subsequent work-up for RVHT. If
the index of clinical suspicion (see Fig. 3-14)
Low Normal
or high ? 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
Captopril test, or captopril renogram,
or stimulated renal vein renins, renogram followed by a renal arteriogram
or (?) duplex ultrasound may be recommended. Strong arguments
against RVHT include 1) long duration (more
than 5 years) of hypertension, 2) old age,
No further work-up Negative Positive Arteriogram + renal 3) generalized atherosclerosis, 4) increased
vein renins serum creatinine, and 5) a normal serum
potassium concentration. For these patients,
particularly if the blood pressure is only mini-
FIGURE 3-20 mally elevated or easily controlled with one or
Suggested work-up for renovascular hypertension. Because the prevalence of renovascular hyper- two antihypertensive medications, further
tension (RVHT) among hypertensive persons in general is approximately 2% or less, widespread work-up for RVHT is not indicated. (Adapted
screening for renovascular disease is not justified. Despite the proliferation of diagnostic tests 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 fol-
lowed 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 indi-
cates 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.
12.0
11.0
10.0
9.0
8.0
Pt. 7
7.0 Pt. 8
6.0
Pt. 3
5.0
Pt. 6
A
4.0
3.0 Pt. 2
Pt. 1
Pt. 4
2.0
Pt. 3
1.0
0
Admission Medical Surgery or
therapy 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 med-
ical management of the hypertension (antihypertensive drug thera-
py), four of the eight patients developed substantial worsening of B
their renal function as measured by serum creatinine; three of these
four patients demonstrated improvement following surgery or FIGURE 3-23
angioplasty. The other four patients (patients one to four) did not Improved renal function demonstrated by intravenous pyelography
demonstrate a worsening serum creatinine level with medical thera- following left renal revascularization. A, preoperative IVP (5-minute
py; but three of these four patients showed improved renal func- film) in a 65-year-old white man with a 15-year history of hyperten-
tion following surgery or angioplasty. (Adapted from Ying and sion; serum creatinine 2.6 mg/dL. Note poorly functioning left kidney,
coworkers [9]; with permission.) 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 hemody-
namically significant obstruction to renal blood flow, or renal failure
due to renal artery occlusive disease.
FIGURE 3-24
ATHEROSCLEROTIC RENAL ARTERY STENOSIS IN 395 PATIENTS Atherosclerotic renal artery stenosis in
WITH GENERALIZED ATHEROSCLEROSIS OBLITERANS AND IN patients with generalized atherosclerosis
PATIENTS WITH CORONARY ARTERY DISEASE obliterans and in patients with coronary
artery disease (CAD). Atherosclerotic renal
artery stenosis is common in older patients
Patients, n Percent of patients with >50% stenosis with and without hypertension simply as a
consequence of generalized atherosclerosis
Abdominal aortic aneurysm 109 38 obliterans. Approximately 40% of consecu-
Aorto-occlusive disease 21 33 tively studied patients undergoing arteriography
Lower extremity disease 189 39* for routine evaluation of abdominal aortic
Suspected renal artery stenosis 76 70† aneurysm, aorto-occlusive disease, or lower
Coronary artery disease 76 29† extremity occlusive disease have associated
817 20‡ renal artery stenosis (more than 50% unilateral
renal artery stenosis) and nearly 30% of
*50% in diabetic patients. patients undergoing coronary angiography
†Data from Vetrovec and coworkers [12]. may have incidentally detected unilateral
‡Data from Harding [13]. 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 hyper-
cholesterolemia and cigarette smoking with
renal artery atherosclerosis are not unequiv-
ocally 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 Clinical presentations of ischemic renal disease. The clinical presen-
ISCHEMIC RENAL DISEASE tation of a patient likely to develop renal failure from atheroscle-
rotic ischemic renal disease is that of an older (more than 50 years)
individual demonstrating progressive azotemia in conjunction with
Acute renal failure, frequently precipitated by a reduction in blood pressure antihypertensive drug therapy, risk factors for generalized athero-
(ie, angiotensin-converting enzyme inhibitors plus diuretics) sclerosis obliterans, known renal artery disease, refractory hyper-
Progressive azotemia in a hypertensive patient with known renal artery stenosis tension, and generalized atherosclerosis. Acute renal failure precipi-
treated medically tated by a reduction in blood pressure below a “critical perfusion
Progressive azotemia in a patient (usually elderly) with refractory hypertension pressure,” and particularly with the use of angiotensin converting-
Unexplained progressive azotemia in an elderly patient enzyme inhibitors (ACEI) or angiotensin II receptor blockers plus
Hypertension and azotemia in a renal transplant patient diuretics, strongly suggests severe intrarenal ischemia from arterio-
lar 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 athero-
sclerotic disease of the left main renal artery
(panel A) that has progressed to high-grade
(75% to 99%) stenosis on a later arteri-
ogram (panel B). Underlying the concept
of renal revascularization for preservation
of renal function is the notion that athero-
sclerotic 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 pro-
gressive occlusive disease. Patients demon-
strating more than 75% stenosis of a renal
artery are at highest risk for progression to
complete occlusion. (From Novick [15];
A B with permission.)
A B
FIGURE 3-27
A, Normal right main renal artery and minimal atherosclerotic stenosis of the right main renal artery (arrow) and total occlusion
irregularity of left main renal artery on initial (1974) aortogram. of left main renal artery (arrow). (From Schreiber and coworkers
B, Repeat aortography (1978) showed progression to moderate [16]; with permission.)
entire renal functioning mass is not threatened by large vessel

CLINICAL CLUES TO BILATERAL ATHEROSCLEROTIC occlusive disease.
RENOVASCULAR 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.
Generalized atherosclerosis obliterans
One third of these patients with a unilateral small kidney have
Presumed renovascular hypertension
high-grade stenosis of the artery involving the contralateral normal-
Unilateral small kidney
sized kidney. Flash pulmonary edema is another clue to bilateral
Unexplained azotemia renovascular disease or high-grade stenosis involving a solitary
Deterioration in renal function with BP reduction and/or ACE inhibitor therapy functioning kidney. These patients, usually hypertensive and with
Flash pulmonary edema 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
FIGURE 3-28 renal artery disease and may occur with or without severe hypertension.
Clinical clues to bilateral atherosclerotic renovascular disease. Renal revascularization to preserve kidney function or to prevent
The patient at highest risk for developing renal insufficiency from life-threatening flash pulmonary edema may be considered in patients
renal artery stenosis (ischemic nephropathy) has sufficient arterial with high-grade arterial stenosis to a solitary kidney or high-grade
stenosis to threaten the entire renal functioning mass. These high- bilateral renal artery stenosis. Pecutaneous transluminal renal
risk patients have high-grade (more than 75%) arterial stenosis angioplasty (PTRA), renal artery stenting, or surgical renal revascu-
to a solitary functioning kidney or high-grade (more than 75%) larization may be employed. Patients with chronic total renal artery
bilateral renal artery stenosis. Patients with two functioning occlusion bilaterally or in a solitary functioning kidney are candidates
kidneys with only unilateral renal artery stenosis are not at for surgical renal revascularization, but are not candidates (from a
significant risk for developing renal insufficiency because the technical standpoint) for PTRA or renal artery stents.
potential for salvable renal function. Clinical clues suggesting

PREDICTORS OF KIDNEY SALVAGEABILITY renal viability include 1) kidney size greater than 9 cm (pole-to-
pole 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
Kidney size >9 cm (laminography)
main renal artery is totally occluded proximally (see Fig. 3-30);
Function on either urogram or renal flow scan
and 4) well-preserved glomeruli with minimal interstitial scarring
Filling of distal renal arteries (by collaterals) angiographically, with total proximal occlusion
(see Fig. 3-31) on renal biopsy. Patients with moderately severe
Glomerular histology on renal biopsy
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 revascu-
larization unlikely. Exceptions to this observation are cases of
FIGURE 3-29 total main renal artery occlusion wherein kidney viability is
Predictors of kidney salvageability. In evaluating patients as maintained via collateral circulation (see Figure 3-30). A kidney
candidates for renal revascularization to preserve or improve biopsy may guide subsequent decision making regarding renal
renal function, some determination should be made of the revascularization for the goal of improving kidney function.
FIGURE 3-30
This abdominal aortogram reveals com-
plete 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.)
A B

Renal biopsy of a solitary left kidney in a 67-year-old woman who Pathologic specimen of kidney beyond a main renal artery occlusion
had been anuric and on chronic dialysis for 9 months. The biopsy in a patient with severe bilateral renal artery stenosis and a serum
shows hypoperfused retracted glomeruli consistent with ischemia. creatinine of 4.5 mg/dL. The biopsy demonstrates glomerular scle-
There is no evidence of active glomerular proliferation or glomerular rosis, tubular atrophy, and interstitial fibrosis. The magnitude of
sclerosis. Note intact tubular basement membranes and negligible glomerular and interstitial scarring predict irreversible loss of kidney
interstitial scarring. Left renal revascularization resulted in recovery viability. (From Pohl [1]; with permission.)
of renal function and discontinuance of dialysis with improvement in
serum creatinine to 2.0 mg/dL. (From Novick [15]; 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.
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 degenera-
tion 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 gener-
alized atherosclerosis or essential hypertension.
FIGURE 3-37
Schematic representation of ischemic nephropathy. Patients with atherosclerotic renal artery
Atherosclerosis Nephrosclerosis
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
Atheroembolism
simply due to atherosclerotic renal artery stenosis. In addition, in the azotemic patient with ASO-
RAD, 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% FIGURE 3-38
Miscellaneous Distribution of endstage renal disease diagnoses. Atherosclerotic renal artery disease (ASO-
11%
Other RAD) 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
12% 1991 incident patients entered ESRD programs because of “hypertension (HBP).” No reno-
CGN 36% vascular disease diagnosis is listed. Crude estimates of the percentage of patients entering
DM
ESRD programs because of ASO-RAD range from 1.7% to 15%. Precise bases for making
5% these estimates are both unclear and confounded by the high likelihood of coexisting arterio-
Urology 29% lar nephrosclerosis, type II diabetic nephropathy, and atheroembolic renal disease. ASO-RAD
High blood as a major contributor to the ESRD population is probably small on a percentage basis, occu-
3% pressure
Cyst pying some portion of the ESRD diagnosis “hypertension (HBP).” For dialysis-dependent
patients with ASO-RAD, predictors of recovery of renal function following renal revascular-
ization and allowing for discontinuance of dialysis (temporary or permanent) include 1) bilat-
eral (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-to-
moderate arteriolar nephrosclerosis angiographically.
Treatment of Renovascular Hypertension

and Ischemic Nephropathy
FIGURE 3-39
TREATMENT OPTIONS FOR RENOVASCULAR Treatment options for renovascular hypertension and ischemic
HYPERTENSION AND ISCHEMIC NEPHROPATHY nephropathy. The main goals in the treatment of renovascular hyper-
tension or ischemic nephropathy are to control the blood pressure,
to prevent target organ complications, and to avoid the loss of renal
Pharmacologic antihypertensive therapy function. Although the issue of renal function may be viewed as
PTRA mutually exclusive from the issue of blood pressure control, uncon-
Renal artery stents
trolled hypertension may hasten a decline in renal function, and
renal insufficiency may produce worsening hypertension. Even in the
Surgical renal revascularization
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 anti-
hypertensive therapy is covered in more detail separately in this Atlas.
FIGURE 3-40
INCREASING COMORBIDITY IN PATIENTS Comorbidity in patients undergoing renovascular surgery. Patients
UNDERGOING RENOVASCULAR SURGERY presenting for renovascular surgery or endovascular renal revascu-
larization are at high-risk for complications during intervention
because of age, and frequently associated coronary, cerebrovascular,
Comorbidity, % or peripheral vascular disease. As the population ages, the percentage
of patients being considered for interventive maneuvers on the
Condition 1970–1980 1980–1993 renal artery has increased significantly. Approximately 30% of
Angina 21.4 29.9 patients currently undergoing interventive approaches to renal
Prior MI 16.3 27.0 artery disease have angina, or have had a previous myocardial
CHF 12.2 23.7* infarction. Congestive heart failure, cerebrovascular disease (eg, carotid
Cerebrovascular disease 11.2 24.8* artery stenosis), diabetes mellitus, and claudication are frequent
Diabetes 7.1 18.1* comorbid conditions in these patients. Their aortas are often laden
Claudication 35.7 56.4* with extensive atherosclerotic plaque (Fig. 3-33), making angiographic
investigation or endovascular renal revascularization hazardous.
(Adapted from Hallet and coworkers [17]; with permission.)
*P <0.001.
bypass with saphenous vein grafting is

a frequently used surgical approach in
DIMINISHED OPERATIVE MORBIDITY AND MORTALITY FOLLOWING SURGICAL
patients with nondiseased abdominal aortas.
REVASCULARIZATION FOR ATHEROSCLEROTIC RENOVASCULAR DISEASE
Severe atherosclerosis of the abdominal
aorta may render an aortorenal bypass or
renal endarterectomy technically difficult
Preoperative screening and correction of coronary and carotid artery disease and potentially hazardous to perform.
Avoidance of operation on severely diseased aorta Effective alternate bypass techniques include
Unilateral revascularization in patients with bilateral renovascular disease splenorenal bypass for left renal revascular-
ization, hepatorenal bypass for right renal
revascularization, ileorenal bypass, bench
surgery with autotransplantation, and use
FIGURE 3-41 of the supraceliac or lower thoracic aorta
Diminished operative morbidity and mortality following surgical revascularization for (usually less ravaged by atherosclerosis).
atherosclerotic renovascular disease. Operative morbidity and mortality in patients under- Simultaneous aortic replacement and renal
going surgical revascularization have been minimized by selective screening and/or correc- revascularization are associated with an
tion of significant coexisting coronary and/or carotid artery disease before undertaking increased risk of operative mortality in
elective surgical renal revascularization for atherosclerotic renal artery disease. Screening comparison to renal revascularization alone.
tests for carotid artery disease include carotid ultrasound and carotid arteriography. Some surgeons advocate unilateral renal
Screening tests for coronary artery disease include thallium stress testing, dipyridamole revascularization in patients with bilateral
stress testing, dobutamine echocardiography, and coronary arteriography. Aortorenal 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.
A B
C D
A B
FIGURE 3-43
Percutaneous transluminal renal angioplasty (PTRA) of the renal artery. PTRA of the renal artery has emerged as an important inter-
A, High-grade (more than 75%) nonostial atherosclerotic stenosis of the ventional modality in the management of patients with renal
left main renal artery in a patient with a solitary functioning kidney (right artery stenosis. PTRA is most successful and should be the initial
renal artery totally occluded). Note gradient of 170 mm Hg across the interventive therapeutic maneuver for patients with the medial
stenotic lesion. B, Balloon angioplasty of the left main renal artery was fibroplasia type of fibrous renal artery disease (eg, Fig.3-5A).
successfully performed with reduction in the gradient across the stenotic Excellent technical success rates have also been attained for
lesion from 170 mm Hg pre-PTRA to 15 mm Hg post-PTRA. Repeat nonostial atherosclerotic lesions of the main renal artery, as
aortogram 3 years later demonstrated patency of the left renal artery. shown here.
FIGURE 3-44
High-grade athero-
sclerotic renal artery
stenosis at the
ostium of the right
main renal artery in
a 68-year-old man
with a totally
occluded left main FIGURE 3-45
renal artery. Several Palmaz stent, expanded. Because percutaneous transluminal renal
attempts at balloon angioplasty (PTRA) has suboptimal long-term benefits for athero-
dilatation were sclerotic ostial renal artery stenosis, endovascular stenting has gained
unsuccessful. Over wide acceptance. Renal artery stenting may be performed at the time
the subsequent 10 of the diagnostic angiogram, or at some time thereafter, depending
days, severe renal on the physician’s preference and the risk to the patient of repeated
insufficiency devel- angiographic procedures. From a technical standpoint, indications
oped (serum creati- for renal artery stenting include 1) as a primary procedure for ostial
nine increasing from atherosclerotic renal artery disease (ASO-RAD), 2) technical difficul-
2.0 to 12.0 mg/dL) ties in conjunction with attempted PTRA, 3) post-PTRA dissection,
requiring dialysis. 4) post-PTRA abrupt occlusion, and 5) restenosis following PTRA.
Renal function never It is unclear what the long-term patency and restenosis rates will be
improved and the for renal artery stenting for ostial disease. Preliminary observations
patient remained suggest that the 1-year patency rate for stents is approximately twice
on dialysis. that for PTRA.
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 B. SURGICAL REVASCULARIZATION VERSUS

FOR ATHEROSCLEROTIC RENAL ARTERY DISEASE PTRA FOR FIBROUS RENAL ARTERY DISEASE
Successful surgical Successful surgical

Lesion Successful PTRA, % revascularization, % Lesion Successful PTRA, % revascularization, %
Nonostial 80–90 90 Main 80–90 90
(20%) (50%)
Ostial 25–30 90 Branch NA 90
(80%) (50%)
FIGURE 3-47
Surgical revascularization vs percutaneous transluminal renal The “percent success” for PTRA and surgical revascularization
angioplasty (PTRA) for renal artery disease. A, Success rates for depicted above are estimates, and reflect primarily “technical” success
atherosclerotic renal artery disease (ASO-RAD). B, Success rates for both nonostial and ostial lesions in ASO-RAD. Technical success
for fibrous renal artery disease. Success of either PTRA or surgi- rates for surgical revascularization are high, approximating 90%,
cal renal revascularization is viewed in terms of “technical” suc- with little difference in the technical success rates between ostial
cess and “clinical” success. For PTRA, technical success reflects and nonostial lesions. For PTRA, technical success rates are much
a lumen patency with less than 50% residual stenosis (ie, suc- higher for nonostial lesions. There is a high rate of restenosis at 1
cessful establishment of a patent lumen). For surgical revascular- year (≈50% to 70%) for ostial ASO-RAD, which has promoted the
ization, technical success is the demonstration of good blood use of renal artery stents for these lesions.
flow to the revascularized kidney determined during surgery, or The success rates of surgical renal revascularization and PTRA
postoperatively by DPTA renal scan or other immediate postop- for stenosis of the main renal artery in fibrous renal artery disease
erative imaging procedures. Technical success with either PTRA are comparable, approximately 90%. Hypertension is more pre-
or surgical revascularization is rarely defined by postoperative dictably improved with surgical revascularization and PTRA in
angiography. “Clinical” success may be defined as improved fibrous renal artery disease in comparison with ASO-RAD. Technical
blood pressure or improvement in kidney function, and/or reso- success rates with surgical renal revascularization are high for
lution of flash pulmonary edema. Technical and clinical success- branch fibrous renal artery disease, but long-term technical and
es do not necessarily occur together because technical success clinical success rates are not available for PTRA of branch lesions
may be apparent, but without improvement in blood pressure due to fibrous dysplasia. NA—not available. (Adapted from Pohl
or renal function. [18]; with permission.)
COMPLICATIONS OF TRANSLUMINAL FACTORS TO CONSIDER IN SELECTION OF TREATMENT

ANGIOPLASTY OF THE RENAL ARTERIES FOR PATIENTS WITH RENAL ARTERY DISEASE
Contrast-induced ARF (mild or severe) Is renal artery disease causing hypertension?

Atheroembolic renal failure Severity of hypertension
Rupture of the renal artery Specific type of renal artery disease and threat to renal function
Dissection of the renal artery General medical condition of patient
Thrombotic occlusion of the renal artery Relative efficacy and risk of medical antihypertensive therapy, PTRA,
Occlusion of a branch renal artery renal artery stenting, surgical revascularization
Balloon malfunction (may lead to inability to remove balloon)
Balloon rupture
Puncture site hematoma, hemorrhage, or vessel tear
Median nerve compression (axillary approach) FIGURE 3-49
Renal artery spasm Selection of treatment for patients with renal artery disease. In
Mortality (≤1%) 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
FIGURE 3-48 with atherosclerotic renal artery disease (ASO-RAD), the likeli-
Complications of transluminal angioplasty of the renal arteries. hood for a cure of hypertension is small. The more severe the
The more common complications of PTRA are contrast-induced hypertension, the greater the inclination to intervene with either
acute renal failure (ARF) and atheroembolic renal failure. surgery or balloon angioplasty. For children, adolescents, and
Dissection of the renal artery, occlusion of a branch renal artery, younger adults, most of whom will have fibrous renal artery dis-
and occasionally thrombotic occlusion of the main renal artery ease, intervention is usually recommended to avoid lifelong anti-
may occur. In experienced hands, rupture of the renal artery is hypertensive therapy. Cardiovascular comorbidity is high for
rare. Minor complications relate primarily to the puncture site. patients with ASO-RAD and appropriate caution in approaching
When the axillary approach is used (because of severe iliac and these patients is warranted, weighing the relative efficacy and risk
lower abdominal aortic atherosclerosis), median nerve compression of medical antihypertensive therapy, percutaneous transluminal
may transpire. Some of these complications of percutaneous trans- renal angioplasty (PTRA), renal artery stenting, and surgical
luminal renal angioplasty, particularly atheroembolic renal failure revascularization. Local experience and expertise of the treating
and/or contrast-induced acute renal failure (ARF) may also be physicians must be considered as well in selection of treatment
observed with renal artery stent procedures. options for these patients.
References
1. Pohl MA: Renal artery stenosis, renal vascular hypertension and ischemic 11. Olin JW, Melia M, Young JR, et al.: Prevalence of atherosclerotic
nephropathy. In Diseases of the Kidney, edn 6. Edited by Schrier RW, renal artery stenosis in patients with atherosclerosis elsewhere. Am J
Gottschalk CW. Boston: Little, Brown & Co; 1997: 1367–1427. Med 1990, 88:46N–51N.
2. Rimmer JM, Gennari FJ: Atherosclerotic renovascular disease and 12. Vetrovec GW, Landwehr DM, Edwards VL: Incidence of renal artery
progressive renal failure. Ann Intern Med 1993, 118:712–719. stenosis in hypertensive patients undergoing coronary angiography. J
3. Brown JJ, Davies DL, Morton JJ, et al.: Mechanism of renal hyper- Intervent Cardiol 1989, 2:69–76.
tension. Lancet 1976, 1:1219–1221. 13. Harding MB, Smith LR, Himmelstein SI, et al.: Renal artery stenosis:
4. Hoffmann U, Edwards JM, Carter S, et al.: Role of duplex scanning prevalence and associated risk factors in patients undergoing routine
for the detection of atherosclerotic renal artery disease. Kidney Int cardiac catheterization. J Am Soc Nephrol 1992, 2:1608–1616.
1991, 39:1232–1239. 14. Jacobson HR: Ischemic renal disease: an overlooked clinical entity?
5. Olin JW, Piedmonte MR, Young JR, et al.: The utility of duplex [clinical conference]. Kidney Int 1988, 34:729–743.
ultrasound scanning of the renal arteries for diagnosing significant 15. Novick AC: Patient selection for intervention to preserve renal
renal artery stenosis. Ann Intern Med 1995, 122:833–838. function in ischemic renal disease. In Renovascular Disease. Edited
6. Muller FB, Sealey JE, Case DB, et al.: The captopril test for identifying ren- by Novick AC, Scoble J, Hamilton G. London: WB Saunders;
ovascular disease in hypertensive patients. Am J Med 1986, 80:633–644. 1996:323–335.
7. Nally JV, Olin JW , Lammert MD: Advances in noninvasive screening for 16. Schreiber MJ, Pohl MA, Novick AC: The natural history of athero-
renovascular hypertension disease. Cleve Clin J Med 1994, 61:328–336. sclerotic and fibrous renal artery disease. Urol Clin North Am 1984,
8. Mann SJ, Pickering TG: Detection of renovascular hypertension: state 11:383–392.
of the art: 1992. Ann Intern Med 1992, 117:845–853. 17. Hallett JW Jr, Textor SC, Kos PB, et al.: Advanced renovascular
9. Ying CY, Tifft CP, Gavras H, Chobanian AV: Renal revascularization hypertension and renal insufficiency: trends in medical comorbidity
in the azotemic hypertensive patient resistant to therapy. N Engl J and surgical approach from 1970 to 1993. J Vasc Surg 1995,
Med 1984, 311:1070–1075. 21:750–759.
10. Novick AC, Pohl MA: Atherosclerotic renal artery occlusion extend- 18. Pohl MA: Renovascular hypertension: An internist’s point of view. In
ing into branches: successful revascularization in situ with a branched Hypertension. Edited by Punzi HA, Flamenbaum W. Mt. Kisco, NY:
saphenous vein graft. J Urol 1979, 122:240–242. Futura Publishing Co Inc; 1989:367–393.
Goldblatt H, Lynch J, Hanzal RF, Summerville WW: Studies on experimental Mailloux LU, Napolitano B, Bellucci AG, et al.: Renal vascular disease
hypertension. I. The production of persistent elevation of systolic blood causing end-stage renal disease, incidence, clinical correlates, and
pressure by means of renal ischemia. J Exp Med 1934, 59:347–381. outcomes: a 20-year clinical experience. Am J Kidney Dis 1994,
Morris GC Jr, DeBakey ME, Cooley MJ: Surgical treatment of renal failure 24:622–639.
of renovascular origin. JAMA 1962, 182:113–116. Appel RG, Bleyer AJ, Reavis S, Hansen KJ: Renovascular disease in older
Novick AC, Ziegelbaum M, Vidt DG, et al.: Trends in surgical revascular- patients beginning renal replacement therapy. Kidney Int 1995,
ization for renal artery disease: ten years’ experience. JAMA 1987, 48:171–176.
257:498–501. Hansen KJ, Thomason RB, Craven TE, et al.: Surgical management of dialysis-
Dustan HP, Humphries AW, DeWolfe VG, et al.: Normal arterial pressure dependent ischemic nephropathy. J Vasc Surg 1995, 21:197–209.
in patients with renal arterial stenosis. JAMA 1964, 187:1028–1029. Hallett JW Jr, Fowl R, O’Brien PC, et al.: Renovascular operations in
Holley KE, Hunt JC, Brown ALJ, et al.: Renal artery stenosis: a clinical- patients with chronic renal insufficiency: do the benefits justify the
pathological study in normotensive and hypertensive patients. Am J risks? J Vasc Surg 1987, 5:622–627.
Med 1964, 34:14–22. Conlon PJ, Athirakul K, Kovalik E, et al.: Survival in renal vascular disease.
Page IH: The production of persistent arterial hypertension by cellophane J Am Soc Nephrol 1998, 9:252–256.
perinephritis. JAMA 1939, 113:2046–2048. Textor SC, McKusick MA, Schirger AA, et al.: Atherosclerotic renovascular
McCormack LJ, Poutasse EF, Meaney TF, et al.: A pathologic-arteriographic disease in patients with renal failure. Adv Nephrol Necker Hosp
correlation of renal arterial disease. Am Heart J 1966, 72:188–198. 1997, 27:281–295.
Pohl MA, Novick AC: Natural history of atherosclerotic and fibrous renal Novick AC, Straffon RA, Stewart BH, et al.: Diminished operative morbidity
artery disease: clinical implications. Am J Kidney Dis 1985, 5:A120–A130. and mortality in renal revascularization. JAMA 1981, 246:749–753.
Zierler RE, Bergelin RO, Davidson RC, et al.: A prospective study of disease Khauli RB, Novick AC, Ziegelbaum M: Splenorenal bypass in the treatment
progression in patients with atherosclerotic renal artery stenosis. of renal artery stenosis: experience with sixty-nine cases. J Vasc Surg
Am J Hypertens 1996, 9:1055–1061. 1985, 2:547–551.
Caps MT, Zierler RE, Polissar NL, et al.: Risk of atrophy in kidneys with Chibaro EA, Libertino JA, Novick AC: Use of the hepatic circulation for
atherosclerotic renal artery stenosis. Kidney Int 1998, 53:735–742. renal revascularization. Ann Surg 1984, 199:406–411.
Goncharenko V, Gerlock AJ Jr, Shaff MI, Hollifield JW: Progression of Novick AC, Stewart R: Use of the thoracic aorta for renal revascularization.
renal artery fibromuscular dysplasia in 42 patients as seen on angio- J Urol 1990, 143:77–79.
graphy. Radiology 1981, 139:45–51.
Tarazi RY, Hertzer NR, Beven EG, et al.: Simultaneous aortic reconstruction
Vaughan ED Jr, Carey RM, Ayers CR, et al.: A physiologic definition of and renal revascularization: risk factors and late results in eighty-nine
blood pressure response to renal revascularization in patients with patients. J Vasc Surg 1987, 5:707–714.
renovascular hypertension. Kidney Int 1979, 15:S83–S92.
Hollenberg NK: Medical therapy of renovascular hypertension: efficacy and
Textor SC: Renovascular hypertension. Curr Opin Nephrol Hyperten
safety of captopril in 269 patients. Cardiovasc Rev Rpts 1983, 4:852–879.
1993, 2:775–783.
Pohl MA: Medical management of renovascular hypertension. In Renal
Working Group on Renovascular Hypertension: Detection, evaluation, and
Vascular Disease. Edited by Novick AC, Scoble J, Hamilton G.
treatment of renovascular hypertension. Final report. Arch Intern Med
London: WB Saunders; 1996, 339–349.
1987, 147:820–829.
Palmaz JC, Kopp DT, Hayashi H, et al.: Normal and stenotic renal arteries:
Hughes JS, Dove HG, Gifford RW Jr, Feinstein AR: Duration of blood
Experimental balloon-expandable intraluminal stenting. Radiology
pressure elevation in accurately predicting surgical cure of renovascular
hypertension. Am Heart J 1981, 101:408–413. 1987, 164:705–708.
Svetkey LP, Himmelstein SI, Dunnick NR, et al.: Prospective analysis of Blum U, Krumme B, Flugel P, et al.: Treatment of ostial renal-artery
strategies for diagnosing renovascular hypertension. Hypertension stenoses with vascular endoprostheses after unsuccessful balloon
1989, 14:247–257. angioplasty. N Engl J Med 1997, 336:459–465.
Setaro JF, Saddler MC, Chen CC, et al.: Simplified captopril renography Harden PN, MacLeod MJ, Rodger RSC, et al.: Effect of renal-artery
in diagnosis and treatment of renal artery stenosis. Hypertension stenting on progression of renovascular renal failure. Lancet 1997,
1991, 18:289–298. 349:1133–1136.
Novick AC, Pohl MA, Schreiber M, et al.: Revascularization for preservation Fiala LA, Jackson MR, Gillespie DL, et al.: Primary stenting of atherosclerotic
of renal function in patients with atherosclerotic renovascular disease. renal artery ostial stenosis. Ann Vasc Surg 1998, 12:128–133.
J Urol 1983, 129:907–912. Canzanello VJ, Millan VG, Spiegel JE, et al.: Percutaneous transluminal
Gifford RW Jr, McCormack LJ, Poutasse EF: The atrophic kidney: its role renal angioplasty in management of atherosclerotic renovascular
in hypertension. Mayo Clin Proc 1965, 40:834–852. hypertension: results in 100 patients. Hypertension 1989,
Pickering TG, Herman L, Devereux RB, et al.: Recurrent pulmonary oedema 13:163–172.
in hypertension due to bilateral renal artery stenosis: treatment by Plouin PF, Chatellier G, Darne B, Raynaud A, for the Essai Multicentrique
angioplasty or surgical revascularisation. Lancet 1988, 2:551–552. Medicaments vs. Angioplastie (EMMA) Study Group: Blood pressure
United States Renal Data System Coordinating Center: Incidence and causes outcome of angioplasty in atherosclerotic renal artery stenosis:
of treated ESRD. In The USRDS 1994 Annual Data Report. Edited a randomized trial. Hypertension 1998, 31:823–829.
by Agodoa LYC, Held PJ, Port FK. Bethesda: USRDS Coordinating Textor SC: Revascularization in atherosclerotic renal artery disease
Center; 1994:43–54. [clinical conference]. Kidney Int 1998, 53:799–811.
Adrenal Causes of
Hypertension
Myron H. Weinberger
T
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 produc-
tion 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 aldos-
teronism, Cushing’s syndrome, and pheochromocytoma are discussed.
CHAPTER
4
Adrenal Hypertension
FIGURE 4-1
PHYSIOLOGIC MECHANISMS IN ADRENAL HYPERTENSION The causes and pathophysiologies of the
three major forms of adrenal hypertension
and the proposed mechanisms by which
Disorder Cause Pathophysiology Pressure mechanism blood pressure elevation results.
Primary aldosteronism Autonomous hypersecretion Increased renal sodium and Extracellular fluid volume
of aldosterone (hyperminer- water reabsorption, expansion, hypokalemia
alocorticoidism) increased urinary (?), alkalosis
excretion of potassium
and hydrogen ions
Cushing’s syndrome Hypersecretion of cortisol Increased activation of Extracellular fluid volume
(hyperglucocorticoidism) mineralocorticoid expansion (?), increased
receptor (?), increased angiotensin II (vasocon-
angiotensinogen (renin striction and increased
substrate) concentration peripheral resistance)
Pheochromocytoma Hypersecretion of Vasoconstriction, increased Increased peripheral
catecholamines heart rate resistance, increased
cardiac output
Histology of the Adrenal

FIGURE 4-2
Capsule
Histology of the adrenal. A cross section of the normal adrenal
Zona before (left) and after (right) stimulation with adrenocorticotropic
glomerulosa 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 produc-
Zona tion of aldosterone and other mineralocorticoids and is chiefly
fasciculata 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
Zona Zuckerkandl located at the aortic bifurcation) (see Fig. 4-25.)
reticularis
Medulla
Normal human Human suprarenal

suprarenal gland gland after
administration
of crude ACTH
Adrenal Causes of Hypertension 4.3
Adrenal Steroid Biosynthesis

FIGURE 4-3
CH3 CH3 Adrenal steroid biosynthesis. The sequence of
C=O 17α−Hydroxylase C=O O adrenal steroid biosynthesis beginning with
OH cholesterol is shown as are the enzymes
responsible for production of specific steroids
[2]. Note that aldosterone production nor-
HO HO HO
Pregnenolone 17-Hydroxypregnenolone Dehydroepiandrosterone mally occurs only in the zona glomerulosa
(see Fig. 4-2). (From DeGroot and coworkers
3 β-OH-Dehydrogenase: ∆5 ∆4 Isomerase [2]; with permission.)
CH3 CH3
C=O C=O O
–OH
O O O
Pregnenolone 17-Hydroxypregnenolone ∆4 Androstene 3,17-dione
21-Hydroxylase
OH2OH CH2OH
C=O C=O
OH
O O
11-Deoxycorticosterone 11-Deoxycortisol
11β-Hydroxylase
CH2OH CH2OH
C=O C=O
HO HO OH
O O
Corticosterone Cortisol
18-Hydroxylase
18-OH-Dehrydrogenase
CH2OH
O
HO
OHC C=O
Aldosterone
} Zona
glomerulosa
only
FIGURE 4-4
Circadian rhythmicity of steroid production and major stimulatory
factors. Aldosterone and cortisol and their respective major stimulatory
ACTH 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
PRA need for active steroid production is minimal. ACTH levels increase
early before awakening, stimulating cortisol production in prepara-
Aldosterone tion for the physiologic changes associated with arousal. PRA increas-
es abruptly with the assumption of the upright posture, followed by
an increase in aldosterone production and release. Both steroids
Cortisol demonstrate their highest values through the morning and early after-
noon. Cortisol levels parallel those of ACTH, with a marked decline
Morning 6 AM Noon 6 PM Morning in the afternoon and evening hours. Aldosterone demonstrates a
broader peak, reflecting the postural stimulus of PRA.
sodium and water

Kidney Kidney reabsorption (8) at the
expense of increased
↓Perfusion pressure Juxtaglomerular ↑Perfusion pressure Juxtaglomerular potassium and hydrogen
1 apparatus 9 apparatus ion excretion in the
↓Sodium content ↑Sodium content urine. The increase in
6 12 sodium and volume then
Renin 2 Renin 10 increase systemic blood
pressure and renal
perfusion pressure and
↑Extracellular fluid volume Angiotensin II ↑Extracellular fluid volume Angiotensin II
11 sodium content (9),
5 8
thereby suppressing
↑Sodium reabsorption Adrenal complex ↑Sodium reabsorption Adrenal complex further renin release
(10) and angiotensin II
4 7 production (11). Thus,
Aldosterone Zona glomerulosa Aldosterone Zona glomerulosa
in contrast to the nor-
mal situation depicted
14 13
in panel A, the levels of
K+ ACTH K+ ACTH
A Normal B Primary aldosteronism angiotensin II are highly
suppressed and therefore
FIGURE 4-5 do not contribute to an
Control of mineralocorticoid production. A, Control of aldosterone production under normal circumstances. increase in systemic
A decrease in renal perfusion pressure or tubular sodium content (1) at the level of the juxtaglomerular apparatus blood pressure (12). In
and macula densa of the kidney triggers renin release (2). Renin acts on its substrate angiotensinogen to generate primary aldosteronism,
angiotensin I, which is converted rapidly by angiotensin-converting enzyme to angiotensin II. Angiotensin II ACTH (13) has a domi-
then induces peripheral vasoconstriction to increase perfusion pressure (6) and acts on the zona glomerulosa nant modulatory role in
of the adrenal cortex (3) (see Fig. 4-2) to stimulate production and release of aldosterone (4). Potassium and influencing aldosterone
adrenocorticotropic hormone (ACTH) also play a minor role in aldosterone production in some circumstances. production and hypo-
Aldosterone then acts on the cells of the collecting duct of the kidney to promote reabsorption of sodium (and kalemia, resulting from
passively, water) in exchange for potassium and hydrogen ions excreted in the urine. This increased secretion increased urinary potas-
promotes expansion of extracellular fluid volume and an increase in renal tubular sodium content (5) that further sium exchange for
suppresses renin release, thus closing the feedback loop (servomechanism). B, Abnormalities present in primary sodium, which has a
aldosteronism. Autonomous hypersecretion of aldosterone (7) leads to increased extracellular fluid volume negative effect on aldos-
expansion and increased renal tubular sodium content. These elevated levels are a result of increased renal terone production (14).
Aldosteronism
TYPES OF PRIMARY ALDOSTERONISM SCREENING TESTS FOR PRIMARY ALDOSTERONISM
Types Relative frequency, % Test Sensitivity, % Specificity, %

Solitary adrenal adenoma 65 Serum potassium ≤3.5 mEq/L 75 ≈20
Bilateral adrenal hyperplasia 30 Plasma renin activity ≤4 ng/mL/90 min >99 40–60
Unilateral adrenal hyperplasia 2 Urinary aldosterone ≥20 µg/d 70 60
Glucocorticoid-remediable aldosteronism <1 Plasma aldosterone ≥15 ng/dL 90 60
Bilateral solitary adrenal adenomas <1 Plasma aldosterone–plasma renin 99.8 98
Adrenal carcinoma <1 activity ratio ≥15
Plasma aldosterone–plasma renin 96 100
activity ratio ≥30
FIGURE 4-6
Types of primary aldosteronism. (Data from Weinberger and
FIGURE 4-7
coworkers [3].)
Screening tests for primary aldosteronism. Serum potassium levels
range from 3.5 to normal levels of patients with primary aldostero-
nism. Most hypertensive patients with hypokalemia have secondary
rather than primary aldosteronism. The plasma aldosterone-to-plas-
ma renin activity (PRA) ratio (disregarding units of measure) is the
most sensitive and specific single screening test for primary aldos-
teronism. 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 Sensitivity, % Specificity, %

Adrenal computed tomographic scan ≈50 ≈60
Adrenal isotopic scan ≈50 ≈65
Adrenal venography ≈70 ≈80
Adrenal magnetic resonance imaging ? ?
Adrenal venous blood sampling with >92 >95
adrenocorticotropic hormone infusion
FIGURE 4-8 A
Localizing tests for primary aldosteronism. Adrenal venous blood
sampling with determination of both aldosterone and cortisol FIGURE 4-9
concentrations during adrenocorticotropic hormone stimulation Normal and abnormal adrenal isotopic scans. A, Normal scan.
provides the most accurate way to identify unilateral hyperaldos- Increased bilateral uptake of I131-labeled iodo-cholesterol of nor-
teronism. This approach minimizes artefact owing to episodic mal adrenal tissue is shown above the indicated renal outlines.
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].)

B, Intense increase in isotopic uptake by the left adrenal (as viewed
from the posterior aspect) containing an adenoma.
FIGURE 4-10
Adrenal venography in primary aldostero-
nism. A, Typical leaflike pattern of the nor-
mal right adrenal venous drainage. B, In
contrast, marked distortion of the normal
venous anatomy by a relatively large (3-cm-
diameter) adenoma of the left adrenal.
Most solitary adenomas responsible for pri-
mary aldosteronism are smaller than 1 cm
in diameter and thus usually cannot be seen
using anatomic visualizing techniques.
A B
In normal persons the increase in plasma

renin activity associated with upright posture
Normal Adenoma Hyperplasia results in a marked increase in plasma aldos-
60
terone at noon compared with that at 8 AM
Plasma aldosterone, ng/dL
50 (see Fig. 4-4). In adenomatous primary

aldosteronism, the plasma renin activity is
40
markedly suppressed and does not increase
30 appreciably with upright posture. Moreover,
aldosterone production is modulated by
20 adrenocorticotropic hormone (which decreases
10 from high levels at 8 AM to lower values at
noon (see Fig. 4-4). Thus, these patients
0 typically demonstrate lower levels of aldos-
8 AM Noon 8 AM Noon 8 AM Noon
terone at noon than they do at 8 AM. In
Supine Upright Supine Upright Supine Upright
A B C patients with bilateral adrenal hyperplasia,
the plasma renin activity tends to be more
responsive to upright posture and aldos-
terone production also is more responsive
FIGURE 4-11 to the renin-angiotensin system. Thus, pos-
Changes in plasma aldosterone with upright posture. A–C, Depicted are individual data tural increases in aldosterone usually are
for persons showing temporal and postural changes in plasma aldosterone concentration seen. Exceptions to these changes occur in
in normal persons (panel A), and in patients with primary aldosteronism owing to a solitary both forms of primary aldosteronism, how-
adrenal adenoma (panel B) or to bilateral adrenal hyperplasia (panel C). Blood is sampled ever, making the postural test less sensitive
at 8 AM, while the patient is recumbent, and again at noon after 4 hours of ambulation. and specific [3].
TH
TH
AC
AC
AC
AC
TH
TH
A A
C C
A A
C C
A A
C C
A Bilateral aldosteronism B Unilateral aldosteronism
FIGURE 4-12
Adrenal venous blood sampling during infusion of adrenocortico- venous blood compared with that of the left adrenal and the inferior
tropic hormone (ACTH) [3]. A, Bilateral aldosteronism. A schematic vena cava. Even if the venous effluent cannot be accurately sampled
representation of the findings in primary aldosteronism owing to from one side (as judged by the levels of cortisol during ACTH
bilateral adrenal hyperplasia is shown on the left. When blood is infusion), when the contralateral adrenal venous effluent has an
sampled from both adrenal veins and the inferior vena cava during aldosterone-to-cortisol ratio lower than that in the inferior vena
ACTH infusion, the aldosterone-to-cortisol ratio is similar in both cava, it can be inferred that the unsampled side is the source of
adrenal effluents and higher than that in the inferior vena cava. In excessive aldosterone production (unless there is an ectopic source).
such cases, medical therapy (potassium-sparing diuretic combinations In such cases, surgical removal of the solitary adrenal lesion usually
such as hydrochlorothiazide plus triamterene, amiloride, or spiro- results in normalization of blood pressure and the attendant metabolic
lactone and calcium channel entry blockers) usually is effective. B, abnormalities. Medical therapy also is effective but often requires
Unilateral aldosteronism. On the right is depicted the findings in a high doses of Aldactone® (GD Searle & Co., Chicago) (200 to 800
patient with a unilateral right adrenal lesion. This lesion can be mg/d), which may be intolerable for some patients because of side
diagnosed by an elevated aldosterone-to-cortisol ratio in right adrenal effects. A—aldosterone; C—cortisol.

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.
FIGURE 4-14
180
Father Glucocorticoid-remediable aldosteronism. A–C, Seen are the effects
160
of dexamethasone and spironolactone on blood pressure in a father
140 (panel A) and two sons, one aged 6 years (panel B) and the other
120 aged 8 years (panel C). Blood pressure levels are shown before and
after treatment with dexamethasone (left) or spironolactone (right) [5].
100
Note that the maximum blood pressure reduction with dexamethasone
80 required more than 2 weeks of treatment. Similarly, the maximum
mg response to spironolactone was both time- and dose-dependent.
60 200
100
A
160 Son 1
Dexamethasone Spironolactone
140
Blood pressure
120
100
80
60
200
100
B 40
160 Son 2
140
120
100
80
60 200
100
40
C 0 1 2 3 4 5 6 0 2 4 6 8
Weeks Months
elevated in only one

Changes with dexamethasone patient before dexametha-
sone administration. The
25 25 diagnosis was made by
Plasma cortisol, µg/ 100 mL
demonstrating that
Urinary aldosterone,
20 20
the plasma aldosterone
concentration failed to
µg/ 24 h
15 15
suppress normally after
10 10 intravenous saline infu-
Dexamethasone
sion (2 L/4 h) [6]. After
5 5 dexamethasone adminis-
tration, both plasma and
urinary aldosterone levels
A 0 1 2 3 4 5 B 0 1 2 3 4 5
decreased markedly
(except for one occasion
Plasma renin activity, ng AI/mL- 3hr
1.0 50 7 when it is suspected that
Serum potassium, mEq/L

the patient did not com-
Plasma aldosterone,
0.8 40 6
ply with dexamethasone
ng/100 mL
0.6 30 5 therapy). PRA, which was

markedly suppressed
0.4 20 4 before treatment,
increased with dexa-
0.2 10 3 methasone. Note also
that serum potassium
0
levels were normal in
C 0 1 2 3 4 5 D 0 1 2 3 4 5 E 0 1 2 3 4
two of the three patients
Weeks before treatment with
dexamethasone but
increased with therapy
FIGURE 4-15 in all three [5]. All of
Humoral changes in glucocorticoid-remediable aldosteronism with dexamethasone. A–E, Depicted are the changes these changes reverted to
in plasma cortisol (panel A), urinary aldosterone (panel B), plasma renin activity (PRA) (panel C), plasma aldos- control baseline values
terone (panel D), and serum potassium (panel E) before and after dexamethasone administration in the patients when dexamethasone
in Figure 4-14. Note that before dexamethasone administration, serum cortisol was in the normal range and was therapy was discontinued.
markedly suppressed after treatment. Urinary aldosterone was completely normal and plasma aldosterone was
FIGURE 4-16
Glomerulosa Glomerulosa
Normal and chimeric aldosterone synthase
AII AII in glucocorticoid-remedial aldosteronism
Aldosterone Aldosterone Aldosterone Aldosterone (GRA). A, Normal relationship between the
stimuli and site of adrenal cortical steroid
production. Aldosterone synthase normally
Cortisol responds to angiotensin II (AII) in the zona
ACTH ACTH + glomerulosa, resulting in aldosterone synthe-
Cortisol Aldosterone
sis and release (see Figs. 4-2 and 4-3). B, In
+
18–OH cortisol
GRA, a chimeric aldosterone synthase gene
Chimeric
Aldos + results from a mutation, which stimulates
18–OXO cortisol production of aldosterone and other steroids
from the zona glomerulosa under the control
of adrenocorticotropic hormone (ACTH)
Fasciculata Fasciculata (Fig. 4-17). Thus, when ACTH production is
A B suppressed by steroid administration, aldos-
terone production is reduced.
FIGURE 4-17
11–OHase 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
5' 3' 5' 3' glucocorticoid-remedial aldosteronism is described.
Unequal crossing over
5' 3' 5' 3'
5' 3' 5' 3' 5' 3'
Aldosterone synthase Chimeric gene 11–OHase
Cushing’s Syndrome
B
Physical characteristics of Cushing’s syndrome. A, Side profile of a patient with Cushing’s
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 Cushing’s syndrome. Such striae also can be observed on the inner
A parts of the legs in some patients.
Pituitary Pituitary
Pituitary CRF
(–)
(–) (–)
ACTH Cortisol
ACTH ↑ Cortisol ↑ ACTH ↑ Cortisol
Adrenal cortex
(zona fasciculata
zona reticularis)
Adrenal cortex Adrenal cortex
(zona fasciculata (zona fasciculata
FIGURE 4-19 zona reticularis) zona reticularis)
Normal pituitary-adrenal axis. Corticotropin-
releasing factor (CRF) acts to stimulate the FIGURE 4-20 FIGURE 4-21
release of adrenocorticotropic hormone
Pituitary Cushing’s disease. Pituitary Cushing’s Adrenal Cushing’s syndrome. Adrenal
(ACTH) from the anterior pituitary. ACTH
disease results from excessive production of Cushing’s syndrome typically is caused by
then stimulates the adrenal zona fasciculata
adrenocorticotropic hormone (ACTH), typ- a solitary adrenal adenoma (rarely by carci-
and zona reticularis to synthesize and release
ically owing to a benign adenoma. Excess noma) producing excessive amounts of
cortisol (see Figs. 4-2 and 4-3). The increased
ACTH stimulates both adrenals to produce cortisol autonomously. The increased levels
levels of cortisol feed back to suppress addi-
excessive amounts of cortisol and results in of cortisol feed back to suppress release of
tional release of ACTH. As shown in Figure
bilateral adrenal hyperplasia. The increased adrenocorticotropic hormone (ACTH) and
4-4, ACTH and cortisol have circadian
cortisol production does not suppress ACTH corticotropin-releasing factor. The finding
patterns.
release, however, because the pituitary tumor of very low ACTH levels in the face of
is unresponsive to the normal feedback sup- elevated cortisol values and a loss of the
pression of increased cortisol levels. The circadian pattern of cortisol confirm the
diagnosis usually is made by demonstration diagnosis (see Fig. 4-4). Additional anatomic
of elevated levels of ACTH in the face of studies of the adrenal (computed tomographic
elevated cortisol levels, particularly in the scan and magnetic resonance imaging) usually
afternoon or evening, representing loss of disclose the source of excessive cortisol pro-
the normal circadian rhythm (see Fig. 4-4). duction. Surgical removal usually is effective.
Radiographic studies of the pituitary (com-
puted tomographic scan and magnetic reso-
nance imaging) will likely demonstrate the
source of increased ACTH production. When
the pituitary is the source, surgery and irra-
diation are therapeutic options.
Cushing's syndrome: ectopic etiology

SCREENING TESTS FOR CUSHING’S SYNDROME
Ectopic
Tumor
Test Sensitivity, % Specificity, %
Pituitary
Elevated PM serum cortisol ≈75 ≈60
Elevated urinary 17-hydroxy corticosteroids >90 ≈60
Elevated urinary free cortisol >95 >95
(–)
FIGURE 4-23
Screening tests for Cushing’s syndrome. Whereas elevated evening
plasma cortisol levels typically indicate abnormal circadian rhythm,
other factors such as stress also can cause increased levels late in
ACTH Cortisol
the day. Urinary levels of 17-hydroxy corticosteroids may be
increased in association with obesity. In such cases, repeat measure-
ACTH ment after a period of dexamethasone suppression may be required
to distinguish this form of increased glucocorticoid excretion from
Cushing’s 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 Cushing’s syndrome. Rarely, Cushing’s syn-
drome 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 Cushing’s syndrome often are wasted and
have other manifestations of malignancy.
the morning hours (see Fig. 4-4). In pitu-

itary Cushing’s disease and ectopic forms
of Cushing’s 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 lev-
els points to the adrenal as the source of
FIGURE 4-24 excessive cortisol production, and anatomic
Algorithm for differentiation of Cushing’s syndrome. The first step in the differentiation studies of the adrenal are indicated. CT—
of Cushing’s syndrome after diagnosing hypercortisolism is measurement of plasma computed tomography; MRI—magnetic
adrenocorticotropic hormone (ACTH) levels. Typically, these should be reduced after resonance imaging.
Catecholamines
FIGURE 4-25
Synthesis, actions, and metabolism of catecholamines. Depicted catecholamines and their metabolites, as noted here. The kidney
is the synthesis of catecholamines in the adrenal medulla [9]. also can contribute catecholamines to the urine. The relative
Epinephrine is only produced in the adrenal and the organ of contributions of norepinephrine and epinephrine to biologic
Zuckerkandl at the aortic bifurcation. Norepinephrine and dopamine events is noted by the plus signs. BMR—basal metabolic rate;
can be produced and released at all other parts of the sympathetic CNS—central nervous system; NEFA—nonesterified fatty acids;
nervous system. The kidney is the primary site of excretion of VMA—vanillylmandelic acid.
Pheochromocytoma
Blood pressure taken at

2-min intervals 5-min intervals
Calibrate
250
240
230
220
210
200
190
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
8:30 10 2 5:00 7:45 9 10 11 12 1

PM PM AM AM AM AM AM AM Noon PM
During the attack:

Blood pressure, 192/100 mm Hg
Pulse 108
Respirations, 24
FIGURE 4-26
Paroxysmal blood pressure pattern in pheochromocytoma. range, episodic increases to levels of 200/140 mm Hg were
Note the extreme variability of blood pressure in this patient observed. Such paroxysms can be spontaneous or associated
with pheochromocytoma during ambulatory blood pressure with activity of many sorts. (Adapted from Manger and Gifford
monitoring [9]. Whereas most levels were within the normal [9]; with permission.)
FIGURE 4-28
Café au lait lesions
in a patient with
pheochromocytoma.
These light-brown-
colored (coffee-
with-cream-colored)
lesions, sometimes
seen in patients with
pheochromocytoma,
usually are larger
than 3 cm in the
largest dimension.
In this particular
patient, neurofibro-
mas also are present
FIGURE 4-27 (see Color Plate) and can be seen in
Neurofibroma associated with pheochromocytoma. Neurofibromas profile.
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.
FIGURE 4-29
DISORDERS ASSOCIATED WITH Disorders associated with pheochromocytoma. In addition to the neurofibromas and
PHEOCHROMOCYTOMA café au lait lesions depicted in Figures 4-27 and 4-28, several other associated abnormal-
ities have been reported in patients with pheochromocytoma. (From Ganguly et al. [9];
with permission.)
Cholelithiasis
Renal artery stenosis
Neurofibromas
Café au lait lesions
Multiple endocrine neoplasia, types II and III
Von Hippel-Lindau syndrome
(hemangioblastoma and angioma)
Mucosal neuromas
Medullary thyroid carcinoma
FIGURE 4-30
COMMON SYMPTOMS Common symptoms SCREENING AND DIAGNOSTIC TESTS
AND FINDINGS IN and findings in pheo- IN PHEOCHROMOCYTOMA
PHEOCHROMOCYTOMA chromocytoma. Note
that severe hyperten-
sive retinopathy, Test Sensitivity, % Specificity, %
Patients, % indicative of intense
vasoconstriction, Elevated 24-h urinary catecholamines, ≈85 ≈80
Symptoms frequently is vanillylmandelic acid, homovanillic
Severe headache 82 acid, metanephrines
observed. (Adapted
Perspiration 67 Abnormal clonidine suppression test ≈75 ≈85
from Ganguly
Palpitations, tachycardia 60 Elevated urinary “sleep” norepinephrine >99 >99
et al. [10].)
Anxiety 45
Tremulousness 38
Chest, abdominal pain 38
Nausea, vomiting 35 FIGURE 4-31
Weakness, fatigue 26 Screening and diagnostic tests in pheochromocytoma. Drugs, incom-
Weight loss 15 plete urine collection, and episodic secretion of catecholamines can
Dyspnea 15 influence the tests based on 24-hour urine collections in a patient
Warmth, heat intolerance 15 with a pheochromocytoma. The clonidine suppression test is fraught
Visual disturbances 12
with false-negative and false-positive results that are unacceptably
high for the exclusion of this potentially fatal tumor. The “sleep”
Dizziness, faintness 7
norepinephrine test eliminates the problems of incomplete 24-hour
Constipation 7
urine collection because the patient discards all urine before retiring;
Finding
saves all urine voided through the sleep period, including the first
Hypertension:
specimen on arising; and notes the elapsed (sleep) time [10]. The sleep
Sustained 61
period is typically a time of basal activity of the sympathetic nervous
Paroxysmal 24 system, except in patients with pheochromocytoma (see Fig. 4-32).
Pallor 44
Retinopathy:
Grades I and II 40
Grades III and IV 53
Abdominal mass 9
Associated multiple endocrine 6
adenomatosis
FIGURE 4-32
Nocturnal (sleep) urinary norepinephrine. The values for urinary
excretion of norepinephrine are shown for normal persons and
1000
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
Patient I µg, whereas the lowest value for a patient with pheochromocytoma
Patient II
was about 75 µg. Most patients with pheochromocytomas had val-
Patient III
ues an order of magnitude higher than the highest value for
Sleep urinary norepinephrine excretion, µg
Patient IV
Patient V
patients with essential hypertension.
100 Patient VI
Maximum for normal
Maximum for hypertensive
10 Hypertensive
Normal mean + SD
mean + SD
FIGURE 4-34
LOCALIZATION OF PHEOCHROMOCYTOMA Intravenous pyelo-
gram in pheochro-
mocytoma. Note the
Test Sensitivity, % Specificity, % displacement of the
left kidney (right) by
Abdominal plain radiograph ≈40 ≈50 a suprarenal mass.
Intravenous pyelogram ≈60 ≈75
Adrenal isotopic scan ≈85 ≈85
(meta-iodobenzoylguanidine)
Adrenal computed tomographic scan >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.
A B
C D
FIGURE 4-35
A–D, Computed tomographic scans in four patients with pheochro- these four patients. Three patients have left adrenal tumors, and in
mocytoma [10]. The black arrows identify the adrenal tumor in one patient (panel B) the tumor is on the right adrenal.
A B
FIGURE 4-36 (see Color Plates)
A and B, Pathologic appearance of pheochromocytoma before tumor had gross areas of hemorrhage noted by the dark areas
(panel A) and after (panel B) sectioning. This 3.5-cm-diameter visible in the photographs.
References
1. Netter FH: Endocrine system and selected metabolic diseases. In Ciba 7: Lifton RP, Dluhy RG, Powers M: Hereditary hypertension caused by
Collection of Medical Illustrations, vol. 4; 1981:Section III, Plates 5, 26. chimeric gene duplications and ectopic expression of aldosterone syn-
2. DeGroot LJ, et al.: Endocrinology, edn 2. Philadelphia: WB Saunders; thase. Nat Genet 1992, 2:66–74.
1989:1544. 8. Lifton RP, Dluhy RG, Powers M: A glucocorticoid-remediable aldos-
3. Weinberger MH, Grim CE, Hollifield JW, et al.: Primary aldostero- terone synthase gene causes glucocorticoid-remediable aldosteronism
nism: diagnosis, localization and treatment. Ann Intern Med 1979, and human hypertension. Nature 1992, 355:262–265.
90:386–395. 9. Manger WM, Gifford RW Jr: Pheochromocytoma. New York:
4. Weinberger MH, Fineberg NS: The diagnosis of primary aldosteronism Springer-Verlag; 1977:97.
and separation of subtypes. Arch Intern Med 1993, 153:2125–2129. 10. Ganguly A, Henry DP, Yune HY, et al.: Diagnosis and localization of
5. Grim CE, Weinberger MH: Familial, dexamethasone-suppressible pheochromocytoma: detection by measurement of urinary norepineph-
normokalemic hyperaldosteronism. Pediatrics 1980, 65:597–604. rine during sleep, plasma norepinephrine concentration and computed
axial tomography (CT scan). Am J Med 1979, 67:21–26.
6. Kem DC, Weinberger MH, Mayes D, Nugent CA: Saline suppression
of plasma aldosterone and plasma renin activity in hypertension. Arch
Intern Med 1971, 128:380–386.
Insulin Resistance
and Hypertension
Theodore A. Kotchen
R
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 hyperin-
sulinemia, 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 insulin-
sensitizing 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.
Non–insulin-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 non–insulin-depen-
dent diabetes, and antihypertensive drug therapy has a beneficial
impact on both macrovascular and microvascular disease [5]. Despite CHAPTER
the potential concern that diuretics may augment insulin resistance,
diabetic patients benefit from antihypertensive therapy with diuretics.
5
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.
This benefit is independent of an effect on blood pressure dihydropyridine calcium antagonists accelerate the progres-
and may be related specifically to the capacity of these agents sion of diabetic nephropathy, particularly in the short term.
to dilate the efferent renal arteriole. Results of studies evalu- Additional studies are required to evaluate the antihyperten-
ating the effects of calcium antagonists on the progression of sive potential of insulin-sensitizing agents in patients with
diabetic nephropathy are varied. Some studies suggest that non–insulin-dependent diabetes.
Men Women
7.0
50–54 y
Total cholesterol, mmol/L
6.5 40–49 y
40–49 y B. NATIONAL HEALTH AND NUTRITION
EXAMINATION SURVEY II
6.0 30–39 y
30–39 y
5.5 1. Persons with blood pressure >140/90 mm Hg or taking medication for hypertension:
20–29 y 20–29 y
40% have cholesterol >240 mg/dL
5.0 2. Persons with blood cholesterol >240 mg/dL:
46% have blood pressure >140/90 mm Hg
70 80 90 100 70 80 90 100
A Diastolic blood pressure, mm Hg
FIGURE 5-1
Hyperlipidemia and hypertension. A, Epidemiologic studies docu- and Nutrition Examination Survey II, persons with hypertension
ment an association between serum cholesterol and blood pressure have a high prevalence of hyperlipidemia and vice versa [6].
in men and women. B, Based on data from the National Health (Panel A from Bonna and Thelle [7]; with permission.)
FIGURE 5-2
Epidemiologic + clinical association B. HYPERTENSION AND Insulin resistance and hypertension.
Hereditary + acquired mechanisms
INSULIN RESISTANCE A, Genetic and nutritional factors con-
tribute to insulin resistance and resultant
hyperinsulinemia. In addition to obesity
and type II diabetes, hyperlipidemia and
Glucose tolerance ↓ Type II diabetes mellitus
Insulin-resistance Obesity hypertension also may be associated with
Obesity Diabetes type II
Hyperinsulinemia insulin resistance. Insulin resistance may
Essential hypertension
Salt sensitive (?) account for the association of hyperlipi-
Experimental hypertension demia with hypertension. B, Insulin resis-
Dahl-salt-sensitive rats tance is associated with hypertension in a
Spontaneously hypertensive rats number of clinical and experimental set-
Dyslipidemia, hypertension tings. (Panel A from Ferrari and
Weidmann [8]; with permission.)
Insulin Resistance and Hypertension 5.3

140 10
Hypertensive patients Insulin resistance Salt sensitivity.
based on glucose 1 mmol/l = 0.0555 mg/dL Persons who have
Glucose, mmol/L
Plasma glucose, mg/100 mL
120 and insulin responses 8 salt-sensitive hyper-

* to glucose load. In tension tend to
* response to an oral be more insulin-
80 Control group 6
glucose load of 75 g, resistant than are
Salt-sensitive
compared with per- Salt-resistant
those who are salt-
40 sons with normal 4 resistant. That is,
blood pressure, 0 30 60 90 120 150 patients who are salt-
patients with hyper- 800 sensitive have higher
0 tension tend to have plasma glucose and
60
higher plasma glucose 600 insulin responses to
Insulin, pmol/L
Plasma insulin, µU/mL
and insulin levels. a glucose load than

These data suggest 400 * do those who are
40 *
* that patients with salt-resistant.
hypertension are 200 (From Bigazzi and
1 pmol/L = 7.175 µU/mL
20 insulin resistant. coworkers [10];
(From Ferrannini 0 with permission.)
0 30 60 90 120 150
0 and coworkers [9];
Time, min
0 30 60 90 120 with permission.)
Time, min
FIGURE 5-5
16
Insulin sensitivity. Insulin sensitivity also
Hypertensive subjects
14 may be assessed using the euglycemic insulin
Control subjects
clamp technique. The frequency distribution
12 for insulin-mediated glucose disposal during
euglycemic insulin clamping (M value) differs
10 in persons with normal blood pressure and
those with hypertension. The percentage of
Count
8 persons with hypertension considered

insulin-resistant depends on the definition
6
of insulin resistance. In this study, 27% of
4 patients with hypertension were classified
as being insulin-resistant based on an M value
2 over two SDs above the mean for persons
with normal blood pressure. (From Lind
0 and coworkers [2]; with permission.)
0 2 4 6 8 10 12 14
M value at clamp, mg/kg/min
FIGURE 5-6
SYNDROME X AND As originally defined, syndrome X includes hypertension, hyperinsulinemia, increased
ASSOCIATED CONDITIONS plasma triglycerides, and decreased HDL cholesterol. The syndrome also may be
associated with clustering of additional cardiovascular disease risk factors.
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 5-7
Obesity Nutrition Genetic predisposition Hypertension associated with insulin resis-
tance. It is unclear whether hyperinsuline-
mia associated with insulin resistance caus-
Resistance to es hypertension, although a number of
Compensatory insulin-stimulated Hyperglycemia
hyperinsulinemia Hyperlipidemia potential mechanisms have been proposed.
glucose uptake
Increased Vascular Increased α1– Impaired endothelium-

Antinatriuresis
sympathetic nervous growth adrenegic dependent vasodilation
system activity receptors

Hypercholesterolemia Metabolic conse- High glucose Results of high glu-
(low-density lipoprotein, lipoprotein (a)) quences of insulin cose concentrations.
resistance. These High glucose con-
Decreased nitric Protein kinase C
consequences also oxide production activation centrations may
Endothelial injury
may affect peripher- inhibit nitric oxide
al vascular resistance. production and alter
Increased endothelial superoxide Hypercholesterolemia Increased ion transport in vas-
anion production may result in vascular sodium-hydrogen cular smooth muscle
antiport activity
endothelial injury cells, favoring vaso-
and, hence, impaired constriction.
Increased degradation of nitric oxide vasodilation.
Impaired endothelium-dependent vasodilation
FIGURE 5-10
Sulfonylureas Biguanides Thiazolidinediones Effects of chemically
distinct oral hypo-
R1 glycemic agents on
R1 SO2 NH C NH R2 N C NH C NH2 R1 O CH2 S O blood pressure.
R2
NH NH Sulfonylureas stimulate
O NH
endogenous insulin
C1 O secretion and do not
H 3C N
C NH CH2CH2 SO2 NH C NH N C NH C NH2 CH3CH2 CH2CH2 O CH2 S lower blood pressure.
H 3C O
O NH NH In contrast, biguanides
O NH and thiazolidinediones
increase insulin sensitivity
Glyburide Metformin Pioglitazone
without stimulating
endogenous insulin
secretion, and drugs in
these classes lower
blood pressure.
FIGURE 5-11
160
Control Pioglitazone in the treatment of hypertension in rats. A, Systolic
Pioglitazone blood pressures in Dahl-salt-sensitive rats treated with either vehicle or
Systolic blood pressure,
140 pioglitazone (a thiazolidinedione) for 3 weeks. Pioglitazone attenuated

development of hypertension in this animal model. Weight gain did
mm Hg
120 not differ in the two groups.

100
80
0 2 4 6 8 10 12 14 16 18 20 22
A Day
B. HEMODYNAMIC MEASUREMENTS IN DAHL-SALT-SENSITIVE RATS MODELS IN WHICH

THIAZOLIDINEDIONES LOWER
BLOOD PRESSURE
Mean intra-arterial Cardiac index, Total peripheral resistance,
pressure, mm Hg mL/min/100 g mm Hg/mL/min/100 g
Dahl-S rat
Control group 129 ±1 51.4 ±1.6 2.50 ±0.07
1-Kidney, 1-clip rat
Group treated with pioglitazone 121 ±3* 59.1±1.7* 2.07 ±0.07*
Obese Zucker rat
Fructose-fed rat
*P<0.05 L-NNA–treated rat
SHR
Obese rhesus monkey
Watanabe hyperlipidemic rabbit
B, Direct intra-arterial pressure and cardiac index (thermodilution) in these same chronically
Obese human
instrumented, conscious pioglitazone-treated and control rats. Compared with control ani-
mals, 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.)
FIGURE 5-12
Thiazolidinediones lower blood pressure in
several models of experimental hyperten-
sion and in obese humans.
FIGURE 5-13
AGENTS THAT INCREASE INSULIN SENSITIVITY, DECREASE PLASMA LIPID Agents that increase insulin sensitivity,
CONCENTRATIONS, AND LOWER BLOOD PRESSURE IN ANIMAL MODELS decrease plasma lipid concentrations, and
AND PRELIMINARY STUDIES IN HUMANS lower blood pressure in animal models and
preliminary studies in humans.
Thiazolidinediones Etomoxir Lovastatin/pravastatin

Metformin Spontaneously hypertensive rats Dahl-salt-sensitive rats
Spontaneously hypertensive rats Clofibrate Spontaneously hypertensive rats
Humans (?) Dahl-salt-sensitive rats Human (?)
Vanadyl sulfate Fenfluramine derivatives
Spontaneously hypertensive rats Fructose-fed rats
Fructose-fed rats Humans
200
EFFECT OF CHOLESTEROL REDUCTION ON BLOOD PRESSURE RESPONSE
Mean arterial pressure, mm Hg
180 TO MENTAL STRESS IN PATIENTS WITH NORMAL BLOOD PRESSURE AND

160
HIGH CHOLESTEROL
140
120 Systolic blood pressure Diastolic blood pressure

Baseline Stress Baseline Stress
100
Placebo group 122 141 69 78
80
Group treated with lovastatin 119 133* 67 75
Clofibrate Vehicle Clofibrate Vehicle
Dahl-S Dahl-R

Clofibrate in prevention of hypertension in In humans with normal blood pressure who have high serum cholesterol concentrations,
rats. Clofibrate prevents the development of treatment with lovastatin lowers serum cholesterol and attenuates the systolic blood
hypertension in Dahl salt-sensitive rats. pressure response to mathematics-induced stress. (From Sung and coworkers [13];
This agent does not affect blood pressure in with permission.)
Dahl salt-resistant rats. (From Roman and
coworkers [12]; with permission.)
FIGURE 5-16
ANTIHYPERTENSIVE MECHANISMS OF Insulin-sensitizing and lipid-lowering agents may lower blood
INSULIN-SENSITIZING AGENTS pressure by a number of different mechanisms. Different agents
may act through different mechanisms.
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
1.05 0.95 Arginine vasopressin

R172 #1–8 + 20 ng/mL PDGF R172 #31–41 + 2 ug/mL ciglitazone
1.00 + 20 ng/mL PDGF 350 Control
0.90 (73)
300 Metformin
0.95 0.85
Intracellular [Ca2+]i
Intracellular [Ca2+]i
* * P<0.05
0.90 250 (59)
[Ca2+]i(nM)
0.80
0.85 200
0.75
0.80 150 (286) (290)
0.75 0.70 100 *
0.70 0.65 50
0.65 0.60 0
0 100 200 300 400 500 600 700 800 0 100 200 300 400 500 600 700 800 Basal Peak Delta
A Time, s B Time, s 450
Thrombin
400 (213)
* P<0.05
350 *
FIGURE 5-17 (231)
Use of ciglitazone to abolish calcium concentration elevation. Ciglitazone, a thiazolidinedione, 300
[Ca2+]i(nM)
abolishes agonist-stimulated sustained elevations of intracellular calcium concentrations. 250

Shown are time-dependent plots of changes in intracellular calcium (in arbitrary units; *
200
[Ca2+]i) induced by platelet-derived growth factor (PDGF) in human gliobastoma cells
(286) (290)
with and without preincubation with ciglitazone. A, Addition of PDGF to control cells is 150
indicated by the vertical line. B, An identical experiment conducted on cells pretreated with 100
ciglitazone. The capacity of this agent to shorten the duration of agonist-stimulated
50
increases in intracellular calcium may result in attenuation of both growth of vascular
smooth muscle cells and vasoconstriction. (From Pershadsingh and coworkers [14]; 0
with permission.) Basal Peak Delta
FIGURE 5-18
Use of metformin to attenuate intracellular
calcium concentration elevation. Metformin
is a biguanide that attenuates agonist-stimu-
lated increases of intracellular calcium con-
centrations in vascular smooth muscle. (From
Bhalla and coworkers [15]; with permission.)
FIGURE 5-19
28
Effect of pioglitazone on insulin-induced proliferation of arterial
24 Insulin smooth muscle cells. Inhibition of insulin-stimulated vascular
hyperplasia and hypertrophy is one potential mechanism by which
Cell number (x104)
20 Insulin + pioglitazone
(days 0–6) insulin-sensitizing and lipid-lowering agents may decrease peripheral
16
resistance. Two kinds of evidence suggest that thiazolidinediones
12 inhibit the growth of vascular smooth muscle cells in vitro. Shown
8 Insulin + pioglitazone here, pioglitazone inhibits insulin-stimulated proliferation of vascular
smooth muscle cells. Pioglitazone also inhibits 3H-thymidine incor-
4 0.4% FCS
poration in vascular smooth muscle cells (Fig. 5-19). FCS—fetal
0 calf serum. (From Dubey and coworkers [11]; with permission.)
0 2 4 6 8 10 12 14
Days in culture
FIGURE 5-20
120
Effect of pioglitazone on 3H-thymidine incorporation in vascular smooth muscle cells.
H-Thymidine incorporation,
100 3H-thymidine incorporation is stimulated by insulin, fetal calf serum (FCS), and epidermal
80 growth factor (EGF). Pioglitazone inhibits 3H-thymidine incorporation stimulated by each

% of control
of these mitogens. Similar observations have been made with pravastatin and lovastatin.
60 (From Dubey and coworkers [11]; with permission.)
40 Insulin = 1 mU/mL
20 EGF = 100 mg/mL
5% FCS
3
0
0.001 0.01 0.1 1 10 100
Pioglitazone concentration, uM
FIGURE 5-21
50 Control 50 Control Decreases in mean arterial pressure in rats treated with pioglita-
Pioglitazone Pioglitazone zone and control Dahl-salt-sensitive rats in response to graded
40 40 infusions of norepinephrine and angiotensin II. In vivo, pressor
Percent of change
Percent of change
responses to norepinephrine and angiotensin are II attenuated in

30 30 Dahl-salt-sensitive rats treated with pioglitazone [16]. (From
Kotchen and coworkers [16]; with permission.)
20 20
10 10
0 0
0 100 200 300 400 500 0 100 200 300 400 500
Norepinephrine, Angiotensin II,
ng/kg/min ng/kg/min
FIGURE 5-22
3 * Half-maximal values for norepinephrine-induced contraction in aortic strips preincubated
Norepinephrine x 10–8 (log M)
with insulin, pioglitazone, or both. In vitro, pressor responsiveness of aortic strips to norep-
inephrine-induced contraction is inhibited by preincubation with insulin plus pioglitazone
2
[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)
1 but not in strips incubated with insulin alone or pioglitazone alone.
0
Control Insulin Pioglitazone Insulin
+
pioglitazone
FIGURE 5-23
Substance P
Acetylcholine Bradykinin Impaired endothelium-dependent vascular
Sodium P B relaxation and insulin resistance. Insulin
nitroprusside M Gq protein resistance is associated with impaired
Endothelium
Gi protein endothelium-dependent vascular relaxation,
Nitric oxide
which is a defect that may be corrected by
L-arginine synthase Nitric oxide
insulin-sensitizing agents. One approach to
EDRF-nitric oxide evaluating vascular endothelial function is
Smooth muscle
to measure vascular relaxation in response
to acetylcholine. EDRF—endothelium
derived relaxing factor.
5 20-Hydroxy-eicosotetraenoic acid
(+)
Acetylcholine x 10–7 (log M)
Control, n = 9 * P<0.05
60 + + + +
4 Clofibrate, n = 12 * Na K Ca2 Mg2
All
50
Protein, pmol/min/mg
* 2 Cl– AA bradykinin
3 R
40 Na
+ PLA vasopressin
+ +
2 * K PLC Ca2
30 20-HETE
1 20 + + 3 Na
+
K K
+
0 10 2K
* –
Control Insulin Pioglitazone Insulin Cl
+ 0
pioglitazone Cortex Outer medulla Liver

Half-maximal values for acetylcholine- Effect of clofibrate on 20-hydroxy-eicosate- FIGURE 5-26
induced vasodilation in aortic strips prein- traenoic (20-HETE) production in Dahl- 20-Hydroxy-eicosotetraenoic acid inhibits
cubated with insulin, pioglitazone, or both. In salt-sensitive rats. Insulin stimulates sodium chloride transport in the thick ascending
the presence of insulin, pioglitazone augments reabsorption in the proximal tubule. limb of the loop of Henle. This inhibition
endothelium-dependent vasodilation. In vitro, Consequently, lowering plasma insulin con- results in a natriuretic effect in the
the half-maximal values for acetylcholine- centrations by increasing insulin sensitivity Dahl-salt-sensitive rat. This may be the
induced vasodilation is less in aortic strips would potentially result in less sodium mechanism by which clofibrate prevents
incubated with insulin plus pioglitazone (ie, retention. In addition, clofibrate induces hypertension in this animal model.
the strips are more responsive to acetylcholine) renal P-450 fatty acid w-hydroxylase activity
than in control strips or strips incubated and, hence, increases metabolism of arachi-
with insulin alone or pioglitazone alone [16]. donic acid to 20-HETE. (From Roman and
FIGURE 5-27
BENEFITS OF CONTROL OF Benefits of hypertension control and blood glucose controls are well established in diabetic
HYPERTENSION AND DIABETES 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
Hypertension cardiovascular disease morbidity and mortality are reduced in diabetic patients with
Decreased nephropathy hypertension by antihypertensive therapy with regimens that include diuretics.
Decreased retinopathy
Decreased stroke, myocardial infarction
Drug specific (?)
Diabetes (type I)
Decreased nephropathy
Decreased retinopathy
Decreased neuropathy
FIGURE 5-28
Start of antihypertensive treatment Course of diabetic
Mean arterial blood
EFFECT OF ANTIHYPERTENSIVE AGENTS ON

pressure, mm Hg
125 nephropathy during INSULIN SENSITIVITY AND RENAL FUNCTION

115 effective antihyper- IN DIABETIC PATIENTS
tensive treatment in
105
patients with overt
95 diabetic nephropa- Agent Insulin sensitivity Renal protection
105 thy. Effective antihy-
GFR: 0.94 pertensive therapy Angiotensin-converting enzyme inhibitors Increase +

95 (mL/min/mo) Diuretics Decrease ?
mL/min/1-73 m2
with regimens that

85 GFR: 0.29 include diuretics -Blockers Decrease 0
(mL/min/mo)
also decreases the 1-Blockers Increase 0
75 GFR: 0.10
(mL/min/mo) rate of progression Calcium ion antagonists
65 of renal failure Dihydropyridines 0 -?
55 (both the glomerular Others Increase +?
1250
filtration rate and
albumin excretion)
Albuminuria,
750 in patients with dia-

µg/min
betic nephropathy. FIGURE 5-29

250 (From Parving and Different antihypertensive agents have different effects on insulin
coworkers [17]; sensitivity, and in diabetic patients, on renal function. Question
with permission.) mark indicates inconsistent study results; plus sign indicates a
–2 –1 0 1 2 3 4 5 6
Time, y protective effect; minus sign indicates no protection.
50 0.5
Percent doubling of baseline creatinine
Placebo Risk reduction = 50.5%

45
Captopril P = 0.006
40 0.4
Proportion with event
35 Percent risk reduction = 48.5% (16–69)

30 P = 0.007 0.3
25
20 0.2
Placebo
15
10 0.1
5 Captopril
0 0.0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 0 1 2 3 4 4.5
A Years of follow-up B Years from randomization
FIGURE 5-30
Cumulative incidence of events in patients with diabetic nephropathy decreases proteinuria and retards the rate of progression of renal
in captopril and placebo groups. A, Time to doubling of serum cre- insufficiency. The cumulative incidence of doubling of serum creati-
atinine. B, Time to end-stage renal disease or death. In type I diabetic nine concentrations over time and development of end-stage renal
patients with nephropathy and either normal blood pressure or hyper- disease are less in patients treated with captopril than in those treat-
tension, treatment with angiotensin-converting enzyme inhibitors ed with placebo. (From Lewis and coworkers [18]; with permission.)
CHANGES OF MEAN BLOOD PRESSURE, PROTEINURIA, AND GLOMERULAR FILTRATION RATE IN TREATMENT WITH
DIFFERENT ANTIHYPERTENSIVE AGENTS IN PATIENTS WITH INSULIN-DEPENDENT DIABETES MELLITUS AND
NON–INSULIN-DEPENDENT DIABETES MELLITUS WHO HAVE MICROALBUMINURIA OR MACROALBUMINURIA
Treatment type Patients, n MBP, % UProt, % GFR, %

Placebo 244 -2 +39 -8
Conventional (diuretics and -blockers) 213 -10 -20 -9
Angiotensin-converting enzyme inhibitors 489 -16 -52 -1
Calcium antagonists:
All except nifedipine and nitrendipine 63 -16 -42 +2
Nifedipine 63 -12 +2 -48
Nitrendipine 39 -17 -48 +30
FIGURE 5-31
Despite similar control of hypertension, different classes of antihyper- diabetic nephropathy. GFR—glomerular filtration rate; MBP—mean
tensive agents have different effects on renal function in patients with blood pressure; Uprot—urine protein. (From Bretzel [19]; with permission.)
References
1. Kotchen TA, Kotchen JM, O’Shaughnessy IM: Insulin and hyperten- 11. Dubey RK, Zhang HY, Reddy SR, et al.: Pioglitazone attenuates
sive cardiovascular disease. Curr Opin Cardiol 1996, 11:483–489. hypertension and inhibits growth in renal arteriolar smooth muscle in
2. Lind L, Berne C, Lithell H: Prevalence of insulin resistance in essential rats. Am J Physiol 1993, 265:R726–R732.
hypertension. J Hypertens 1995, 17:1457–1462. 12. Roman RJ, Ma Y-H, Frohlich B, et al.: Clofibrate prevents the devel-
3. Reaven GM: Role of insulin resistance in human disease. Diabetes opment of hypertension in Dahl salt-sensitive rats. Hypertension
1993, 21:985–988.
1988, 37:1595–1607.
13. Sung BH, Izzo JL, Wilson MF: Effects of cholesterol reduction on BP
4. Kotchen TA: Attenuation of hypertension by insulin-sensitizing
response to mental stress in patients with high cholesterol. Am J
agents. Hypertension 1996, 28:219–223.
Hypertens 1997, 10:592–599.
5. Nadig V, Kotchen TA: Insulin sensitivity, blood pressure and cardio-
14. Pershadsingh H, Szollosi J, Benson S, et al.: Effects of ciglitazone on
vascular disease. Cardiol Rev 1997, 5:213–219.
blood pressure and intracellular calcium metabolism. Hypertension
6. National High Blood Pressure Education Program and National 1993, 21:1020–1023.
Cholesterol Education Program: Working Group Report on 15. Bhalla RC, Toth KF, Tan EQ, et al.: Vascular effects of metformin:
Management of Patients with Hypertension and High Blood possible mechanisms for its antihypertensive action in the sponta-
Cholesterol. National Institutes of Health Publication No. 90-2361. neously hypertensive rat. Am J Hypertens 1996, 9:570–576.
National Institutes of Health, 1990.
16. Kotchen TA, Zhang HY, Reddy S, et al.: Effect of pioglitazone on
7. Bonna KH, Thelle DJ: Association between blood pressure and serum vascular reactivity in vivo and in vitro. Am J Physiol 1996,
lipids in a population: the Tromso study. Circulation 1991, 260:R660–R666.
83:1305–1324.
17. Parving H-H, Andersen AR, Smidt UM, et al.: Effect of antihypertensive
8. Ferrari P, Weidmann P: Insulin, insulin sensitivity and hypertension. treatment on kidney function in diabetic nephropathy. Br Med J 1987,
J Hypertens 1990, 8:491–500. 294:1443–1447.
9. Ferrannini E, Buzzigoli E, Bonadonna R, et al.: Insulin resistance in 18. Lewis EJ, Hunsicker LG, Bain RP, et al.: The effect of angiotensin-
essential hypertension. N Engl J Med 1987, 317:350–357. converting-enzyme inhibition on diabetic nephropathy. N Engl J Med
10. Bigazzi R, Bianchi S, Baldari G, et al.: Clustering of cardiovascular 1993, 329:1456–1462.
risk factors in salt-sensitive patients with essential hypertension: role 19. Bretzel RG: Effects of antihypertensive drugs on renal function in patients
of insulin. Am J Hypertens 1996, 9:24–32. with diabetic nephropathy. Am J Hypertens 1997, 10:208S–217S.
The Role of Hypertension
in Progression of
Chronic Renal Disease
Lance D. Dworkin
Douglas G. Shemin
H
ypertension is a cause and consequence of chronic renal dis-
ease. 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 dis-
ease, 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 replace-
ment of normal kidney tissue by fibrosis. An important factor contribut-
ing to progressive renal disease is activation of the renin-angiotensin sys-
tem, which not only tends to increase blood pressure but also promotes
cell proliferation, inflammation, and matrix accumulation.
Numerous studies in experimental animals suggest that antihyper-
CHAPTER
tensive drugs can slow the progression of chronic renal disease. Drugs
that inhibit the renin-angiotensin system may be more effective than
6
are other agents in retarding renal disease progression.
For many reasons, the effects of angiotensin II receptor antago-
nists and angiotensin-converting enzyme (ACE) inhibitors may not
be identical. Calcium channel blockers also are beneficial in classes of calcium channel blockers have equivalent renal pro-
some settings; however, this effect is critically dependent on tective effects is uncertain.
the degree of blood pressure reduction. Patients with hypertension and chronic renal disease should
The relationship between hypertension and progression of be treated aggressively. A 24-hour urine collection determines
chronic renal disease has been examined in a number of clinical the extent of proteinuria. The patient who excretes more than
trials. Individuals with systemic hypertension are at increased 1 g/24 h of protein or who has diabetes mellitus should receive
risk for developing end-stage renal disease. The rate at which an ACE inhibitor. The target in this group of patients is to
kidney function is lost increases in patients with poorly con- reduce the blood pressure to lower than 120/80 mm Hg. Most
trolled systemic hypertension. Antihypertensive therapy can often, reaching this goal requires the use of combinations of
slow the rate of loss of kidney function in patients with diabet- antihypertensive agents, diuretics, or calcium channel blockers.
ic and nondiabetic renal disease. Studies suggest that ACE Patients who excrete less than 1 g/24 h of protein may be treated
inhibitors are particularly useful in patients with hypertension according to standard recommendations with diuretics, beta
and proteinuria of over 1g/24 h. Calcium channel blockers also blockers, ACE inhibitors, or other agents. The target blood
may slow the progression of renal disease; however, whether all pressure for this group of patients is lower than 130/85 mm Hg.
Hypertension and Kidney Damage

appropriately suppressed for the degree of
volume expansion, elevation in blood pres-
Partial loss
of function sure, or both. Activation of the renin-
angiotensin system and the relative salt and
water excess contribute to the development
of systemic hypertension in most patients
Renin AII with chronic renal disease. Systemic hyper-
Fibrosis Compensatory activation Afferent
tension and a decrease in preglomerular vas-
apoptosis growth vasodilation
cular resistance lead to an increase in
hydraulic pressure within the glomerular
Systemic capillaries. Glomerular hypertension has a
hypertension number of adverse effects, including
increased protein filtration, which promotes
Release of release of cytokines and growth factors by
cytokines and Increased Glomerular mesangial cells and downstream tubular
growth factors wall tension hypertension
epithelial cells. A partial loss of kidney func-
tion also is a potent stimulus for compen-
satory renal growth. Glomerular hypertro-
phy and hypertension combine to increase
capillary wall tension, promoting endothe-
lial cell activation and injury, again causing
Capillary release of cytokines and growth factors and
Proteinuria
injury
recruitment of inflammatory cells. These
mediators stimulate processes such as apop-
tosis, causing loss of normal kidney cells
FIGURE 6-1 and increased matrix production, which
Hypothesis identifying systemic hypertension as a central factor contributing to the progres- leads to glomerular and interstitial fibrosis
sion of chronic renal disease. After partial loss of kidney function resulting from an unde- and scarring. As additional nephrons are
fined primary renal disease, a number of secondary processes develop that promote progres- damaged secondarily the cycle is repeated
sive kidney failure. Activation of the renin-angiotensin system is a common event in patients and amplified, causing progression to end-
with chronic renal disease. In these patients, renin levels are either elevated or at least not stage renal failure. AII—antiotensin II.
The Role of Hypertension in Progression of Chronic Renal Disease 6.3
FIGURE 6-2
Typical autoregulatory response in Imaginary autoregulation curves in normal and diseased kidneys.
normal kidneys Plotted on the y-axis are renal plasma flow (RPF), glomerular
RPF, GRF, and PGC vary with filtration rate (GFR), and glomerular capillary hydraulic pressure
perfusion pressure in chronic (PGC) with undefined units. Ordinarily, RPF, GFR, and PGC remain
renal failure relatively constant over a wide range of perfusion pressures within
PGC, RPF, or GFR
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.
40 60 80 100 120 140 160 180

Renal perfusion pressure, mm Hg
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 fac-
tors: mean arterial pressure (MAP) or perfusion pressure, and the
PGC = PGC 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
RE ↓RE resistance (RE) also may decline. This decrease decompresses the
MAP ↑MAP glomerulus, helping to limit the increase in glomerular capillary
RA ↑RA
hydraulic pressure (PGC), and maintains constant renal plasma flow.
Baseline Increased perfusion pressure
A B
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
PGC < PGC include a reduction in afferent (RA) and efferent (RE) arteriolar
resistances, tending to increase renal plasma flow and the glomeru-
lar filtration rate. In this setting, an increase in mean arterial pres-
sure (MAP) is transmitted directly to the glomerular capillaries,
↓RE →RE resulting in glomerular capillary hypertension, increased protein
MAP ↑MAP
filtration, and hemodynamically mediated capillary injury. PGC—
↓RA ↓RA
glomerular capillary hydraulic pressure.
Baseline Increased perfusion pressure
A B
Effects of Antihypertensive Agents

on Experimental Kidney Injury
five separate studies. In these studies, rats with experimental renal
disease were given similar antihypertensive agents. Studies were
60 Results of the linear regression analysis
conducted in several different animal models of hypertension and
Effects of going from low to high dose of
triple therapy
renal disease, including the following: uninephrectomized sponta-
40
neously hypertensive rats (Unx SHR); rats with a remnant kidney
given either relatively high-dose (remnant-HD) or low-dose (rem-
20 nant-LD) drug therapy; rats with desoxycorticosterone-
salt–induced hypertension (Doc-salt); and rats with nephrotoxic
Change in sclerosis, %
0 serum nephritis (NSN), an immune-mediated form of glomerular

disease (NSN) [1–5]. In all these studies, untreated rats were com-
-20 pared with those receiving a combination of three antihypertensive
agents (triple therapy), including hydralazine, reserpine, and a thi-
-40 azide diuretic. In rats with remnant kidneys, separate studies
Unx–SHR examined the effects of low or high doses of these agents. A close
Remnant–HD correlation was revealed between the degree of reduction in
-60 Remnant–LD glomerular capillary pressure produced by triple therapy and sub-
Doc–salt sequent development of glomerular sclerosis. The data are consis-
-80 NSN tent with the hypothesis that antihypertensive agents lessen
glomerular injury by reducing glomerular capillary pressure. In the
-100 studies in rats with remnant kidneys, only a relatively high dose of
-1 -2 -3 -4 -5 -6 -7 -8 -9 -10 the drugs was effective in reducing pressure and injury, suggesting
Change in PGC, mm Hg 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,
FIGURE 6-5 such as the triple-therapy regimen. By dilating the afferent arteri-
Effects of triple therapy on glomerular pressure and injury. ole, regimens such as these tend to further impair autoregulation
Relationship between the change in glomerular capillary hydraulic of glomerular pressure in the setting of chronic renal disease.
pressure (PGC) and the extent of glomerular injury (sclerosis) in (From Weir and Dworkin [6]; with permission.)
FIGURE 6-6
400 Correlation between systolic blood pressure and glomerular injury
No treatment in rats with remnant kidneys. In these rats, blood pressure was con-
350 Enalapril tinuously monitored by implanting a blood pressure sensor in the
Low dose triple therapy abdominal aorta connected telemetrically to a receiver. The time-
Glomerular injury score
300 High dose triple therapy

averaged blood pressure in rats with remnant kidneys that were
250 untreated or given the angiotensin-converting enzyme inhibitor
enalapril or triple therapy (combination of hydralazine, reserpine,
200 and a thiazide diuretic) was correlated with morphologic evidence of
150 glomerular injury. A close correlation was found between the aver-
age blood pressure and extent of glomerular injury that developed in
100 these rats. It is proposed that, because of impaired autoregulation in
chronic renal disease, elevations in systemic blood pressure are asso-
50
ciated with glomerular hypertension in these rats. The higher the sys-
temic pressure, the higher the glomerular pressure is predicted to be
0 and the more glomerular injury is observed. These data provide
80 100 120 140 160 180 200 additional evidence that systemic hypertension produces glomerular
Overall averaged systolic blood pressure at final 8 week, mm Hg injury by causing elevation in glomerular pressure, and that antihy-
pertensive therapy reduces injury by reducing glomerular capillary
pressure. (From Griffen and coworkers [7]; with permission.)
FIGURE 6-7
Tension=pressure x radius 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 compen-
satory renal growth associated with an increase in the radius of the
RGC
RGC glomerular capillaries. According to the LaPlace equation, wall ten-
PGC PGC sion in a blood vessel is equal to the product of the transmural pres-
sure and the radius of the vessel. In a surviving glomerular capillary
T of a damaged kidney, therefore, wall tension increases not only
because of the increase in glomerular pressure but also because of
T
an increase in capillary radius. Elevations in wall tension contribute
A B to progressive renal disease by damaging the endothelial and epithe-
lial cells lining the glomerular capillaries. By reducing wall tension,
maneuvers that decrease either glomerular pressure or glomerular
capillary radius are predicted to be beneficial. PGC—glomerular
capillary hydraulic pressure; RGC—glomerular capillary radius;
T—tension. (From Dworkin and Benstein [8]; with permission.)
FIGURE 6-8
Scanning electron micrographs of vascular
casts of glomeruli from normal or uni-
nephrectomized rats. A, A glomerulus from
a rat having had a sham operation, showing
a uniform capillary pattern. (Panels B–D
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
A B damage is most likely to occur. The segmen-
tal nature of the capillary dilation may
explain why glomerular sclerosis that even-
tually develops in remnant kidneys is also
focal in early stages of the disease process.
(Panels A–D ≈320.) (From Nagata and
C D
Role of the Renin Angiotensin System

and progression of renal disease. AII may promote renal injury by
Release of cytokines several mechanisms. Activation of the renin-angiotensin system is
and growth factors 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, con-
Increased protein Hyperplasia and
filtration
A II
hypertrophy tributing to an increase in glomerular pressure. Glomerular hyper-
tension 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,
Systemic and glomerular evidence suggests that AII alters the permeability of the glomerular
hypertension capillary wall to macromolecules, directly increasing protein filtra-
tion. By activating mesangial and epithelial cells, proteinuria itself
is a factor promoting progressive kidney failure. Evidence also exists
FIGURE 6-9 that AII directly stimulates production of various growth factors
The central role of angiotensin II(AII) in promoting progressive kid- and cytokines by kidney cells, including fibrogenic cytokines such as
ney failure. Based on studies in which the renin-angiotensin system transforming growth factor-beta and platelet-derived growth factor.
has been blocked and renal injury ameliorated, it has been suggest- Release of these factors has been linked to the development of
ed that activation of this system is a crucial factor promoting pro- glomerular sclerosis and interstitial fibrosis. AII also stimulates pro-
gressive kidney failure. Increased activity of the renin-angiotensin liferation and growth of kidney cells that contribute to progression
system also may help explain the association between hypertension of renal disease.
FIGURE 6-10
120 80 Angiotensin-converting enzyme (ACE)
inhibitors and low-dose triple therapy. The

100 effects of ACE inhibitors are compared with
60 those of low-dose triple therapy on systemic

80 * and glomerular pressure, proteinuria, and
* *
60 40
morphologic evidence of glomerular injury
in rats with remnant kidneys. Both ACE
40 inhibitors and triple therapy caused similar
20 reductions in mean arterial pressure in rats
20 with remnant kidneys; however, glomerular
pressure declined only in the group treated
0 0 with ACE inhibitors, by approximately
Remnant AC
EI Triple Remnant AC
EI Triple 10 mm Hg. ACE inhibitor—induced reduc-
tions in systemic and glomerular pressure
120 30 were associated with a reduction in protein-
uria and morphologic evidence of glomerular
100 injury. The data suggest that ACE inhibitors
Proteinuria, g/24
h
Glomerular injury, %
are superior to low-dose triple therapy in pre-

80 20 venting glomerular injury in chronic renal
disease. The data support the importance of
60
increased glomerular pressure as a determi-
10 nant of glomerular injury. ACE inhibitors
40
may be more effective than are other agents,
20 specifically because of their ability to reduce
* * glomerular pressure. It should be noted, how-
0 0 ever, that significant reductions in glomerular
Remnant AC
EI Triple Remnant AC
EI Triple pressure and injury may be achieved even
with the triple-therapy regimen when signifi-
cantly 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].)
Small selective
Small selective
pores
1 pores 1
at CA=0
Fractional volume flux at CA=0
0.1 0.1
volume flux
0.01 0.01
Large nonselective
Large nonselective pores
Fractional
0.001 pores 0.001
0.0001 0.0001
0.0005 0.0005
30 40 50 60 30 40 50 60
A Effective pore radius, A B Effective pore radius, A
FIGURE 6-11
Effect of renal vein constriction on glomerular protein filtration. The constriction (open bars). Renal vein constriction causes an increase
role of angiotensin II (AII) in modulating macromolecular clearance in filtration through large nonselective pores, which accounts for
across the glomerular capillary wall has been examined by Yoshioka increased protein filtration. B, Effects of renal vein constriction
and coworkers [11]. These authors used a model of renal vein were again examined, alone (open bars) and during administration
constriction to increase glomerular pressure and markedly increase of the AII receptor antagonist saralasin (hatched bars). Saralasin
protein filtration. They calculated the volume flux through the small reduced volume flux through the large pores, indicating that
selective pores (effective pore radius, 40–50 Å) within the glomerular increased endogenous AII action was largely responsible for
capillary wall and through the large nonselective pores. A, Volume proteinuria during renal vein constriction. (From Yoshioka and
fluxes under control conditions (hatched bars) and during renal vein coworkers [11]; with permission.)

Local activation of the renin-angiotensin sys-
tem 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 trans-
forming growth factor-beta (TGF-beta). Rats
still had not developed widespread morpholog-
ic evidence of glomerular injury 24 days after
subtotal nephrectomy. A, At this point in time
(arrows), staining for angiotensinogen messen-
ger RNA (mRNA) was observed along the
A B wall of a dilated capillary loop (CL) and in an
adjacent cluster of mesangial cells. B, TGF-
beta 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 nephrec-
tomy. 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 TGF-
beta and progressive glomerular fibrosis. (From
C D Lee and coworkers [12]; with permission.)
100
** * P< 0.05 vs cells treated * P<0.05 vs control medium
with A II alone ** P<0.05 vs A II medium without *
90
** P< 0.01 vs unstimulated 15 antibody
Migrated monocytes
80 controls *
**
70
fg RANTES/ 104 cells
10
60
**
50 *
* 5
40
30
20 0
m m b Ab G A II
ediu me
diu ES A TE S t Ig
m
A II
NT N goa -6 M
10 trol i- R A i-R A m a l + 1 0
Con ant ant nor EM
0 i u m+ i u m+ m +m DM
d d di u
me me me
Control A II CGP CGP+ PD PD + los los + trol A II A II
A A II A II A II B Con
FIGURE 6-13
Angiotensin II (AII) may be a proinflammatory molecule. The effect was assessed using a modified Boyden chamber. Migration of monocytes
of AII on production of the chemokine RANTES was examined in was stimulated by conditioned medium from glomerular endothelial cells
cultured glomerular endothelial cells. A, Effects of AII on secretion that were exposed to AII. This effect was blocked by incubation of the
of RANTES by cultured glomerular endothelial cells. AII markedly medium with an anti-RANTES antibody but not by control serum.
stimulated RANTES secretion. Of note is that AII-induced RANTES The anti-RANTES antibody alone was also without effect, as was AII
secretion was prevented by incubation with the AT2 receptor antag- in the absence of conditioned media. The findings are consistent with
onists SCP-42112A (CGP) or PD 1231777 (PD) but not by the AT1 the hypothesis that AII promotes glomerular inflammation by binding
receptor antagonist losartan (los). These finding suggest AT2 recep- to AT2 receptors, promoting RANTES secretion and infiltration of
tors mediate the increase in secretion of RANTES. B, Results of a inflammatory monocytes and macrophages. fg—femtograms. (From
chemotactic assay for human monocytes. Migration of monocytes Wolf and coworkers [13]; with permission.)
FIGURE 6-14
Renin-angiotensin systems
Renin-angiotensin systems. For many reasons the effects of
Angiotensinogen angiotensin-converting enzyme (ACE) inhibitors and angiotensin
II (AII) type 1 AT1 receptor antagonists on the progression of
Bradykinin chronic renal disease may not be identical. In the classic path-
Substance P Renin
Enkephalin way, renin cleaves angiotensinogen to form AI, which is further
Angiotensin I tPA cleaved by ACE to form biologically active AII. ACE inhibitors
Cathepsin G inhibit the renin-angiotensin system by reducing the activity of
CAGE
Tonin ACE and decreasing AII formation. ACE also catalyzes other
ACE Cathepsin G important pathways, however, including the breakdown of
Tonin 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
Inactive Angiotensin II
fragments these substances would not increase after administration of an
AT1 receptor antagonist. In contrast, inhibition of the renin-
Other
proteases angiotensin system by ACE inhibitors may be incomplete
because other proteases may catalyze to conversion of angio-
tensinogen to AII (on the right). CAGE— chymostatin-sensitive
Angiotensin III and IV
angiotensin II–generating enzyme; t-PA—tissue plasminogen
activator. (Adapted from Dzau and coworkers [14].)
FIGURE 6-15
Subclasses of angiotensin receptors. Another theoretic reason the
Vasoconstriction
Aldosterone AT 1 actions of angiotensin-converting enzyme (ACE) inhibitors and
Growth angiotensin II (AII) receptor antagonists may differ. All of the AII
receptor antagonists currently available for clinical use selectively block
Angiotensin II
the AT1 receptor. This receptor appears to transduce most of the well-
known effects of AII, including vasoconstriction, stimulation of cell
Clearance growth, and secretion of aldosterone. Increasingly, however, potentially
Proteases AT 2
Apoptosis 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
Angiotensin III and IV Vasodilation AT 4 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 receptor–mediated events are blocked by drugs cur-
rently available. Whether these differences will have important conse-
quences for progression of renal disease is currently unknown.
FIGURE 6-16
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS VERSUS Shown are results of studies comparing the
ANGIOTENSIN II ANTAGONISTS IN EXPERIMENTAL RENAL DISEASE effects of angiotensin II (AII) receptor antago-
nists and angiotensin-converting enzyme
(ACE) inhibitors on experimental renal injury.
Angiotensin II antagonists equivalent to Angiotensin II antagonists inferior to AII receptor antagonists were as effective as
angiotensin-converting enzyme inhibitors angiotensin-converting enzyme inhibitors were ACE inhibitors in the remnant kidney
model; streptozotocin-induced diabetic rats;
Remnant kidney Uninephrectomized spontaneously hypertensive rats the puromycin aminonucleoside model of
Passive Heymann nephritis Obese Zucker rats progressive glomerular sclerosis, preventing
Chronic rejection Passive Heymann nephritis interstitial fibrosis associated with obstructive
Two-kidney, one-clip hypertension uropathy; and an inherited model of glomeru-
Streptozocin-induced diabetes lar sclerosis, the Munich-Wistar Furth/Ztm
Puromycin aminonucleoside rat [17–21]. In contrast, AII receptor antago-
Obstructive uropathy nists were somewhat less effective than were
Munich-Wistar Furth/Ztm rat ACE inhibitors in several other animal mod-
els of chronic renal disease, including
uninephrectomized spontaneously hyperten-
sive rats, obese Zucker rats, and the passive
Heymann nephritis model of membranous
glomerulonephritis [22–24]. 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 ani-
MAP PGC PROT SCLER mals. The results of several studies examining the effects of three dif-
0 ferent dihydropyridine calcium channel blockers on hemodynamics
and injury in the uninephrectomized spontaneously hypertensive rat
model of progressive glomerular sclerosis are summarized. The three
Reduction, %
-20
drugs produced graded declines in mean arterial pressure (MAP),
with nifedipine causing the greatest and amlodipine the least reduc-
-40 tion in systemic pressure. Micropuncture determinations of glomeru-
lar capillary hydraulic pressure (PGC) revealed that only nifedipine
Nifedipine
Felodipine and felodipine caused glomerular pressure to decline significantly.
-60
Amlodipine These drugs reduced both the protein excretion rate (PROT) and
morphologic evidence of glomerular injury (SCLER). The data are
-80 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.)
The Effect of Hypertension on Renal Disease

100
ROLE OF HYPERTENSION IN CHRONIC RENAL DISEASE
90
Cause Contributors to disease progression 80
Renal artery stenosis or occlusion Diabetes mellitus 70

Atheroembolic disease Glomerulonephritis
Hypertensive persons, %
Hypertensive nephrosclerosis Tubulointerstitial disease (?) 60
Adult-onset polycystic kidney disease (?)
50
40
FIGURE 6-18 30
The impact of hypertension on the incidence of end-stage renal
disease (ESRD) is vastly underestimated if one considers only 20
those patients in whom systemic hypertension is the primary
process resulting in loss of kidney function. The group of 10
patients in whom ESRD is attributed to hypertension undoubt-
edly includes persons with renal disease of several causes. Some 0
of these causes are occlusive disease of the main renal arteries as 0 10 20 30 40 50 60 70 80 90
a result of atherosclerotic disease, atheroembolic disease of the Mean GFR, mL/min/1.73m 2
kidneys, and hypertensive nephrosclerosis. The exact incidence

of these processes within the hypertensive population with
chronic renal disease is unknown. Even more commonly, poorly FIGURE 6-19
controlled systemic hypertension accelerates the rate of loss of Hypertension prevalence corresponds with decreased glomerular
kidney function in many patients in whom the primary cause of filtration rate (GFR). Hypertension is common in glomerular,
renal injury is another process altogether. This fact is particular- tubular, vascular, and interstitial renal disease and becomes
ly true in patients with glomerular diseases such as diabetic increasingly prevalent as renal function declines. In almost 200
nephropathy and chronic glomerulonephritis [27,28]. Whether patients screened for the Modification of Diet in Renal Disease
systemic hypertension also contributes to loss of kidney function study, the prevalence of hypertension increased as the GFR
in patients with tubulointerstitial or cystic disease of the kidney decreased and hypertension was almost universal as the GFR
is less certain [29]. 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 sympa-
thetic tone and involvement of the renin-angiotensin system, which is inappropriately
stimulated in the setting of volume expansion, have been demonstrated in renal failure.
Volume/ total body sodium Decreased activity of nitric oxide and other vasorelaxants and increased activity of
excess endothelin and other endogenous vasoconstrictors also are probably contributory.
Stimulation of Augmented
renin-angiotensin sympathetic
system tone
100 1.0
(53)
80 (30)
Free of renal failure, %
(18)
0.8
60 (17)
Probability of survival
40 (7) 0.6 HBP before age 35 NBP after age 35
(2)
20 Normotensive (n=79)
Hypertensive (n=69)
0.4
0
0 5 10 15
Time since biopsy, y
0.2
FIGURE 6-21
Consistent relationship between hypertension and progressive 0
renal disease. Analysis of the Modification of Diet in Renal 0 10 20 30 40 50 60 70 80 90
Disease study, which involved patients with a heterogeneous mis- Age, y
cellany 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 con- FIGURE 6-22
firmed in cohorts of patients with the same renal disease. In Relationship between hypertension and renal failure. Johnson and
immunoglobulin A (IgA) nephropathy, eg, the presence of high Gabow [32] studied over one thousand patients with autosomal domi-
blood pressure at diagnosis is a strong predictor for development nant polycystic kidney disease. These authors demonstrated that the time
of end-stage renal disease. In this study by Radford and cowork- of renal survival was much shorter for patients with hypertension com-
ers [31] of 148 patients with IgA nephropathy, 69 patients with pared with patients whose blood pressure was normal (see Fig. 6-21).
hypertension had a much higher risk of proceeding to renal fail- Renal survival was defined as the time period before the need for dialy-
ure than did the 79 patients who were normotensive. sis. HBP–high blood pressure; NBP–normal blood pressure.
FIGURE 6-23
Systolic blood pressure
Hypertension accelerates progression of renal failure in children and adults. For 2 years,
100
Wingen and coworkers [33] followed almost 200 children and adolescents with renal dis-
ease, aged 2 to 18 years. Here, renal survival is defined as stability of the creatinine clear-
ance 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
80 of renal death. Renal death was defined as a decrease in the creatinine clearance rate by
10 mL/min/1.73 m2.
Free of renal endpoints, %
P<0.001
60
40
<120 mm Hg
>120 mm Hg
0
0 1 2
Time, y
hypertension to later development of renal failure. In over

4.0 Optimal 300,000 men screened for the Multiple Risk Factor Intervention
3.5
Normal but not optimal Trial, Klag and coworkers [34] showed that a single blood pres-
High normal
Stage 1 hypertension
sure measurement was strongly correlated with the risk of end-
ESRD due to any cause, %
3.0 Stage 2 hypertension stage renal disease (ESRD) later in life. Even men with high-nor-
2.5
Stage 3 hypertension mal blood pressures (defined as a systolic pressure of 130 to 139
Stege 4 hypertension
mm Hg or a diastolic blood pressure of 85 to 89 mm Hg) were at
2.0 a statistically significant greater risk for ESRD than were men
1.5 with blood pressures under 120/80 mm Hg. This risk increases
sequentially with the higher stage of hypertension. This study
1.0 used definitions of hypertension discussed in the Fifth Report of
0.5 the Joint National Committee on Detection, Evaluation and
Treatment of High Blood Pressure (JNC-5). Stage I hypertension
0 is defined as a systolic pressure of 140 to 159 mm Hg and a dias-
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 tolic pressure of 90 to 99 mm Hg. Stage II hypertension is
Years since screening defined as a systolic pressure of 160 to 179 mm Hg and a dias-
tolic 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
FIGURE 6-24 110 to 119 mm Hg. Stage IV hypertension is a systolic pressure
There long has been controversy over whether hypertension of 210 mm Hg or higher and a diastolic blood pressure of 120
alone, without renal disease, can cause renal failure, especially in mm Hg or greater. The highest relative risk for renal failure was
whites. Recent convincing epidemiologic evidence, however, links among persons with stage III or IV hypertension.
FIGURE 6-25
Deteriorating Deteriorating Hypertension and impact on progression of renal disease caused by
renal renal
hypertension. In a study of 94 patients with essential hypertension
function function
and an initially normal serum creatinine concentration, Rostand
Stable Stable and coworkers [35] showed that hypertension control apparently
renal 16% renal 12%
had little impact on progression of renal disease. When patients
function function
were divided into those with diastolic blood pressures higher and
lower than 90 mm Hg, the percentage whose renal function deteri-
orated was equivalent in both groups. Blacks were at especially
high risk; 23% of black patients with diastolic blood pressures
Controlled Uncontrolled below 90 mm Hg had worsened renal function over time, com-
diastolic blood pressure diastolic blood pressure pared with 11% of white patients with diastolic blood pressures
<90 min Hg <90 min Hg lower than 90 mm Hg.
FIGURE 6-26
Blood pressure
0 Lower-than-usual blood pressure (BP) target. The Modification of
Low BP group Diet in Renal Disease study [36] also prospectively examined the
Decline in GFR mL/min
Usual BP group
3 effect of a lower-than-usual BP target in a larger cohort of patients
with renal insufficiency. Patients were randomized to two target
6 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
9 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 3-
12 year follow-up period are depicted. (The y-axis depicts the changes
in GFR, and the x-axis represents months. For example, F36 means
15 36 months after initiation of the study.) Patients in the two groups
B3 F4 F12 F20 F28 F36 had statistically equivalent declines in GFR. Over the last 6 months
Time, mo of the study, however, a trend toward greater stabilization in renal
function occurred in the group randomized to the lower target.
FIGURE 6-27
Patients randomized to low BP target Two patient groups in the study of diet in
Patients randomized to the usual BP target renal disease. The Modification of Diet in
Renal Disease (MDRD) study involved two
Study 1 Study 2
0 0 patient groups. The group in which patients
had moderate renal dysfunction (glomerular
filtration rate [GFR] between 25 and 55
Mean rate of GFR decline, mL/min/y
mL/min) was called Study 1. The other group,

which included patients who had more severe
4 4 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
8 8 2 are shown. The y-axis divides patients in
Studies 1 and 2 into three groups, depending
on urinary protein excretion. The x-axis rep-
resents the rate of GFR decline. In the subset
n=420 n=101 n=54 n=136 n=63 n=32 of patients in the MDRD trial in both Studies
12 12
<1 1–<3 3 <1 1–<3 3 1 and 2 who had massive proteinuria (protein
Baseline urinary protein, g/d
over 3 g/24 h), the lower blood pressure had
an especially salutary effect: the decline in
GFR was much slower [37].
Renal survival
100
1.00
90
0.95 80
0.90 70
0.85 60
Proteinuria: <1g/24h 50
0.80
mean BP: <107 mm Hg
40
0.75 Proteinuria: <1g/24h
mean BP: >107 mm Hg 30
0.70 Proteinuria: <1–3g/24h
20
mean BP: <107 mm Hg
0.65 Proteinuria: <1–3g/24h 10
mean BP: >107 mm Hg -12 -6 0 6 12 18 24 30 36
0.60 Group A Group B
0 6 12 18 24 30
Evolution of creatinine clearance
Time, mo

Proteinuria as a marker for progressive renal disease. Nephrotic The effect of reduction of proteinuria on the stabilization of renal
proteinuria may be a more important and independent marker for function. The observations that the potentially correctable factors of
progression of renal disease than is hypertension. That is, patients hypertension and proteinuria predict the decline of renal function lead
in whom massive proteinuria and hypertension coexist have the to the hypothesis that antihypertensive agents in the angiotensin-con-
worst renal prognosis. In a study of over 400 patients with renal verting enzyme (ACE) inhibitor class may be especially important in
insufficiency followed over 2 years, Locatelli and coworkers [38] treatment of hypertension in renal disease. Praga and coworkers [39]
found that patients who had both a mean blood pressure (BP) investigated 46 patients with nondiabetic renal disease and massive
higher than 107 mm Hg and protein excretion of 1 to 3 g/24 h had proteinuria treated with the ACE inhibitor captopril. These authors
the lowest rates of renal survival. 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.
50
45
40 1.6
Percentage with doubling
Ramipril
of baseline creatinine
35
Placebo 1.4 Placebo
30
Mean rate of GFR, mL/min/mo

25
1.2
20 P=0.007
15
1.0
10 Captopril
5
0.8
0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
0.6
Years of follow-up
0.4
FIGURE 6-30
Large study of patients with diabetes mellitus and renal disease 0.2
randomly assigned to captopril or placebo. Lewis and coworkers
[40] have studied the use of the angiotensin-converting enzyme
0
inhibitor captopril in patients with type I diabetes mellitus who n=61 n=36 n=20
have diabetic nephropathy and proteinuria. Captopril provides
strong protection against progression of renal disease. Those Baseline urinary protein excretion, 1g/24h
patients treated with captopril had a significant decrease in pro-
teinuria and a slower rate of disease progression, as defined by
FIGURE 6-31
the time to doubling of the serum creatinine, as compared with
patients randomized to placebo. Study of patients with renal disease not associated with diabetes
randomly assigned to ramipril or placebo. A study structured simi-
larly to that in Figure 6-30 examined the use of the angiotensin-
converting 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 sig-
nificantly in the patients treated with ramipril. This group had sig-
nificantly 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.
FIGURE 6-32
Favors ACE inhibitors Favors other drugs
Meta-analysis of over 1500 patients with
Reference Country Year Patients, n
renal insufficiency. A recent meta-analysis
Zucchelli et al. [43] IT 1992 121 examined randomized studies comparing
Kamper et al. [44] DEN 1992 70 an angiotensin-converting enzyme inhibitor
Brenner (Unpublished data) USA 1993 112 (ACE) to other antihypertensive agents
Toto (Unpublished data) USA 1993 124 [42]. None of the individual studies
van Essen et al. [45] HOL 1994 103 showed that the relative risk for develop-
Hannedouche et al. [46] FR 1994 100 ment of end-stage renal disease (ESRD)
Bannister et al. [47] AUS 1994 51 was statistically lower in patients treated
Himmelmann et al. [48] SW 1995 260 with ACE inhibitors. The pooled relative
Becker et al. and AUS 1996 70 risk, incorporating data from all the stud-
Ihle et al. [49,50]
ies, however, was lower in the cohort
Maschio et al. [51] EUR 1996 583
groups treated with ACE inhibitors.
Overall
0.01 0.02 0.05 0.1 0.2 0.5 1 2 5 10 20 50 100
Relative risk for ESRD

Podocytes 100
Glomerular 80
Renal survival, %
basement
membrane
60
40
No change in Decreased 20 Captopril

proteinuria proteinuria Nifedipine
0
0 6 12 18 24 30 36 42
Time, mo
Dihydropyridine Non-dihydropyridine
calcium channel blockers calcium channel blockers
FIGURE 6-34
Nifedipine Diltiazem The effect of calcium channel blockers on preservation of renal func-
Amlodipine Verapamil tion. Most studies of angiotensin-converting enzyme (ACE) inhibitors
Felodipine versus other agents did not examine calcium channel blockers. In a
Isradipine
Nisolodipine 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 ran-
domized to treatment with the dihydropyridine calcium entry antago-
FIGURE 6-33 nist nifedipine or to the ACE inhibitor enalapril. The rate of decline
Calcium channel blockers. Calcium channel blockers are prescribed in renal function was most rapid in the pre-randomization phase in
widely to patients with normal renal function and affect renal pro- patients treated with conventional antihypertensive agents, mostly
tein excretion variably. The general consensus is that the nondihy- adrenergic antagonists. The rate of decline then slowed after random-
dropyridine calcium channel blockers diltiazem and verapamil ization. No significant difference in rates of decline was seen in
decrease proteinuria, whereas the dihydropyridine agents have min- patients treated with nifedipine compared with those treated with
imal or minor effects on proteinuria. captopril. (From Zucchelli and coworkers [43]; with permission.)
FIGURE 6-35
The effect of angiotensin-converting
enzyme inhibitors and other antihyperten-
sive agents on stabilization of renal func-
tion in non–insulin-dependent diabetes.
60
Bakris and coworkers [52] studied patients
Creatinine clearance, mL/min/1.73 m2
with non–insulin-dependent diabetes melli-

Lisinopril tus, hypertension, proteinuria, and pre-
sumed diabetic nephropathy. These patients
were randomized to treatment with the
NDCCBs angiotensin-converting enzyme inhibitor
40 lisinopril; the beta-blocker atenolol; or a
nondihydropyridine calcium channel block-
er (NDCCB), either verapamil or diltiazem.
The primary conclusion of the study is sum-
marized. The change in glomerular filtra-
20 Atenolol
tion rate as a function of time is depicted in
groups of patients receiving lisinopril, calci-
um channel blockers, or atenolol. The crea-
tinine clearance rate declined in all three
1998 1989 1990 1991 1992 1993 1994 groups. However, the slope of the decline
Lisinopril 18 18 18 18 16 16 15 was significantly greater in the group treat-
NDCCBs 18 18 18 17 16 15 15 ed with atenolol and not significantly dif-
Atenolol 16 16 16 15 13 11 11
ferent between the groups treated with
lisinopril and the calcium entry antagonist.
FIGURE 6-36
120
Race and ethnicity in choice of antihypertensive agents. Racial and
ethnic differences also may be important in determining the choice
115
of antihypertensive agent to delay progression of chronic renal dis-
110 ease. Blacks are at much higher risk than are whites for progres-
sion of renal disease. In addition, a more aggressive antihyperten-
Mean BP, mm Hg
105 sive program may be beneficial to blacks. In the Modification of

Diet in Renal Disease study, a trend toward a more gradual decline
100 in renal function in blacks randomized to the low mean blood
Atenolol pressure target was seen [36]. Blacks tend to have a better blood
95 Amiodipine pressure response to administration of diuretics than do whites. In
Enalapril a large study of patients with normal renal function, blacks also
90 responded well to calcium channel blockers [53]. The African-
0 Baseline GFR1 GFR2 RV FV3 FV6 American Study of Kidney Disease and Hypertension (AASK), cur-
Time, mo rently in progress, is examining the hypothesis that a lower-than-
usual 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]. GFR–glomerular 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
Yes No
If hyperkalemia or acute renal failure Treatment with ACE inhibitor Treatment with diuretic,
develops, evaluate possible causes Target blood pressure: ACE inhibitor, or
125/75 mm Hg or lower calcium channel
If no other precipitant, decrease ACE inhibitor dose
blocker
Add diuretic, calcium channel blocker
A B
FIGURE 6-37
Treatment of patients with renal disease and high-normal or elevated B, When protein excretion is less than 1 g/24 h, the blood pres-
blood pressure (BP). A, All patients should have a measurement of sure should be lowered to at least 130/85 mm Hg. No conclusive
24-hour protein excretion. If the protein excretion is over 1 g/24 h, an evidence exists to support the use of one antihypertensive agent
angiotensin-converting enzyme (ACE) inhibitor should be started. The or class of agents over another. However, in patients at risk for
goal of hypertension control in patients with azotemia who have mas- progressive proteinuria (eg, diabetic patients with microalbumin-
sive proteinuria should be a blood pressure of 125/75 mm Hg or lower. uria), ACE inhibitors should be used. Given the importance of
It is unlikely that an ACE inhibitor alone will be able to decrease the sodium retention in the hypertension in renal disease, a loop
blood pressure to this level before hyperkalemia or hemodynamically or thiazide diuretic is a reasonable initial treatment. An ACE
mediated acute renal failure intervenes. A diuretic and medications from inhibitor or calcium channel blocker should be added as a
other classes, such as a calcium channel blocker, should then be added. second-line agent.
References
1. Dworkin LD, Grosser M, Feiner HD, et al.: Renal vascular effects of 21. Remuzzi A, Malanchini B, Battaglia C, et al.: Comparison of the
antihypertensive therapy in uninephrectomized spontaneously hyper- effects of angiotensin-converting enzyme inhibition and angiotensin II
tensive rats. Kidney Int 1989, 35:790–798. receptor blockade on the evolution of spontaneous glomerular injury
2. Anderson S, Meyer T, Rennke HG, Brenner BM: Control of glomeru- in male MWF/Ztm rats. Experimental Nephrol 1996, 4:19–25.
lar hypertension limits glomerular injury in rats with reduced renal 22. Anderson AE, Tolbert EM, Esparza AR, Dworkin LD: Effects of an
mass. J Clin Invest 1985, 76:612–619. ACE inhibitor vs. an AII antagonist on hemodynamics, growth and
3. Kakinuma Y, Kawamura T, Bills T, et al.: Blood pressure indepen- injury in spontaneously hypertensive rats. J Am Soc Nephrol 1996,
dent effect of angiotensin inhibition on the glomerular and non- 7:A3014.
glomerular vascular lesions of chronic renal failure. Kidney Int 23. Crary GS, Swan SK, O’Donnell MP, et al.: The angiotensin II receptor
1996, 42: 46–55. antagonist losartan reduces blood pressure but not renal injury in
4. Dworkin LD, Feiner HD, Randazzo J: Glomerular hypertension and obese Zucker rats. J Am Soc Nephrol 1995, 6:1295–1299.
injury in desoxycorticosterone-salt rats on antihypertensive therapy. 24. Hutchinson FN, Webster SK: Effect of ANGII receptor antagonist on
Kidney Int 1987, 31:718–724. albuminuria and renal function in passive Heymann nephritis. Am J
5. Neugarten J, Kaminetsky B, Feiner H, et al.: Nephrotoxic serum Physiol 1992, 263:F311–F318.
nephritis with hypertension: amelioration by antihypertensive therapy. 25. Dworkin LD, Feiner HD, Parker M, Tolbert E: Effects of nifedipine
Kidney Int 1985, 28:135–139. and enalapril on glomerular structure and function in uninephrec-
6. Weir MR, Dworkin LD: Antihypertensive drugs, dietary salt and renal tomized spontaneously hypertensive rats. Kidney Int 1991,
protection: How low should you go and with which therapy. Am J 39:1112–1117.
Kidney Dis 1998, 32:1–22. 26. Dworkin LD, Tolbert E, Recht PA, et al.: Effects of amlodipine on
7. Griffen KA, Picken M, Bidani AK: Radiotelemetric BP monitoring, glomerular filtration, growth, and injury in experimental hyperten-
antihypertensives and glomeruloprotection in remnant kidney model. sion. Hypertension 1996, 27:245–250.
Kidney Int 1994, 46:1010–1018. 27. Breyer JA, Bain RP, Evans JK, et al.: Predictors of the progression
8. Dworkin LD, Benstein JA: Antihypertensive agents, glomerular hemo- of renal insufficiency in patients with insulin-dependent diabetes and
dynamics and glomerular injury. In Calcium Antagonists and the overt diabetic nephropathy. Kidney Int 1996, 50:1651–1658.
Kidney. Edited by Epstein M, Loutzenhiser R. Philadelphia, Hanley & 28. Gisen Group: Randomized placebo-controlled trial of effect of
Belfus; 1990:155–176. ramipril on decline in glomerular filtration rate and risk of terminal
9. Nagata M, Scharer K, Kriz W: Glomerular damage after uninephrec- renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997,
tomy in young rats. I. Hypertrophy and distortion of the capillary 349:1857–1863.
architecture. Kidney Int 1992, 42:136–147. 29. Klahr S, Levey AS, Beck GJ, et al.: The effects of dietary protein
10. Anderson S, Rennke HG, Brenner BM: Therapeutic advantage of con- restriction and blood-pressure control on the progression of chronic
verting enzyme inhibitors in arresting progressive renal disease associ- renal disease. Modification of Diet in Renal Disease Study Group.
ated with systemic hypertension. J Clin Invest 1986, 77:1993–2000. N Engl J Med 1994, 330:877–884.
11. Yoshioka T, Mitarai T, Kon V, et al.: Role for angiotensin II in an 30. Modification of Diet in Renal Disease Study Group: Predictors of the
overt functional proteinuria. Kidney Int 1986, 30:538–545. progression of renal disease in the modification of diet in renal disease
study. Kidney Int 1997, 51:1908–1919.
12. Lee LK, Meyer TM, Pollock AS, Lovett DH: Endothelial cell injury
initiates glomerular sclerosis in the rat remnant kidney. J Clin Invest 31. Radford MG, Donadio JV, Bergstralh EJ, Grande JP: Predicting renal
1995, 96:953–964. outcome in IgA nephropathy. J Am Soc Nephrol 1997, 8199–207.
13. Wolf G, Ziyadeh FN, Thaiss F, et al.: Angiotensin II stimulates expres- 32. Johnson AM, Gabow PA: Identification of patients with autosomal
sion of the chemokine RANTES in rat glomerular endothelial cells. dominant polycystic kidney disease at highest risk for end-stage kid-
J Clin Invest 1997, 100:1047–1058. ney disease. J Am Soc Nephrol 1997, 8:1560–1567.
14. Dzau VJ, Sasamura H, Hein L: Heterogeneity of angiotensin synthetic 33. Wingen A-M, Fabian-Bach C, Shaefer F, Mehls O for the European
pathways and receptor subtypes: physiological and pharmacological Study Group for Nutritional Treatment of Chronic Renal Failure in
implications. J Hypertension 1993, 11(suppl 3):S13–S18. Childhood. Lancet 1997, 349:1117–1123.
15. Yamada T, Horiuchi M, Dzau VJ: Angiotensin II type 2 receptor 34. Klag MJ, Whelton PK, Randall BL, et al.: Blood pressure and end-
mediates programmed cell death. Proc Natl Acad Sci U S A 1996, stage renal disease in men. N Engl J Med 1996, 334:13–18.
93:156–160. 35. Rostand SG, Brown G, Kirk KA, et al.: Renal insufficiency in treated
16. Pörsti I, Bara AT, Busse R, Hecker M: Release of nitric oxide by essential hypertension. N Engl J Med 1989, 320:684–688.
angiotensin (1-7) from porcine coronary endothelium: implications for 36. Klahr S, Levey A, Beck GJ, et al. for the Modification of Diet in Renal
a novel angiotensin receptor. Br J Pharmacol 1994, 111:652–654. Disease Study Group. N Engl J Med 1994, 330:877–884.
17. Lafayette RA, Mayer G, Park SK, Meyer TM: Angiotensin II receptor 37. Peterson JC, Adler S, Burkart JM, et al. for the Modification of Diet
blockade limits glomerular injury in rats with reduced renal mass. in Renal Disease Study Group. Ann Intern Med 1995, 123:754–762.
J Clin Invest 1992, 90:766–771. 38. Locatelli F, Marcelli D, Comelli M, et al. for the Northern Italian
18. Remuzzi A, Perico N, Amuchastegui CS, et al.: Short- and long-term Cooperative Study Group: proteinuria and blood pressure as causal
effect of angiotensin II receptor blockade in rats with experimental components of progression to end-stage renal failure. Nephrol Dial
diabetes. J Am Soc Nephrol 1993, 4:40–49. Transplant 1996, 11:461–467.
19. Tanaka R, Kon V, Yoshioka T, et al.: Angiotensin converting enzyme 39. Praga M, Hernandez E, Montoyo C, et al.: Long-term beneficial
inhibitor modulates glomerular function and structure by distinct effects of angiotensin-converting enzyme inhibition in patients with
mechanisms. Kidney Int 1994, 45:537–543. nephrotic proteinuria. Am J Kidney Dis 1992, 20:240–248.
20. Ishidoya S, Morrissey J, McCracken R, et al.: Angiotensin receptor 40. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD for the Collaborative
antagonist ameliorates renal tubulointerstitial fibrosis caused by uni- Study Group: The effect of angiotensin-converting enzyme inhibition
lateral ureteral obstruction. Kidney Int 1995, 47:1285–1294. on diabetic nephropathy. N Engl J Med 1993, 329:1456–1462.
41. Gruppo Italiano di Studi Epidemiologici in Nefrologia: Randomised 48. Himmelmann A, Hansson L, Hannson BG, et al.: ACE inhibition
placebo-controlled trial of effect of ramipril on decline in glomerular preserves renal function better than beta-blockers in the treatment
filtration rate and risk of renal failure in proteinuric, non-diabetic of essential hypertension. Blood Pressure 1995, 4:85–90.
nephropathy. Lancet 1997, 349:1857–1863. 49. Becker GJ, Whitworth JA, Ihle BU, et al.: Prevention of progression
42. Giatras I, Lau J, Levey AS for the Angiotensin-Converting Enzyme in non-diabetic chronic renal failure. Kidney Int Suppl 1994,
Inhibition and Progressive Renal Disease Study Group: Effect of 45:S167–S170.
angiotensin-converting enzyme inhibitors on the progression of nondi- 50. Ihle BU, Whitworth JA, Shahinfar S, et al.: Angiotensin-converting
abetic renal disease: a meta-analysis of randomized trials. Ann Intern enzyme inhibition in nondiabetic progressive renal insufficiency: a
Med 1997, 127:337–345. controlled double-blind trial. Am J Kidney Dis 1996, 27:489–495.
43. Zucchelli P, Zuccala A, Borghi M, et al.: Long-term comparison 51. Maschio G, Aliberti D, Janin G, et al.: Effect of the angiotensin-
between captopril and nifedipine in the progression of renal insuffi- converting enzyme inhibitor benazepril on the progression of renal
ciency. Kidney Int 1992, 42:452–458. insufficiency. N Engl J Med 1996, 334:939–945.
44. Kamper AI, Strandgaard S, Leyssac PP: Effect of enalapril on the 52. Bakris GL, Copley JB, Vicknair N, et al.: Calcium channel blockers
progression of chronic renal failure: a randomized controlled trial. versus other antihypertensive therapies on progression of NIDDM
Am J Hypertens 1992, 5:423–430. associated nephropathy. Kidney Int 1996, 50:1641–1650.
45. van Essen GG, Apperloo AJ, Sluiter WJ, et al.: Is ACE inhibition 53. Materson BJ, Reda DJ, Cushman WC, et al.: Single-drug therapy for
superior to conventional antihypertensive therapy in retarding progres- hypertensive men: a comparison of six antihypertensive agents with
sion in non-diabetic renal disease? J Am Soc Nephrol 1996, 7:1400. placebo. N Engl J Med 1993, 328:914–921.
46. Hannedouche T, Landais P, Goldfarb B, et al.: Randomized controlled 54. Hall WD, Kusek JW, Kirk KA, et al. for the African-American Study
trial of enalapril and beta-blockers in non-diabetic chronic renal of Kidney Disease and Hypertension Pilot Study Investigators. Am J
failure. BMJ 1994, 309:833–837. Kidney Dis 1997, 29:720–728.
47. Bannister KM, Weaver A, Clarkson AR, Woodroffe AJ: Effect of
angiotensin-converting enzyme and calcium channel inhibition on
progression of IgA nephropathy. Contrib Nephrol 1995, 111:184–193.
Pharmacologic Treatment
of Hypertension
Garry P. Reams
John H. Bauer
T
his chapter reviews the currently available classes of drugs used
in the treatment of hypertension. To best appreciate the com-
plexity 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 under-
standing 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 mecha-
nisms to alter favorably the hemodynamic pattern associated with
high blood pressure.
CHAPTER
7
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 ↑ Contractility Functional Structural

constriction hypertrophy
↑ Fluid volume Volume

redistribution
Renal Decreased Sympathetic Renin- Cell Hyper-

sodium filtration nervous over- angiotensin membrane insulinemia
retention surface activity excess alteration
Excess Genetic Stress Genetic Obesity Endothelium-

sodium alteration alteration derived
intake factors
FIGURE 7-1
Pathogenesis of hypertension. Mean arterial pressure (MAP) is the (PVR). There are a large number of control mechanisms involved
product of cardiac output (CO) and peripheral vascular resistance 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 non–salt-sensi-
20 tive (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];
Increase, %
with permission.)
10
0
SS NSS
Mean arterial pressure
Pharmacologic Treatment of Hypertension 7.3
FIGURE 7-3
Cardiac output. An increase in cardiac output has been suggested
Extracellular fluid
20 33 %
as a mechanism for hypertension, particularly in its early border-
volume, L
19
18 line phase [3,4]. Sodium and water retention have been theorized
17 to be the initiating events. Sequential changes following salt load-
16 4%
ing are depicted [3]. The resultant high cardiac output perfuses the
15
peripheral tissues in excess of their metabolic requirements, result-
ing in a normal autoregulatory (vasoconstrictor) pressure. The
Blood volume,
20 %
6.0 early phase of high cardiac output and normal peripheral vascular
resistance gradually changes to the characteristic feature of the
L
5.5 5%
sustained hypertensive state: normal cardiac output and high
5.0 peripheral vascular resistance. Shown here are segmental changes
in the important cardiovascular hemodynamic variables in the first
Pressure gradient Mean circulatory
filling pressure,
60 %
16 few weeks following the onset of short-term salt-loading hyperten-
mm Hg
14
20 %
sion. Note especially that the arterial pressure increases ahead of
12 the increase in total peripheral resistance. (From Guyton and
10 coworkers [3]; with permission.)
35 %
return, mm Hg
13
for venous
12
11 44 %
10
70 40 %
Cardiac output,
65
L/min
60
55 5%
50
40
Total peripheral
mm Hg/L/min
35 38 %
resistance,
30
25
20
–11 %
15
150 Set-point elevated

Arterial pressure,
140 45 %
130
mm Hg
120 22.5 %
110
100
0 4 8 12 16
Days
4000
200
TPRI dyn s cm–5 m–2

SAP 150
HR beats min–1
3000
180
100 2000
160
BP, mm Hg
60 1000
140 MAP
70 10
SI mL stroke–1 m–2
120
CI L min–1 m–2
DAP 50
5
100
30
500 1000 500 1000 500 1000

VO2 mL min–1 m–2 VO2 mL min–1 m–2 VO2 mL min–1 m–2
FIGURE 7-4
Peripheral vascular resistance. Most established cases of hypertension dashed line indicates results after 10 years; dotted line indicates results
are associated with an increase in peripheral vascular resistance [5]. after 20 years. BP—blood pressure; CI—cardiac index; DAP—diastolic
These alterations may be related to a functional constriction, the arterial blood pressure; HR—heart rate; MAP—mean arterial pressure;
type observed under the influence of circulating or tissue-generated SAP—systolic arterial blood pressure; SI—stroke index; TPRI—total
vasoconstrictors, or may be a result of structural alterations in the peripheral resistance index; VO2—oxygen consumption. (From Lund-
blood vessel. Solid line indicates values at start of the study [9]; Johansen [5]; with permission.)
Classes of Antihypertensive Drugs and Their Side Effects

FIGURE 7-5
CLASSES OF ANTIHYPERTENSIVE DRUGS Classes of antihypertensive drugs. There are 12 currently available
classes of antihypertensive agents.
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
Angiotensin-converting enzyme inhibitors
Tyrosine hydroxylase inhibitor
Angiotensin II receptor antagonists
FIGURE 7-6
Hemodynamic response to diuretics. Diuretics reduce mean arterial
BP 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 renin-
PV
angiotensin system. During sustained diuretic therapy, cardiac output
returns to pretreatment levels, probably reflecting restoration of
ISF plasma volume. Chronic blood pressure control now correlates with
a reduction in peripheral vascular resistance. BP—blood pressure;
CO CO—cardiac output; ISF—interstitial fluid; PRA—plasma renin
CO activity; PV—plasma volume; Rx—treatment; TPR—total peripheral
TPR TPR resistance. (Adapted from Tarazi [7].)
Rx No Rx
PRA
Time
A. DIURETICS: BENZOTHIADIAZIDES (PARTIAL LIST) AND RELATED DIURETICS
Generic (trade) name First dose, mg Usual dose Maximum dose Duration of action, h
Hydrochlorothiazide (G) 12.5 12.5–50 mg QD 100 6–12
(Hydrodiuril, Microzide)
Chlorthalidone (G) 12.5 12.5–50 mg QD 100 48–72
(Hygroton)
Indapamide 1.25 2.5–5.0 mg 5 15–18
(Lozol)
Metolazone
(Mykrox)*; 0.5 0.5–1.0 1 12–24
(Zaroxolyn) 2.5 2.5–10 mg QD 20 12–24
*Marketed only for treatment of hypertension.

(G)—generic available.
B. DIURETICS: LOOP
Bumetanide (G) 0.5 0.5–2 mg bid 10 4–6
(Bumex)
Ethacrynic Acid 25 25–50 mg bid 200 6–8
(Edecrin)
Furosemide (G) 20 20–120 mg bid 600 6–8
(Lasix)
Torsemide 5 5–50 mg bid 100 6–8
(Demadex)
C. DIURETICS: POTASSIUM-SPARING DIURETICS
Spironolactone (G) 25 50–1 00 mg QD 400 48–72
(Aldactone)
Amiloride (G) 5 5–10 mg QD 20 24
(Midamor)
Triamterene (G) 50 50-100 mg bid 300 7–9
(Dyrenium)
FIGURE 7-7
A–C. Diuretics: benzothiadiazides and related agents, loop diuretics, diuretics. Because of their steep dose-response curves and natri-
and potassium-sparing agents. A partial list of benzothiadiazides uretic potency, they are especially useful when the glomerular
and their related agents is given [6]. With the exception of inda- filtration rate is less than 30 mL/min/1.73 m2. The third group
pamide and metolazone, their dose-response curves are shallow; is the potassium-sparing diuretics. The major therapeutic use of
they should not be used when the glomerular filtration rate is these drugs is to attenuate the loss of potassium induced by the
less than 30 mL/min/1.73 m2. The second group listed is loop other diuretics.
Lumen Blood Lumen Blood

Na
DCT Na 3Na 3Na

~ Na channel ~
diuretics Cl 2K K 2K
blockers
DCT PC
PT
DT
Lumen Blood
HCO3 Na 3Na
~ Lumen Blood
H 2K
HCO3
H2CO3
H2CO3
CAI CA Loop Na 3Na
CA CAI diuretics K ~
H2O + CO2 2Cl 2K
H2O + CO2
CD
PT
TAL
LH
FIGURE 7-8
Mechanisms of action of diuretics. This figure depicts the The diuretic/natriuretic action of potassium-sparing diuretics is
major sites and mechanisms of action of diuretic drugs [8]. predicated on their gaining access to the luminal side of the principal
The diuretic/natriuretic action of benzothiadiazide-type diuretics cells located in the late distal tubule and cortical collecting duct and
is predicated on their gaining access to the luminal side of the blocking luminal sodium channels. Because Na+ uptake is blocked,
distal convoluted tubule and inhibiting Na+ - Cl- cotransport the lumen negative voltage is reduced, inhibiting K+ secretion. The
by competing for the chloride site. potassium-sparing diuretic spironolactone does this indirectly by
The diuretic/natriuretic action of loop diuretics is competing with aldosterone for its cytosolic receptor. CA—carbonic
predicated on their gaining access to the luminal side of anhydrase; CAI—carbonic anhydrase inhibitor; CD—collecting duct;
the thick ascending limb of the loop of Henle and inhibiting DCT—distal convoluted tubule; DT—distal tubule; LH—loop of
Na+ - K+ -2Cl- electroneutral cotransport by competing for Henle; PC—principal cell; PT—proximal tubule; TAL—thick ascend-
the chloride site. ing limb. (From Ellison [8]; with permission.)
FIGURE 7-9
THE SIDE EFFECT PROFILE OF DIURETIC THERAPY The side effect profile of diuretic therapy.
The complications of diuretic therapy are
typically related to dose and duration of
Side effects Mechanisms therapy, and they decrease with lower
dosages. This table lists the most common
Thiazide-type diuretic side effects of diuretics and their proposed
Azotemia Enhanced proximal fluid and urea reabsorption secondary mechanism of action [6].
to volume depletion
Hypochloremia, hypokalemia, metabolic alkalosis Increased delivery of sodium to distal tubule facilitating Na+-
K+ and Na+-H+ exchange; increased net acid excretion;
increased urinary flow rate; secondary aldosteronism
Hypomagnesemia Increase fractional Mg2+ excretion by inhibiting reabsorp-
tion in ascending limb of loop of Henle
Hyponatremia Impaired free water clearance
(distal cortical diluting segment)
Hypercalcemia May reflect an increased protein-bound fraction secondary
to volume depletion
Hyperuricemia Impair enhanced proximal fluid and urate reabsorption
secondary to volume depletion
Carbohydrate intolerance Hypokalemia impairing insulin secretion; decreased
insulin sensitivity
Hyperlipidemia
Increased total triglyceride May be due to extracellular fluid depletion
Increased total cholesterol
Loop-type diuretics
Ototoxicity High plasma concentration of furosemide or
ethacrynic acid
Hypocalcemia Increase fractional excretion of calcium by interfering with
reabsorption in loop of Henle
Potassium-sparing diuretics
Hyperkalemia Blocks potassium excretion
Decreased sexual function, gynecomastia, menstrual Spironolactone only; lower circulatory testosterone levels
irregularity, hirsutism by increasing metabolic clearance and/or preventing
compensatory rise in testicular androgen production
Renal stone Triamterene only
FIGURE 7-10
Adrenal gland
-adrenergic antagonists. -adrenergic antagonists attenuate sym-
pathetic 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
Heart ↓ CO in peripheral vascular resistance proportional to the degree of cardio-
β1 depression; blood pressure is unchanged. Chronically, there is a gradual
Kidney decrease in blood pressure proportional to the fall in peripheral
β-blockers
Effector cell
E vascular resistance, which is dependent on the degree of cardiac
BP sympathetic drive. -adrenergic antagonists with sufficient partial
NE
agonist activity to maintain heart rate and cardiac output may not
β2 evoke acute reflex vasoconstriction: Blood pressure falls propor-
Blood
vessels ↑ TPR
tional to the decrease in peripheral resistance (see Fig. 7-11) [10].
+ BP—blood pressure; CO—cardiac output; E—epinephrine; NE—
NE
norepinephrine; TPR—total peripheral resistance.
Sympathetic
neuron
FIGURE 7-11
100 Hemodynamic changes associated with -adrenergic blockade. Time course of hemody-
MAP, %
namic changes after treatment with a -adrenergic blocker devoid of partial agonist activ-
90
ity (PAA) (solid line) as compared with hemodynamic changes after administration of a
80 -adrenergic blocker with sufficient PAA to replace basal sympathetic tone (eg, pindolol)
(broken line). MAP—mean arterial pressure. (From Man in’t Veld and Schalekamp [10];
Cardiac output, %
100 with permission.)

90
80
130
120
Vascular resistance, %
110
100
90
80
Time (hours to days)

A. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: NON-SELECTIVE (1 AND 2)

ADRENERGIC ANTAGONISTS THAT LACK PARTIAL AGONIST ACTIVITY
Generic (trade) name First dose, mg Usual daily dose, mg Maximum daily dose, mg Duration of action, h
Nadolol (G) 40 40–240 QD 320 >24
(Corgard)
Propranolol (G)
(Inderal) 40 40–120 bid 480 >12
(Inderal LA) 80 80–240 QD 480 >12
Timolol (G)
(Blockadren) 10 10–30 bid 60 >12
G—generic available.
B. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: NON-SELECTIVE

(1 AND 2) ADRENERGIC ANTAGONISTS WITH PARTIAL AGONIST ACTIVITY
Pindolol (G) 5 10–30 bid 60 12
(Visken)
Carteolol 2.5 2.5–10 QD 10 24
(Cartrol)
Penbutolol 10 10–20 QD 40 24
(Levatol)
C: DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-SELECTIVE

ADRENERGIC ANTAGONISTS THAT LACK PARTIAL AGONIST ACTIVITY
Atenolol (G) 50 50–100 QD 200 24
(Tenormin)
Metoprolol Tartrate (G) 50 50–150 bid 400 12
(Lopressor)
Metoprolol Succinate 50 100–300 QD 400 12
(Toprol-XL)
Betaxolol 5 10–20 QD 40 >24
(Kerlone)
Bisoprolol 5 5–20 QD 40 12
(Zebeta)
FIGURE 7-12
Dosing schedules for -adrenergic antagonists. A, Nonselective - -adrenergic antagonists with partial agonist activity. C, 1-selective
adrenergic antagonists that lack partial agonist activity. B, Nonselective adrenergic antagonists that lack partial agonist activity.
D. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS: 1-SELECTIVE

ADRENERGIC ANTAGONISTS WITH WEAK PARTIAL AGONIST ACTIVITY
Acebutolol 200 400–800 QD 1200 24
(Sectrol)
E. DOSING SCHEDULES FOR -ADRENERGIC ANTAGONISTS:

1-NONSELECTIVE -ADRENERGIC ANTAGONISTS LABETALOL (G)
Labetalol (G) 100 100-600 bid 2400 12
(Normodyne)
(Trandate)
Carvedilol 6.25 6.25-25 bid 50 6
(Coreg)

D, 1-selective adrenergic antagonists with weak partial agonist
activity. E, 1-nonselective -adrenergic antagonists.
PHARMACOKINETICS OF -ADRENERGIC ANTAGONISTS
First-pass hepatic Peak Plasma Dose reduction

Solubility Absorption metabolism concentration, h Active metabolite half-life, h in renal failure
Nadolol Hydrophilic 30%–40% <10% 2–4 None 20–24 Yes
Propranolol Lipophilic >90% 60% 1–3 Yes 3–4 No
Propranolol LA Lipophilic >90% 80% 6 Yes 10 No
Timolol Lipophilic >90% 50% 1–2 None 3–4 No
Pindolol Lipophilic >90% <10% 1–2 None 3–4 Yes
Carteolol Hydrophilic >90% <10% 1–3 Yes 5–6 Yes
Penbutolol Lipophilic >90% <10% 2–3 Yes 5 Yes
Atenolol Hydrophilic 50–60% <10% 2–4 None 6–7 Yes
Metoprolol tartrate Lipophilic >90% 50% 1–2 None 3–7 No
Metoprolol succinate Lipophilic >90% 50% 7 None 3–7 No
Betaxolol Lipophilic >90% <10% 1.5–6 None 14–22 Yes
Bisoprolol Equal >90% 20% 2–4 None 9–12 Yes
Acebutolol Lipophilic 70% 30% 2–4 Yes 3–4 Yes
Labetalol Lipophilic >90% 60% 1–2 None 3–4 No
Carvedilol Lipophilic >90 70–80% 1–2 Yes 7–10 No
FIGURE 7-13
Pharmacokinetics of -adrenergic antagonists.
FIGURE 7-14
THE SIDE EFFECT PROFILE OF -ADRENERGIC ANTAGONISTS The side effect profile of -adrenergic
antagonists. The side effect profile of beta-
blockers is related to the specific blockade
Side effects Mechanisms of 1 or 2 receptors. This table lists the
more common side effects and their pro-
Bronchospasm Blockade of 2-adrenergic receptors; increased airway resistance posed mechanism(s) of action [6,9].
Bradycardia Blockade of atrial 1/2-adrenergic receptors; decrease in heart rate
Congestive heart failure; decrease in Blockade of ventricular 1-adrenergic receptors
exercise tolerance
Claudication Blockade of peripheral vascular 2-adrenergic receptors
Constipation, dyspepsia Blockade of gastrointestinal 1/2-adrenergic receptors; decreased motili-
ty and relaxation of sphincter tone
Central nervous system manifestations Blockade of CNS 1/2-adrenergic receptors
(sleep disturbances, depression)
Sexual dysfunction (impotence, Unknown
decrease libido)
Impaired glucose tolerance Impaired 2-adrenergic–mediated islet cell insulin secretion; increase
hepatic glucose, and/or decrease insulin-stimulated glucose disposal
Prolonged insulin-induced Block epinephrine-mediated counterregulatory mechanisms
hypoglycemia
Hepatocellular necrosis Labetalol only, idiosyncratic reaction
Withdrawal syndrome Acute overshoot in heart rate with increased myocardial oxygen demand
Unstable angina due to increase in number and/or sensitivity of -adrenergic receptors
Myocardial infarction during chronic blockade
Dyslipidemia Increased -adrenergic tone; reduced lipoprotein lipase activity
Increased total triglycerides
Decreased high-density lipoproteins
cholesterol
FIGURE 7-15
Phsysiologic effect of central
α2-adrenergic agonists 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].
α-Methyldopa Stimulation of these receptors decreases sympathetic tone, brain turnover of norepinephrine,
guanfacine Clonidine and central sympathetic outflow and activity of the preganglionic sympathetic nerves. The
guanabenz
net effect is a reduction in norepinephrine release. The central 2-adrenergic agonist clonidine
Stimulates Stimulates 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 2-
Central α2 I1-Imidazoline adrenergic receptors that mediate vasoconstriction; this effect predominates at high plasma
adrenoceptor receptor
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.
NTS RVLM
Nucleus Rostral
tractus ventrolateral
solitarii medulla
Inhibition of central
sympathetic activity
Blood pressure
reduction
CENTRAL 2-ADRENERGIC ANTAGONISTS
Generic (trade) name First dose, mg Usual daily dose Maximum daily dose Duration of action
-Methyldopa (G) (Aldomet) 250 250–1000 mg bid 3000 24–48 h
Clonidine (G) (Catapres) 0.1 0.1–0.6 mg bid/tid 2.4 6–8 h
Clonidine TTS (Catapres-TTS) 2.5 mg (TTS-1) 2.5–7.5 mg (TTS–1 to TTS–3) qwk 15 mg (TTS-3x2) 9 wk 7d
Guanabenz (Wytensin) 4 4–16 mg bid 64 12 h
Guanfacine (Tenex) 1 1–3 mg QD 3 36 h
G—generic available; TTS—transdermal patch.
FIGURE 7-16
Central 2-adrenergic agonists. -Methyldopa is a methyl-substituted insufficiency, the plasma half-life (12 to 16 hours) may be extended
amino acid that is active only after decarboxylation and conversion to more than 40 hours; dose reduction is required. When clonidine
to -methyl-norepinephrine. The antihypertensive effect results from is administered transdermally, therapeutic plasma levels are achieved
accumulation of 2-adrenergic receptors, displacing and competing with within 2 to 3 days.
endogenous catecholamines. Methyldopa is absorbed poorly Guanabenz, a guanidine derivative, is highly selective for central
(<50%); peak plasma concentrations occur in 2 to 4 hours. It is 2-adrenergic receptors. It is absorbed well (>75%); peak plasma
metabolized in the liver and excreted in the urine mainly as the inactive levels are reached in 2 to 5 hours. Guanabenz undergoes extensive
O-sulfate conjugate. The plasma half-life of methyldopa (1 to 2 hours) hepatic metabolism; less than 2% is excreted unchanged in the urine.
and its metabolites is prolonged in patients with renal insufficiency; The plasma half-life (approximately 6 hours) is not prolonged in
dose reduction is required. patients with renal insufficiency.
Clonidine, an imidazoline derivative, acts by stimulating either Guanfacine is a phenylacetyl-guanidine derivative with a longer
central 2-adrenergic receptors or imidazole receptors. Clonidine may plasma half-life than guanabenz. It is absorbed well (>90%); peak
be administered orally or by a transdermal delivery system (TTS). plasma concentrations are reached in 1 to 4 hours. The drug is
When given orally, it is absorbed well (>75%); peak plasma con- primarily metabolized in the liver. Guanfacine and its metabolites
centrations occur in 3 to 5 hours. Clonidine is metabolized mainly are excreted primarily by the kidneys; 24% to 37% is excreted as
in the liver; fecal excretion ranges from 15% to 30%, and 40% to unchanged drug in the urine. The plasma half-life (15 to 17 hours)
60% is excreted unchanged in the urine. In patients with renal is not prolonged in patients with renal insufficiency [6,9].
FIGURE 7-17
THE SIDE EFFECT PROFILE OF CENTRAL The side effect profile of central 2-adrenergic agonists. The side
2-ADRENERGIC AGONISTS effect profile of these agents is diverse [6,9].
Side effects Mechanisms

Sedation/drowsiness Stimulation of 2-adrenergic receptors in
the brain
Xerostoniia (dry mouth) Centrally mediated inhibition of
cholinergic transmission
Gynecomastia in men, galactorrhea Reduced central dopaminergic inhibition
in women of prolactin release (methyldopa only)
Drug fever, hepatotoxicity, positive Long-term tissue toxicity
Coombs test with or without (methyldopa only)
hemolytic anemia
Sexual dysfunction, depression, Stimulation of 2-adrenergic receptor
decreased mental acuity in the brain
“Overshoot hypertension” Acute excessive sympathetic discharge
Restlessness in the face of chronic downregulation
Insomnia of central 2-adrenergic receptors in
Headache an inhibitory circuit during chronic
Tremor treatment when treatment is stopped
Anxiety
Nausea and vomiting
A feeling of impending doom
Indicates blockade FIGURE 7-18

Brain stem 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
Preganglionic deplete stores of norepinephrine (NE) by competitively inhibiting
neuron
the uptake of dopamine by storage granules and by preventing the
Ganglion incorporation of norepinephrine into the protective chromaffin
granules; the free catecholamines are destroyed by monoamine
oxidase. The predominant pharmacologic effect is a marked
Postganglionic decrease in peripheral resistance; heart rate and cardiac output
adrenergic are either unchanged or mildly decreased.
NE nerve ending
NE
NE
NE
β1
α1 α2
Vascular smooth muscle cells

CENTRAL PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENT
Generic (trade) name First dose, mg Usual daily dose, mg Maximum daily dose, mg Duration of action
Reserpine (G) (Serpasil) 0.1 0.1–.25 QD 0.5 2–3 wk
FIGURE 7-19
Central and peripheral adrenergic neuronal blocking agents. Reserpine pressure is maximally lowered 2 to 3 weeks after beginning therapy.
is the most popular rauwolfia product used. It is absorbed poorly Reserpine is metabolized by the liver; 60% of an oral dose is recovered
(approximately 30%); peak plasma concentrations occur in 1 to 2 in the feces. Less than 1% is excreted in the urine as unchanged drug.
hours. Catecholamine depletion begins within 1 hour of drug The plasma half-life (12 to 16 days) is not prolonged in patients
administration and is maximal in 24 hours. Catecholamines are with renal insufficiency.
restored slowly. Chronic doses of reserpine are cumulative. Blood
Peripheral Indicates blockade

THE SIDE EFFECT PROFILE OF RESERPINE adrenergic
nerve ending

Altered CNS function Depletion of serotonin and/or NE
Inability to concentrate catecholamine
Decrease mental acuity
Sedation NE
Sleep disturbance
Depression
Nasal congestion/rhinitis Cholinergic effects NE NE
Increased GI motility, Cholinergic effects
NE
increased gastric acid secretion NE
Increased appetite/weight gain Unknown
Sexual dysfunction Unknown
Impotence NE
Decreased libido
β1
α2 α1
FIGURE 7-20 Vascular smooth muscle cells

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. CNS—central nervous
system; GI—gastrointestinal.
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 nor-
epinephrine release from sympathetic nerve terminals by a negative
feedback mechanism (see Fig. 7-22) [11]. NE—norepinephrine.
FIGURE 7-22
Varicosity Vesicle Adrenergic synapse. Nerve activity releases
containing NA the endogenous neurotransmitter noradren-
Postganglionic Nerve impulse aline (NA) and also adrenaline from the
sympathetic neuron induces Sympathetic varicosities. Noradrenaline and adrenaline
exocytotic NA release + – C-fiber reach the postsynaptic -adrenoceptors (or
Presynaptic β Presynaptic -adrenoceptors) on the cell membrane of
α
β-receptor α-receptor
the target organ by diffusion. On receptor
NA Synaptic
stimulation, a physiologic or pharmacologic
cleft
Varicosities effect is initiated. Presynaptic 2-adrenocep-
α
Effector tors on the membrane (enlarged area), when
cell activated by endogenous noradrenaline as
Synaptic Postsynaptic
well as by exogenous agonists, inhibit the
cleft α-receptor Response
amount of transmitter noradrenaline released
per nerve impulse. Conversely, the stimulation
NA of presynaptic 2-receptors enhances nora-
drenaline release from the varicosities. Once
noradrenaline has been released, it travels
Target through the synaptic cleft and reaches both
Postsynaptic
organ - and -adrenoceptors at postsynaptic
α- receptors
sites, causing physiologic effects such as
vasoconstriction or tachycardia. (Adapted
from Van Zwieten [11].)
PERIPHERAL 1-ADRENERGIC ANTAGONISTS
Prazosin (G) (Minipress) 1 2-6 bid/tid 20 6-12 w
Terazosin (Hytrin) 1 2-5 QD/bid 20 12-24 h
Doxazosin (Cardura) 1 2-4 QD 16 24 h
FIGURE 7-23
Peripheral 1-adrenergic antagonists. Prazosin is a lipophilic metabolized by the liver and predominantly excreted in the
highly selective 1-adrenergic antagonist. It is absorbed well feces. The plasma half-life of terazosin (approximately 12 hours)
(approximately 90%) but undergoes variable first-pass hepatic is not prolonged in patients with renal insufficiency.
metabolism. Peak plasma concentrations occur in 2 to 3 hours. Doxazosin is also a water-soluble quinazoline analogue of
It is extensively metabolized by the liver and predominantly prazosin, with about half its potency. It is absorbed well but
excreted in the feces. The plasma half-life of prazosin (2 to undergoes significant first-pass hepatic metabolism; bioavail-
4 hours) is not prolonged in patients with renal insufficiency. ability is approximately 65%. Peak concentrations occur in
Terazosin is a water-soluble quinazoline analogue of prazosin 2 to 3 hours. It is extensively metabolized by the liver and
with about one third of its potency. It is completely absorbed primarily eliminated in the feces. The plasma half-life of doxa-
and undergoes minimal first-pass hepatic metabolism. Peak zosin (approximately 22 hours) is not prolonged in patients
plasma concentrations occur in 1 to 2 hours. It is extensively with renal insufficiency [6,9].
FIGURE 7-24
150 Placebo Lying The side effect profile of the peripheral 1-adrenergic antagonists.
Standing
140 1-Adrenergic antagonists are associated with relatively few side
effects [6,9]; the most striking is the “first-dose effect” [12]. It
Mean BP, mm Hg
130 occurs 30 to 90 minutes after the first dose and is dose dependent.
120 It is minimized by initiating therapy in the evening and by careful
dose titration. The “first-dose effect” is exaggerated by fasting,
110 upright posture, volume contraction, concurrent -adrenergic
100 antagonism, or excessive catecholamine activity (eg, pheochromo-
Day 0
cytoma). (From Graham and coworkers [12]; with permission.)
Prazosin, 2 mg
140
130
120
110
Mean BP, mm Hg
100
90
80
70
60
50
Day 1
140
Prazosin, 2 mg
130
120
Mean BP, mm Hg
110
100
90
80 Day 4
0700 0900 1100 1300 1500 1700

Time, h
Peripheral Indicates blockade FIGURE 7-25

adrenergic Moderately selective peripheral 1-adrenergic antagonists.
nerve ending 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
NE
of sympathomimetic amines to initiate action at these sites.
Phenoxybenzamine also increases the rate of turnover of norepi-
NE nephrine (NE) owing to increased tyrosine hydroxylase activity,
and it increases the amount of norepinephrine released by each
α2
nerve impulse owing to blockade of presynaptic 2-adrenergic
NE
NE receptors [11]. The net physiologic effect is a decrease in peripheral

resistance and increases in heart rate and cardiac output. Postural
NE
hypotension may be prominent, related to blockade of compensatory

NE
responses to upright posture and hypovolemia. The degree of
vasodilation is dependent on the degree of adrenergic vascular tone.
NE
β1
α2 α1
MODERATELY SELECTIVE PERIPHERAL 1-ADRENERGIC ANTAGONIST
Generic (trade) name First dose, mg Usual daily dose, mg Maximum of action, mg Duration of action
Phenoxybenzamine (Dibenzyline) 10 20-40 bid 120 3–4 d
FIGURE 7-26
Moderately selective peripheral 1-adrenergic antagonists. approximately 3 to 4 days. Phenoxybenzamine is primarily used in
Phenoxybenzamine is the only drug in its class. Absorption is variable the management of preoperative or inoperative pheochromocytoma.
and incomplete (20% to 30%). Peak blockade occurs in 3 to 4 Efficacy is dependent on the degree of underlying excessive -adrenergic
hours. Its plasma half-life is 24 hours. The duration of action is vascular tone [6,9].
FIGURE 7-27
THE SIDE EFFECT PROFILE OF PHENOXYBENZAMINE The side effect profile of phenoxybenzamine. The common side
effects are listed [6,9].

Nasal congestion -adrenergic receptor blockade
Miosis -adrenergic receptor blockade
Sedation Unknown
Weakness, lassitude Impairment of compensatory vasoconstriction producing
orthostatic hypotension
Sexual dysfunction -adrenergic receptor blockade
Inhibition of ejaculation
Tachycardia Uninhibited effects of epinephrine, norepinephrine and
direct or reflex sympathetic nerve stimulation on the heart

adrenergic Peripheral adrenergic neuronal blocking agents. Peripheral adrenergic
nerve ending neuronal blocking agents are selectively concentrated in the adren-
ergic nerve terminal by an active transport mechanism, or “norepi-
nephrine pump” [6,9]. They act by interfering with the release of
norepinephrine (NE) from neuronal storage sites in response to nerve
NE
stimulation and by depleting norepinephrine from nerve endings.
Acutely, cardiac output is reduced, caused by diminished venous
NE 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
NE
NE
heart rate and cardiac output.
β1
α1 α2

PERIPHERAL ADRENERGIC-NEURONAL BLOCKING AGENTS
Guanethidine (Ismelin) 10 25–75 QD 150 7–21 d
Guanadrel (Hylorel) 5 10–50 bid 150 4–14 h
FIGURE 7-29
Peripheral adrenergic neuronal blocking agents. Guanethidine is 87.5% of a steady-state level. By administering loading doses of
the prototype peripheral adrenergic neuronal blocking agent. guanethidine at 6-hour intervals (the nearly maximal effect from a
Absorption is incomplete and variable; only 3% to 30% is absorbed single oral dose), blood pressure can be lowered in 1 to 3 days. In
over 12 hours. Peak plasma levels are reached in 6 hours. The drug patients with severe renal insufficiency, drug excretion is decreased;
rapidly leaves the plasma for extravascular storage sites, including dose reduction is required.
sympathetic neurons. Guanethidine is eliminated with a plasma Guanadrel is a guanethidine derivative with a short therapeutic
half-life of 4 to 8 days, a time course that corresponds with its anti- half-life. Absorption is greater than 85%; peak plasma concentra-
hypertensive effect. Approximately 24% of the drug is excreted tions are reached in 1 to 2 hours. Guanadrel is metabolized by the
unchanged in the urine; the remainder is metabolized by the liver liver. Elimination occurs through the kidney; approximately 40%
into more polar, less active, metabolites that are excreted in the of the drug is excreted unchanged in the urine. In patients with
urine and feces. When therapy is initiated or the dosage is changed, renal insufficiency, the plasma half-life (10 to 12 hours) is pro-
three half-lives (approximately 15 days) are required to accumulate longed; dose reduction is required [6,9].
FIGURE 7-30
THE SIDE EFFECT PROFILE OF PERIPHERAL The side effect profile of peripheral adren-
ADRENERGIC-NEURONAL BLOCKING AGENTS ergic neuronal blocking agents. The specific
side effects of this class are related to either
excessive sympathetic blockade or a relative
Side effects Mechanisms increase in parasympathetic activity. GFR—
glomerular filtration rate.
Decrease renal function (GFR) Decreased renal perfusion; effect is magnified in the upright position
Fluid retention/weight gain Decreased filtered load and fractional excretion of sodium; diuretic should be
used in combination
Dizziness/weakness Postural hypotension accentuated by hot weather, alcohol ingestion, and/or
Syncope physical exercise
Intestinal cramping/diarrhea Unopposed parasympathetic activity, increasing gastrointestinal motility
Sexual dysfunction Inhibition of bladder neck closure, unknown
Retrograde ejaculation
Impotence
Decreased libido
Sinus bradycardia Interferes with cardiac sympathetic compensating reflexes
Atrioventricular block
Bronchospasm Catecholamine depletion aggravates airway resistance
Congestive heart failure Decreased cardiac output
FIGURE 7-31
Plasma Direct-acting vasodilators. Direct-acting vasodilators may have an
membrane VGC Leak ROC VGC 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 relax-
ation and reason for selectivity are unknown. By altering cellular calci-
Ca2+ Ca2+ um metabolism, they interfere with the calcium movements respon-
sible for initiating or maintaining a contractile state. The net physi-
Ca2+
Altered calcium
metabolism (?)
ologic 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
Ca2+ SR Ca2+ SR
sympathetic stimulation and indirectly to the baroreceptor reflex
response. ROC—receptor-operated channel; SR—sarcoplasmic
reticulum; VGC—voltage-gaited channels.
Activation of
Myofilaments
Contraction of vascular
smooth muscle
Hypertension
DIRECT-ACTING VASODILATORS
Hydralazine (G) (Apresoline) 10 50–100 bid/tid 300 10–12
Minoxidil (G) (Loniten) 5 10–20 QD/bid 80 75
FIGURE 7-32
Direct-acting vasodilators. Hydralazine is the prototype of direct- Minoxidil is a substantially more potent direct-acting vasodilator
acting vasodilators. Absorption is more than 90%. Peak plasma than hydralazine. Absorption is greater than 95%. Peak plasma levels
levels occur within 1 hour but may vary widely among individuals. occur within 1 hour. Following a single oral dose, blood pressure
This is because hydralazine is subject to polymorphic acetylation; declines within 15 minutes, reaches a nadir between 2 and 4 hours,
slow acetylators have higher plasma levels and require lower drug and recovers at an arithmetically linear rate of 30% per day.
doses to maintain blood pressure control compared with rapid Approximately 90% is metabolized by conjugation with glucuronic
acetylators. Bioavailability for slow acetylators ranges from 30% acid and by conversion to more polar products. Known metabolites,
to 35%; bioavailability for rapid acetylators ranges from 10% to which are less pharmacologically active than minoxidil, are excreted
16%. Hydralazine undergoes extensive hepatic metabolism; it is in the urine. The plasma half-life of minoxidil is approximately 4
mainly excreted in the urine in the form of metabolites or as hours; dose adjustments are unnecessary in patients with renal insuf-
unchanged drug. The plasma half-life is 3 to 7 hours. Dose reduction ficiency. Minoxidil and its metabolites are removed by hemodialysis
may be required in the slow acetylator with renal insufficiency. and peritoneal dialysis; replacement therapy is required [6,9].
FIGURE 7-33
Side effects of direct-acting vasodilators
The side effect profile of direct-acting
↑ Heart rate vasodilators. The most common and most
serious effects of hydralazine and minoxidil
↑ Myocardial ↑ Cardiac
contractility output
are related to their direct or reflex-mediated
VASODILATORS
↑ Sympathetic hemodynamic actions, including flushing,
function ↓ Venous headache, palpitations, anginal attacks, and
capacitance electrocardiographic changes of myocardial
↑ Peripheral ischemia [6,9]. These effects may be pre-
↓ Peripheral vascular vented by concurrent administration of a
vascular resistance PROPRANOLOL -adrenergic antagonist. Sodium retention
resistance with expansion of extracellular fluid volume
is a significant problem. Large doses of
potent diuretics may be required to prevent
↓ Arterial ↑ Plasma ↑ Circulating ↑ Aldosterone
fluid retention and the development of
pressure renin angiotensin secretion pseudotolerance [13]. (From Koch-Weser
activity [13]; with permission.)
Repeated administration of hydralazine
DIURETICS can lead to a reversible syndrome that
resembles disseminated lupus erythematosus.
↑ Plasma and The incidence is dose dependent; it rarely
↓ Sodium extracellular
excretion
occurs in patients receiving less than 200
fluid volume mg/day. Hypertrichosis is a common trouble-
some 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
Plasma antihypertensive mechanism of action: inhibition of calcium ion
membrane VGC ROC VGC 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 extra-
Ca2+ Ca2+ cellular to the intracellular space, inhibits the essential role of calci-
um as an intracellular messenger, uncoupling excitation to contrac-
Ca2+
tion. Calcium ions may also enter cells through receptor-operated
channels. The opening of these channels is induced by binding neu-
rohumoral mediators to specific receptors on the cell membrane.
Ca2+ SR Ca2+ SR
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 ago-
nist and angiotensin II on vascular smooth muscle tone. The net
physiologic effect is a decrease in vascular resistance.
Myofilaments 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. ROC—receptor-operated
channel; SR—sarcoplasmic reticulum; VGC—voltage-gaited channels.
A. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: PHENYLALKAMINE DERIVATIVE
Generic (trade) name First dose, mg Usual dose, mg Maximum daily dose, mg Duration of action, h
Verapamil (G) (Isoptin, Calan) 80 80–120 tid 480 8
Verapamil SR (Isoptin SR, Calan SR) 90 90–240 bid 480 12–24
Verapamil SR—pellet (Veralan) 120 240–480 QD 480 24
Verapamil COER-24 (Covera HS) 180 180–480 qhs 480 24
B. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: DIHYDROPYRIDINE DERIVATIVES
Amlodipine (Norvasc) 5 5–10 QD 10 24
Felodipine (Plendil) 5 5–1 0 QD 20 24
Isradipine (DynaCirc) 2.5 2.5-5 bid 20 12
Isradipine CR (DynaCirc CR) 5 5–20 QD 20 24
Nicardipine SR (Cardine SR) 30 30–60 bid 120 12
Nifedipine Caps (G) (Procardia) 10 10–30 tid/qid 120 4–6
Nifedipine ER (Adalat CC) 30 30–90 QD 120 24
Nifedipine GITS (Procardia XL) 30 30–90 QD 120 24
Nisoldipine (Sular) 20 20–40 QD 60 24
C. DOSING SCHEDULES FOR CALCIUM ANTAGONISTS: BENZODIAZEPINE DERIVATIVE
Diltiazem (G) (Cardizem) 60 60–120 tid/qid 480 8
Diltiazem SR (Cardizem SR) 180 120–240 bid 480 12
Diltiazem CD (Cardizem CD) 180 240–480 QD 480 24
Diltiazem XR (Dilacor XR) 180 180–480 QD 480 24
Diltiazem ER (Tiazac) 180 180–480 QD 480 24
FIGURE 7-35
A–C. Dosing schedules for calcium antagonists: phenylalkamine derivatives,
dihydropyridine derivatives, and benzothiazepine derivatives.
PHARMACOKINETICS OF CALCIUM ANTAGONISTS
Absorption, % First-pass hepatic Peak concentration Route of elimination Active metabolite Plasma half-life, h Dose reduction
Verapamil >90 70%–80% 1–2 h (tablet) Liver Yes 4–12 (tablet) No
5 h (SR caplet) 12 (SR pellet)
7–9 h (SR pellet)
11 h (COER)
Amlodipine >90 Minimal 6–12 h Liver No 30–50 No
Felodipine >90 Extensive 2.5–5 h Liver No 11–16 No
Isradipine >90 Extensive 1–2 h (tablet) Liver No 8 No
7–18 h (CR)
Nicardipine >90 Extensive 1–4 h (SR) Liver No 8–9 No
Nifedipine >90 20%–30% <30 min (cap) Liver No 2 No
2.5–5 h (ER) 24
6 h GITS) 24
Nisoldipine >85 Extensive 6–12 h Liver Yes 7–12 No
Diltiazem >80 50% 2–3 h (tablet) Liver Yes 4–6 Yes
6–11 h (SR) 5–7
10–14 h (CD) 5–8
4–6 h (XR) 5–10
7 h (ER) 4–10
FIGURE 7-36
Pharmacokinetics of the calcium antagonists: phenylalkamine derivatives,
dihydropyridine derivatives, and benzothiazepine derivatives.
FIGURE 7-37
THE SIDE EFFECTS PROFILE OF CALCIUM ANTAGONISTS The side effect profile of calcium antagonists
[10,13,18]. AV—atrioventricular.
Side effects Mechanism

Dihydropyridine Potent peripheral vasodilator
Headache, flushing, palpitation, edema
Phenylalkylamine Negative inotropic, dromotropic, chronotropic effects
Constipation
Bradycardia, AV block congestive heart failure
Benzodiazepine Negative inotropic, dromotropic, chronotropic effects
Bradyarrhythmia, AV block congestive heart failure
ACE inhibition and angiotensin II type I receptor antagonists: mechanisms for decrease in peripheral vascular resistance
Functions::
+
– Renal tubular
sodium reabsorption
+
Aldosterone
release
Angiotensinogen Non-renin enzymes + Vasoconstriction, +
AT1 Blood
(renin substrate) vascular smooth
receptor pressure
muscle
1 Non-ACE enzymes +
Renin Remodeling,
3
vascular smooth
muscle
Angiotensin I Angiotensin II +
(decapeptide) (octapeptide) Sympathetic activity
2 (central and peripheral)
–
ACE 4 Baroreceptor
sensitivity
Inactive
AT2 receptor ? Function
fragments
Nitric oxide
+ –
Bradykinin Prostaglandin E2
Prostaglandin I2
–
FIGURE 7-38
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II Mechanisms proposed for the observed decrease in peripheral
type I receptor antagonists. Angiotensin-converting enzyme resistance are shown [15]. Sites of pharmacologic blockade in the
inhibitors and angiotensin II type I receptor antagonists lower renin angiotensin system: 1) renin inhibitors, 2) ACE inhibitors,
blood pressure by decreasing peripheral vascular resistance; there 3) angiotensin II type I receptor antagonists, 4) angiotensin II
is usually little change in heart rate or cardiac output [6,9,15]. type II receptor antagonists.
A. DOSING SCHEDULES FOR SULFHYDRYL-CONTAINING ACE INHIBITOR
Generic (trade) name First dose, mg Usual dose, mg Maximum dose, mg Duration of action, h
Captopril (G) (Capoten) 12.5 12.5–50 bid/tid 150 6–12
B. DOSING SCHEDULES FOR CARBOXYL-CONTAINING ACE INHIBITORS
Benazepril (Lotensin) 10 10–20 QD 40 24
Enalapril (Vasotec) 5 5–10 QD/bid 40 12–24
Lisinopril (Prinivil,Zestril) 10 20–40 QD 40 24
Moexipril (Univasc) 7.5 7.5–15 QD/bid 30 24
Quinapril (Accupril) 5–10 20–40 QD 40 24
Ramipril (Altace) 2.5 2.5–20 QD/bid 40 24
Trandolapril (Mavik) 1 2–4 QD 8 24
C. DOSING SCHEDULES FOR PHOSPHINIC ACID–CONTAINING ACE INHIBITOR
Fosinopril (Monopril) 10 20–40 QD/bid 40 24
FIGURE 7-39
A–C. Classification of and dosing schedule for angiotensin-converting conformation, and lipophilicity [6,9]. They are generally classified
enzyme (ACE) inhibitors. Angiotensin-converting enzyme inhibitors into one of three main chemical classes according to the ligand of
differ in prodrug status, ACE affinity, potency, molecular weight and the zinc ion of ACE: sulfhydryl, carboxyl, or phosphinic acid.
PHARMACOKINETICS OF ACE INHIBITORS
Peak concentration Dose reduction

Absorption, % Prodrug (active component), h Route of elimination Plasma half-life, h (renal disease)
Captopril 60–75 No 1 Kidney 2 Yes
Benazepril 37 Yes 1–2 Kidney/liver 10–11 Yes
Enalapril 55–75 Yes 3–4 Kidney 11 Yes
Lisinopril 25 Yes 6–8 Kidney 12 Yes
Moexipril > 20 Yes 1–2 Kidney 2–9 Yes
Quinapril 60 Yes 2 Kidney 25 Yes
Ramipril 50–60 Yes 2–4 Kidney/liver 13–17 Yes
Trandolapril 70 Yes 4–10 Kidney/liver 16–24 Yes
Fosinopril 36 Yes 3 Kidney/liver 12 No
FIGURE 7-40
Pharmacokinetics of angiotensin-converting enzyme (ACE) inhibitors: sulfhydryl-
containing, carboxyl-containing, and phosphinic acid–containing.
FIGURE 7-41
THE SIDE EFFECTS PROFILE OF ACE INHIBITORS The side effect profile of angiotensin-con-
verting enzyme (ACE) inhibitors. ACE
inhibitors are well tolerated; there are few
Side effects Mechanisms side effects [6,9].
Cough, angioedema Laryngeal edema Potentiation of tissue kinins

Lightheadedness, syncope Excessive hypotension in patients with high basal peripheral vascular resistance—
high renin states, like volume contraction, impaired cardiac output
Hyperkalemia Decreased aldosterone; potassium-containing salt substitutes and
supplements should be avoided
Acute renal failure Extreme hypotension with impaired efferent arteriolar autoregulation
FIGURE 7-42
230 Renal artery Essential Angiotensin-converting enzyme (ACE) inhibition in acute renal failure.
pressure, mm Hg
stenosis hypertension ACE inhibitors may produce functional renal insufficiency in patients
190 with essential hypertension and hypertensive nephrosclerosis, in
Arterial
patients with severe bilateral renal artery stenosis, or in patients

150 with stenosis of the renal artery of a solitary kidney. The postulated
110 mechanism for this effect is diminished renal blood flow (decrease
in systemic pressure, compromising flow through a fixed stenosis)
70 in combination with diminished postglomerular capillary resistance
(ie, decrease in angiotensin II–mediated efferent arteriolar tone). In
renal plasma flow,
Total effective
440 unilateral renal artery stenosis, a drop in the critical perfusion and
mL/min
360 filtration pressures may result in a marked drop in single-kidney

glomerular filtration rate (GFR); however, the contralateral kidney
280 may show an increase in both effective renal plasma flow (ERPF)
and GFR due to attenuation of the intrarenal effects of angiotensin
110
II on vascular resistance and mesangial tone. Thus, total “net”
Total glomerular
filtration rate,
GFR may be normal, giving the false appearance of stability [16].

mL/min
100
Although ACE inhibition may invariably decrease the GFR of the
90 stenotic kidney, it is unlikely to cause renal ischemia owing to
preservation of ERPF; GFR usually returns to pretreatment values
80 following cessation of therapy.
Shown is the effect of captopril (50 mg) on total clearances of
1000 131I-sodium iodohippurate (ERPF) and 126I-thalamate (GFR) in 14
patients with unilateral renal artery stenosis and in 17 patients with
Plasma renin, mU/L
essential hypertension. The effects after 60 minutes of captopril on

100 systolic and diastolic intra-arterial pressure (P < 0.001) and of renin
were significant. (From Wenting and coworkers [16]; with permission.)
10 Captopril 50 mg Captopril 50 mg
–15 0 30 60 –15 0 30 60
Time, min

adrenergic Tyrosine hydroxylase inhibitor. Metyrosine (-methyl-para-tyrosine)
nerve ending 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
Tyrosine activity results in decreased endogenous levels of circulating cate-
Tyrosine hydroxylase cholamines. In patients with excessive production of catecholamines,
Dihydroxyphenylalanine metyrosine reduces biosynthesis 36% to 79%; the net physiologic
effect is a decrease in peripheral vascular resistance and increases in
NE heart rate and cardiac output resulting from the vasodilation. The
degree of vasodilation is dependent on the degree of blockade of
adrenergic vascular tone. NE—norepinephrine.
β1
α1 α2

TYROSINE HYDROXYLASE INHIBITOR
Generic (trade) name First dose, mg Usual daily dose, mg Maximum dose, mg Duration of action, h
Metyrosine (Demser) 250 25 qid 1000 qid 3–4
FIGURE 7-44
Tyrosine hydroxylase inhibitor. Metyrosine is the only drug in its Following discontinuation of therapy, the clinical and biochemical
class. The initial recommended dose is 1 g/d, given in divided doses. effects may persist 2 to 4 days. Metyrosine is variably absorbed
This may be increased by 250 to 500 mg daily to a maximum of from the gastrointestinal tract; bioavailability ranges from 45%
4 g/d. The usual effective dosage is 2 to 3 g/d. The maximum bio- to 90%. Peak plasma concentrations are reached in 1 to 3 hours.
chemical effect occurs within 2 to 3 days. In hypertensive patients in The plasma half-life is 3 to 4 hours. Metyrosine is not metabolized;
whom there is a response, blood pressure decreases progressively the unchanged drug is recovered in the urine. Drug dosage should
during the first days of therapy. In patients who are usually nor- be reduced in patients with renal insufficiency. Metyrosine is exclu-
motensive, the dose should be titrated to the amount that will sively used in the management of preoperative or inoperative
reduce circulating or urinary catecholamines by 50% or more. pheochromocytoma [6,9].
FIGURE 7-45
THE SIDE EFFECTS PROFILE OF METYROSINE 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
Side effects Mechanisms (needles or rods), which is due to the poor solubility of the drug in
the urine, has been observed in patients receiving doses greater
CNS symptoms Depletion of CNS dopamine than 4 g/d. To minimize this risk, patients should be well hydrated.
Sedation CNS—central nervous system.
Extrapyramidal signs
Drooling
Speech difficulty
Tremor
Trismus
Parkinsonian syndrome
Psychic dysfunction
Anxiety
Depression
Disorientation
Confusion
Crystalluria, uroliathiasis Poor urine solubility
Diarrhea Direct irritant to bowel mucosa
Insomnia (temporary) Following drug withdrawal
ANGIOTENSIN II RECEPTOR ANTAGONISTS
Losartan (Cozaar) 50 50–100 QD/bid 100 12–24
Valsartan (Diovan) 80 80–160 QD 320 24
Irbesaftan (Avapro) 150 150–300 QD 300 24
FIGURE 7-46
Angiotensin II receptor antagonists. These drugs antagonize longer half-life (between 4 and 9 hours). The metabolite is cleared
angiotensin II–induced biologic actions, including proximal sodium equally by the liver and the kidney; there may be enhanced hepatic
reabsorption, aldosterone release, smooth muscle vasoconstriction, clearance in renal insufficiency [15]. Dose reduction is not required
vascular remodeling, and baroreceptor sensitivity. Antihypertensive in patients with renal insufficiency.
efficacy appears dependent on an activated renin-angiotensin system; Valsartan is a nonpeptide, specific angiotensin II antagonist acting
bilateral nephrectomy and volume expansion abolish their activity. on the AT1 subtype receptor. Peak response occurs within 6 hours
Losartan is a nonpeptide, specific angiotensin II receptor antagonist of dosing. Peak plasma concentrations are reached 2 to 4 hours
acting on the antagonist AT1 subtype receptor. Peak response occurs after dosing. The average elimination half-life is about 6 hours.
within 6 hours of dosing. It is readily absorbed; peak plasma concen- Oral bioavailability is approximately 25%. Dose reduction is not
trations are achieved within 1 hour. It has a relatively short terminal required in patients with renal insufficiency [15].
half-life of 1.5 to 2.5 hours. Oral bioavailability is approximately Irebsartan is a nonpeptide, specific angiotensin II antagonist acting
33%. Losartan undergoes extensive first-pass hepatic metabolism on the AT1 subtype receptor. Peak response occurs in 4 to 8 hours.
to the predominant circulatory form of the drug Exp-3174. This There is no active metabolite. Dose reduction is not required in
metabolite is 15 to 30 times more potent than losartan with a patients with renal insufficiency [15].
FIGURE 7-47
THE SIDE EFFECTS PROFILE OF ANGIOTENSIN II The side effect profile of angiotensin II receptor antagonists.
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 antihy-
Side effects Mechanisms pertensive drug. Similar to ACE inhibitors, however, hyperkalemia
and acute renal failure may occur in patients at risk [15].
Hyperkalemia Blockade of angiotensin II
Reduced aldosterone secretion
Acute renal dysfunction Hypotension with impaired efferent anteriolar
autoregulation
Prevention and Treatment of High Blood Pressure

FIGURE 7-48
JNC VI CLASSIFICATION OF HYPERTENSION Prevention and treatment of high blood pressure. The aim of anti-
hypertensive therapy is risk reduction. Since the relationship
between blood pressure and cardiovascular risk is continuous, the
Category* Systolic (mm Hg) Diastolic (mm Hg) goal of treatment might be the maximum tolerated reduction in
blood pressure. There is controversy concerning what constitutes
Optimal† <120 and <80 hypertension and how far systolic or diastolic blood pressure
Normal <130 and <85 should be lowered, however. The Sixth Report of the Joint
High normal 130–139 or 85–89 National Committee on Detection, Evaluation, and Treatment of
Hypertension‡ High Blood Pressure (JNC VI) [17] provides a new classification of
Stage 1 140/159 or 90/99 hypertension and recommends that risk stratification be used to
Stage 2 160/179 or 100/109 determine if lifestyle modification or drug therapy with adjunctive
Stage 3 ≥-180 or ≥110
lifestyle modification be initiated according to the patient’s blood
pressure classification (see Fig. 7-50). Major risk factors include
*Not taking anithypertensive drugs and not acutely ill. When systolic and diastolic smoking, dyslipidemia, diabetes mellitus, an age of 60 or older,
blood pressures fall into different categories, the higher category should be selected to male sex or postmenopausal state for women, and a family history
classify the individual’s blood pressure status. For example, 160/92 mm Hg should be
of cardiovascular disease in women younger than 65 and in men
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 younger than 55. Target organ damage includes heart disease (left
mm Hg or greater and diastolic blood pressure of less than below 90 mm Hg and ventricular hypertrophy, angina pectoris, prior myocardial infarction,
staged appropriately (eg, 170/82 mm Hg is defined as stage 2 isolated hypertension). heart failure), stroke or transient ischemic attack, and nephropathy.
In addition to classifying stages of hypertension on the basis of average blood pressure Prevention and management of hypertension-related morbidity and
levels, clinicians should specify presence of target organ disease and additional risk mortality may best be accomplished by achieving a systolic blood
factors. This specifically is important for risk classification. pressure below 140 mm Hg and a diastolic blood pressure below
†Optimal blood pressure with respect to cardiovascular risk is below 120/80 mm Hg.
90 mm Hg; lower if tolerable. Recently, more aggressive blood
Unusually low readings should be evaluated for clinical significance. pressure control has been advocated in patients with renal disease
‡Based on the average of two or more readings taken at each of two or more visits
and hypertension, particularly in those patients with a urinary protein
after an initial screening. JNC—Joint National Committee.
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.
FIGURE 7-49
JNC VI DECISION ANALYSIS FOR TREATMENT Decision analysis for treatment based on the
Sixth Report of the Joint National Committee
on Detection, Evaluation, and Treatment of
Risk group B Risk Group C High Blood Pressure (JNC VI) [17].
Risk group A (at least 1 risk factor, (TOD/CCD and/or
Blood pressure stages (no risk factors, no not including diabetes; diabetes, with or with-
(mm Hg) TOD/CCD)* no TOD/ CCD) out other risk factors)†
High normal Lifestyle modification Lifestyle modification Drug therapy‡
(130–139/85–89)
Stage 1 Lifestyle modification Lifestyle modification Drug therapy
(140–159/90–99) (up to 12 months) (up to 6 months)
Stages 2 and 3 Drug therapy Drug therapy Drug therapy
(>160/≥100)
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.
FIGURE 7-50
CRITERIA FOR INITIAL DRUG THERAPY 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
Reduce peripheral vascular resistance either a diuretic or a -blocker be chosen as initial drug therapy,
No sodium retention based on numerous randomized controlled trials that show reduction
No compromise in regional blood flow
in morbidity and mortality with these agents [17]. Not all authorities
agree with this recommendation.
No stimulation of the renin-angiotensin-aldosterone system
In selecting an initial drug therapy to treat a hypertensive patient,
Favorable profile with concomitant diseases
several criteria should be met [6,9]. The drug should decrease
Once a day dosing
peripheral resistance, the pathophysiologic hallmark of all hypertensive
Favorable adverse effect profile
diseases. It should not produce sodium retention with attendant
Cost effective (low direct and indirect cost)
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 drug’s 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.
CANDIDATES FOR INITIAL DRUG THERAPY OF MILD TO MODERATE HYPERTENSIVE DISEASE
1-adrenergic Angiotensin II type I 1-adrenergic Thiazide-type

ACE inhibitors antagonists receptor antagonists antagonists Calcium antagonists diuretics
Peripheral vascular resistance Decrease Decrease Decrease Decrease Decrease Decrease
Sodium homeostasis
Urinary sodium excretion Increase/no change May decrease Increase/no change No change Increase/no change Increase
Extracellular fluid volume No change May increase No change No change No change Decrease
Pseudotolerance No No No No No No
Target organ function
Heart rate, cardiac output No change May increase No change Decrease Class specific No change
Cerebral function Preserve Preserve Preserve Preserve Preserve Preserve
Renal function (GFR) No change/increase No change No change No change/decrease No change/increase No change
Renin-angiotensin-aldosterone
Plasma renin activity Increase No change Increase Decrease No change Increase
Plasma angiotensin II Decrease No change Increase Decrease No change Increase
Plasma aldosterone Decrease/no change No change Decrease/no change Decrease/no change No change Increase
Concurrent disease efficacy
Coronary disease No effect No effect No effect Benefit Benefit No effect
Peripheral vascular disease No effect No effect No effect May aggravate May benefit No effect
Obstructive airway disease No effect No effect No effect May aggravate No effect No effect
Diabetes mellitus May benefit No effect May benefit May aggravate No effect May aggravate
Dyslipidemia No effect Benefit No effect May aggravate No effect Aggravate
Systolic dysfunction Benefit No effect Benefit May aggravate No effect Benefit
FIGURE 7-51
Options for monotherapy. Given the drugs that we have and their 6) thiazide-type diuretics [6,9,15]. All these drugs, given as monotherapy,
pharmacologic profiles, what are the best classes for initial drug therapy? are effective in lowering blood pressure in 50% to 60% of patients
Alphabetically, they include 1) angiotensin-converting enzyme (ACE) with mild to moderate hypertension. 1-adrenergic antagonists, ACE
inhibitors, 2) 1-adrenergic antagonists, 3) angiotensin II type I receptor inhibitors, and angiotensin II receptor antagonists are less efficacious
antagonists, 4) 1-adrenergic antagonists, 5) calcium antagonists, and in blacks than in whites.
FIGURE 7-52
Options for subsequent antihypertensive therapy
Options for subsequent antihypertensive
therapy. The majority of patients with mild
Not at goal blood pressure (<140/<90 mm Hg); to moderate hypertension can be controlled
lower goal in patients with diabetes mellitus or renal disease 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
No response or troublesome side effects Inadequate response but well tolerated
drug therapy may be considered: 1) increase
the dose of the initial drug, 2) discontinue
the initial drug and substitute a drug from
Add a second agent from a different class
Sustitute another drug from a different class (diuretic if not already used) 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
Not a goal blood pressure Treatment of High Blood Pressure (JNC VI)
are provided [17].
Continue adding agents from other classes

Consider referral to a hypertension specialist
FIGURE 7-53
COMBINATION THERAPIES Combination therapies. If a second drug is required, the addition of a low-dose thiazide-
type 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
Mild to moderate (stage 1 or 2) hypertension 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
Addition of low-dose thiazide-type diuretic to: control mild to moderate (JNC VI stage 1 or 2) hypertension. More severe (JNC VI stage 3)
ACE inhibitor cases of hypertension that are unresponsive to this therapeutic strategy may respond either
1-adrenergic antagonist to a variety of combination therapies given together as separate formulations or to classic
1-adrenergic antagonist triple-drug therapy (ie, diuretic, -adrenergic antagonist, and direct-acting vasodilator) [6,9].
Angiotensin III receptor antagonist ACE—angiotensin-converting enzyme; JNC—Joint National Committee.
Severe (Stage 3) hypertension
Classic triple drug therapy
Diuretic
1-adrenergic antagonist
Direct-acting vasodilator
ACE inhibitor plus calcium antagonist
1-adrenergic antagonist plus 1-adrenergic antagonist
1-adrenergic antagonist plus dihydropyridine
calcium antagonist
FIGURE 7-54
JNC VI LIFE STYLE MODIFICATIONS 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.
Lose weight if overweight Cessation of therapy in patients who were correctly diagnosed as
Limit alcohol intake to no more than 1 oz (30 mL) ethanol (eg, 24 oz [720 mL] beer, hypertensive is usually (but not always) followed by a return of
10 oz [300 mL] wine, or 2 oz [60 mL] 100-proof whiskey) per day or 0.5 oz (15 mL) blood pressure to pretreatment levels. After blood pressure has
ethanol per day for women and lighter weight people been controlled for 1 year and at least four visits, however, attempts
Increase aerobic physical activity (30 to 45 minutes most days of the week) should be made to reduce antihypertensive drug therapy “in a
Reduce sodium intake to no more than 100 mmol/d deliberate, slow, and progressive manner;” such “step-down therapy”
(2.4 g sodium or 6 g sodium chloride) may be successful in patients following lifestyle modification [17].
Maintain adequate intake of dietary potassium (approximately 90 mmol/d) Patients for whom drug therapy has been reduced or discontinued
Maintain adequate intake of dietary calcium and magnesium for general health should have regular follow-up, since blood pressure may increase
Stop smoking and reduce intake of dietary saturated fat and cholesterol for again to hypertensive levels. JNC—Joint National Committee.
overall cardiovascular health
FIGURE 7-55
CAUSES OF RESISTANT HYPERTENSION Resistant hypertension. Causes of failure to achieve or sustain control
of blood pressure with drug therapy are listed [6,9].
Patient’s failure to adhere to drug therapy

Physician’s 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, Cushing’s syndrome)
Coarctation of the aorta
Hormonal disturbances (eg, thyroid, parathyroid, growth hormone, serotonin)
Neurologic syndromes (eg, Guillain-Barré syndrome, porphyria, sleep apnea)
Physician’s failure to recognize an adverse drug–drug interaction
See Physician’s Desk Reference
Physician’s 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
FIGURE 7-56
DIURETIC RESISTANCE Diuretic resistance. Diuretic resistance may
result from patient noncompliance, impaired
bioavailability in an edematous syndrome,
Problem Mechanism Solution impaired diuretic secretion by the proximal
tubule, protein binding in the tubule lumen
Limits active transport of diuretics Reduced renal blood flow Use of large doses of a diuretic and (eg, nephrotic syndrome), reduced glomerular
into proximal tubular fluid, reducing appropriate dosing interval to achieve filtration rate, or enhanced sodium chloride
inhibitory effect at a more distal a therapeutic tubular drug concentration
intraluminal membrane site
reabsorption [7,8]. Resultant fluid retention
will attenuate the effectiveness of most anti-
Limits absolute amount of sodium Reduced glomerular filtration rate Use loop diuretics with steep dose
filtered response curve and/or block multiple hypertensive drugs. Renal mechanisms,
sites of sodium reabsorption: loop problems, and solutions are provided in this
diuretic with thiazide-like diuretic table [6,8,9].
Sodium recaptured at late distal Secondary hyperaldosteronism Addition of a potassium-sparing diuretic
tubule and collecting duct to above, to maintain urine
sodium/potassium ratio > 1
References
1. Kaplan NM: Clinical Hypertension, edn 6. Baltimore: Williams & 11. Van Zwieten PA: Antihypertensive drug interacting with -and -adreno-
Wilkins; 1994:50. ceptors: a review of basic pharmacology. Drugs 1988, 35(suppl 6):6–19.
2. Kawasaki T, Delea CS, Bartter FC, Smith H: The effect of high-sodium 12. Graham RM, Thornell IR, Gain JM, et al.: Prazosin: the first dose
and low-sodium intakes on blood pressure and other related variables phenomenon. Br Med J 1976, 2:1293–1294.
in human subjects with idiopathic hypertension. Am J Med 1978, 13. Koch-Weser J: Vasodilation drugs in the treatment of hypertension.
64:193–198. Arch Intern Med 1974, 133:1017–1025.
3. Guyton AC, Coleman TG, Yang DB, et al.: Salt balance and long-term 14. Entel SI, Entel EA, Clozel J-P: T-type Ca2+ channels and pharmacological
blood pressure control. Annu Rev Med 1980, 31:15–27. blockade: potential pathophysiological relevance. Cardiovasc Drugs
4. Julius S, Krause L, Schork NJ: Hyperkinetic borderline hypertension Ther 1997, 11:723—739.
in Tecumseh, Michigan. J Hypertens 1991, 9:77–84. 15. Bauer JH, Ream GP: The angiotensin II type 1 receptor antagonists.
5. Lund-Johansen P: Cetra haemodynamics in essential hypertension at Arch Intern Med 1995, 155:1361–1368.
rest and during exercise: a 20-year follow-up study. J Hypertens 1989, 16. Wenting GJ, Tan-Tjiong HL, Derkx FMH, et al.: Split renal function
7(suppl 6): 552–555. after captopril in unilateral renal artery stenosis. Br Med J 1974,
6. Bauer JH, Reams GP: Mechanisms of action, pharmacology, and use 288:886–890.
of antihypertensive drugs. In The Principles and Practice of Nephrology. 17. JNC VI: The Sixth Report of the Joint National Committee on
Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby; Detection, Evaluation, and Treatment of High Blood Pressure. Arch
1995:399–415. Intern Med 1993, 153:154–183.
7. Tarazi RC: Diuretic drugs: mechanisms of antihypertensive action. In 18. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control,
Hypertension: Mechanisms and Management. The 26th Hahnemann proteinuria, and the progression of renal disease. Ann Intern Med
Symposium. Edited by Oneti G, Kim KE, Moer JH. New York: Grune 1995, 123:754–762.
and Stratton; 1973:255.
19. Hebert LA, Kusek JW, Greene T, et al.: Effects of blood pressure con-
8. Ellison DH: The physiologic basis of diuretic synergism: its role in trol on progressive renal disease in blacks and whites. Hypertension
treating diuretic resistance. Ann Intern Med 1991, 114:886–894. 1997, 30 (part 1):428–435.
9. Bauer JH, Reams GP: Antihypertensive drugs. In The Kidney, edn 5.
Edited by Brenner BM. Philadelphia: W.B. Saunders Co.; 1995:
2331–2381.
10. Man in’t 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, 13:2455–2575.
Hypertensive Crises
Charles R. Nolan
M
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 patient’s 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 hyper-
tensive 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
FIGURE 8-1
HYPERTENSIVE CRISES Malignant hypertension is a clinical syndrome characterized by
marked elevation of blood pressure, with widespread acute arterio-
lar injury (hypertensive vasculopathy). Funduscopy reveals hyper-
Malignant hypertension tensive neuroretinopathy with flame-shaped hemorrhages, cotton-
(Hypertensive neuroretinopathy present) wool spots (soft exudates), and sometimes papilledema. Regardless
Benign (nonmalignant) hypertension with acute complications
of the severity of blood pressure elevation, malignant hypertension
cannot be diagnosed in the absence of hypertensive neuroretinopa-
(Acute organ system dysfunction without hypertensive neuroretinopathy)
thy. Thus, hypertensive neuroretinopathy is an extremely important
Hypertensive encephalopathy (also common in malignant hypertension)
clinical finding, indicating the presence of a hypertension-induced
Acute hypertensive heart failure (also common in malignant hypertension)
arteriolitis that may involve the kidneys, heart, and central nervous
Acute aortic dissection
system. In malignant hypertension, rapid and relentless progression
Central nervous system catastrophe
to end-stage renal disease occurs if effective blood pressure control
Intracerebral hemorrhage is not implemented. Mortality can result from acute hypertensive
Subarachnoid hemorrhage heart failure, intracerebral hemorrhage, hypertensive encephalopa-
Severe head trauma thy, or complications of uremia. Malignant hypertension represents
Acute myocardial infarction or unstable angina a hypertensive crisis given that adequate control of blood pressure
Active bleeding, including postoperative bleeding clearly prevents these morbid complications. Even in patients with
Uncontrolled hypertension in patients requiring surgery so-called benign (nonmalignant) hypertension, in which hyperten-
Severe postoperative hypertension sive neuroretinopathy is absent, a hypertensive crisis may occur based
Post–coronary artery bypass hypertension on the development of concomitant acute end-organ dysfunction.
Post–carotid endarterectomy hypertension Hypertensive crises caused by benign hypertension with acute
Catecholamine excess states complications include hypertension in the setting of hypertensive
Pheochromocytoma encephalopathy, acute hypertensive heart failure, acute aortic
Monoamine oxidase inhibitor–tyramine interactions dissection, intracerebral hemorrhage, subarachnoid hemorrhage,
Miscellaneous hypertensive crises severe head trauma, acute myocardial infarction or unstable angina,
Preeclampsia and eclampsia and active bleeding. Poorly controlled hypertension in patients
Scleroderma renal crisis requiring surgery increases the risk of intraoperative cerebral or
Autonomic hyperreflexia in quadriplegic patients myocardial ischemia and postoperative acute renal failure. Severe
postoperative hypertension, including post–coronary artery bypass
hypertension and post–carotid 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 8.3
FIGURE 8-2
HYPERTENSIVE SYNDROMES SOMETIMES Hypertensive syndromes sometimes misdiagnosed as hypertensive
MISDIAGNOSED AS HYPERTENSIVE CRISES 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
Severe uncomplicated hypertension as urgent hypertension) in which severe hypertension is not accom-
(Severe hypertension without hypertensive neuroretinopathy or acute end-organ panied by evidence of malignant hypertension or acute end-organ
dysfunction, formerly known as urgent hypertension) dysfunction, eventual complications due to stroke, myocardial
Benign hypertension with chronic end-organ complications infarction, or congestive heart failure tend to occur over months to
Chronic renal insufficiency from primary renal parenchymal disease years, rather than hours to days. Long-term control of blood pressure
Chronic congestive heart failure from systolic or diastolic dysfunction can prevent these eventual complications. However, a hypertensive
Atherosclerotic coronary vascular disease (previous myocardial infarction, stable angina)
crisis cannot be diagnosed because no evidence exists that acute
reduction of blood pressure results in improvement in short- or
Cerebrovascular disease (history of transient ischemic attack or cerebrovascular accident)
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 end-
organ function in each of these conditions. However, no evidence
exists that rapid control of blood pressure is necessary to prevent fur-
ther complications. Therefore, a true hypertensive crisis does not exist.
in thickening and remodeling of arteriolar

walls that may be an adaptive mechanism
Pathophysiology of malignant hypertension
to prevent vascular damage from the
mechanical stress of hypertension. However,
Essential Renal parenchymal disease when the blood pressure increases suddenly
Severe
hypertension Renal artery stenosis or increases to a critical level, these adaptive
hypertension Endocrine hypertension mechanisms may be overwhelmed, resulting
in vascular damage. As a result of the
Spontaneous Critical level or mechanical stress of increased transmural
natriuresis Rate of increase pressure, focal segments of the arteriolar
vasculature become dilated, producing a
Volume sausage-string pattern. Endothelial perme-
Forced vasodilation
depletion (sausage-string) ability increases in the dilated segments,
leading to extravasation of fibrinogen, fibrin
Decreased prostacyclin deposition in the media, and necrosis of
↑ Catecholamines Oral contraceptives
smooth muscle cells (fibrinoid necrosis).
↑ Vasopressin Vascular damage Cigarette smoking
↑ Renin/Angiotensin II Platelet adherence to damaged endothelium
with release of platelet-derived growth factor
induces migration of smooth muscle cells to
↑ Endothelial permeability
the intima where they proliferate (neointimal
Denudation of epithelium
proliferation) and produce mucopolysac-
Localized charide. These cells also produce collagen,
Platelet adherence Extravasation intravascular resulting in proliferative endarteritis,
PDGF release Fibrinogen coagulation musculomucoid hyperplasia, and eventually,
fibrotic obliteration of the vessel lumen.
Low potassium Smooth muscle Fibrin deposition Occlusion of arterioles leads to accelerated
Lumen glomerular obsolescence and end-stage
diet proliferation Arteriolar wall
renal disease. Other factors may synergize
with hypertension to damage the arterial
Deposition of Necrosis of
mucopolysaccharide smooth muscle vasculature. Renal ischemia leads to activa-
tion of the renin-angiotensin system that can
cause further elevation of blood pressure and
Renal Musculomucoid intimal Fibrinoid
ischemia progressive vascular damage. Spontaneous
hyperplasia necrosis
natriuresis early in the course of malignant
hypertension leads to volume depletion with
Narrowing of vascular lumen activation of the renin-angiotensin system or
catecholamines that further elevates blood
pressure. It also is possible that angiotensin
Renal ischemia II may be directly vasculotoxic. Activation
of the clotting cascade within the lumen of
damaged vessels may lead to fibrin deposition
Accelerated glomerular Tubular Interstitial with localized intravascular coagulation.
obsolescence atrophy fibrosis 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
FIGURE 8-3 and thereby inhibiting repair of hypertension-
Pathophysiology of malignant hypertension. The vicious cycle of malignant hypertension induced vascular injury. Low dietary intake
is best demonstrated in the kidneys. This cycle also applies equally well to the vascular of potassium may help promote vascular
beds of the retina, pancreas, gastrointestinal tract, and brain [1]. In this scheme, severe smooth muscle proliferation and therefore
hypertension is central. Hypertension may be either essential or secondary to any one of a predisposes to the development of malig-
variety of causes. Because not all patients develop malignant hypertension despite equally nant hypertension in Blacks with severe
severe hypertension, the interaction between the level of blood pressure and the adaptive essential hypertension. PDGF—platelet-
capacity of the vasculature may be important. In this regard, chronic hypertension results derived growth factor.
FIGURE 8-4
Vascular lesions in malignant hypertension Distribution of vascular lesions in malignant
hypertension. Malignant hypertension is
essentially a systemic vasculopathy induced
Malignant hypertension
by severe hypertension. Fibrinoid necrosis and
proliferative endarteritis occur throughout the
body in numerous vascular beds, leading to
Fibrinoid necrosis Proliferative endarteritis ischemic changes. In the retina, striate hem-
orrhages and cotton-wool spots develop.
The finding of hypertensive neuroretinopathy
Occlusion of vessels is the clinical sine qua non of malignant
hypertension. Vascular lesions in the gastro-
intestinal tract (GI) can lead to hemorrhage
Ischemia 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
Retinal CNS Cardiac Renal GI Pancreatic autoregulation with cerebral overperfusion
Hemorrhages Intracerebral Left ventricular Glomerulosclerosis Hemorrhage Necrosis
Cotton-wool hemorrhage and edema (Fig. 8-22). Vascular lesions also
dysfunction Tubular atrophy Bowel necrosis Hemorrhage
spots Hypertensive Interstitial fibrosis can develop in the myocardium; however,
Papilledema encephalopathy acute hypertensive heart failure is largely the
result of acute diastolic dysfunction induced
by the marked increase in afterload that
accompanies malignant hypertension (Figs. 8-
24 and 8-25). CNS—central nervous system.
become apparent when a renal biopsy is performed. Recently,

immunoglobulin A (IgA) nephropathy has been reported as an
COMMON CAUSES OF MALIGNANT HYPERTENSION 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
Primary (essential) malignant hypertension* a result of underlying vesicoureteral reflux, is the most common cause
Secondary malignant hypertension of malignant hypertension [4]. In Australia, malignant hypertension
Primary renal disease complicates up to 7% of cases of analgesic nephropathy [5].
Chronic glomerulonephritis* Transient malignant hypertension responsive to volume expansion
Chronic pyelonephritis* has been reported in analgesic nephropathy. It has been suggested
Analgesic nephropathy* that interstitial disease with salt-wasting is important in the patho-
Immunoglobulin A nephropathy* genesis by causing profound volume depletion with activation of
Acute glomerulonephritis
the renin-angiotensin axis. Malignant hypertension is both an early
Radiation nephritis
and late complication of radiation nephritis that can occur up to
Renovascular hypertension*
Oral contraceptives
11 years after radiotherapy. Renovascular hypertension from either
Atheroembolic renal disease (cholesterol embolism) fibromuscular dysplasia or atherosclerosis is a well-recognized
Scleroderma renal crisis cause of malignant hypertension. In a series of 123 patients with
Antiphospholipid antibody syndromes malignant hypertension, renovascular hypertension was found in
Chronic lead poisoning 43% of Whites and 7% of Blacks [6]. Among women of childbearing
Endocrine hypertension age, oral contraceptives can cause malignant hypertension [7]. In
Aldosterone-producing adenoma (Conn’s syndrome) the absence of underlying renal disease, with discontinuation of the
Cushing’s syndrome drug, long-term prognosis is excellent. Severe hypertension that
Congenital adrenal hyperplasia may become malignant is a common complication of atheroembolic
Pheochromocytoma 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
*Most common causes of malignant hypertension. 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
FIGURE 8-5 phase. Even in the absence of hypertensive neuroretinopathy sug-
Malignant hypertension is not a single disease entity but, rather, a gesting malignant hypertension, the renal lesion in scleroderma
syndrome in which the hypertension can be either primary (essential) renal crisis is virtually indistinguishable from primary malignant
or secondary to any one of a number of different causes [2]. Among nephrosclerosis [8]. Patients with antiphospholipid antibody syn-
Black patients the underlying cause is almost always essential hyper- drome, either primary or secondary to systemic lupus erythematosus,
tension that has entered a malignant phase. The most common can develop malignant hypertension with renal insufficiency as
secondary causes of malignant hypertension are primary renal a result of thrombotic microangiopathy [9]. The endocrine causes
parenchymal disorders. Chronic glomerulonephritis is thought to of hypertension only rarely lead to malignant hypertension.
be the cause of malignant hypertension in up to 20% of cases. Unless Pheochromocytoma can cause hypertensive crises owing to hyper-
a history of an acute nephritic episode or long-standing hematuria or tensive encephalopathy or acute hypertensive heart failure in the
proteinuria is available, the underlying glomerulonephritis may only absence of hypertensive neuroretinopathy (malignant hypertension).
FIGURE 8-6
Tertiary hyperaldosteronism after treatment Tertiary hyperaldosteronism after treatment of malignant hyperten-
of malignant hypertension sion. The diagnosis of primary hyperaldosteronism must be made
with caution in patients with a history of malignant hypertension.
Malignant hypertension After successful treatment of malignant hypertension, plasma renin
Vascular
activity rapidly normalizes, whereas aldosterone secretion may
Antihypertensive
lesions heal treatment with remain elevated for up to a year. This phenomenon has been attrib-
Renal ischemia resolution of malignant uted to persistent adrenal hyperplasia induced by long-standing
hypertension hyperreninemia during the malignant phase [10]. During this phase
Activation
of renin- Renin levels of tertiary hyperaldosteronism, despite suppressed renin activity,
angiotensin decrease rapidly hypokalemia, metabolic alkalosis, and aldosterone levels that are
axis not suppressible, mimic primary hyperaldosteronism. Adrenal
imaging studies reveal bilateral nodular adrenal hyperplasia. With
Resolves slowly over
Bilateral adrenal hyperplasia 1 year after control continued long-term control of blood pressure this hyperaldostero-
of blood pressure nism remits spontaneously.
Nonsuppressible aldosteronism
Renal potassium-wasting
Metabolic alkalosis
with hypokalemia
hypertension (diagnostic of malignant hypertension) is quite differ-

ent from the clinical significance of a hard exudate in the fundus of
RENAL CHANGES IN HYPERTENSION
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
Retinal arteriosclerosis and arteriosclerotic retinopathy (benign hypertension) this reason, the Keith and Wagener classification has been sup-
Focal or diffuse arteriolar narrowing
planted by the more clinically useful classification of hypertensive
Arteriovenous crossing changes
Broadening of the light reflex
retinopathy shown here. This classification system draws a distinc-
Copper or silver wiring tion between retinal arteriosclerosis with arteriosclerotic retinopa-
Perivasculitis (parallel white lines around the arteries) thy, which is characteristic of benign hypertension, and hyperten-
Solitary round hemorrhages sive neuroretinopathy, which defines the existence of malignant
Hard exudates hypertension [12,13]. Retinal arteriosclerosis, which is character-
Central or branch venous occlusion ized histologically by the accumulation of hyaline material in arte-
Hypertensive neuroretinopathy (malignant hypertension) rioles, occurs in elderly normotensive persons or in the setting of
Generalized arteriolar narrowing long-standing benign hypertension. Funduscopic findings reflecting
Striate (flame-shaped) hemorrhage* retinal arteriosclerosis include arteriolar narrowing, arteriovenous
Cotton-wool spots* crossing changes, perivasculitis, and changes in the light reflex with
Papilledema* copper or silver wiring. Arteriosclerotic retinopathy manifests as
Star figure at the macula solitary round hemorrhages in the periphery of the fundus and
hard exudates. The finding of retinal arteriosclerosis is of no prog-
*Features that distinguish hypertensive neuroretinopathy from retinal arteriosclerosis. nostic significance with regard to the risk of coronary atherosclero-
sis or cerebrovascular disease. The arteries visualized with the oph-
thalmoscope are technically arterioles with a diameter of 0.1 mm.
FIGURE 8-7 Hyaline arteriolosclerosis of the retinal vessels is a process entirely
Funduscopic findings are pivotal in the diagnosis of malignant distinct from the atherosclerotic process that affects larger muscu-
hypertension. Keith and Wagener [11] graded retinal findings in lar arteries. Thus, the finding of retinal arteriosclerosis cannot pre-
hypertensive patients as follows: grade I, arteriolar narrowing; dict the presence of atherosclerosis of the coronary or cerebral ves-
grade II, arteriovenous crossing changes; grade III, hemorrhages sels. This lack of clinical significance of retinal arteriosclerosis in
and exudates; grade IV, the changes in grade III plus papilledema. hypertensive patients contrasts dramatically with the importance
Although this classification of hypertensive retinopathy is of great and prognostic significance of the finding of hypertensive neu-
historical importance, its clinical utility has several limitations, eg, roretinopathy. This finding is the clinical sine qua non of malignant
it is extremely difficult to quantify arteriolar narrowing. In this hypertension. The appearance of striate hemorrhages or cotton-
regard, a tendency exists for significant observer bias such that wool spots with or without papilledema closely parallels the devel-
patients with mild hypertension and questionable narrowing are opment of fibrinoid necrosis and proliferative endarteritis in the
invariably assigned to grade I. More importantly, this classification kidney and other organs. Thus, the presence of hypertensive neu-
does not distinguish the retinal changes of benign and malignant roretinopathy predicts the development of end-stage renal disease,
hypertension. For example, the clinical significance of a cotton- or other life-threatening hypertensive complications, within a year
wool spot appearing in the fundus of a young man with severe if adequate control of the blood pressure is not achieved.

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.

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 hyper-
tension-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 find-
ings 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 cot-
ton-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 vascu-
lopathy–induced 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.
FIGURE 8-14
1–0 Prognosis in accelerated hypertension versus malignant hypertension.
No papilledema In the original Keith and Wagener [11] classification of hypertensive
Papilledema 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
0–8 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
Estimated survival
present. In this regard, the World Health Organization has recom-

mended that accelerated hypertension and malignant hypertension be
0–6 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
0–4
serum creatinine concentration, and initial and achieved blood
pressure, the presence of papilledema did not influence prognosis.
96 74 45 26 14 No. with papilledema (From McGregor [14] et al.; with permission.)
43 28 16 10 6 No. without papilledema
0
0 2 4 6 8 10
Years

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 frag-
mented 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 coag-
ulation 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.)
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
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
FIGURE 8-16 (see Color Plate) albuminuria to end-stage renal disease (ESRD) indistinguishable
Micrograph of proliferative endarteritis in malignant hypertension from that seen in primary renal parenchymal disease. In patients
(musculomucoid intimal hyperplasia). In malignant nephrosclerosis, initially exhibiting preserved renal function, in the absence of adequate
the interlobular (cortical radial) arteries reveal characteristic lesions. blood pressure control, it is common to observe subacute deterio-
These lesions are variously referred to as proliferative endarteritis, ration of renal function to ESRD over a period of weeks to months.
endarteritis fibrosa, musculomucoid intimal hyperplasia, or the Transient deterioration of renal function with initial control of
onionskin lesion. The typical finding is marked thickening of the blood pressure is a well-documented entity in patients initially
intima that obstructs the vessel lumen. In severely affected vessels exhibiting mild to moderate renal impairment. Occasionally,
the luminal diameter may be reduced to the caliber of a single ery- patients with malignant hypertension initially exhibit oliguric acute
throcyte. Occasionally, complete obliteration of the lumen by a renal failure, necessitating initiation of dialysis within a few days of
superimposed fibrin thrombus occurs. hospitalization. Because erythrocyte casts sometimes appear in the
Traditionally, three patterns of intimal thickening have been urine sediment, malignant nephrosclerosis initially may be misdiag-
described [15]. (1) The onionskin pattern consists of pale layers of nosed as a rapidly progressive glomerulonephritis or systemic vasculitis
elongated concentrically arranged myointimal cells along with deli- [18]. Careful examination of the fundus for evidence of hypertensive
cate connective tissue fibrils that give rise to a lamellar appearance. neuroretinopathy confirms the diagnosis of malignant hypertension.
The media often appears as an attenuated layer stretched around Patients with malignant hypertension can also present with estab-
the expanded intima. (2) In the mucinous pattern, intimal cells are lished renal failure. Often, it is impossible to determine clinically
sparse. Seen is an abundance of lucent, faintly basophilic-staining whether a patient initially exhibiting hypertensive neuroretinopathy
amorphous material. (3) In fibrous intimal thickening, seen are few and renal failure has primary malignant hypertension or secondary
cells with an abundance of hyaline deposits, reduplicated bands of malignant hypertension with underlying primary renal parenchymal
elastica, and coarse layers of collagen. The renal histology in Blacks disease. The presence of normal-sized kidneys on ultrasonography
with malignant hypertension demonstrates a characteristic finding supports a diagnosis of primary malignant nephrosclerosis that
in the larger arterioles and interlobular arteries known as musculo- potentially is reversible with long-term blood pressure control.
mucoid intimal hyperplasia, with an abundance of cells and a small However, a renal biopsy may be required for definitive diagnosis.
amount of myxoid material (that is light blue in color on hema- All patients with malignant hypertension should receive aggressive
toxylin and eosin staining) between the cells [16, 17]. These various antihypertensive therapy to prevent further renal damage, regardless
intimal findings may represent progression over time from an ini- of the degree of renal impairment. Control of blood pressure in
tially cellular lesion to fibrosis of the intima. Electron microscopy patients with malignant hypertension and renal insufficiency often
demonstrates that in each type of intimal thickening the most abun- causes further deterioration of renal function, especially when the
dant cellular element is a modified smooth muscle cell. This cell is initial glomerular filtration rate (GFR) is less than 20 mL/min.
called a myointimal cell. Proliferative endarteritis is thought to However, a fall in GFR is not a contraindication to intensive blood
occur as a result of phenotypic modulation of medial smooth mus- pressure control aimed at normalization of blood pressure. Control
cle cells that dedifferentiate from the normal contractile phenotype of hypertension protects other vital organs, such as the heart and
to acquire a more embryologic proliferative-secretory phenotype. It brain, whose function cannot be replaced. Moreover, with rigid
has been proposed that the endothelial injury in malignant hyper- blood pressure control, renal function may eventually recover over
tension results in attachment of platelets with release of platelet- the ensuing months, even in patients with apparent ESRD owing to
derived growth factor (PDGF) that may induce the phenotypic primary malignant nephrosclerosis [19,20].
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 extracellu-
lar matrix proteins, resulting in proliferative endarteritis, musculo-
mucoid hyperplasia, and ultimately fibrous intimal thickening.
(Hematoxylin and eosin stain, original magnification 100.)

Micrograph of hyaline arteriolar nephrosclerosis in benign hyper-
tension. It is important to draw a clear distinction between malig-
nant 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 arteriosclero-
sis there is expansion of the intima of afferent arterioles with hya-
line material that stains a pale-pink color on periodic acid–Schiff
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 thin-
ning 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 dis-
ease or superimposed malignant hypertension, despite well-estab-
lished 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 hypotheti-
cal patients with ESRD and hypertension in which the race is arbi-
trarily 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
acid–Schiff stain, original magnification 100.)
FIGURE 8-19
INDICATIONS FOR PARENTERAL THERAPY Malignant hypertension must be treated expeditiously to prevent
IN MALIGNANT HYPERTENSION 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 par-
Hypertensive encephalopathy enteral agents. Listed are the settings in which parenteral antihy-
Rapidly failing vision pertensive therapy is mandatory in the initial management of
Pulmonary edema
malignant hypertension. Parenteral therapy generally should be
used in patients with evidence of acute end-organ dysfunction or
Intracerebral hemorrhage
those unable to tolerate oral medications. Nitroprusside is the
Rapid deterioration of renal function
treatment of choice for patients requiring parenteral therapy.
Acute pancreatitis
Diazoxide, employed in minibolus fashion to avoid sustained over-
Gastrointestinal hemorrhage or acute abdomen from mesenteric vasculitis
shoot hypotension, may be advantageous in patients for whom
Patients unable to tolerate oral therapy because of intractable vomiting
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 patient’s 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 patient’s 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.
FIGURE 8-20
Role of diuretics to treat malignant hypertension 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
Malignant hypertension with potent vasodilator therapy during the initial phase of manage-
ment of malignant hypertension. However, evidence now exists to
suggest that parenteral diuretic therapy during the acute management
Abrupt increase in blood pressure phase actually may be deleterious. In experimental animals, sponta-
neous natriuresis appears to be the initiating event in the transition
Pressure-induced natriuresis and diuresis 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,
Vicious
Intravascular volume depletion
circle
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
Activation of the renin-angiotensin axis [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
Angiotensin II–mediated vasoconstriction
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 hyper-
tensive 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.
FIGURE 8-21
Pathogenesis and treatment of hypertensive encephalopathy Pathogenesis and treatment of hypertensive encephalopathy.
Hypertensive encephalopathy is a hypertensive crisis in which acute
Malignant hypertension Sudden or severe nonmalignant cerebral dysfunction is attributed to sudden or severe elevation of
(hypertensive neuroretinopathy hypertension blood pressure [25–27]. Hypertensive encephalopathy is one of the
present) (hypertensive neuroretinopathy absent) most serious complications of malignant hypertension. However,
malignant hypertension (hypertensive neuroretinopathy) need not
be present for hypertensive encephalopathy to develop. Hypertensive
Sudden onset or severe hypertension 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
Failure of autoregulation of cerebral blood flow
(breakthrough of autoregulation)
postinfectious glomerulonephritis, catecholamine excess states, or
eclampsia. Under normal circumstances, autoregulation of the cerebral
microcirculation occurs, and therefore, cerebral blood flow remains
Forced vasodilation of cerebral arterioles constant over a wide range of perfusion pressures. However, in the
setting of sudden severe hypertension, autoregulatory vasoconstric-
tion fails and there is forced vasodilation of cerebral arterioles with
Endothelial damage Cerebral hyperperfusion endothelial damage, extravasation of plasma proteins, and cerebral
(increased permeability to (increased capillary hyperperfusion with the development of cerebral edema. This
plasma proteins) hydrostatic pressure) 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
Cerebral edema 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
Hypertensive encephalopathy
occurs at much lower blood pressure in previously normotensive
(headache, vomiting, altered mental status, seizures)
persons than it does in those with chronic hypertension. Clinical
features of hypertensive encephalopathy include severe headache,
Prompt blood pressure reduction with nitroprusside 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, convul-
sions, and death can occur within hours. The sine qua non of
New or progressive focal findings Dramatic clincal improvement hypertensive encephalopathy is the prompt and dramatic clinical
(suspect primary central nervous (diagnostic of hypertensive improvement in response to antihypertensive drug therapy. When a
system process) encephalopathy) diagnosis of hypertensive encephalopathy seems likely, antihyper-
tensive 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 dysfunc-
tion, 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 patient’s 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.
FIGURE 8-22
CAUSES OF HYPERTENSIVE ENCEPHALOPATHY Hypertensive encephalopathy can complicate malignant hyperten-
sion of any cause. However, not all patients with hypertensive
encephalopathy have hypertensive neuroretinopathy, indicating the
Malignant hypertension of any cause presence of malignant hypertension. In fact, hypertensive
Acute glomerulonephritis, especially postinfectious encephalopathy most commonly occurs in previously normotensive
Eclampsia
persons who experience a sudden onset or worsening of hyperten-
sion. In acute postinfectious glomerulonephritis, the abrupt onset
Catecholamine-induced hypertensive crises
of even moderate hypertension may cause breakthrough of
Pheochromocytoma
autoregulation of cerebral blood flow, resulting in hypertensive
Monoamine oxidase inhibitor–tyramine interactions
encephalopathy. Eclampsia can be viewed as a variant of hyperten-
Abrupt withdrawal of centrally acting 2-agonists
sive encephalopathy that complicates preeclampsia. Moreover,
Phenylpropanolamine overdose
hypertensive encephalopathy is a common complication of cate-
Cocaine-hydrochloride or alkaloid (crack cocaine) intoxication cholamine-induced hypertensive crises such as pheochromocytoma,
Phencyclidine (PCP) poisoning monoamine oxidase inhibitor–tyramine interactions, clonidine
Acute lead poisoning in children withdrawal, phencyclidine (PCP) poisoning, and phenyl-
High-dose cyclosporine for bone marrow transplantation in children propanolamine overdose. Cocaine use also can induce a sudden
Femoral lengthening procedures increase in blood pressure accompanied by hypertensive
Scorpion envenomation in children encephalopathy. In children, acute lead poisoning, high-dose
Acute renal artery occlusion from thrombosis or embolism cyclosporine for bone marrow transplantation, femoral lengthening
Atheroembolic renal disease (cholesterol embolization) procedures, and scorpion envenomation may be accompanied by
Recombinant erythropoietin therapy the sudden onset of hypertension with hypertensive encephalopa-
Transplantation renal artery stenosis thy. Acute renal artery occlusion resulting from thrombosis or renal
Acute renal allograft rejection embolism can induce hypertensive encephalopathy. Likewise,
Paroxysmal hypertension in acute or chronic spinal cord injuries atheroembolic renal disease (cholesterol embolization) can cause a
Post–coronary artery bypass or post–carotid endarterectomy hypertension 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 hyper-
tension 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 com-
plicate the rebound hypertension that follows coronary artery
bypass procedures or carotid endarterectomy.
MAP, mm Hg Heart rate, beats/min Cardiac index, L/min/m2 AHHF

200 NF
pressure, mm Hg
200 120 5.0
Mean arterial
150 B B
90
100 NP
100 60 2.5 NP
50
30 0
AHHF NF
0 0 0 P<0.005 P<0.005
NS NS NS
Stroke work index, g m/m2 LVEDP, mm Hg LVEDV, mL/m2
Cardiac output, L/min

40 B
150 60 200
LVEDP, mm Hg
9 30
45 NP
6 NP 20
B B NP
75 30 100 10
3 B NP
15 0 0
0 0 0 P<0.005 NS P<0.005 P<0.025
NS P<0.005 NS
Hemodynamic parameters at baseline (B) and during nitroprusside (NP) infusion
A Baseline hemodynamics in acute hypertensive heart failure (AHHF) vs no failure (NF) B
in both groups had electrocardiographic evidence of LV hypertrophy

60
AHHF: baseline caused by long-standing hypertension.
AHHF: with nitroprusside A, Baseline hemodynamic measurements before treatment
No failure: baseline
50 No failure: with nitroprusside 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
40 LV end-diastolic volume (LVEDV) was similar in both groups. In
LVFP, mm Hg
fact, the only hemodynamic difference between the groups was a

significant elevation of LV filling pressure (LVFP) (pulmonary capil-
30
lary wedge pressure) in the group with pulmonary edema. In acute
hypertensive heart failure the finding of elevated LV end-diastolic
20 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
10 LVEDV, can only be explained by a decrease in LV compliance in
patients with acute hypertensive heart failure. B, The importance
0 of an acute decrease in LV compliance in the pathogenesis of acute
40 80 120 160 200 240 hypertensive heart failure (AHHF) was confirmed in these patients
LVEDV, mL/m2 by the hemodynamic response to vasodilator therapy. Sodium
C Left ventricular compliance at baseline and with nitroprusside 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 pres-
FIGURE 8-23 sure during nitroprusside therapy in patients with AHHF was not
Pathogenesis of acute hypertensive heart failure. Both malignant caused by venodilation with decreased venous return because the
hypertension and severe benign hypertension can be complicated by LVEDV actually increased during nitroprusside infusion. Thus, the
acute pulmonary edema caused by isolated diastolic dysfunction. In response to sodium nitroprusside therapy was mediated through a
acute hypertensive heart failure the compromise of left ventricular (LV) decrease in systemic vascular resistance that led to an immediate
diastolic function occurs as a result of a decrease in LV compliance improvement in LV compliance and reduction in wedge pressure
caused by an increased workload imposed on the heart by the marked despite an increase in LVEDV. These findings suggest that the prox-
elevation in systemic vascular resistance. Illustrated are the hemody- imate cause of AHHF is an elevation of the systemic vascular resis-
namic derangements in acute hypertensive heart failure in a study that tance that precipitates acute diastolic dysfunction (decreased LV
compared five patients with severe essential hypertension complicated compliance) with elevated pulmonary capillary wedge pressure,
by acute pulmonary edema with a control group of five patients with resulting in pulmonary edema. NS— not significant. (Adapted from
equally severe hypertension but no pulmonary edema [28]. Patients Cohn and coworkers [28]; with permission.)
FIGURE 8-24
Treatment of acute hypertensive heart failure. The left ventricular
60
(LV) end-diastolic pressure-volume relationships (compliance
curves) in acute hypertensive heart failure (AHHF) before and after
50 treatment with sodium nitroprusside are represented schematically.
Left ventricular end-diastolic
In AHHF, the pressure-volume curve is shifted up and to the left,

pressure, mm Hg
40 reflecting an acute decrease in LV compliance caused by severe

Nitroprusside systemic hypertension. In this setting, a higher than normal LV
30 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
20
HF
at the expense of a very high wedge pressure that results in acute
AH
al
rm pulmonary edema. Treatment with sodium nitroprusside causes
10 No
a reduction in the elevated systemic vascular resistance, with a
concomitant decrease in impedance to LV ejection. As a result, LV
0 compliance improves. Pulmonary edema resolves owing to a reduc-
40 80 120 160 200 240 tion in LVEDP, despite the fact that LVEDV actually increases dur-
Left ventricular end-diastolic volume, mL/m2 ing treatment. Sodium nitroprusside is the preferred drug for treat-
ment of AHHF. There is no absolute blood pressure goal. The infu-
sion should be titrated until signs and symptoms of pulmonary
edema resolve or the blood pressure decreases to hypotensive lev-
els. 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 symp-
toms 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 pres-
sure may require therapy with more than one drug. Potent direct-
acting 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.
FIGURE 8-25
Aortic dissection
Aortic dissection. Classification of aortic dissection is based on the
presence or absence of involvement of the ascending aorta [29].
Transverse
aortic arch Descending The dissection is defined as proximal if there is involvement of the
aorta ascending aorta. The primary intimal tear in proximal dissection
may arise in the ascending aorta, transverse aortic arch, or descending
Ascending aorta. In distal dissections, the process is confined to the descending
aorta
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 aorta–hemopericardium
Proximal Distal with tamponade, aortic arch–mediastinum, descending thoracic
(Type A) (Type B) aorta–left 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, sur-
gical 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.)
is imperative [32]. Even though the blood pressure in patients with

Poorly controlled hypertension in surgical patients 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
Postpone elective surgery until Inadequate preoperative
blood pressure control as hypovolemia, electrolyte abnormalities, and marked intraoperative
blood pressure adequately
controlled for 2–3 weeks (diastolic blood pressure >110 mm Hg blood pressure lability. General anesthesia is accompanied by a 30%
or mild to moderate hypertension decrease in cardiac output. In normotensive persons and patients
in patients with history of
cerebrovascular accident, with adequately treated hypertension, anesthesia is not associated
Administer blood pressure and myocardial ischemia, heart with a decrease in systemic vascular resistance. Therefore, the
antianginal medications the failure, or renal insufficiency decrease in mean arterial pressure (MAP) is modest (25–30%).
morning of surgery General However, in patients with inadequate preoperative blood pressure
anesthesia control, anesthesia is associated with a concomitant decrease in
Decreased cardiac output (30%)
systemic vascular resistance (SVR) of approximately 27%. The
Manage intraoperative Decreased systemic vascular
hypertension with resistance (27%) combined decrease in cardiac output and SVR leads to a profound
sodium nitroprusside decrease in MAP (45%) during anesthesia [33]. This intraoperative
hypotension predisposes to myocardial ischemia, cerebrovascular
Hypotension
(45% Decrease in mean accidents, and acute renal failure. Therefore, in patients with diastolic
Manage postoperative blood pressure over 110 mm Hg or these other high-risk groups,
arterial pressure)
hypertension with nitroprusside
in patients with complications elective surgery should be postponed and blood pressure brought
or labetalol in patients under control for a few weeks before surgery, if possible. Ideally,
Increased risks of
without complications Cerebral ischemia sustained adequate preoperative blood pressure control should be
Myocardial ischemia the goal in all hypertensive patients [34]. In patients with adequately
Acute renal failure treated hypertension, oral antihypertensive, and antianginal med-
Carefully institute oral ications should be continued up to and including the morning of
antihypertensives at low-dose
and titrate based on orthostatic surgery, administered with small sips of water. Because hypovolemia
Increased perioperative morbidity
blood pressure measurements and mortality 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
FIGURE 8-26 overload. Adequate potassium repletion should be given to correct
hypokalemia well in advance of surgery. Continuation of -blockers
Poorly controlled hypertension in the patient requiring surgery.
Hypertension in the preoperative patient is a common problem. to within a few hours of surgery does not impair cardiac function
Poor control of preoperative hypertension, with a diastolic blood and has been shown to decrease the risks of dysrhythmia and
pressure higher than 110 mm Hg, is a relative contraindication to myocardial ischemia during surgery. In patients with complications
elective surgery. In such patients, perioperative morbidity and mor- and a history of cardiovascular disease or heart failure, or after
tality are increased because of a higher incidence of intraoperative coronary artery bypass surgery, postoperative hypertension should
hypotension accompanied by myocardial ischemia and a heightened be managed with short-acting agents such as nitroglycerin or
risk of acute renal failure [31]. Malignant hypertension clearly nitroprusside. In patients without complications, intermittent
represents an excessive surgical risk and all but lifesaving emergency intravenous infusions of labetalol may be useful for management
surgery should be deferred until the blood pressure can be controlled of mild to moderate postoperative hypertension until the preoperative
and organ function stabilized. Mild to moderate uncomplicated oral antihypertensive agents can be resumed. Many patients with
hypertension with diastolic blood pressure less than 110 mm Hg long-standing hypertension, even if severe, require much smaller
does not appear to increase the risk of surgery significantly and doses of antihypertensive medications in the early postoperative
therefore is not an absolute indication to postpone elective surgery. course. Thus, the preoperative regimen should not be restarted
However, patients with mild to moderate hypertension and preexist- automatically. Measurement of orthostatic blood pressures should
ing complications such as ischemic heart disease, cerebrovascular be used as a guide to dosage adjustment during the postoperative
disease, congestive heart failure, or chronic renal insufficiency, recovery period. In most instances, the need for antihypertensive
represent a subgroup with significantly increased perioperative risk. medications will gradually increase over a few days to weeks to
In these patients, adequate preoperative control of blood pressure eventually equal the preoperative requirement.
may develop precipitous hypotension with

Hypertensive crises after bypass surgery even low-dose infusions of nitroglycerin or
nitroprusside. Hypertension in this setting
should be treated using careful volume
Coronary artery bypass expansion with crystalloid solutions or
graft surgery blood if required. Post–coronary artery
Paradoxical hypertensive response Increased sympathetic tone owing to bypass hypertension represents a hypertensive
to intravascular volume depletion activation or pressor reflexes from heart, crisis because the heightened SVR increases
coronary arteries, or great vessels
the impedance to left ventricular (LV) ejection
(afterload) that can result in an acute decrease
Increased systemic vascular resistance in ventricular compliance with elevation of
LV end-diastolic pressure (LVEDP) and acute
Treat with nitroprusside hypertensive heart failure with pulmonary
Systemic hypertension or intravenous nitroglycerin edema (Figs. 8-23 and 8-24). The increase
in LVEDP also impairs subendocardial
perfusion and can cause myocardial
ischemia. Moreover, the elevated blood
Increased risk of postoperative Increased impedance to Hypertensive encephalopathy pressure increases the risk of mediastinal
mediastinal bleeding left ventricular ejection (Fig. 8-21)
bleeding in these recently heparinized patients.
The initial management of postbypass hyper-
tension should focus on attempts to amelio-
Acute diastolic dysfunction
rate reversible causes of sympathetic activa-
(decreased left ventricular compliance)
tion, including patient agitation on emergence
from anesthesia, tracheal or nasopharyngeal
Increased left ventricular end-diastolic pressure irritation from the endotracheal tube, pain,
hypothermia with shivering, ventilator asyn-
chrony, hypoxia, hypercarbia, and volume
depletion. If these general measures fail to
Impaired subendocardial perfusion
Acute hypertensive heart failure control the blood pressure, further therapy
with pulmonary edema should be guided by measurement of systemic
causing myocardial ischemia
(Figs. 8-23 and 8-24) hemodynamics. Intravenous nitroglycerin or
nitroprusside is the drug of choice to provide
a controlled decrease in SVR and blood
FIGURE 8-27 pressure. Nitroglycerin may be the preferred
Hypertensive crisis after coronary artery bypass surgery. Paroxysmal hypertension in the drug because it dilates intracoronary collateral
immediate postoperative period is a frequent and serious complication of cardiac surgery arteries [35,36]. Therapy with -blockers is
[35,36]. Paroxysmal hypertension is the most frequent complication of coronary artery not indicated in this setting and may be
bypass surgery, occurring in 30% to 50% of patients. It occurs just as often in normotensive detrimental because these drugs impair cardiac
patients as it does in those with a history of chronic hypertension. The increase in blood output and cause a further increase in SVR.
pressure usually occurs during the first 4 hours after surgery. The hypertension results Labetalol also has been shown to cause a
from a dramatic increase in systemic vascular resistance (SVR) without a change in the significant reduction in cardiac output in
cardiac output and is most commonly mediated by an increase in sympathetic tone owing postbypass hypertension. Postbypass hyper-
to activation of pressor reflexes from the heart, great vessels, or coronary arteries. Hyper- tension is usually transient and resolves by
volemia, although often cited as a potential mechanism of postoperative hypertension, is a 6 to 12 hours postoperatively, so that the
rare cause of postbypass hypertension except in patients with renal failure. In fact, increased vasodilatory therapy can be weaned. The
SVR owing to marked sympathetic overreaction to volume depletion is a common, often hypertension usually does not recur after
unrecognized, cause of severe postoperative hypertension [37]. Patients with this paradoxical the initial episode in the immediate postop-
hypertensive response to hypovolemia are exquisitely sensitive to vasodilator therapy and erative period.
FIGURE 8-28
Hypertensive crises after carotid endarterectomy Hypertensive crisis after carotid endarterectomy. Hypertension in
the immediate postoperative period occurs in up to 60% of patients
Carotid endarterectomy 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
Postoperative hypertension Repair of high-grade
(mechanism unknown) stenosis 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
Sudden increase in perfusion pressure intracerebral hemorrhage and increases the postoperative mortality
in arteriocapillary bed that was rate [39]. A mechanism for the development of post–carotid
previously protected from hypertension endarterectomy cerebral hemorrhage owing to postoperative hyper-
tension has been proposed. In patients with high-grade carotid
artery stenosis, the distal cerebral circulation has been relatively
Failure of autoregulation of cerebral blood flow
(breakthrough of autoregulation) protected from systemic hypertension. In this regard, the autoregu-
latory curve may be shifted to a lower threshold to compensate for
reduced perfusion pressure. After repair of the obstructing lesion, a
Overperfusion of cerebral circulation relative increase in perfusion pressure occurs in the cerebral arterio-
capillary bed. In the setting of systemic hypertension the increased
blood flow and perfusion pressure may overwhelm the autoregula-
Vessel rupture tory mechanisms. Overperfusion and rupture may then occur,
(hemorrhage and infarction)
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.
infarction, hypertension tends to be very labile and exquisitely sensitive

to hypotensive therapy. Thus, even modest doses of oral antihyper-
Risks of antihypertensive therapy in acute cerebral infarction
tensive agents can lead to profound and devastating overshoot
hypotension with extension of the infarct [42]. An additional rationale
Acute cerebral infarction
for not treating hypertension in the acute setting is based on evidence
that local autoregulation of cerebral blood flow is impaired in the
Altered blood flow so-called ischemic penumbra, which surrounds the area of acute
Reflex increase in
systemic blood pressure autoregulation in the infarction [43]. Without intact autoregulation, the regional blood
ischemic penumbra flow in this marginal zone of ischemia becomes critically dependent
surrounding the infarct on the perfusion pressure. Thus, the presence of mild to moderate
Even with cautious blood
pressure reduction using systemic hypertension may actually be protective, and acute reduction
parenteral agents 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
Exaggerated response to the first few days to weeks after the event. In most cases the hyper-
oral antihypertensives
tension tends to resolve spontaneously, without any specific therapy,
Spontaneous resolution Failure of autoregulation over the first week as brain function recovers. When hypertension
within first week with worsening ischemia persists for more than 3 weeks after a completed infarction, reduction
of the blood pressure into the normal range with oral antihyperten-
sives is appropriate. Although benign neglect of mild to moderate
Extension of infarct
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
FIGURE 8-29 reduction of blood pressure into the ranges of 160 to 170 mm Hg
Risks of antihypertensive therapy in acute cerebral infarction. Cerebral systolic and 100 to 110 mm Hg diastolic may be appropriate. In
infarction results from partial or complete occlusion of an artery stroke patients requiring anticoagulation therapy, moderate control
by an atherosclerotic plaque or embolization of atherothrombotic of severe hypertension also should be considered. Cautious blood
debris from a more proximal plaque. These atherothrombotic pressure reduction is indicated when stroke is accompanied by other
infarcts typically involve the cerebral cortex, cerebellar cortex, or hypertensive crises such as acute myocardial ischemia or acute
pons; these infarcts are to be contrasted with hypertension-induced hypertensive heart failure. Stroke caused by carotid occlusion by a
lipohyalinosis of the small penetrating cerebral end-arteries that is proximal aortic dissection mandates aggressive blood pressure
the principal cause of the small lacunar infarcts occurring in the reduction into the normal range to halt the dissection process. In
basal ganglia, pons, thalamus, cerebellum, and deep hemispheric the setting of sudden severe hypertension, it may be difficult to
white matter. Hypertension occurs in up to 85% of patients with distinguish hypertensive encephalopathy with focal neurologic findings
acute cerebral infarction, even in previously normotensive persons from cerebral infarction. Because rapid reduction of blood pressure
[40]. This early elevation of blood pressure probably represents a is lifesaving in patients with hypertensive encephalopathy, a cautious
physiologic response to brain ischemia. Because of the known benefits diagnostic trial of blood pressure reduction may be warranted (Fig. 8-
of antihypertensive therapy with regard to stroke prevention, it 21). If blood pressure reduction is deemed necessary in patients with
previously had been assumed that acute reduction of blood pressure acute cerebral infarction, treatment should be initiated using small
would also be of benefit in acute cerebral infarction. However, no doses of a short-acting parenteral agent such as sodium nitroprusside.
evidence exists to suggest that acute reduction of blood pressure is Use of oral or sublingual nifedipine is associated with excessive risk of
beneficial in this setting. In fact, reports exist of worsening neurologic prolonged overshoot hypotension. Oral clonidine loading also is con-
status, apparently precipitated by emergency treatment of hypertension traindicated because of the risk of hypotension and because sedative
in patients with cerebral infarction [41]. In the setting of acute cerebral side effects interfere with the assessment of mental status.
Hypertensive crises from intracerebral hemorrhage
Intracerebral hemorrhage
Reflex increase in blood pressure

(Cushing's reflex)
Hypertension may
help maintain
blood flow in
ischemic areas
Cerebral hyperperfusion Impairment of autoregulation of Increased risk of rebleeeding
with cerebral edema blood flow in ischemic area (expansion of hematoma)
surrounding hematoma
(shift of lower limit of
autoregulation)
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, cere-
bellum, 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 patient’s
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 pre-
carious 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.
Hypertensive crisis with pheochromocytoma
Pheochromocytoma
Acute treatment with
Episodic release of nitroprusside or phentolamine
catecholamines followed by β-blockers
Paroxysmal hypertension
Acute hypertensive heart

failure with pulmonary edema
Pressure-induced Intracerebral (Figs. 8-23 and 8-24)
natriuresis and diuresis hemorrhage
Intravascular volume Hypertensive encephalopathy

depletion (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 natriure-
sis 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 intra-
operative 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 intraop-
erative and postoperative hypotension [46]. Pressors only should be employed when
hypotension is unresponsive to volume repletion.
Hypertension crises secondary to monoamine

oxidase inhibitor–tyramine interactions
Monoamine oxidase inhibitor therapy
Impaired degradation of intracellular amines Ingestion of

(epinephrine, norepinephrine, dopamine) tyramine-containing food
Accumulation of catecholamines in
Hepatic monamine
nerve terminal storage granules
oxidase inhibition
with decreased
Increased circulating
oxidative metabolism
tyramine level
of tyramine
Massive release of catecholamines Tachyarrhythmias
Vasoconstriction
(increased systemic vascular resistance)
Severe paroxysm of hypertension
Hypertensive encephalopathy Acute hypertensive heart failure

with pulmonary edema Intracerebral hemorrhage
(Fig. 8-21) (Figs. 8-24 and 8-25)
FIGURE 8-32
Hypertensive crises secondary to monoamine oxidase inhibitor–tyramine 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 tyramine-
containing 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 hyper-
adrenergic 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 inhibitor–tyramine
hypertensive crisis is self-limited, parenteral antihypertensive agents can be weaned without
institution of oral antihypertensive agents.
FIGURE 8-33
Mechanism of action and metabolism of nitroprusside Mechanism of action and metabolism of nitroprusside. Sodium
nitroprusside is the drug of choice for management of virtually all
+
NO hypertensive crises, including malignant hypertension, hypertensive
encephalopathy, acute hypertensive heart failure, intracerebral
CN- CN- hemorrhage, perioperative hypertension, catecholamine-related
t1/2=3–4 min
Fe++ Free cyanide hypertensive crises, and acute aortic dissection (in combination
CN- CN- Metabolized by (CN-) with a -blocker) [1,50]. Sodium nitroprusside is a potent intravenous
direct combination hypotensive agent with immediate onset and brief duration of action.
CN- with -SH groups The site of action is the vascular smooth muscle. Nitroprusside has
in erythrocytes
and tissues Thiocyanate no direct action on the myocardium, although it may affect cardiac
Nitroprusside performance indirectly through alterations in systemic hemodynamics.
t1/2=1 wk
Combination of nitroso Nitroprusside is an iron (Fe) coordination complex with five cyanide
group with cysteine moieties and a nitroso (NO) group. The nitroso group combines with
Renal excretion
cysteine to form nitrosocysteine and other short-acting S-nitrosothiols.
Nitrosocysteine
Nitrosocysteine is a potent activator of guanylate cyclase, thereby
causing cyclic guanosine monophosphate (cGMP) accumulation
Activation of
and relaxation of vascular smooth muscle [51,52]. Nitroprusside
guanylate cyclase causes vasodilation of both arteriolar resistance vessels and venous
capacitance vessels. Its hypotensive action is a result of a decrease
t1/2=2–3min
in systemic vascular resistance. The combined decrease in preload
Metabolized by
cGMP accumulation in and afterload reduces myocardial wall tension and myocardial oxygen
cGMP-specific
vascular smooth muscle
phosphodiesterases 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
Venodilation Dilation of arteriolar resistance vessels volume and cardiac output as a result of afterload reduction and
(increased venous capacitance) (decreased systemic vascular resistance)
heart rate may actually decrease in response to improved cardiac
performance. In contrast, in the absence of LV dysfunction, venodi-
lation and preload reduction can result in a reflex increase in sym-
Decreased blood pressure
pathetic tone and heart rate. For this reason, nitroprusside must be
Afterload reduction
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 phos-
phodiesterases. 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 ery-
throcytes 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 µg/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 µg/kg/min) are used to induce deliberate
hypotension during surgery [50].
VARIOUS ANTIHYPERTENSIVE DRUGS FOR PARENTERAL USE IN THE MANAGEMENT OF MALIGNANT HYPERTENSION AND OTHER HYPERTENSIVE CRISES
FIGURE 8-34
Mechanism of Method of
Drug action Onset of action Peak effect Duration of action administration Advantages Disadvantages Side effects Comments
Sodium Direct arteriolar Instantaneous Immediate 2–3 min after infusion Continuous infusion: Precise titration of Monitoring in ICU Nausea, vomiting, Discontinue if
nitroprusside vasodilation and stopped Initial, 0.5 µg/kg/min BP. Consistently required apprehension. thiocyanate level
venodilation Average, 3 µg/kg/min effective when Thiocyanate toxic- >10 mg/dL
Maximum, 10 µg/kg/min other drugs fail. ity with prolonged
Parenteral agent infusion, renal
of choice for insufficiency
hypertensive crises
Diazoxide Direct arteriolar 1–2 min 10–15 min 4–24 h IV minibolus: 50–100 mg Long duration of Sustained Nausea, vomiting, Contraindicated in
vasodilation IV given rapidly over action. Constant hypotension with hyperglycemia, aortic dissection,
5–10 min. Total dose, monitoring not CNS and myocar- myocardial cerebrovascular
150–600 mg required after ini- dial ischemic can ischemia, uterine disease, myocardial
tial titration occur. Reflex sym- atony ischemia
pathetic cardiac
stimulation
Trimethaphan Ganglionic blockage Minutes Minutes 5–10 min after infu- Continuous infusion: Blocks barorecep- Parasympathetic Dry mouth, blurred Tilt-bed enhances
camsylate with venodilation and sion stopped Initial, 0.5 mg/min tor-mediated blockade vision, urinary effect; tachyphylaxis
arteriolar vasodilation Maximum, 5.0 mg/min sympathetic retention, paralyt- after 24–48 h;
cardiac stimulation ic ileus, respirato- contraindicated
ry arrest in respiratory
insufficiency and
glaucoma;
potentiates
succinylcholine
Nitroglycerin Direct venodilation at Minutes Minutes 1–5 min after infusion Continuous infusion: Theoretic advan- Fails to control BP Headache, nausea, Dilates intracoronary
Sodium nitroprusside remains the treatment of choice in virtually

all hypertensive crises requiring rapid blood pressure control with
low doses; combined stopped Initially, 5 µg/min tages over nitro- in some patients vomiting, collaterals
venodilation and Increase by 5 µg/min prusside in setting palpitations,
arteriolar dilation at over 3–5 min of myocardial abdominal pain
higher doses ischemia
Labetalol Selective 1- and Minutes 5–50 min 16–18 h IV minibolus: Initial, 20 Continuous -blockage can Nausea, vomiting, Contraindicated in
noncardioselective mg over 2 min Then monitoring not worsen congestive paresthesias, pheochromocytoma,
-blocker; arteriolar 40–80 mg over 10 min. required heart failure, headache, heart failure, asthma,
and venous dilation Maximum, 300 mg bronchospasm, bradycardia heart block >1
heart block degree, after coro-
nary artery bypass
graft surgery
Phentolamine Nonselective -blocker 2–3 min 5 min 15–30 min IV bolus: 1–5 mg Useful in Short duration of Tachycardia, Nitroprusside equally
over 5 min catecholamine- action arrhythmias, efficacious in
related crises nausea, vomiting, catecholamine-
diarrhea, exacer- related crises
bation of peptic
ulcer disease
Hydralazine Direct arteriolar 10–30 min 30–60 min 3–9 h IV bolus: 5–10 mg over Proven efficacy Delayed onset Headache, angina Contraindicated in
vasodilation 20–30 min or continu- and safety in of action, aortic dissection,
ous infusion 400 µg/mL hypertensive crises unpredictable atherosclerotic
solution Loading dose: of pregnancy hypotensive effect coronary vascular
200–300 µg/min for disease
30–60 min Maintenance
infusion: 50–150 µg/min
Methyldopa Decrease sympathetic 2–4 h 4–6 h 4–6 h IV of 250–500 mg None—not Delayed onset Sedation Contraindicated in
nervous system activi- over 6–8 h recommended for of action, hypertensive
ty via CNS 2 stimula- use in hyperten- unpredictable encephalopathy,
tion, decrease systemic sive crises hypotensive effect CNS catastrophe
agents may be useful in certain circumstances.

Hypertensive Crises
vascular resistance
Reserpine Sympathetic dysfunc- 2–4 h 2–4 h 2–8 h Intramuscular: None—not Delayed onset Nasal congestion, Contraindicated in
tion owing to central Initial, 0.5–1.0 mg recommended for of action, CNS sedation, hypertensive
and peripheral cate- 2–4 mg over 3 h use in hyperten- unpredictable bradycardia, encephalopathy,
cholamine dysfunc- 2–4 mg over 3–12 h sive crises hypotensive effect exacerbates pep- CNS catastrophe,
tion; decreased SVR, tic ulcer disease, cumulative hypoten-
decreased CO depression sive response
parenteral therapy. However, other parenteral antihypertensive

BP—blood pressure; CNS—central nervous system; CO—cardiac output; ICU—intensive care unit; IV—intravenous; SVR—systemic vascular resistance.
8.27
blood pressure required to reach the autoregulatory limit. Thus, a

200 Uncontrolled hypertensives (n=13)
reduction in MAP of approximately 20% to 25% was required in
Controlled hypertensives (n=9) each group to reach the threshold. This result indicates that a
Normotensives (n=10) considerable safety margin exists for blood pressure reduction
150 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
100 substantially below the autoregulatory threshold because even in
the face of reduced blood flow, cerebral metabolism can be main-
79
72 tained and ischemia prevented by an increase in oxygen extraction
50 ± 45
10% ±
74 by the tissues. The lowest tolerated MAP, defined as the level at
±
29% ± 46 45
12% 6% ± ±
which mild symptoms of brain hypoperfusion developed (ie, yawning,
16% 12% nausea, and hyperventilation), was 65 ±10 mm Hg in patients with
0
uncontrolled hypertension, 53 ±18 mm Hg in persons with treated
Baseline mean Lower limit of Lowest tolerated mean hypertension, and 43 ±8 mm Hg in normotensive persons. The
arterial pressure autoregulation arterial pressure
numbers on the bars illustrate that these MAP values were approx-
imately 45% of the baseline blood pressure level in each group.
FIGURE 8-35 Thus, symptoms of cerebral hypoperfusion did not occur until the
Risks of rapid blood pressure reduction in hypertensive crises. It MAP was reduced by an average of 55% from the presenting level.
has been argued over the years that rapid reduction of blood pressure In the reported cases of neurologic sequelae sustained during rapid
in the setting of hypertensive crises may have a detrimental effect reduction of blood pressure in patients with hypertensive crises, the
on cerebral perfusion because the autoregulatory curve of cerebral MAP was reduced by more than 55% of the presenting blood pres-
blood flow is shifted upward in patients with chronic hypertension. sure. This frank hypotension was sustained for a period of hours to
Conversely, this upward shift protects the brain from hypertensive days, mostly as a result of treatment with bolus diazoxide, which
encephalopathy in the face of severe hypertension. However, this has long duration of action [54]. The general guideline for acute
autoregulatory shift could be deleterious when the blood pressure blood pressure reduction in the treatment of hypertensive crises is
is reduced acutely because the lower limit of autoregulation is shifted reduction of systolic blood pressure to 160 to 170 mm Hg and
to a higher level of blood pressure. Theoretically, aggressive reduction diastolic pressure to 100 to 110 mm Hg, which equates to MAPs
of the blood pressure in chronically hypertensive patients could of 120 to 130 mm Hg. Alternatively, the initial goal of antihyper-
induce cerebral ischemia. Nonetheless, in clinical practice, moderately tensive therapy can be a 20% reduction of the MAP from the
controlled reduction of blood pressure in patients with hypertensive patient’s initial level at presentation. This level should be above the
crises rarely causes cerebral ischemia. This clinical observation may predicted autoregulatory threshold. Once this goal is obtained the
be explained by the fact that even though the cerebral autoregulatory patient should be evaluated carefully for evidence of cerebral
curve is shifted in patients with chronic hypertension, a considerable hypoperfusion. Further reduction of blood pressure can then be
difference still exists between the initial blood pressure at presentation undertaken in a controlled fashion based on the overall clinical
and the lower limit of autoregulation. Illustrated are the differences status of the patient. Of course, in previously normotensive persons
in the lower autoregulatory threshold during blood pressure reduction in whom hypertensive crises develop, such as patients with acute
with trimethaphan in patients with uncontrolled hypertension and glomerulonephritis complicated by hypertensive encephalopathy,
treated hypertension, and those in the control group [53]. At least the autoregulatory curve should not yet be shifted. Therefore, the
eight of the 13 patients with uncontrolled hypertension had hyper- initial goal of therapy should be normalization of blood pressure.
tensive neuroretinopathy consistent with malignant hypertension. In terms of avoiding sustained overshoot hypotension in the treat-
The control groups included nine patients with a history of severe ment of hypertensive crises, the use of potent parenteral agents
hypertension in the past whose blood pressure was effectively with short duration of action, such as sodium nitroprusside or
controlled at the time of study and a group of 10 normotensive intravenous nitroglycerin, has obvious advantages. If neurologic
persons. Baseline mean arterial pressures (MAPs) in the three sequelae develop during blood pressure reduction with these agents,
groups were 145 ±17 mm Hg, 116 ±18 mm Hg, and 96 ±17 mm these sequelae can be reversed quickly by tapering the infusion and
Hg, respectively. The lower limit of blood pressure at which autoreg- allowing the blood pressure to stabilize at a higher level. Agents
ulation failed was 113 ±17 mm Hg in persons with uncontrolled with a long duration of action have an inherent disadvantage in
hypertension, 96 ±17mm Hg in persons with treated hypertension, that excessive reduction of blood pressure cannot be reversed
and 73 ±9 mm Hg in normotensive persons. Although the absolute easily. Thus, bolus diazoxide, labetalol, minoxidil, hydralazine,
level at which autoregulation failed was substantially higher in converting enzyme inhibitors, calcium channel blockers, and
patients with uncontrolled hypertension, the percentage reduction central 2-agonists should be used with extreme caution in patients
in blood pressure from the baseline level required to reach the requiring rapid but controlled blood pressure reduction in the
autoregulatory threshold was similar in each group. The numbers setting of hypertensive crises. (Adapted from Strandgaard [53];
on the bars indicate the percentage reduction from the baseline with permission.)
heart failure tend to occur over months to

Severe uncomplicated hypertension years, rather than hours to days. Although
long-term control of blood pressure clearly can
prevent these eventual complications, a hyper-
Severe hypertension
(diastolic blood pressure > 115 mm Hg) tensive 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
Hypertensive neuroretinopathy present Hypertensive neuroretinopathy absent pressure in patients with severe uncomplicated
(striate hemorrhages, cotton-wool spots hypertension with sublingual nifedipine or oral
with or without papilledema)
clonidine loading was once the de facto stan-
dard of care. This practice, however, often was
Treat malignant hypertension No acute end-organ Acute end-organ an emotional response on the part of the treat-
(Fig. 8-20) dysfunction dysfunction ing physician to the dramatic elevation of
blood pressure or motivated by the fear of
medico-legal repercussions in the unlikely
Treat as hypertensive crisis
(see preceding figures) event of a hypertensive complication occurring
Severe uncomplicated
hypertension
within hours to days [55]. Although observing
and documenting the dramatic decrease in
blood pressure is a satisfying therapeutic
Step 1 Step 2 Step 3 maneuver, there is no scientific basis for this
Patient education regarding the Evaluate reason for inadequate Arrange outpatient follow-up to approach. At present, no literature exists to
chronic nature of hypertension blood pressure control and document adequate blood support the notion that some goal level of
and importance of long-term adjust maintenance pressure control over the ensuing blood pressure reduction must be achieved
compliance and blood pressure antihypertensive drug regimen days to weeks and change drug
control to prevent complications treatment regimen as required 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
Noncompliant Compliant with current untoward side effects that render the patient
blood pressure regimen less likely to comply with long-term drug
therapy. Instead, the therapeutic intervention
should focus on tailoring an effective well-
"Ran out" of Drug Cannot afford Add low-dose thiazide tolerated maintenance antihypertensive regi-
medications side effects drugs diuretic to existing men with patient education regarding the
monotherapy with CCB, chronic nature of the disease process and the
CEI, β-blocker, α2-agonist importance of long-term compliance and med-
Restart Switch to drug Switch to generic ical follow-up. If the patient has simply run
of another class thiazide diuretic out of medicines, reinstitution of the previous-
ly effective drug regimen should suffice. If the
patient is thought to be compliant with an
FIGURE 8-36 existing drug regimen, a sensible change in the
Severe uncomplicated hypertension. The benefits of acute reduction in blood pressure in the regimen is appropriate, such as an increase in
setting of true hypertensive crises are obvious. Fortunately, true hypertensive crises are relatively a suboptimal dosage of an existing drug or
rare events that almost never affect hypertensive patients. Another type of presentation that is the addition of a drug of another class. In
much more common than are true hypertensive crises is that of the patient who initially this regard, addition of a low dose of a thi-
exhibits severe hypertension (diastolic blood pressure >115 mm Hg) in the absence of hyperten- azide diuretic as a second-step agent to exist-
sive neuroretinopathy or acute end-organ damage that would signify a true crisis. This entity, ing monotherapy with converting enzyme
known as severe uncomplicated hypertension, is very commonly seen in the emergency depart- inhibitor (CEI), angiotensin II receptor blocker,
ment or other acute-care settings. Of patients with severe uncomplicated hypertension, 60% are calcium channel blocker (CCB), -blocker, or
entirely asymptomatic and present for prescription refills or routine blood pressure checks, or central 2-agonist often is remarkably effec-
are found to have elevated pressure during routine physical examinations. The other 40% of tive. Another essential goal of the acute inter-
patients initially exhibit nonspecific findings such as headache, dizziness, or weakness in the vention should be to arrange suitable outpa-
absence of evidence of acute end-organ dysfunction. In the past, this entity was referred to as tient follow-up within a few days. Gradual
urgent hypertension, reflecting the erroneous notion that acute reduction of blood pressure, reduction of blood pressure to normotensive
over a few hours before discharge from the acute-care facility, was essential to minimize the levels over the next few days to a week should
risk of short-term complications from severe hypertension. Commonly employed treatment be accomplished in conjunction with frequent
regimens included oral clonidine loading or sublingual nifedipine. However, in recent years the outpatient visits to modify the drug regimen
practice of acute blood pressure reduction in severe uncomplicated hypertension has been ques- and reinforce the importance of lifelong com-
tioned [55,56]. In the Veterans Administration Cooperative Study of patients with severe hyper- pliance with therapy. Although less dramatic
tension, there were 70 placebo-treated patients who had an average diastolic blood pressure than acute reduction of blood pressure in the
of 121 mm Hg at entry. Among these untreated patients, 27 experienced morbid events at a acute-care setting, this type of approach to the
mean of 11 ± 8 months of follow-up. However, the earliest morbid event occurred only after treatment of chronic hypertension is more like-
2 months [57]. These data suggest that in patients with severe uncomplicated hypertension in ly to prevent long-term hypertensive complica-
which severe hypertension is not accompanied by evidence of malignant hypertension or acute tions and recurrent episodes of severe uncom-
end-organ dysfunction, eventual complications from stroke, myocardial infarction, or congestive plicated hypertension.
References
1. Nolan CR, Linas SL: Malignant hypertension and other hypertensive 31. Goldman L, Caldera DL: Risks of general anesthesia and elective
crises. In Diseases of the Kidney, edn 6. Edited by Schrier RW, operation in the hypertensive patient. Anesthesiology 1979, 50:285.
Gottschalk CW. Boston: Little, Brown; 1997:1475–1554. 32. Breslin DR, et al.: Elective surgery in hypertensive patients: preoperative
2. Derow HA, et al.: The nature of malignant hypertension. Ann Intern considerations. Surg Clin North Am 1970, 50:585.
Med 1941, 14:1768. 33. Prys-Roberts C: Hypertension and anesthesia: fifty years on.
3. Perez-Fontan M, et al.: Idiopathic IgA nephropathy presenting as Anesthesiology 1979, 50:281.
malignant hypertension. Am J Nephrol 1986, 6:482. 34. Reichgott MJ: Hypertension in the perioperative patient. In Medical Care
4. Holland NH, et al.: Hypertension in children with chronic of the Surgical Patient: A Problem-Oriented Approach to Management.
pyelonephritis. Kidney Int 1975, 8(suppl):S234. Edited by Goldman DR, Brown FH, Levy KW et al. Philadelphia:
5. Nanra RS, et al.: Analgesic nephropathy: etiology, clinical syndrome, Lippincott; 1982:78–86.
and clinicopathologic correlations in Australia. Kidney Int 1978, 13:79. 35. Estafanous RG, Tarazi RC: Systemic arterial hypertension associated
6. Davis BA, et al.: Prevalence of renovascular hypertension in patients with cardiac surgery. Am J Cardiol 1980, 46:685.
with grade III or grade IV hypertensive neuroretinopathy. N Engl J 36. Fouad FM, et al.: Hemodynamics of postmyocardial revascularization
Med 1979, 301:1273. hypertension. Am J Cardiol 1978, 41:564.
7. Lim K, et al.: Malignant hypertension in women of childbearing age 37. Cohn JN: Paroxysmal hypertension and hypovolemia. N Engl J Med
and its relation to the contraceptive pill. Br Med J 1987, 294:1057. 1966, 275:643.
8. Traub YM, et al.: Hypertension and renal failure (scleroderma renal 38. Skydell JL, et al.: Incidence and mechanism of post-carotid
crisis) in progressive systemic sclerosis. Medicine 1983, 62:335. endarterectomy hypertension. Arch Surg 1987, 122:1153.
9. Cacoub P, et al.: Malignant hypertension with antiphospholipid syndrome 39. Towne JB, Bernhard VM: The relationship of postoperative hypertension
without overt lupus nephritis. Clin Exp Rheumatol 1993, 11:479–485. to complications after carotid endarterectomy. Surgery 1980, 88:575.
10. McAllister RG, et al.: Malignant hypertension: effect of therapy on 40. Wallace JD, et al.: Blood pressure after stroke. JAMA 1981, 246:2177.
renin and aldosterone. Circ Res 1971, 28(suppl II):II–160.
41. Britton M, et al.: Hazards of therapy for excessive hypertension in
11. Keith NM, Wagener HP, Barker NW: Some different types of essential acute stroke. Acta Med Scand 1980, 207:253.
hypertension: their course and prognosis. Am J Med Sci 1939, 197:332.
42. Lavin P: Management of hypertension in patients with acute stroke.
12. Kirkendall WM: Retinal changes of hypertension. In The Eye in Systemic Arch Intern Med 1986, 146:66.
Disease. Edited by Mausolf FA. St Louis: Mosby; 1975:212–222.
43. Meyer JS, et al.: Impaired neurogenic cerebrovascular control and
13. Dollery CT: Hypertensive retinopathy. In Hypertension: Pathophysiology dysautoregulation after stroke. Stroke 1973, 4:169.
and Treatment. Edited by Genest O, Kuchel O, Hamet P. New York:
McGraw-Hill; 1983:723–732. 44. Cuneo RA, et al.: The neurologic complications of hypertension. Med
Clin North Am 1977, 61:565.
14. McGregor E, Isles CG, Jay JL, et al.: Retinal changes in malignant
hypertension. Br Med J 1986, 292:233–234. 45. Kaneko T, et al.: Lower limit of blood pressure in treatment of acute
hypertensive intracranial hemorrhage. J Cerebral Blood Flow Metab
15. Sinclair RA, Antonovych TT, Mostofi FL: Renal proliferative arteri- 1983, 3(suppl 1):S51.
opathies and associated glomerular changes: a light and electron
microscopy study. Hum Pathol 1976, 7:565. 46. Shapiro B, Rig LM: Management of pheochromocytoma. Endocrinol
Metab Clin North Am 1989, 18:443.
16. Pitcock JA, et al.: Malignant hypertension in blacks: malignant intrarenal
arterial disease as observed by light and electron microscopy. Hum 47. Pinaud M, et al.: Preoperative acute volume loading in patients with
Pathol 1976, 7:33. pheochromocytoma. Care Med 1985, 13:460.
17. Jones DB: Arterial and glomerular lesions associated with severe 48. Glazener RS, et al.: Pargyline, cheese, and acute hypertension. JAMA
hypertension. Lab Invest 1974, 31:303. 1964, 188:754.
18. Mattern WD, Sommers SC, Kassiere JP: Oliguric acute renal failure in 49. Blackwell B, et al.: Hypertensive interactions between monoamine
malignant hypertension. Am J Med 1972, 52:187. oxidase inhibitors and foodstuffs. Br J Psychiatry 1967, 113:349.
19. Isles CG, McLay A, Boulton-Jones JM: Recovery in malignant hyper- 50. Palmer RF, Lasseter KC: Sodium nitroprusside. N Engl J Med 1975,
tension presenting as acute renal failure. Q J Med 1984, 53:439. 292:294.
20. Bacon BR, Ricanatie ES: Severe and prolonged renal insufficiency. 51. Gruetter CA, et al.: Relationship between cyclic guanosine 3’:5’
Reversal in a patient wit malignant hypertension. JAMA 1978, 239:1159. monophosphate formation and relaxation of coronary arterial smooth
muscle by glyceryl trinitrate, nitroprusside, nitrite and nitric oxide.
21. Shirley D, et al.: Clinical documentation of end-stage renal disease due J Pharmacol Exp Ther 1981, 219:181.
to hypertension . Am J Kidney Dis 1994, 23:655.
52. Ignarro IJ, et al.: Mechanism of vascular smooth muscle relaxation by
22. Freedman BI, Iskander SS, Appel RG: The link between hypertension organic nitrates, nitrites, nitroprusside, and nitric oxide. J Pharmacol
and nephrosclerosis. Am J Kidney Dis 1995, 25:207. Exp Ther 1981, 218:739.
23. Rerneger TV, et al.: Diagnosis of hypertensive end-stage renal disease: 53. Strandgaard S: Autoregulation of cerebral blood flow in hypertensive
effect of patient’s race. Am J Epidemiol 1995, 141:10. patients. Circulation 1976, 53:720.
24. Möhring J, et al.: Effects of saline drinking on the malignant course of 54. Franklin SS: Hypertensive emergencies: the case for more rapid lowering
renal hypertension in rats. Am J Physiol 1976, 230:849. of blood pressure. In Controversies in Nephrology and Hypertension.
25. Gifford RW Jr, et al.: Hypertensive encephalopathy: mechanisms, clin- Edited by Narins RG. New York: Grune & Stratton; 1973:191–197.
ical features, and treatment. Progr Cardiovasc Dis 1974, 17:115. 55. Fagan TC: Acute reduction of blood pressure in asymptomatic
26. Dinsdale HB: Hypertensive encephalopathy. Neurol Clin 1983, 1:83. patients with severe hypertension. An idea whose time has come–and
27. Ziegler DK, et al.: Hypertensive encephalopathy. Arch Neurol 1965, gone. Arch Intern Med 1989, 149:2169.
12:472. 56. Ferguson RK, Vlasses PH: Hypertensive emergencies and urgencies.
28. Cohn JN, Rodriguera E, Guiha NH: Left ventricular function in JAMA 1986, 255:1607.
hypertensive heart disease. In Hypertension Mechanisms and 57. Veterans Administration Cooperative Study Group on
Management. Edited by Onesti O, Kim KE, Moyer JH. New York: Antihypertensive Agents. Effects of treatment on morbidity in hyper-
Grune & Stratton; 1973:191–197. tension. Result in patients with diastolic blood pressure averaging 115
29. Wheat MW Jr: Acute dissecting aneurysms of the aorta: diagnosis and through 129 mm Hg. JAMA 1967, 202:1028.
treatment, 1979. Am Heart J 1980, 99:373. 58. Zeller KR, et al.: Rapid reduction of severe asymptomatic hyperten-
30. DeSanctis RW, et al.: Aortic dissection. N Engl J Med 1987, 317:1060. sion. Arch Intern Med 1989, 149:2186.
Diabetic Nephropathy:
Impact of Comorbidity
Eli A. Friedman
T
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 summa-
tive 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 predomi-
nantly 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 wide-
spread thinking to the contrary, vasculopathic complications of dia-
betes, 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
CHAPTER
of proteinuria, azotemia, and ultimately ESRD. Both types of diabetes
1
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].
1.2 Systemic Diseases and the Kidney
Overview and Prevalence

FIGURE 1-1
DIABETIC NEPHROPATHY 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
Epidemiology renal disease (ESRD) suffer a higher death rate than do nondiabetic patients with ESRD
IDDM vs. NIDDM owing to greater incidence rates for cardiac decompensation, stroke, sepsis, and pulmonary
Natural history
disease. Concurrent extrarenal disease—especially blindness, limb amputations, and cardiac
disease—limits and may preempt their rehabilitation. For most diabetic patients with ESRD,
Intervention measures
the difference between rehabilitation and heartbreaking invalidism hinges on attaining a
ESRD options
renal transplant as well as comprehensive attention to comorbid conditions.
Promising strategies
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 avail-
able 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 preva-
lence) 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 trans-
plantation failed in diabetes, however, was stimulated. IDDM—insulin dependent diabetes
mellitus; NIDDM—non–insulin-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 mainte-
nance 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 hemodialy-
sis 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 1.3
FIGURE 1-3
Statistical increase in diabetes. In the past 20 years, since the diabetic patient with end-
Diabetes stage renal disease (ESRD) is no longer excluded from dialytic therapy or kidney trans-
28,740 40% plantation, 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
43,135 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
All other in that a relaxation in policy for referral of diabetic kidney patients would be indistin-
60% guishable from a true increase in incidence.
25 PERCENTAGE OF PATIENTS WITH END-STAGE

Country of origin 23
United States RENAL DISEASE WITH TYPE II DIABETES
Prevalence of diabetes, %
20 19
18 18
15 15 16 Country Percentage
15 14
Japan 99
10 Germany 90
10 9
7 8
United States Pima Indians 95
5
5 4
0
FIGURE 1-5
Black Mexican Puerto Japanese Filipinos Chinese Koreans
Rican 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
FIGURE 1-4 recent survey of hemodialysis units in Brooklyn, New York, found
Prevalence of diabetes mellitus in minority populations. Attack that 97% of the mainly African-American patients had type II dia-
rates (incidence) for diabetes are higher in nonwhite populations betes. Thus, there has been a reversal of the previously held
than in whites. Type II diabetes accounts for more than 90% of all impression that uremia was primarily a late manifestation of type I
patients with end-stage renal disease (ESRD) with diabetes. As diabetes. (From Ritz and Stefanski [14] and Nelson and coworkers
studied by Carter and colleagues [13], the effect of improved nutri- [15]; with permission.)
tion 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.)
termed non–insulin-dependent diabetes mellitus (NIDDM) or

maturity-onset diabetes, the variety of diabetes observed in indus-
Infrequent feeding Overfeeding trialized overfed populations is now classified as type II disease.
According to the Thrifty Gene hypothesis, the ability to survive
Insulin resistance Obesity
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 dia-
betes). A study by Ravussin and colleagues of American and
Fat in muscle Mexican Pima Indian tribes illustrates the effect of overfeeding on
NIDDM 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
FIGURE 1-6 reservation that restricted hunting and other activities, the preva-
Thrifty gene. In addition to the artificial increase in incident lence of type II diabetes progressively increased to 37% in women
patients with end-stage renal disease (ESRD) and diabetes that fol- and 54% in men. In contrast, Pimas living in Mexico with shorter
lowed relaxation of acceptance criteria, industrialized nations have stature, lower body mass, and lower cholesterol had a lower preva-
experienced a real increase in type II diabetes that correlates with lence of type II diabetes (11% in women and 6% in men). (From
an increase in body mass attributed to overfeeding. Formerly Shafrir [16] and Schalin-Jantti [17]; with permission.)
Type I and Type II Classified
C-PEPTIDE CRITERIA
IGT Type II Type I 70
60
60
Proportion on insulin, %
Type I (90% concordence between clinical criteria
50 and C-peptide testing)
Insulin requiring 40 Basal C-peptide <0.17 pmol/mL
33
Type II Type I Increment above basal at 6 min <0.07 pmol/mL
30
decreased insulin β-cell destruction
secretion/sensitvity 20
13
10
FIGURE 1-9
0
FIGURE 1-7 C-peptide criteria. Multiple strategies have
0–5 5–10 10–15
Type I and type II compared. Differentiating been proposed to distinguish type I from
Years of NIDDM
type I from type II diabetes may be difficult, type II diabetes. Each has limitations. Service
especially in young nonobese adults with and colleagues [20] employed baseline and
minimal insulin secretion. Furthermore, FIGURE 1-8 stimulated C-peptide levels to differentiate
with increasing duration of type II diabetes, Increasing insulin treatment in non–insulin- between the two. They found satisfactory
beta cells may decrease their insulin secre- dependent diabetes mellitus (NIDDM). A differentiation of type I from type II diabetes
tion, sometimes to the range diagnostic of decision to treat diabetes with insulin does with minimal overlap using the screening
type I diabetes. Shown here is a modifica- not necessarily equate with establishing a levels shown. (From Service and coworkers
tion of the schema devised by Kuzuya and diagnosis of type I diabetes. Terms such as [20]; with permission.)
Matsuda [18] that suggests a continuum of “insulin-requiring” do not help because the
diabetes classification based on amount of need for insulin is physician-determined and
insulin secreted. Lacking in this construction will vary from clinician to clinician. After
is the realization of the genetic determina- 10 to 15 years of metabolic regulation of
tion of type I diabetes (all?) and the clear type II diabetes, treatment with insulin has
hereditary predisposition (despite inconstant been initiated in more than half of individu-
genetic analyses) of many individuals with als with this disorder. Even in patients with
type II diabetes. At present, classification of type II diabetes treated with insulin, mea-
diabetes is pragmatic and will likely change sured secretion of insulin may fall in the
with larger-population screening studies. normal range. (From Clauson and cowork-
IGT—impaired glucose tolerance. (From ers [19]; with permission.)
Kuzuya and Matsuda [18]; with permission.)
FIGURE 1-10
TERMINOLOGY IN DIABETIC NEPHROPATHY Terminology. Clarification of the course of both types of diabetes
was made possible by recognizing two functional perturbations:
microalbuminuria and glomerular hyperfiltration. Additionally,
Hyperfiltration early glomerular mesangial expansion was noted to be a constant
A supernormal glomerular filtration rate associated with hyperglycemia during the finding in diabetic nephropathy.
early years of diabetes
Microalbuminuria
Urinary albumin excretion of 30 to 300 mg/day or 20 to 200 g/min—a predictor of
nephropathy
Mesangial expansion
An increase in mesangial matrix often but not always associated with basement
membrane thickening
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 his-
tologic 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 nor-
mal, suggesting that hyperglycemia is the cause of nephromegaly.
A 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 concen-
tration 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 inter-
capillary glomerulosclerosis is shown.
C
A B
C D
FIGURE 1-13
Glomerular basement membrane thickening. B and D, Glomerular panel B. In panel D, a mesangial nodule (MN) is present. A and C,
basement membrane thickening is a constant abnormality in diabetic Electron photomicrographs from a normal kidney. BM—basement
nephropathy, as seen in these photomicrographs from a biopsy speci- membrane; C—capillary; E—epithelial cell; MN—mesangial nodule;
men in type I diabetes. Note the loss of epithelial foot processes in M—mesangial cell.
FIGURE 1-15
Key pathologic findings. Nondiabetic renal disorders (eg, amyloido-
sis, cryoglobulinemia, nephrosclerosis) may simulate the nodular and
diffuse intercapillary glomerulosclerosis of diabetes (both type I and
FIGURE 1-14 type II). When associated with afferent and efferent arteriolosclero-
Diabetic nephropathy is a microvasculopathy. Microaneurysms are sis, nodular and diffuse intercapillary glomerulosclerosis is pathogno-
visible in the retina and occasionally in glomerular capillaries. A monic for diabetic nephropathy. A—afferent artery arteriosclerosis;
microaneurysm in a biopsy specimen from a 42-year-old woman D—diffuse intercapillary glomerulosclerosis; E—efferent artery arte-
with type I diabetes is shown. riosclerosis; N—nodular intercapillary glomerulosclerosis.

Diabetic nodules. Diabetic nodules are characterized by clear cen- Nodular size variability. Great variability in nodular size in diabetic
ters with cells along the periphery of the nodule, as shown here in nodular glomerulosclerosis is usual, as illustrated in this totally
a kidney biopsy specimen from a 44-year-old man with type II dia- obliterated glomerulus obtained by biopsy from a 65-year-old
betes (hematoxylin and eosin stain). woman with type II diabetes (periodic acid–Schiff stain).
>4
4.0
3.5
3.0
Urinary albumin, g/d
2.5
2.0
1.5
Clinical
1.0 nephropathy
0.5
0
0 3 6 9 12 15 18 21 24 27
A Hyperglycemia, y
B
FIGURE 1-18
A and B, Progression of nephropathy. Microalbuminuria, the excretion Typically, proteinuria increases to the nephrotic range, leading to
of minute quantities of albumin in the urine (more than 20 mg/day), is edema of the extremities and subsequent anasarca, which are often
a marker of subsequent renal deterioration in diabetic nephropathy. the presenting complaints in diabetic nephropathy.
180 Type 2 diabetes

10 (12)
160 Type 1 diabetes
140 (13)
Clinical
chronic renal failure, %

nephropathy
Cumulative incidence
120 (69)
GFR, mL/min
100
5 (205)
80
60
(447)
40
(812) (30)
(1,377)
20 (1,832)
0
0 (136) (112) (75) (49)
0 3 6 9 12 15 18 21 24 27 0 5 10 15 20 25 30 35
Hyperglycemia, y Years from diagnosis of diabetes

Hyperfiltration. Almost immediately after the onset of hyperglycemia Renal failure cumulative incidence. Before careful studies of the nat-
(signaling the onset of diabetes), glomerular filtration rate (GFR) ural history of type II diabetes were reported, it was not appreciated
increases to the limit of renal reserve function (hyperfiltration). Over that diabetic nephropathy was a real endpoint risk. Older diabetic
subsequent years of hyperglycemia, a steady decline in glomerular fil- individuals with a “touch of sugar” are now known to be subject to
tration rate ensues in the 20% to 40% of diabetic individuals destined the same microvascular and macrovascular complications that
to manifest diabetic nephropathy. There is great variability in the rate afflict individuals with type I disease. Population studies indicate
of decline of GFR, from as rapid as 20 mL/min/year to 1 to 2 that the rate of loss of glomerular filtration is superimposable in
mL/min/year (usually seen in aging). Projection of future loss of GFR type I and type II diabetes. Humphrey and colleagues [21] document-
on the basis of the slope of the curve of prior decline in function con- ed the development of end-stage renal disease in diabetic subjects in
tains errors as high as 37%. The importance of an inconstant and thus Rochester, Minnesota. They showed that chronic renal failure was as
unpredictable decline in GFR lies in interpretation of interventive stud- likely to develop at a superimposable rate in both diabetic subsets.
ies designed to protect kidney function. Careful attention to both selec- Numbers in parentheses indicate number of patients for each line.
tion of sufficient untreated controls and a “run-in” period is vital. (From Humphrey and coworkers [21]; with permission.)
130 130
120 120
Type I diabetic patients Type II diabetic patients

110 110
100 100
90 90
80 80
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 1 2 3 4 5 6 7 8 9 10 11 0 1 2 3 4 5 6 7 8 9 10 11
A Time, y B Time, y
FIGURE 1-21
Creatinine clearance. Further evidence of the similarity in course of in creatinine clearance over the course of a decade in subjects with
diabetic nephropathy in type I (A) and type II (B) diabetes was pre- either type of diabetes in Heidelberg, Germany. (From Ritz and
sented in Ritz and Stefansky’s study [22] of equivalent deterioration Stefanski [22]; with permission.)
14
Hyperfiltration >4
>4 12
4.0

4.0
10
3.5 3.5
Urinary albumin, g/d

3.0 3.0 8 Window for
conservative
GFR, mL/min
2.5 Clinical 2.5

6 management
nephropathy
2.0 2.0
4
1.5 1.5
Clinical
1.0 nephropathy 1.0 2
0.5 0.5 0
Microalbuminuria
0 0 0 15 30 45 60 75 90 105 120 135 150 165
0 3 6 9 12 15 18 21 24 27 Creatinine clearance, mL/min
Hyperglycemia, y
FIGURE 1-23
Clinical recognition of diabetic nephropathy. The timing of reno-
FIGURE 1-22 protective therapy in diabetes is a subject of current inquiry.
Diabetic nephropathy in types I and II. Whereas microalbuminuria Certainly, hypertension, poor metabolic regulation, and hyperlipi-
and glomerular hyperfiltration are subtle pathophysiologic manifes- demia should be addressed in every diabetic individual at discovery.
tations of early diabetic nephropathy, transformation to overt clini- Discovery of microalbuminuria is by consensus reason to start
cal diabetic nephropathy takes place over months to many years. In treatment with an angiotensin-converting enzyme inhibitor in
this figure, the curve for loss of glomerular filtration rate is plotted either type of diabetes, regardless of blood pressure elevation. As is
together with the curve for transition from microalbuminuria to true for other kidney disorders, however, nearly the entire course of
gross proteinuria, affording a perspective of the course of diabetic renal injury in diabetes is clinically silent. Medical intervention
nephropathy in both types of diabetes. While not all microalbumin- during this “silent phase,” however (comprising blood pressure
uric individuals progress to proteinuria and azotemia, the majority regulation, metabolic control, dietary protein restriction, and
are at risk for end-stage renal disease due to diabetic nephropathy. administration of angiotensin-converting enzyme inhibitors), is
GFR—glomerular filtration rate. renoprotective, as judged by slowed loss of glomerular filtration.
FIGURE 1-24
50 Renoprotection with enzyme inhibitors. Streptozotocin-induced dia-
betic rats manifest slower progression to proteinuria and azotemia
Doubling of base-line creatinine, %
45
when treated with angiotensin-converting enzyme inhibitors than
40
with other antihypertensive drugs. The consensus supports the view
35
that angiotensin-converting enzyme inhibitors afford a greater level of
30 Placebo
renoprotection in diabetes than do other classes of antihypertensive
25 P=0.007 drugs. Large long-term direct comparisons of antihypertensive drug
20 regimens in type II diabetes are now in progress. In the study shown
15 here by Lewis and colleagues [23], treatment with captopril delayed
10 Captopril the doubling of serum creatinine concentration in proteinuric type I
5 diabetic patients. Trials of different angiotensin-converting enzyme
inhibitors in both types of diabetes confirm their effectiveness but not
0 their unique renoprotective properties in humans. For patients who
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 cannot tolerate angiotensin-converting enzyme inhibitors because of
Follow-up, y
cough, hyperkalemia, azotemia, or other side effects, substitution of
Placebo 202 184 173 161 142 99 75 45 22 an angiotensin-converting enzyme receptor blocker (losartan) may be
Captopril 207 199 190 180 167 120 82 50 24 renoprotective, although clinical trials of its use in diabetes are
uncompleted. (From Lewis and coworkers [23]; with permission.)
FIGURE 1-25
Normoalbuminuric Microalbuminuric Albumin excretion rate. In the recently completed Italian Euclid mul-
10 70
ticenter study, both microalbuminuric and normalbuminuric type I
60 diabetic patients showed benefit from treatment with lisinopril, an
8
angiotensin-converting enzyme inhibitor. Although microalbumin-
50
uria, with or without hypertension, is now sufficient reason to start
AER, µg/min
AER, µg/min
6 40 treatment with an angiotensin-converting enzyme inhibitor, the ques-
tion of whether normalbuminuric, normotensive diabetic individuals
4 30
should be started on drug therapy is unanswered. AER—albumin
20 excretion rate. (From Euclid study [24]; with permission.)
2
Lisinopril 10
Placebo
0 0
0 6 12 18 24 0 6 12 18 24
Time from randomization, m
n 227 202 201 179 193 34 33 29 25 32
n 213 196 179 170 191 45 37 34 32 37
FIGURE 1-26
120
Normal diet Restricting protein. Dietary protein restriction in limited trials in
small patient cohorts has slowed renal functional decline in type I
100 diabetes. Because long-term compliance is difficult to attain, the
place of restricted protein intake as a component of management

80 is not defined. A, Normal diet. B, Protein-restricted diet. Dashed
mL/min/1.73 m2
line indicates trend line slope. (From Zeller and colleagues [25];
60 with permission.)
40
20
0
0 10 20 30 40 50
A Time, mo
120
Protein-restricted diet
100
80
mL/min/1.73 m2
60
40
20
0
0 10 20 30 40 50
B Time, mo
125 80
100
60
Rate of change in AER, % /year
Rate of change in AER, % /year

75
40
50
20
25
0 0
0 10 12 14 6 8 10 12 14
A Mean Hb A1, % B Mean Hb A1, %
FIGURE 1-27
Metabolic regulation studies. Multiple studies of the strict metabolic hyperglycemia, as indicated by hemoglobin A1 (Hb A1) levels in
regulation of type I and type II diabetes all indicate that reduction of both type I (A) and type II (B) diabetes. As for other studies using
hyperglycemic levels to near normal slows the rate of renal function- different markers, the courses of both types of diabetes over time
al deterioration. In this study, the albumin excretion rate (AER)— were found to be equivalent. (From Gilbert and coworkers [26];
another way of expressing albuminuria—correlates directly with with permission.)
FIGURE 1-28
Function Pathology Stages of nephropathy. The interrelationships between functional
and morphologic markers of the stages of diabetic nephropathy are
Hyperfiltration shown. Additional pathologic studies are needed to time with pre-
Mesangial expansion
cision exactly when glomerular basement membrane (GBM) thick-
ening and glomerular mesangial expansion take place. ESRD—end-
Microalbuminuria stage renal disease.
GBM thickening
Proteinuria Glomerulosclerosis
ESRD

Type I and II nephro- Hyperglycemia Major therapeutic
DIABETIC NEPHROPATHY:
COMPLICATIONS pathic equivalence. A Normotension maneuvers to slow
summation about the loss of glomerular
equivalence of type I Euglycemia filtration rate are
Rate of GFR Loss and type II diabetes in Protein restriction shown. Recent
Course of proteinuria terms of nephropathy recognition of the
Nephropathology
is listed. Both types adverse effect of
have similar compli- hyperlipidemia is
Comorbidity
cations. ESRD—end- reason to include
Progression to ESRD
stage renal disease; Glomerulosclerosis dietary and, if nec-
GFR—glomerular essary, drug treat-
filtration rate. ment for elevated
blood lipid levels.
PROGRESSION OF COMORBIDITY COMORBIDITY INDEX HEART DISEASE

IN TYPE II DIABETES*
Persistent angina or myocardial infarction Hyperlipidemia

Complication Initial, % Subsequent, % Other cardiovascular problems Hypertension
Retinopathy 50 100 Respiratory disease Volume overload
Cardiovascular 45 90 Autonomic neuropathy ACE inhibitor
Cerebrovascular 30 70 Musculoskeletal disorders Erythropoietin
Peripheral vascular 15 50 Infections including AIDS
Liver and pancreatic disease
Hematologic problems
*Creatinine clearance declined from 81 mL/min over 74 Spinal abnormalities FIGURE 1-33
(40—119) mo.
Vision impairment Heart disease. Heart disease is the leading
Endpoint: dialysis or death.
Limb amputation cause of morbidity and death in both type I
Mental or emotional illness and type II diabetes. Throughout the course
FIGURE 1-31 of diabetic nephropathy, periodic screening
Comorbidity in type II. In both type I and for cardiac integrity is appropriate. We have
Score 0 to 3: 0 = absent; 1 = mild; 2 = moderate;
type II diabetes, comorbidity, meaning 3 = severe. Total = Index.
elicited symptomatic improvement in angina
extrarenal disease, makes every stage of and work tolerance by using erythropoietin
progressive nephropathy more difficult to to increase anemic hemoglobin levels.
manage. In the long-term observational FIGURE 1-32 ACE—angiotensin-converting enzyme.
study in type II diabetes done by Bisenbach Comorbidity index. We devised a Comor-
and Zazgornik [27], the striking impact of bidity Index to facilitate initial and subse-
eye, heart, and peripheral vascular disease quent evaluations of patients over the
was noted in a cohort over 74 months. course of interventive studies. Each of 12
(From Bisenbach and Zazgornik [27]; areas is rated as having no disease (0) to
with permission.) 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.
report of the United States Renal Data System

(USRDS) [1]. Fewer than five in 100 diabet-
ic 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 follow-
ing 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 eval-
uated 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
A B survivors return to occupational, school,
and home responsibilities.
FIGURE 1-34 Failure to continue monitoring of car-
Heart disease and renal transplants. A, Pretransplantation. B, Five years after kidney transpla- diac integrity may have disastrous results,
tion. Experienced clinicians managing renal failure in diabetes rapidly reach the conclusion as in this relatively young type I diabetic
that quality of life following successful kidney transplantation is far superior to that attained recipient of a cadaver renal allograft for
during any form of dialytic therapy. In the most favorable series, as illustrated by a single- diabetic nephropathy Although her allo-
center retrospective review of all kidney transplants performed between 1987 and 1993, there graft maintained good function, coronary
is no significant difference in actuarial 5-year patient or kidney graft survival between diabetic artery disease progressed silently until a
and nondiabetic recipients overall or when analyzed by donor source. It is equally encouraging myocardial infarction occurred We now
that no difference in mean serum creatinine levels at 5 years was noted between diabetic and perform annual cardiac testing in all dia-
nondiabetic recipients [28]. Remarkably superior survival following kidney transplantation betic patients who have ESRD and are
compared with survival after peritoneal dialysis and hemodialysis is documented in the 1997 receiving any form of treatment.
FIGURE 1-35
RETINOPATHY Retinopathy. Blindness due to the hemorrhagic and fibrotic changes of diabetic retinopathy
is the most dreaded extrarenal complication feared by diabetic kidney patients. The patho-
genesis of proliferative retinopathy reflects release by retinal and choroidal cells of growth
Hyperglycemia (angiogenic) factors triggered by hypoxemia, which is caused by diminished blood flow. The
Hypertension interrelationship among hyperglycemia, hypertension, hypoxemia, and angiogenic factors is
Volume overload
now being defined. There is reason to hope that specifically designed interdictive measures
may halt progression of loss of sight.
Photocoagulation
Erythropoietin
FIGURE 1-36
Retinopathic changes. Proliferative retinopathy, microcapillary
aneurysms, and dot plus blot hemorrhages are present in this fun-
duscopic photograph taken at the time of initial renal evaluation of
a nephrotic 37-year-old woman with type I diabetes. After pre-
scription of a diuretic regimen, immediate consultation with a
laser-skilled ophthalmologist was arranged.
A B
FIGURE 1-37
Panretinal photocoagulation (PRP). A, PRP is the therapeutic of proliferative retinopathy were attained with PRP, as shown in
technique performed for proliferative retinopathy using an argon this fundus, photographed 6 weeks after the one shown in panel
laser to deliver approximately 1500 discrete retinal burns, avoid- A. Vision stabilized, and sight has been retained through the past
ing the fovea and disk (IA<I). By reducing the amount of retina 6 years of observation. If applied before retinal traction and
to be perfused by 35%, PRP somehow lessens the stimulus to detachment supervene, PRP is effective in preserving sight in
release angiogenic factors, and proliferative retinopathy regresses. more than 90% of diabetic patients undergoing dialytic therapy
B, Disappearance of hemorrhages and nearly complete regression or kidney transplantation.
FIGURE 1-38
AMPUTATION 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
Inspection impaired resistance to infection converts any minor insult to the foot into a major threat
Shoes to the limb and life. Previously regarded as unavoidable in as many as 30% of patients
Socks
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
Nails
incidence of limb amputation to about 5% after 3 years.
Prompt treatment
B
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 Charcot’s
A joint. (From Shaw and Boulton [29]; with permission.)

Charcot’s joint. Diabetic neuropathy may involve the propriocep- Ulcers. A collaborating podiatrist stationed within the renal clinic
tive nerves, removing limitation of joint stretching and resulting in adds a level of protection for diabetic kidney patients. Common
bone shifts and joint destruction, as seen in the Charcot’s joint lesions, like this pressure ulcer overlying the head of the first
shown here. An insensitive deformed foot with a compromised metatarsal, are managed easily with shoe pads that shift weightbear-
blood supply is at risk of ulceration, with slow or absent healing ing. The recent introduction of genetically engineered human skin
after minor trauma. holds promise for closing formerly unhealable diabetic foot ulcers.
CLINICAL STRATEGY AUTONOMIC NEUROPATHY GASTROPARESIS IN DIABETIC

NEPHROPATHY
Main Collaborators Consultants Cardiovascular (rate, QT, R-R)

Orthostatic hypotension Prevalent in majority, often silent
Opththalmologist Neurologist
Gastroparesis Correlates with autonomic neuropathy
Podiatrist Vascular surgeon
Cystopathy Symptoms not linked to delayed emptying
Cardiologist Endocrinologist
Diarrhea, obstipation Management includes
Nutritionist Gastroenterologist
Prokinetic agents: cisapride, erythromycin,
Nurse educator Urologist
metoclopramide, domperidone
Serotoninergic (5-HT-3) antagonists
FIGURE 1-43
FIGURE 1-42 Autonomic neuropathy. Autonomic neu-
ropathy accompanies advanced diabetic
Team management of neuropathy. Proper FIGURE 1-44
nephropathy. While an unvarying R-R
management of diabetic kidney patients
interval may have minimal clinical impor- Gastroparesis. Incomplete and inconstant
requires a skilled team including collaborat-
tance, diabetic cystopathy and reduced gastric emptying due to diabetic autonomic
ing specialists. Depending on the qualifica-
bowel motility, including gastroparesis, may neuropathy (gastroparesis) may preempt
tions of the patient’s primary physician,
seriously impede quality of life. Questioning good glucose regulation because of an
other professionals are recruited as needed.
to discern the presence of travel-limiting inability to match insulin dosing with food
A nurse educator can ease the interface
diarrhea, obstipation, and gastroparesis ingestion. The diagnosis can be established
between otherwise independent specialists.
should be included in each initial evaluation by having the patient ingest a test meal
Without such a team mentality, the diabetic
of a diabetic kidney patient. (From Spallone with a radioisotope tracer. Satisfactory drug
patient is often set adrift, forced to cope
and Menzinger [30]; with permission.) treatment for gastroparesis is usually able
with conflicting instructions and unneeded
to minimize the problem. (From Enck and
repetition of tests. Especially helpful as renal
Frieling [31] and Savkan and coworkers
function declines toward end-stage renal dis-
ease, patient education facilitates the choice
of uremia therapy and, if appropriate, inter-
action with the renal transplant service.
FIGURE 1-45
NEPHROTIC SYNDROME 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
Precedes renal failure includes minimizing protein loss using an angiotensin-converting enzyme inhibitor (ACEi)
May arrest or revert (15±%) and promoting diuresis with a combination of loop diuretics (furosemide) and thiazide
Confused with cardiac failure
diuretics (metolazone). Distinction between congestive heart failure and nephrotic edema
requires assessment of cardiac function. (From Herbert et at. [33] and Gault and
Intensifies risk to feet
Fernandez [34]; with permission.)
Management: ACEi + metolazone + furosemide
FIGURE 1-46
ANASARCA 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 dif-
ficult to maintain. Having the patient measure and record weight daily as a guide for each
Hypoproteinemia (renal loss, liver disease) day’s dose of diuretics (metolazone plus furosemide) is a workable strategy. Once the crea-
Glycated albumin (more permeable) tinine clearance falls below 10 mL/min, ambulatory dialysis may be the only means of
Heart failure (coronary disease)
continuing life outside the hospital.
Management includes
Daily weight
Metolazone + furosemide
Cardiac compensation
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
5 0
[35]. Some enthusiasts believe CAPD to be “a first choice treatment” for diabetic patients
D ia
with ESRD [36]. Consistent with the author’s view, however, is the report of Rubin and col-
be
10
15
5
tic
leagues [37]. They found that in a largely black diabetic population, only 34% of patients
s
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
30
90
cohorts reflecting selection bias. Data subsets from the United States Renal Data System
Creatinine
(USRDS) report for 1997 [1] show that in diabetic patients, all cohorts have a higher risk
clearance,
mL/min
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
45
75
undergoing hemodialysis [38]. Benefits of peritoneal dialysis, including freedom from a

60 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 initi-
FIGURE 1-47 ating maintenance hemodialysis or peritoneal dialysis. As a generalization, diabetic indi-
Uremia therapy, conservative management. viduals with progressive renal disease decompensate with uremic symptoms earlier than
Although enthusiastically favored in Canada nondiabetic individuals. A decision to start dialysis is usually the culmination of unsuccess-
and Mexico, in the United States peritoneal ful efforts to regain compensation after episodic dyspnea due to volume overload or nau-
dialysis sustains the life of only about 12% sea and a reversed sleep pattern characteristic of renal failure. Sometimes, both physician
of diabetic patients with end-stage renal dis- and patient appreciate that lassitude and decreasing activity in a catabolic patient signal
ease (ESRD) [1]. Continuous ambulatory the need to begin dialysis.
FIGURE 1-48
PLANNING FOR ESRD Treatment for end-stage renal disease (ESRD). Ideally, treatment for ESRD should be select-
ed 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
Expose patient to treatment options Patients, and institutional transplant coordinators aid in communicating the information
Establish vascular or peritoneal access required by patients to enable them to select from available options for uremia therapy.
Encourage intrafamilial kidney donation
Schedule visit with transplant surgeon
Monitor creatinine, general well being
Err on side of early dialysis start
FIGURE 1-49
Nondiabetic Diabetic Management with dialysis. As tabulated in the 1997 report of the
United States Renal Data System [1], diabetic patients with end-stage
40–64 y
renal disease (ESRD) are less likely than nondiabetic patients with
51.5% 71.5% ESRD to receive a kidney transplant and are most often managed
Center hemo Center hemo
with maintenance hemodialysis (center hemo). A greater proportion
of diabetic patients with ESRD are managed with continuous ambu-
Transplant latory peritoneal dialysis (CAPD) or machine-based continuous cyclic
13.0% peritoneal dialysis (CCPD) than are nondiabetic patients with ESRD.
Transplant
36.3%
Center hemo
Home hemo
CAPD
CCPD
Transplant
Nondiabetic transplant Diabetic transplant 100 100 94.9

26.2 Nondiabetic dialysis Diabetic dialysis 91.2 90.3
84.3
80 76.3 75.3
24.1 64.7
Surviving, %
60 57.9
205.4
40 36.9
279.9 26.5
20 20.1
3.9
0 50 100 150 200 250 300 0
Deaths per 1000 Patient Years 0 1 2 5 10
Time after initiatling treatment, y
FIGURE 1-50
Survival rates of diabetics and nondiabetics. As tabulated in the FIGURE 1-51
1997 report of the United States Renal Data System [1], there are Survival rates of diabetic ESRD patients. After a decade of treatment,
sharp differences in survival between diabetic and nondiabetic the remarkable superiority of renal transplantation over dialysis
patients with end-stage renal disease (ESRD) as well as between (combined peritoneal dialysis and hemodialysis, lower curve) is
treatment by dialysis versus kidney transplantation. The highest starkly evident in these survival curves drawn from the 1997 report
death rate is suffered by diabetic dialysis patients (combined peri- of the United States Renal Data System [1]. Fewer than 1 in 20
toneal dialysis and hemodialysis), while the best survival is experi- diabetic patients with end-stage renal disease (ESRD) treated with
enced by nondiabetic renal transplant recipients. Selection bias in any form of dialysis will live a decade. In contrast, kidney trans-
choosing more fit ESRD patients for kidney transplantation while plantation from a living donor (upper curve) or a cadaver donor
leaving a residual pool of sicker patients for dialysis accounts for (middle curve) permits substantive cohorts to survive.
some of the difference in mortality. Other variables, especially
extrarenal comorbidity, are probably more important in defining
the less favorable course in diabetes.
42.4
40 Transplant USRDS 1996
Hemodialysis Ages 45–64
Peritoneal dialysis
Deaths per 1000 Patient Years
30.9
30
21.5
20 19
15.1 14.5
10 8.7
7.5 7.5 6.8
6.3 4.5 4.0
2.4 3.7 3.0
2.0 1.8 1.6
1.4 0.4 0.1 1.6 0.1
0
+] [K+] Diab
MI Nondiab MI Diab CVA Nondiab CVA Diab Cancer Nondiab Cancer Diab [K Nondiab
FIGURE 1-52
Comorbidity in ESRD. Death of diabetic patients with end-stage cause of death, rates are higher in patients receiving peritoneal dialy-
renal disease (ESRD) relates to comorbidity, as shown in this table sis than in those receiving hemodialysis and are lowest in renal trans-
abstracted from the 1997 report of the United States Renal Data plant recipients. For undetermined reasons, deaths due to cancer are
System (USRDS) [1]. Representative subsets of patients with ESRD less frequent in diabetic than in nondiabetic patients with ESRD.
with and without diabetes treated by peritoneal dialysis, hemodialy- CVA—cerebrovascular accident; Diab—diabetes; K+—potassium;
sis, or renal transplantation are shown. Note that for each comorbid MI—myocardial infarction.
COMPLICATIONS IN PATIENTS COMPLICATIONS IN PATIENTS COMPLICATIONS IN PATIENTS

RECEIVING HEMODIALYSIS RECEIVING PERITONEAL DIALYSIS UNDERGOING KIDNEY
TRANSPLANTATION
Inadequate vascular access Peritonitis

“Steal,” thrombosis/infection “Tunnel” infection Infections: bacterial (AFB), fungal viral (CMV);
Interdialytic hypotension Abdominal/back pain genitourinary, lung, skin, wound
Progressive eye disease Retinopathy Cancer: skin, lymphoma, solid organ
Progressive vascular disease Progressive vascular disease Drug induced: gout, cataracts
Minimal rehabilitation Minimal rehabilitation Allograft rejection: acute/chronic
Recurrent diabetic nephropathy
Progressive eye, vascular disease

Complications prevalent in diabetic Complications prevalent in diabetic peri-
hemodialysis patients. toneal dialysis patients. FIGURE 1-55
Frequent complications reported in diabetic
kidney transplant recipients. AFB—acid fast
bacteria; CMV—cytomegalovirus.
Rehabilitation
OPTIONS IN DIABETES WITH ESRD 100
CAPD/CCPD Hemodialysis Transplantation Kidney transplant

First-year survival 75% 75% >90%
Survival >10 y <5% <5% >25%
Karnofsky score
Diabetic complications Progress Progress Slow progression Hemodialysis
Rehabilitation Poor Poor Fair to excellent 50 Peritoneal dialysis
Patient acceptance Fair Fair Good to excellent
FIGURE 1-56
Options in diabetes with ESRD. Comparing outcomes of various options for uremia thera- Withdrawal
py in diabetic patients with end-stage renal disease (ESRD) is flawed by the differing crite-
0
ria for selection for each treatment. Thus, if younger, healthier subjects are offered kidney Death
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 FIGURE 1-57
peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), hemodialysis, Karnofsky scores in rehabilitation. Graphic
and transplantation. 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 full-
time employment or other gainful activities.
Originally devised for use by oncologists,
the Karnofsky score is a reproducible, sim-
ple means of evaluating chronic illness from
any cause. A score below 60 indicates mar-
ginal function and failed rehabilitation.
FIGURE 1-58
Complications of the hemodialysis regimen
are more frequent in diabetic than in nondia-
betic patients. A, Axillary vein occlusion
proximal to an arteriovenous graft used for
dialysis access is shown. B, Balloon angio-
plasty proffers only temporary respite owing
to a high rate (70% in 6 months) of resteno-
sis in diabetic patients. The value of an intra-
luminal stent prosthesis is being studied.
A B
76.2
USRDS 1996
LIFE PLAN FOR DIABETIC
75 PD + Hemo NEPHROPATHY
74.4
74
73.1
72.6 Explore and endorse treatment goals
Enlist patient as key team member
Surviving, %
70.9 Prepare patient for probable course

70 Prioritize ESRD options
68.9
67.7
66.2 66.4 FIGURE 1-60

65.9
Life plan. Given the concurrent involvement
65 of multiple consultants in the care of dia-
1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 betic individuals with end-stage renal dis-
ease (ESRD), there is a need for a defined
strategy, here termed a “Life Plan.”
FIGURE 1-59 Switching from hemodialysis to peritoneal
Improving one year survival with dialysis. The summative effect of multiple incremen- dialysis (or the reverse) and deciding on a
tal improvements in management of diabetic patients with end-stage renal disease midcourse kidney transplant are common
(ESRD) is reflected in a continuing increase in survival. Shown here, abstracted from occurrences that ought not to provoke anx-
the 1977 report of the United States Renal Data System (USRDS), is the increasing iety or stress. Reappraisal and reconstruc-
first-year survival rates for hemodialysis (hemo) plus peritoneal dialysis (PD) patients tion of the Life Plan should be performed
with diabetes. by patient and physician at least annually.
References
1. United States Renal Data System: USRDS 1997 Annual Data Report. 21. Humphrey LL, et al.: Chronic renal failure in non-insulin-dependent
Bethesda, MD: The National Institutes of Health, National Institute diabetes mellitus: a population-based study in Rochester, Minnesota.
of Diabetes and Digestive and Kidney Diseases; April, 1997. Ann Intern Med 1989, 111:788–796.
2. Zimmet PZ: Challenges in diabetes epidemiology—from West to the 22. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am J
rest (Kelly West Lecture 1991). Diabetes Care 1992, 15:232–252. Kidney Dis 1996, 27:167–194.
3. Harris M, Hadden WC, Knowles WC, and colleagues: Prevalence of 23. Lewis EJ, et al.: The effect of angiotensin-converting-enzyme inhibition
diabetes and impaired glucose tolerance and plasma glucose levels in on diabetic nephropathy: the Collaborative Study Group. N Engl J
U.S. population aged 20-74 yr. Diabetes 1987, 36:523–534. Med 1993, 329:1456–1462.
4. Stephens GW, Gillaspy JA, Clyne D, and colleagues: Racial differences 24. The Euclid Study Group: Randomised placebo-controlled trial of lisino-
in the incidence of end-stage renal disease in types I and II diabetes pril in normotensive patients with insulin-dependent diabetes and nor-
mellitus. Am J Kidney Dis 1990, 15:562–567. moalbuminuria or microalbuminuria. Lancet 1997, 349:1787–1792.
5. Haffner SM, Hazuda HP, Stern MP, and colleagues: Effects of socioe- 25. Zeller K, et al.: Effect of restricting dietary protein on the progression
conomic status on hyperglycemia and retinopathy levels in Mexican of renal failure in patients with insulin-dependent diabetes mellitus.
Americans with NIDDM. Diabetes Care 1989, 12:128–134. N Engl J Med 1991, 324:78–84.
6. National Diabetes Data Group: Diabetes in America. Bethesda, MD: 26. Gilbert RE, Tsalamandris C, Bach LA, et al.: Long-term glycemic control
NIH Publication No. 85-1468; August, 1985. and the rate of progression of early diabetic kidney disease. Kidney Int
1993, 44:855–859.
7. Mauer SM, Chavers BM: A comparison of kidney disease in type I
and type II diabetes. Adv Exp Med Biol 1985, 189:299–303. 27. Biesenbach G, Zazgornik J: High mortality and poor quality of life
during predialysis period in type II diabetic patients with diabetic
8. Melton LJ, Palumbo PJ, Chu CP: Incidence of diabetes mellitus by
nephropathy. Ren Fail 1994, 16:263–272.
clinical type. Diabetes Care 1983, 6:75–86.
28. Shaffer D, Simpson MA, Madras PN, et al.: Kidney transplantation in
9. Biesenback G, Janko O, Zazgornik J: Similar rate of progression in
diabetic patients using cyclosporine. Five-year follow-up. Arch Surg
the predialysis phase in type I and type II diabetes mellitus. Nephrol
1995, 130:287–288.
Dial Transplant 1994, 9:1097–1102.
29. Shaw JE, Boulton AJ: The pathogenesis of diabetic foot problems: an
10. Wirta O, Pasternack A, Laippala P, Turjanmaa V: Glomerular filtra-
overview. Diabetes 1997, 46 (suppl 2): S58–S61.
tion rate and kidney size after six years disease duration in non-
insulin-dependent diabetic subjects. Clin Nephrol 1996, 45:10–17. 30 Spallone V, Menzinger G: Diagnosis of cardiovascular autonomic
neuropathy in diabetes. Diabetes 1997, 46 (suppl 2):S67–S76.
11. Cheigh J, Raghavan J, Sullivan J, and colleagues: Is insufficient dialysis
a cause for high morbidity in diabetic patients [abstract]? J Am Soc 31. Enck P, Frieling T: Pathophysiology of diabetic gastroparesis. Diabetes
Nephrol 1991, 317. 1997, 46 (suppl 2):S77–S81.
12. Lowder GM, Perri NA, Friedman EA: Demographics, diabetes type, 32. Soykan I, et al.: The effect of chronic oral domperidone therapy on
and degree of rehabilitation in diabetic patients on maintenance gastrointestinal symptoms, gastric emptying, and quality of life in
hemodialysis in Brooklyn. J Diabet Complications 1988, 2:218–226. patients with gastroparesis. Am J Gastroenterol 1997, 92:976–980.
13. Carter JS, et al.: Non-insulin-dependent diabetes mellitus in minorities 33. Hebert LA, Bain RP, Verme D, Cattran Det al.: Remission of nephrotic
in the United States. Ann Intern Med 1996, 125:221–232. range proteinuria in type I diabetes: Collaborative Study Group.
Kidney Int 1994, 46:1688–1693.
14. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am J
Kidney Dis 1996, 27:167–194. 34. Gault MH, Fernandez D: Stable renal function in insulin-dependent
diabetes mellitus 10 years after nephrotic range proteinuria. Nephron
15. Nelson RG, Pettitt DJ, Carraher MJ, et al.: Effect of proteinuria on 1996, 72:86–92.
mortality in NIDDM. Diabetes 1988, 37:1499–1504.
35. Lindblad AS, Nolph KD, Novak JW, Friedman EA: A survey of the
16. Shafrir E: Development and consequences of insulin resistance: lessons NIH CAPD Registry population with end-stage renal disease attributed
from animals with hyperinsulinemia. Diabetes Metab 1996, 22:122–131. to diabetic nephropathy. J Diabet Complications 1988, 2:227-232.
17. Schalin-Jantii C, et al.: Polymorphism of the glycogen synthase gene in 36. Legrain M, Rottembourg J, Bentchikou A, et al.: Dialysis treatment of
hypertensive and normotensive subjects. Hypertension 1996, 27:67–71. insulin dependent diabetic patients: ten years experience. Clin Nephrol
18. Kuzuya T, Matsuda A: Classification of diabetes on the basis of etiologies 1984, 21:72-81
versus degree of insulin deficiency. Diabetes Care 1997, 20:219–220. 37. Rubin J, Hsu H: Continuous anbulatory peritoneal dialysis: ten years
19. Clausson P, Linnarsson R, Gottsater A, et al.: Relationships between at one facility. Am J Kidney Dis 1991, 17: 165-169.
diabetes duration, metabolic control and beta-cell function in a repre- 38. Habach G, Bloembergen WE, Mauger EA, et al.: Hospitalization
sentative population of type 2 diabetic patients in Sweden. Diabet among United States dialysis patients: hemodialysis versus peritoneal
Med 1994, 11:794–801. dialysis. J Am Soc Nephrol 1995, 11:1940-1948.
20. Service FJ, Rizza RA, Zimmerman BR, et al.: The classification of
diabetes by clinical and C-peptide criteria: a prospective population-
based study. Diabetes Care 1997, 20:198–201.
Vasculitis (Polyarteritis
Nodosa, Microscopic
Polyangiitis, Wegener’s
Granulomatosis, Henoch-
Schönlein Purpura)
J. Charles Jennette
Ronald J. Falk
T
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, anti–glomerular
basement membrane [GBM] antibodies, antinuclear antibodies). Specific
CHAPTER
diagnosis of a vasculitis is very important because the prognosis and
appropriate therapy vary substantially among different types of vasculitis.
2
A general overview of the major categories of vasculitis that affect
the kidneys is presented. The focus is primarily on polyarteritis
nodosa, Henoch-Schönlein purpura, Wegener’s granulomatosis, and
microscopic polyangiitis.
Overview
FIGURE 2-1
SELECTED CATEGORIES OF VASCULITIS 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
Large vessel vasculitis Chapel Hill System divides vasculitides into those that have a
Giant cell arteritis predilection for large arteries (ie, the aorta and its major branches),
Takayasu arteritis
medium-sized vessels (ie, main visceral arteries), and small vessels
(predominantly capillaries, venules, and arterioles, and occasional-
Medium-sized vessel vasculitis
ly, small arteries). However, there is so much overlap in the size of
Polyarteritis nodosa
the vessel involved by different vasculitides that other criteria are
Kawasaki disease
very important for precise diagnosis, especially when distinguishing
Small vessel vasculitis
among the different types of small vessel vasculitis. ANCA—anti-
ANCA small vessel vasculitis
neutrophil cytoplasmic antibody.
Microscopic polyangiitis
Wegener’s granulomatosis
Churg-Strauss syndrome
Immune complex small vessel vasculitis
Henoch-Schönlein purpura
Cryoglobulinemic vasculitis
Lupus vasculitis
Serum sickness vasculitis
Infection-induced immune complex vasculitis
Anti–GBM small vessel vasculitis
Goodpasture’s syndrome
FIGURE 2-2
Distribution of renal vascular involvement
Predominant distributions of renal vascular involvement. This diagram
depicts the predominant distributions of renal vascular involvement
Small vessel vasculitis 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
Large vessel vasculitis
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
Medium-sized vessel vasculitis the other two categories [3].
Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura) 2.3
FIGURE 2-3
RENAL INJURY CAUSED BY DIFFERENT The type of renal vessel involved by a vasculitis determines the
CATEGORIES OF VASCULITIS 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
Large vessel vasculitis flow and resultant renovascular hypertension. Medium-sized vessel
Ischemia causing renovascular hypertension (uncommon) vasculitis most often affects lobar, arcuate, and interlobular arter-
Medium-sized vessel vasculitis
ies, resulting in infarction and hemorrhage. Small vessel vasculi-
tides most often affect the glomerular capillaries (ie, cause
Renal infarcts (frequent)
glomerulonephritis), but some types (especially the antineutrophil
Hemorrhage (uncommon)
cytoplasmic antibody vasculitides) may also affect extraglomerular
and rupture (rare)
parenchymal arterioles, venules, and capillaries. Anti-GBM disease
ANCA small vessel vasculitis
is a form of vasculitis that involves only capillaries in glomeruli or
Pauci-immune crescentic glomerulonephritis (common)
pulmonary alveoli, or both. This category of vasculitis is consid-
Arcuate and interlobular arteritis (occasional) ered in detail seperately in this Atlas.
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)
Anti–GBM small vessel vasculitis
Crescentic glomerulonephritis (common)
Extraglomerular vasculitis (only with concurrent ANCA disease)
Large Vessel Vasculitis

FIGURE 2-4
NAMES AND DEFINITIONS FOR The two major categories of large vessel vasculitis, giant cell (tem-
LARGE VESSEL VASCULITIS poral) arteritis and Takayasu arteritis, are both characterized patho-
logically by granulomatous inflammation of the aorta, its major
branches, or both. The most reliable criterion for distinguishing
Giant cell arteritis Granulomatous arteritis of the aorta and its major branches, between these two disease is the younger age of patients with
with a predilection for the extracranial branches of the Takayasu arteritis compared with giant cell arteritis [3]. The pres-
carotid artery. Often involves the temporal artery. Usually ence of polymyalgia rheumatica supports a diagnosis of giant cell
occurs in patients older than aged 50 years and often is arteritis. Clinically significant renal disease is more commonly asso-
associated with polymyalgia rheumatica. ciated with Takayasu arteritis than giant cell arteritis, although
Takayasu arteritis Granulomatous inflammation of the aorta and its major branch- pathologic involvement of the kidneys is a frequent finding with
es. Usually occurs in patients younger than aged 50 years. both conditions [4,5].
Medium-sized Vessel Vasculitis

FIGURE 2-5
NAMES AND DEFINITIONS FOR The medium-sized vasculitides are confined to arteries by the
MEDIUM VESSEL VASCULITIS 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
Polyarteritis nodosa Necrotizing inflammation of medium-sized or small arteries glomerulonephritis, purpura, or pulmonary hemorrhage, would
without glomerulonephritis or vasculitis in arterioles, point away from these diseases and toward one of the small vessel
capillaries, or venules. vasculitides. Both polyarteritis nodosa and Kawasaki disease cause
Kawasaki disease Arteritis involving large, medium-sized, and small arteries, acute necrotizing arteritis that may be complicated by thrombosis
and associated with mucocutaneous lymph node syn- and hemorrhage. The presence of mucocutaneous lymph node syn-
drome. Coronary arteries are often involved. Aorta and drome distinguishes Kawasaki disease from polyarteritis nodosa.
veins may be involved. Usually occurs in children.
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 kid-
ney 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 hemor-
rhagic rims, which are seen best on the surface of the right kidney.
A B C
FIGURE 2-7
Antemortem abdominal CAT scans showing polyarteritis nodosa aneurysms (pseudoaneurysms), and a perirenal hematoma adjacent
(A–E). These are the same kidneys shown in Figure 2-6. Demonstrated to the right kidney (left sides of panels) that resulted from rupture
are echogenic oval defects in both kidneys corresponding to the of one of the aneurysms.

Antemortem abdominal CAT scans showing
polyarteritis nodosa.
D E

Micrograph of transmural fibrinoid necrosis of an arcuate artery in Micrograph of extensive destruction and sclerosis of an arcuate
acute polyarteritis nodosa. The fibrinoid necrosis results from lytic artery in the chronic phase of polyarteritis nodosa. Severe necrotiz-
destruction of vascular and perivascular tissue with spillage of plas- ing injury, probably with thrombosis as well, has been almost com-
ma constituents, including the coagulation proteins, into the zone of pletely replaced by fibrosis. A few small residual irregular foci of
destruction. The coagulation system, as well as other mediator sys- fibrinoid material can be seen. Extensive destruction to the muscu-
tems, is activated and fibrin forms in the zone of necrosis, thus pro- laris can be discerned. Infarction in the distal vascular distribution
ducing the deeply acidophilic (bright red) fibrinoid material. of this artery was present in the specimen. (Hematoxylin and eosin
Marked perivascular inflammation is seen, which is the basis for the stain, 150.)
archaic term for this disease, ie, periarteritis nodosa. Note that the
glomerulus is not inflamed. (Hematoxylin and eosin stain, 200.)
Small Vessel Vasculitis

FIGURE 2-10
NAMES AND DEFINITIONS FOR SMALL VESSEL VASCULITIS The small vessel vasculitides have the high-
est frequency of clinically significant renal
involvement of any category of vasculitis.
Henoch-Schönlein purpura Vasculitis with IgA-dominant immune deposits affecting small vessels, ie, capillaries, This is not surprising given the numerous
venules, or arterioles. Typically involves skin, gut and glomeruli, and is associated with small vessels in the kidneys and their criti-
arthralgias or arthritis. cal roles in renal function. The renal vessels
Cryoglobulinemic vasculitis Vasculitis with cryoglobulin immune deposits affecting small vessels, ie, capillaries, most often involved by all small vessel vas-
venules, or arterioles, and associated with cryoglobulins in serum. Skin and glomeruli culitides are the glomerular capillaries,
are often involved.
resulting in glomerulonephritis. Glomerular
Wegener’s granulomatosis Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis
affecting small to medium-sized vessels, eg, capillaries, venules, arterioles, and arteries. involvement in immune complex vasculitis
Necrotizing glomerulonephritis is common. typically results in proliferative or membra-
Churg-Strauss syndrome Eosinophil-rich and granulomatous inflammation involving the respiratory tract and noproliferative glomerulonephritis, whereas
necrotizing vasculitis affecting small to medium-sized vessels, and associated with ANCA disease usually causes necrotizing
asthma and blood eosinophilia glomerulonephritis with extensive crescent
Microscopic polyangiitis Necrotizing vasculitis with few or no immune deposits affecting small vessels, ie, capil- formation. Involvement of renal vessels
laries, venules, or arterioles. Necrotizing arteritis involving small and medium-sized
arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary other than glomerular capillaries is rare in
capillaritis often occurs. 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)
Cryoglobulins Pauci-immune crescentic

in blood glomerulonephritis
on renal biopsy
IgA nephropathy Type 1 MPGN No granulomatous Granulomatous Granulomatous

on renal biopsy on renal biopsy inflammation inflammation inflammation, asthma,
or asthma but no asthma and eosinophilia
Henoch-Schönlein Cryoglobulinemic Microscopic Wegener's Churg-Strauss

purpura vasculitis polyangiitis granulomatosis 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-Schönlein purpura. Type I membranoproliferative glomeru-
lonephritis (MPGN) suggests cryoglobulinemia and/or hepatitis C infection, and pauci-immune necrotizing and crescen-
tic 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, granuloma-
tous inflammation in Wegener’s 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 Wegener’s 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.
APPROXIMATE FREQUENCY OF ORGAN SYSTEM INVOLVEMENT IN SMALL VESSEL VASCULITIS
Henoch-Schönlein Cryoglobulinemic Microscopic Wegener’s Churg-Strauss

Organ system purpura, % vasculitis, % polyangiitis, % granulomatosis, % syndrome, %
Renal 50 55 90 80 45
Cutaneous 90 90 40 40 60
Pulmonary <5 <5 50 90 70
Gastrointestinal 60 30 50 50 50
Ear, nose, and throat <5 <5 35 90 50
Musculoskeletal 75 70 60 60 50
Neurologic 10 40 30 50 70
FIGURE 2-12
All of the small vessel vasculitides share signs and symptoms of small ally manifests as purpura caused by venulitis, but occasionally is more
vessel injury in multiple different tissues; however, the frequency of nodular or necrotizing secondary to arteritis or granulomatous inflam-
involvement varies among the different diseases [1]. Combined renal mation. Nodular cutaneous lesions, as well as neuropathies, abdomi-
and pulmonary involvement (pulmonary-renal syndrome) is most com- nal pain, and musculoskeletal symptoms also can be caused by medi-
mon in ANCA vasculitis, whereas combined renal and dermal involve- um sized vessel vasculitis (eg, polyarteritis nodosa), and thus these clin-
ment (dermal-renal syndrome) is most common in immune complex ical manifestations are not specific for a small vessel vasculitis; whereas
vasculitis. The cutaneous involvement in small vessel vasculitides usu- glomerulonephritis, purpura, or alveolar capillaritis are.
Henoch-Schönlein Purpura

Cutaneous purpura in a patient with Henoch-Schönlein purpura. Skin biopsy from a patient with small vessel vasculitis demonstrat-
This clinical appearance could be caused by any of the small vessel ing the typical dermal leukocytoclastic angiitis pattern of venulitis
vasculitides, and thus is not specific for Henoch-Schönlein purpu- that results in vasculitic purpura. This histologic lesion is nonspe-
ra. Henoch-Schönlein purpura is the most common small vessel cific and can be a component of any of the small vessel vasculi-
vasculitis in children [7]. In a young child with purpura, nephritis tides. Additional immunohistologic, serologic, and clinical observa-
and abdominal pain, the likelihood of Henoch-Schönlein purpura tions are required to determine what is causing the leukocytoclastic
is approximately 80%; however, in an older adult with the same angiitis (Figs. 2-9 and 2-10). (Hematoxylin and eosin stain.)
clinical presentation, the likelihood of Henoch-Schönlein purpura
is very low and the patient has an approximately 80% chance of
having an ANCA-associated vasculitis.

Direct immunofluorescence microscopy demonstrating granular Direct immunofluorescence microscopy demonstrating granular,
IgA-dominant immune complex deposits in dermal vessels, which is predominantly mesangial IgA-dominant immune complex deposits
indicative of Henoch-Schönlein purpura. This procedure typically in a glomerulus. This is indicative of some form of IgA nephropa-
would show vascular IgM, IgG, and C3 cryoglobulinemic vasculi- thy, including the form that occurs as a component of Henoch-
tis, and little or no staining for immunoglobulins in a specimen Schönlein purpura.
from a patient with an ANCA vasculitis (a paucity of staining for
immunoglobulins in vessel walls indicates pauci-immune vasculitis).

Electron micrograph showing mesangial dense deposits representa- Severe crescentic proliferative glomerulonephritis in a patient
tive of the pattern of deposition seen in patients with Henoch- with Henoch-Schönlein purpura and rapidly progressive glomeru-
Schönlein purpura glomerulonephritis. The dense deposits are lonephritis (Masson trichrome stain). Approximately half of
immediately beneath the paramesangial basement membrane. patients with Henoch-Schönlein 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 pro-
gresses to end-stage renal disease.
FIGURE 2-19
Fibrinoid necrosis obliterating the wall of an arteriole in a renal
biopsy specimen from a patient with Henoch-Schönlein purpura
(hematoxylin and eosin). Involvement of renal vessels other than
glomeruli is rare in Henoch-Schönlein purpura.
ANCA Small Vessel Vasculitis

C-ANCA staining pattern of ethanol-fixed normal human neu-
trophils 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) [8–10].

P-ANCA staining pattern of ethanol-fixed normal human neu-
trophils in an indirect immunofluorescence assay of serum.
Approximately 90% of P-ANCA in patients with nephritis or vas-
culitis 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 neu-
trophils as substrate, nuclear staining caused by anti-nuclear anti-
bodies (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 dif-
ference in staining pattern between ethanol and formalin fixed cells
is due to the artifactual diffusion of solubilized cationic ANCA-
antigens to the nucleus during substrate preparation of the ethanol-
fixed cells, as opposed to immobilization of the antigens in the
cytoplasm by covalent crosslinking during formalin fixation.
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 C-
ANCA/PR3-ANCA in patients with pauci-immune necrotizing and
crescent glomerulonephritis without systemic vasculitis (“renal-limit-
ed vasculitis”), microscopic polyangiitis, and Wegener’s granulo- FIGURE 2-23(see Color Plate)
matosis. Note that most patients with renal-limited disease have P- Early segmental fibrinoid necrosis and infiltration by neutrophils in
ANCA/MPO-ANCA, most patients with Wegener’s granulomatosis an ANCA-positive patient with Wegener’s granulomatosis (Masson
have C-ANCA/PR3-ANCA, and patients with microscopic polyangi- trichrome stain). There also is fibrin (red/fuchsinophilic material) in
itis do not have a major preponderance of either ANCA specificity. Bowman’s space, which is a precursor event to crescent formation.
FIGURE 2-24 FIGURE 2-25(see Color Plate)

Glomerulus from a patient with ANCA and a pauci-immune necro- Direct immunofluorescence microscopy demonstrating intense
tizing and crescentic glomerulonephritis showing a large circumfer- staining of a crescent and adjacent segmental glomerular fibrinoid
ential crescent and segmental lysis of glomerular basement mem- necrosis with an antiserum specific for fibrin in a renal biopsy from a
branes (combined Jones silver and hematoxylin and eosin stain). patient with ANCA small vessel vasculitis. There was no staining of
Also note the adjacent tubulointerstitial inflammation, which often glomeruli in this specimen with antisera specific for IgG, IgA, or IgM.
is pronounced in ANCA disease. This pattern of glomerular injury
can be seen with any of the ANCA-small vessel vasculitides.

Chronic ANCA-associate glomerulonephritis with effacement of Necrotizing arteritis involving an interlobular artery in a renal
the architecture of a glomerulus by extensive sclerosis. Bowman’s biopsy specimen from a patient with ANCA-positive microscopic
capsule has been destroyed and there is periglomerular fibrosis and polyangiitis (hematoxylin and eosin). There is focal transmural fib-
chronic inflammation. rinoid necrosis with intense perivascular inflammation. This pat-
tern of arteritis is nonspecific, and could be seen, for example, in a
patient with polyarteritis nodosa, microscopic polyangiitis, or
Wegener’s granulomatosis. The presence of ANCA or glomeru-
lonephritis in the patient would exclude polyarteritis nodosa.

Direct immunofluorescence microscopy demonstrating intense Medullary leukocytoclastic angiitis involving vasa recta in a patient
staining of the fibrinoid necrosis in the wall of an interlobular with Wegener’s granulomatosis (hematoxylin and eosin). When this
artery with an antiserum specific for fibrin in a renal biopsy from a process is severe, papillary necrosis may result. The frequency of
patient with microscopic polyangiitis. this process is unknown because the medulla often is not sampled
in renal biopsy specimens.

Poorly defined focus of necrotizing granulomatous inflammation Necrotizing granulomatous inflammation in a wedge biopsy of
in the cortex in a renal biopsy obtained from a patient with lung from a patient with Wegener’s granulomatosis (hematoxylin
ANCA-positive Wegener’s granulomatosis (hematoxylin and eosin). and eosin). Note the scattered large multinucleated giant cells on
Granulomatous inflammation is only very rarely observed in renal the left side and the extensive necrosis and neutrophilic infiltration
biopsy specimens. on the right side. The granulomatous inflammation of acute
Wegener’s 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.
Glomerulonephritis
P-ANCA alone
(MPO-ANCA)
disease
Systemic small
vessel vasculitis
(eg, MPA)
Pulmonary–
renal Wegener's
vasculitic granulomatosis
syndrome
C-ANCA
Anti-GBM (PR3-ANCA)
FIGURE 2-32 disease
disease
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 Wegener’s granulomatosis. FIGURE 2-33
The pulmonary hemorrhage of anti-GBM disease usually does not Categorization of patients with crescentic glomerulonephritis with
have conspicuous neutrophils in alveolar capillaries. respect to both the immunopathologic category of disease (immune
complex versus anti-GBM versus ANCA) and the clinicopathologic
expression (glomerulonephritis alone versus Wegener’s granulomato-
sis versus Goodpasture’s syndrome versus other small vessel vasculi-
tis) [11]. Note that most patients with ANCA have some expression
of systemic vasculitis rather than glomerulonephritis alone. Most
patients with Wegener’s 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]).
References
1. Jennette JC, Falk RJ: Small vessel vasculitis. N Engl J Med 1997, 7. Dillon MJ, Ansell BM: Vasculitis in children and adolescents. Rheum
337:1512–1523. Dis Clin North Am 1995, 21:1115–1136.
2. Jennette JC, Falk RJ: The pathology of vasculitis involving the kidney. 8. Gross WL, Schmitt WH, Csernok E: ANCA and associated diseases:
Am J Kidney Dis 1994, 24:130–141. immunodiagnostic and pathogenetic aspects. Clin Exp Immunol
3. Jennette JC, Falk RJ, Andrassy K, et al.: Nomenclature of systemic 1993, 91:1–12.
vasculitides: the proposal of an international consensus conference. 9. Kallenberg CGM, Brouwer E, Weening JJ, Cohen Tervaert JW:
Arthritis Rheum 1994, 37:187–192. Anti-neutrophil cytoplasmic antibodies: current diagnostic and
4. Klein RG, Hunder GG, Stanson AW, et al.: Larger artery involvement pathophysiologic potential. Kidney Int 1994, 46:1–15.
in giant cell (temporal) arteritis. Ann Intern Med 1975, 83:806–812. 10. Jennette JC, Falk RJ: Anti-neutrophil cytoplasmic autoantibodies:
5. Arend WP, Michel BA, Bloch DA, et al.: The American College of discovery, specificity, disease associations and pathogenic potential.
Rheumatology 1990 criteria for the classification of Takayasu arteritis. Adv Pathol Lab Med 1995, 8:363–377.
Arthritis Rheum 1990, 33:1129–1134. 11. Jennette JC: Anti-neutrophil cytoplasmic autoantibody-associated
6. Lhote F, Guillevin L: Polyarteritis nodosa, microscopic polyangiitis, and disease: a pathologist’s perspective. Am J Kidney Dis 1991,
Churg-Strauss syndrome. Rheum Dis Clin North Am 1995, 21:911–947. 18:164–170.
Amyloidosis
Robert A. Kyle
Morie A. Gertz
T
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 charac-
teristic apple-green birefringence. The modification of alkaline Congo red
dye by Puchtler and Sweat [2] is used most often. The amorphous hyaline-
like appearance of amyloid is misleading because it is a fibrous protein. On
electron microscopy, amyloid deposits are composed of rigid, linear, non-
branching 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 non-
immunoglobulin. 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 arthropa-
thy) consist of 2-microglobulin.
Amyloid P component is a glycoprotein composed of 10 identical gly-
cosylated 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 fib-
rils; 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 Alzheimer’s disease. CHAPTER
The physiologic function of SAP and its pathologic role in amyloidosis are
unknown. Glycosaminoglycans are present in amyloid deposits. Their role
3
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.
Microscopic Appearance and Classification

Blood vessel from a bone marrow biopsy specimen indicating pri- Electron photomicrograph showing the fibrillar character of
mary amyloidosis. The specimen was stained with Congo red dye amyloidosis. The fibrils are 7.5- to 10-nm wide and of indefi-
and viewed with a polarizing light source, producing the character- nite length. The fibrils are deposited extracellularly, are insolu-
istic apple-green birefringence. In more than half of patients, ble, and generally resist proteolytic digestion. They ultimately
results of bone marrow testing are positive for amyloidosis. (From lead to disorganization of tissue architecture and loss of normal
Kyle [4]; with permission.) tissue elements.
and contains 76 amino acids. It is derived

CLASSIFICATION OF AMYLOIDOSIS from serum amyloid A, which is an acute-
phase protein. The level of serum amyloid
A is increased in patients with rheumatoid
arthritis and Crohn’s disease. In familial
Amyloid type Classification Major protein component amyloidosis the Portuguese, Swedish, and
Primary amyloidosis (AL) Primary, including multiple myeloma or light chain Japanese variants are characterized by substi-
Secondary amyloidosis (AA) Secondary Protein A tution of methionine for valine at residue 30
Familial amyloidosis (AF) Familial (Met-30) in the transthyretin molecule. This
Neuropathic: Portugal, Sweden, Japan, and Transthyretin mutant (prealbumin) mutation is characterized by the development
other countries of peripheral neuropathy. Cardiomyopathy
Cardiopathic: Denmark and Appalachia in Transthyretin mutant (prealbumin) from a transthyretin mutation has been
the United States reported in Denmark (Met-111) and in the
Nephropathic: familial Mediterranean fever Protein A Appalachian area of the United States
Senile systemic amyloidosis (AS) Senile cardiac Transthyretin normal (prealbumin) (Ala-60). Familial renal amyloid from a
Dialysis amyloidosis (AD) Dialysis arthropathy 2-microglobulin 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 pro-
tein A. Senile systemic amyloidosis involving
FIGURE 3-3 the heart results from the deposition of nor-
Classification of amyloidosis. The fibrils in primary amyloidosis consist of monoclonal mal transthyretin. Long-term dialysis often
or light chains. Rarely, monoclonal heavy chains are responsible. The major component of results in systemic amyloidosis from 2-
the amyloid fibril in secondary amyloidosis is protein A. It has a molecular weight of 8.5 kD microglobulin deposition.
Amyloidosis 3.3
SYSTEMIC AMYLOIDOSIS
Amyloid type Amyloid stains

Congo red or Serum amyloid A 2-microglobulin Transthyretin (prealbumin)
Primary (AL) + + - - -
Secondary (AA) + - + - -
FMF + - + - -
Associated with long-term + - - + -
hemodialysis
Familial (AF) + - - - +
Senile systemic (AS) + - - - +
FIGURE 3-4
Systemic amyloidosis. Types of proteins constituting the amyloid of 2-microglobulin. The amyloid fibrils consist of mutated transthyretin
fibrils. In primary amyloidosis the fibrils consist of monoclonal or or, rarely, fibrinogen or lysozyme in familial amyloidosis. Senile
light chains. In secondary amyloidosis the fibrils consist of protein A. systemic amyloidosis is characterized by the deposition of normal
Systemic amyloidosis associated with long-term hemodialysis consists transthyretin in the heart. (From Kyle and Gertz [5]; with permission.)
FIGURE 3-5
Familial, 3.5% (5) Secondary (AA), 3.5% Distribution of forms of amyloidosis seen in patients at the Mayo Clinic in 1996. Of the
Senile, 2% (2) (5) 135 patients with amyloidosis, 83% had the primary form. Familial, secondary, and senile
Localized, 8% (11) 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
Primary (AL), 83% their serum or urine. Most localized amyloidosis occurs in the respiratory tract, genitouri-
(112) nary tract, or skin.
n=135
Primary Systemic Amyloidosis

FIGURE 3-6
50 Pattern of primary systemic amyloidosis in patients during an 11-
Male: 69% (n=327)
Female: 31% (n=147) year study at the Mayo Clinic. From 1981 to 1992, of the 474
40 Median age: 64 y (n=474) patients seen within 30 days of diagnosis the median age was 64
Age range: 32–90 y 37
years. Only 1% were younger than 40 years, and males were
affected more often than were females. (From Kyle and Gertz [5];
Patients, %
30
with permission.)
23
22
20
10
10
7
1
0
<40 40–49 50–59 60–69 70–79 ≥80
Age, y
FIGURE 3-7
70 Symptoms of primary systemic amyloidosis in patients during an
62 Range: 4–200 lb
60 Median: 23 lb 11-year study at the Mayo Clinic. Weakness or fatigue and weight
52 loss were the most frequent initial symptoms seen within 30 days
of diagnosis. Weight loss occurred in more than half of patients.
With symptoms, %
50
The median weight loss was 23 lb; five patients lost more than
40 100 lb each. Purpura, particularly in the periorbital and facial
areas, was noted in about one sixth of patients. Gross bleeding was
30
reported initially in only 3%. Skeletal pain was a major symptom
20 in only 5% and usually was related to lytic lesions or fractures
15 associated with multiple myeloma. Dyspnea, pedal edema, pares-
10 thesias, light-headedness, and syncope were noted. (From Kyle and
5
Gertz [5]; with permission.)
0
Fatigue Weight loss Purpura Bone pain
Symptoms
FIGURE 3-9
Nodules causing
occlusion of the
auditory canal in a
patient with primary
systemic amyloidosis.
The external audito-
ry canal may be
occluded completely
by nodules of amy-
loid. This condition
frequently produces
deafness, which
may be the initial
symptom. (From
Gertz and Kyle [6];
FIGURE 3-8 with permission.)
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 3-10
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.)
Amyloidosis 3.5
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 displace-
ment of muscle fibers with amyloid. Patients often exhibit stiffness or limitation of move-
ment. (From Kyle and Greipp [7]; with permission.)
FIGURE 3-12
30
Signs of primary systemic amyloidosis in patients during an 11-year
25 24
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
20
infiltration of amyloid or congestion from heart failure. The spleen is
palpable in only 5% of patients and rarely extends more than 5 cm
Patients, %
15
below the left costal margin. Lymphadenopathy occurs infrequently.
(Adapted from Kyle and Gertz [5]; with permission.)
10 9
5
5
3
0
Liver palpable Spleen palpable Lymphadenopathy Macroglossia
Signs of primary amyloidosis
HEMOGLOBIN AND PLATELET VALUES WITHIN 30 DAYS OF DIAGNOSIS ≥2.0

OF PRIMARY SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 1981–1992 20%
<1.2
n=473 1.3–1.9 55%
Factor Median Range 25%
Median: 1.1
Hemoglobin, g/dL (<10 g/dL in 11%) 12.9 6.6–18.6
Range: 0.4–14.6
Platelets, 109/L (>500 109/L in 9%) 288 4–953
FIGURE 3-14
Serum creatinine (mg/dL) in patients at
FIGURE 3-13
diagnosis of primary systemic amyloidosis.
Hemoglobin and platelet values within 30 days of diagnosis of primary systemic amyloidosis. Renal insufficiency was present in almost
Anemia was not a prominent feature. When present, it usually is due to multiple myeloma, renal half of patients. Proteinuria was present in
insufficiency, or gastrointestinal bleeding. Thrombocytosis was relatively common; in 9% of about 75% of patients.
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 Howell-
Jolly bodies and occurs in about one fourth of patients. (Adapted from Kyle and Gertz [5].)
Polyclonal IgM 5% IgD 1%

1%
Hypogammaglobulinemia ≥ 6.0
20% κ only
β band 20%
9%
10%
Negative <1.0
λ only 28% 3.0–5.9
45%
15% 16%
γ band
38% 1.0–2.9
Normal IgA
10% IgG 19%
31% Median:1.2 g/d
n=463 32%
n=430 Range: 0.1–24.1 g/d
n=443

Results of serum protein electro- Serum monoclonal (M-) protein in patients at Urine total protein values in patients at
plasmaphoresis in patients at diagnosis of diagnosis of primary systemic amyloidosis in diagnosis of primary systemic amyloidosis
primary systemic amyloidosis. The serum an 11-year study at the Mayo Clinic. in an 11-year study at the Mayo Clinic.
protein electrophoretic pattern showed Immunoelectrophoresis or immunofixation of More than one third of patients exhibited
hypogammaglobulinemia in 20% of the serum showed an M-protein in 72% of 24-hour urine total protein values of 3.0
patients. Only half of patients had a local- patients. IgG was most common, followed by g/d or more. Over half of patients had a
ized band or spike in the or areas of the IgA. Twenty-four percent of patients had mon- urine protein value of more than 1 g/d. The
electrophoretic pattern. The median size of oclonal immunoglobulin light chains in the electrophoretic pattern showed mainly
the M spike was 1.4 g/dL. In the remaining serum (Bence Jones proteinemia). (Adapted albumin. (Adapted from Kyle and Gertz
patients the pattern was normal. from Kyle and Gertz [5]; with permission.) [5]; with permission.)
S+, U–
κ
16%
23%
S–, U–
λ 11% S+, U+
50% 56%
Negative S–, U+
27% n=429 17%
n=408

Urine monoclonal (M-) protein in patients Serum (S) and urine (U) proteins in
at diagnosis of primary systemic amyloidosis patients with primary systemic amyloidosis
in an 11-year study at the Mayo Clinic. in an 11-year study at the Mayo Clinic.
Almost three fourths of patients had mono- Immunoelectrophoresis or immunofixation
clonal light chains in their urine on immu- of serum and appropriate concentrations in
noelectrophoresis or immunofixation. In urine showed a monoclonal protein in nearly
contrast to the type of protein found in mul- 90% of patients. In the absence of mono-
tiple myeloma, is twice as common as is . clonal protein, one must search for a mono-
The 24-hour total amount of monoclonal clonal population of plasma cells in the bone
(M-) protein in the urine was less than 0.5 marrow or perform immunohistochemical
g/d in more than half of patients. (From staining to identify the type of amyloid. FIGURE 3-20
Kyle and Gertz [5]; with permission.) (From Kyle and Gertz [5]; with permission.) Enlarged kidney in primary systemic amyloi-
dosis. Involvement of the kidneys is the
most common presenting feature. The kid-
ney is frequently normal in size, but in some
instances small kidneys have been found.
Amyloidosis 3.7
100
80
Survival, %
60
40
20
0
0 1 2 3
Years after dialysis

Photomicrograph showing a renal biopsy specimen stained with Survival analysis of patients with primary systemic amyloidosis.
Congo red dye taken from a patient with primary systemic amyloi- The median survival from the onset of dialysis was 8.2 months in
dosis. Note the homogeneous deposition of amyloid in the glomeru- 37 patients. No difference exists between patients treated with
lus. Results of kidney biopsy are positive in about 95% of patients. 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].

Gross specimen of a liver in primary systemic amyloidosis. The Photomicrograph showing extensive amyloid deposition in the liver
liver is grossly enlarged. in primary systemic amyloidosis.
ALKALINE PHOSPHATASE, ASPARTATE AMINOTRANS- PROTHROMBIN TIME, CAROTENE, AND B12 VALUES
FERASE, AND BILIRUBIN VALUES WITHIN 30 DAYS OF WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY
DIAGNOSIS OF PRIMARY SYSTEMIC AMYLOIDOSIS, SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 1981–1992
MAYO CLINIC, 1981–1992
Factor Patients, %
Factor Normal value Values above normal, n (%) Prothrombin time >13 s 16
Alkaline phosphatase ≤250 U/L >250 (26) Carotene <48 µg/dL 6
≥500 (11) Serum B12 <150 pg/mL 3
Aspartate aminotransferase ≤30 U/L >30 (34)
≥100 (3)
Total bilirubin ≤1.1 mg/dL >1.1 (11)
≥5 (1) 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.
FIGURE 3-25 It has been shown that prolongation of thrombin time occurs in
Alkaline phosphatase, aspartate aminotransferase, and bilirubin 40% of patients [10]. A deficiency in factor X occurs in 15% but
values within 30 days of diagnosis of primary systemic amyloido- is not associated with bleeding. Malabsorption as manifested by a
sis. The serum alkaline phosphatase level was increased in one low carotene or serum B12 level occurs infrequently. (Adapted from
fourth of 474 patients at the time of diagnosis. The aspartate Kyle and Gertz [5].)
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].)
PERCENTAGE OF BONE MARROW PLASMA CELLS

WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY SYS-
TEMIC AMYLOIDOSIS, MAYO CLINIC, 1981–1992
Plasma cells, % (median = 7%) Patients, % (n = 391)

≤5 44
6–9 16
10–19 22
≥20 18

Bone marrow aspirate specimen from a patient with primary systemic Percentage of bone marrow plasma cells within 30 days of diagno-
amyloidosis. This specimen contains an increase in plasma cells. sis of primary systemic amyloidosis. Almost half of patients had
5% or fewer plasma cells in the bone marrow at the time of diag-
nosis. About one fifth of patients had bone marrow plasmacytosis
of 20% or more. Multiple myeloma must be considered in this set-
ting. The plasma cells are monoclonal or . (From Kyle and
Gertz [5]; with permission.)
Amyloidosis 3.9
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 100
11% P=0.0003
75
Survival, %
15–19 mm < 15 mm (n=64)
≤11 mm 36% 50
24%
25
≥ 15 mm (n=57)
12–14 mm 0
29% 0 1 2 3 4 5
n=121 Time, y

Septal thickness on echocardiography in Analysis of the association between septal
patients with primary systemic amyloidosis. thickness and survival in patients with pri-
Almost half of patients had septal thickness mary systemic amyloidosis in an 11-year
of 15 mm or more on echocardiography at study at the Mayo Clinic. An increase in
the time of diagnosis. Only 24% had no septal thickness is associated with shorter
increased septal thickness. survival. Patients with a septal thickness of
FIGURE 3-31
15 mm or more had a median survival of
Echocardiogram of a patient with primary 7 months, whereas in those with a septal
systemic amyloidosis showing marked thickness less than 15 mm the median sur-
thickness of the ventricular wall. Results on vival was 26 months. (From Kyle and Gertz
echocardiogram are abnormal in two thirds [5]; with permission.)
of patients at the time of diagnosis. LV–left
ventricle; RV–right ventricle. (From Gertz
and Kyle [3]; with permission.)
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.)
FIGURE 3-35
40 At diagnosis Analysis of previously unexplained syndromes in patients with pri-
During follow-up mary systemic amyloidosis at the time of diagnosis in an 11-year
2 n=474 study at the Mayo Clinic. Nephrotic syndrome or renal failure was
30 present in 28% of patients, congestive heart failure (CHF) in 17%,
and carpal tunnel syndrome in 21%. Peripheral neuropathy and
Patients, %
5 0.5
20 orthostatic hypotension also were common features. The possibility
0.5
of primary systemic amyloidosis must be considered in every
1.5 patient who has monoclonal protein in the serum or urine and who
10 has unexplained nephrotic syndrome, CHF, sensorimotor peripher-
al neuropathy, carpal tunnel syndrome, hepatomegaly, or malab-
28 17 21 17 11 sorption. (Adapted from Kyle and Gertz [5]; with permission.)
0
Nephrotic/ CHF Carpal Peripheral Orthostatic
renal failure tunnel neuropathy hypotension
(142) (104) (102) (81) (58)
Symptoms (number of patients)
FIGURE 3-36
100 97 100 Diagnosis of primary systemic amyloidosis
94
90 86 based on the presence of amyloid in tissue
80 82 83 in an 11-year study at the Mayo Clinic.
80 75
The initial diagnostic procedure should be
an abdominal fat aspirate [11]. The diagno-
Positive, %
60 56
sis will be confirmed in 80% of patients.
Experience in the staining technique and
40
interpretation of the fat aspirate is important
before routine use. A bone marrow aspirate
20
and bone marrow biopsy specimen should
be obtained to determine the degree of plas-
0
Abdominal Bone Rectum Kidney Carpal Liver Small Skin Sural Heart macytosis, and results of amyloid stains are
fat marrow ligament intestine nerve positive in more than half of patients. Either
(212) (394) (194) (81) (20) (32) (23) (19) (21) (16) the abdominal fat aspirate or bone marrow
Presence of amyloid in tissue (number of patients) 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.)
Amyloidosis 3.11
100 Nephrotic/renal failure (n=114)

Congestive heart failure (n=80)
Orthostatic hypotension (n=41)
75 Peripheral neuropathy (n=40)
Total (n=474)
Survival, %
50
25
0
0 1 2 3 4 5 6 7 8
Time, y
Aspirate of subcutaneous abdominal fat from a patient with prima-
FIGURE 3-38
ry systemic amyloidosis. The specimen shows the characteristic
apple-green birefringence when stained with Congo red dye and Analysis of median survival in patients with primary systemic amy-
viewed with a polarizing light source. loidosis in an 11-year study at the Mayo Clinic. The median sur-
vival 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
Infection
8%
Causes of death in patients with primary systemic amyloidosis in an 11-year study at the
Renal Mayo Clinic. Of the 285 patients who died, death was attributed to cardiac involvement
6%
from congestive heart failure or arrhythmias in 48%. The actual percentage of cardiac-
related deaths was probably higher because some patients whose death was attributed to
Other primary amyloidosis almost certainly had terminal cardiac arrhythmia. (Adapted from
8% Kyle and Gertz [5]; with permission.)
Cardiac
Unknown 48%
13%
"Primary
amyloidosis"
17%
n=285
FIGURE 3-40
100
Arm Months Survival curves in patients with primary systemic amyloidosis. Because
MP 18 amyloid fibrils consist of monoclonal immunoglobulin light chains,
80
MPC 17 treatment with alkylating agents that are effective against plasma cell
C 8.5 neoplasms is warranted. We treated 220 patients who had positive
60 results on biopsy. The patients were randomized to receive colchicine
Patients, %
P<0.001 (C, 72 patients), melphalan and prednisone (MP, 77), or melphalan,

prednisone, and colchicine (MPC, 71). Patients were stratified accord-
40 ing to their chief clinical manifestations: renal disease (105 patients),
cardiac involvement (46), peripheral neuropathy (19), or other (50).
20 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,
0
0 1 2 3 4 5 6 7 8 9 10 prednisone, and colchicine (P < 0.001). In patients who had a reduc-
Survival, y
tion 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 sur-
vival was 36 months (P < 0.003). Thirty-four patients (15%) survived
for 5 years or longer. (Adapted from Kyle et al. [12]; with permission.)
FIGURE 3-41
OTHER THERAPY FOR PRIMARY AMYLOIDOSIS 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 dexamethasone high-dose chemotherapy followed by rescue with peripheral stem
Stem cell transplantation cells shows promise [14]. The introduction of 4-iodo-4-deoxy-
4’-iodo-4’-deoxydoxorubicin
doxorubicin, which has an affinity for amyloid fibrils, may be an
important treatment option [15].
Secondary Amyloidosis
CAUSES OF SECONDARY AMYLOIDOSIS PRESENTING CLINICAL FEATURES

OF SECONDARY AMYLOIDOSIS
Cause Patients, n
Rheumatic disease
Feature Patients, %
Rheumatoid arthritis 31 Proteinuria or renal insufficiency 91
Ankylosing spondylitis 5 Diarrhea, obstipation, or malabsorption 22
Other 6 Goiter 9
Total 42 Hepatomegaly 5
Infection Neuropathy or carpal tunnel syndrome 3
Inflammatory bowel disease 6 Lymphadenopathy 2
Bronchiectasis 5 Hematuria 2
Osteomyelitis 5 Cardiac amyloidosis 0
Other 3
Total 19
Malignancy 2
None 1 FIGURE 3-43
Presenting features of secondary amyloidosis. Proteinuria is the
most frequent laboratory finding in patients with secondary amy-
loidosis. Involvement of the gastrointestinal tract as manifested by
FIGURE 3-42 diarrhea, obstipation, or malabsorption occurred in one fifth of
Causes of secondary amyloidosis. Rheumatoid arthritis is the most our patients. Treatment of secondary amyloidosis depends on the
frequent cause of secondary amyloidosis. In our study of 64 underlying disease. Familial Mediterranean fever frequently is asso-
patients, rheumatoid arthritis was present for a median of 18 years ciated with secondary amyloidosis unless the patient is treated with
before the diagnosis was made [16]. Inflammatory bowel disease, colchicine. (From Gertz and Kyle [16]; with permission.)
bronchiectasis, and osteomyelitis are not uncommon causes of sec-
ondary amyloidosis. (From Gertz and Kyle [16]; with permission.)
25 FIGURE 3-44
Proteinuria and renal insufficiency in patients with secondary
20 19 amyloidosis. The clinical target organ was the kidney in 91% of
17 17 17 patients. (From Gertz and Kyle [16]; with permission.)
15 14 14 14
Patients, n
10
7
0
0 1–3 3–8 >8 ≤1 1.1–2 2.1–4 >4
24-h urinary protein, g/d Serum creatinine, mg/dL
n=55 n=64
Amyloidosis 3.13
FIGURE 3-45
100
Creatinine <2.0 mg/dL, n=32
Association between serum creatinine levels and survival in patients
Creatinine ≥2.0 mg/dL, n=32
with secondary amyloidosis. A serum creatinine value of 2 mg/dL or
80 P=0.003
more was associated with a shorter survival than was a value of less
than 2 mg/dL. (From Gertz and Kyle [16]; with permission.)
Survival, %
60
40
20
0
0 24 48 72 96 120
Time, mo
Familial Amyloidosis
FIGURE 3-46
Wide geographic distribution of familial amyloidosis. Familial or
2 1 hereditary amyloidosis has an autosomal dominant pattern of
inheritance. It accounts for 3.5% of our cases of amyloidosis. In
2
1
1 1 our practice, the geographic distribution is wide and not associated
2
1 1
6 1 5 with clustering. Frequently, a family history of amyloidosis was not
1 1 1 2
1 1 3 4
obtained until after amyloidosis was diagnosed [17]. More than 50
2
3 transthyretin mutations have been recognized [18]. (Adapted from
6 7 6 2
Gertz et al. [17]; with permission.)
2
3
2
2 3
Not studied for variant transthyretin

1 Met-30 3
2 Ala-60
3 Tyr-77
4 His-58
5 Leu-33
6 Studied—no variant transthyretin found
7 Leu-64
of bladder and gastrointestinal function are common. Late onset may

CLASSIFICATION OF FAMILIAL AMYLOIDOSIS 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 abdomi-
Classification Major protein component nal pain that begin in childhood.
Neuropathic: Portugal, Japan, Sweden, Transthyretin (prealbumin) Familial amyloidosis involving the kidneys has been reported by
and other countries Ostertag [19] and others [20–22]. Families with apolipoprotein A1
Cardiopathic: Denmark and Appalachia Transthyretin (prealbumin) mutation, as well as mutations in the fibrinogen -chain gene, have
in the United States been recognized. On presentation, patients with renal involvement
Nephropathic: familial Mediterranean Protein A exhibit hypertension and mild renal insufficiency that progresses to end-
fever stage renal failure. The amyloid deposits have mutations in the fibrino-
gen -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 substi-
FIGURE 3-47 tution of glutamic acid for valine at position 526 of the fibrinogen
Classification of familial amyloidosis. Clinically, familial amyloidosis chain. A mutation in fibrinogen has been described at position 554
can be classified most easily as neuropathic, cardiopathic, or nephro- [23,24]. A rare form of inherited secondary amyloidosis produces
pathic. The neuropathic form is characterized by a sensorimotor nephropathy, deafness, and urticaria. This form has been referred to as
peripheral neuropathy beginning in the lower extremities. Disturbances the Muckle-Wells syndrome [25]. (Adapted from Kyle and Gertz [26].)
Dialysis-Associated Amyloidosis
RATE OF AMYLOIDOSIS (2-MICROGLOBULIN)

WITH DIALYSIS
Years of dialysis Patients with amyloidosis, %

10 20
15 30–50
>20 80–100

Radiograph showing carpal tunnel syndrome in a patient Amyloidosis (2-microglobulin) with dialysis. The duration of dialy-
with dialysis-associated amyloidosis. Long-term hemodialysis sis is directly associated with the incidence of amyloidosis. Dialysis-
often results in carpal tunnel syndrome with pain involving associated amyloidosis will develop in more than 80% of patients
the shoulders, hands, wrists, hips, and knees. Cystic radiolucen- after 20 years of dialysis. It occurs with both hemodialysis and peri-
cies are common in the carpal bones. Pathologic fractures have toneal dialysis. The amyloid deposition is systemic; however, involve-
occurred from large amyloid deposits. The major component ment of visceral organs is usually modest [27,28]. Renal transplanta-
of the amyloid is 2-microglobulin. (From Gertz and Kyle [3]; tion often leads to dramatic improvement in joint symptoms. A 2-
with permission.) microglobulin–absorbent column may be useful in therapy [29].
Amyloidosis 3.15
References
1. Virchow R: Cited by Schwartz P: Amyloidosis: Cause and Manifestation 15. Gianni L, Bellotti V, Gianni AM, et al.: New drug therapy of amyloi-
of Senile Deterioration. Springfield, IL: Charles C Thomas; 1970. doses: resorption of AL-type deposits with 4-iodo-4-deoxydoxoru-
2. Puchtler H, Sweat F: Cited by Elghetany MT, Saleem A: Methods for bicin. Blood 1995, 86:855–861.
staining amyloid in tissues: a review. Stain Technol 1988, 63:201–212. 16. Gertz MA, Kyle RA: Secondary systemic amyloidosis: response and
3. Gertz MA, Kyle RA: Amyloidosis. In Neoplastic Diseases of the survival in 64 patients. Medicine 1991, 70:246–256.
Blood, edn 3. Edited by Wiernik PH, Canellos GP, Dutcher JP, et al. 17. Gertz MA, Kyle RA, Thibodeau SN: Familial amyloidosis: a study of
New York: Churchill Livingstone; 1996:635–677. 52 North American-born patients examined during a 30-year period.
4. Kyle RA: Amyloidosis. In Hematology: Basic Principles and Practice. Mayo Clin Proc 1992, 67:428–440.
Edited by Hoffman R, Benz EJ Jr, Shattil SJ, et al. New York: 18. Saraiva MJM: Molecular genetics of familial amyloidotic polyneu-
Churchill Livingstone; 1991:1038–1047. ropathy. J Peripheral Nerv Syst 1996, 1:179–188.
5. Kyle RA, Gertz MA: Primary systemic amyloidosis: clinical and labo- 19. Ostertag B: Demonstration einer eigenartigen familiaren “paraamyloi-
ratory features in 474 cases. Semin Hematol 1995, 32:45–59. dose” [abstract]. Zentralbl Allg Pathol 1932, 56:253–254.
6. Gertz MA, Kyle RA: Primary systemic amyloidosis: a diagnostic 20. Weiss SW, Page DL: Amyloid nephropathy of Ostertag with special
primer. Mayo Clin Proc 1989, 64:1505–1519. reference to renal glomerular giant cells. Am J Pathol 1973,
7. Kyle RA, Greipp PR: Amyloidosis (AL): clinical and laboratory fea- 72:447–460.
tures in 229 cases. Mayo Clin Proc 1983, 58:665–683. 21. Lanham JG, Meltzer ML, De Beer FC, et al.: Familial amyloidosis of
8. Gertz MA, Kyle RA, Greipp PR: Hyposplenism in primary systemic Ostertag. Q J Med 1982, 51:25–32.
amyloidosis. Ann Intern Med 1983, 98:475–477. 22. Mornaghi R, Rubinstein P, Franklin EC: Familial renal amyloidosis:
case reports and genetic studies. Am J Med 1982, 73:609–614.
9. Gertz MA, Kyle RA, O’Fallon WM: Dialysis support of patients with
primary systemic amyloidosis: a study of 211 patients. Arch Intern 23. Benson MD, Liepnieks J, Uemichi T, et al.: Hereditary renal amyloi-
Med 1992, 152:2245–2250. dosis associated with a mutant fibrinogen alpha-chain. Nat Genet
1993, 3:252–255.
10. Gastineau DA, Gertz MA, Daniels TM, et al.: Inhibitor of the throm-
bin time in systemic amyloidosis: a common coagulation abnormality. 24. Uemichi T, Liepnieks JJ, Benson MD: Hereditary renal amyloidosis
Blood 1991, 77:2637–2640. with a novel variant fibrinogen. J Clin Invest 1994, 93:731–736.
11. Gertz MA, Li C-Y, Shirahama T, Kyle RA: Utility of subcutaneous fat 25. Muckle TJ: The “Muckle-Wells” syndrome. Br J Dermatol 1979,
aspiration for the diagnosis of systemic amyloidosis (immunoglobulin 100:87–92.
light chain). Arch Intern Med 1988, 148:929–933. 26. Kyle RA, Gertz MA: Amyloidosis of the liver. In Schiff’s Diseases of
12. Kyle RA, Gertz MA, Greipp PR, et al.: A trial of three regimens for pri- the Liver, edn 8. Edited by Schiff ER, Sorrell MF, Maddrey WC.
mary amyloidosis: colchicine alone, melphalan and prednisone, and mel- Philadelphia: Lippincott-Raven; in press.
phalan, prednisone, and colchicine. N Engl J Med 1997, 336:1202–1207. 27. Gejyo F, Arakawa M: 2-microglobulin-associated amyloidoses. J Intern
13. Dhodapkar M, Jagannath S, Vesole D, et al.: Efficacy of pulse dexam- Med 1992, 232:531–532.
ethasone (DEX) plus maintenance alpha interferon (IFN) in primary 28. Kay J: 2-Microglobulin amyloidosis. Int J Exp Clin Invest 1997,
systemic amyloidosis (AL) [abstract]. Blood 1995, 86(suppl 1):442A. 4:187–211.
14. Comenzo RL, Vosburgh E, Sarnacki DL, et al.: High-dose melphalan 29. Gejyo F, Homma N, Hasegawa S, et al.: A new therapeutic approach
with blood stem-cell support for AL amyloidosis [abstract]. Blood to dialysis amyloidosis: intensive removal of 2-microglobulin with
1995, 86 (suppl 1):206A. adsorbent column. Artif Organs 1993, 17:240–243.
Sickle Cell Disease
L.W. Statius van Eps
H
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 concen-
trate urine normally.
CHAPTER
4
Sickle Cell Nephropathy

The term sickle cell nephropathy encompasses all the structural ease, sickle cell hemoglobin E disease (SE) disease, and sickle
and functional abnormalities of the kidneys seen in sickle cell cell -thalassemia. Identification of this familial autosomal
disease. These renal defects are most pronounced in homozy- codominant disorder as an abnormality of the hemoglobin mol-
gous sickle cell anemia (Hb SS), double heterozygous sickle cell ecule was made in 1949 by Pauling and coworkers [2].
hemoglobin C disease (Hb SC), sickle cell hemoglobin D dis-
Sickle Cell Anemia

In 1959, Ingram [3] discovered the exact nature of the defect: polymerization of Hb S occurs easily and can be regarded as a
substitution of valine for glutamic acid at the sixth residue of the simple crystal solution equilibrium [4].
chain, establishing sickle cell anemia as a disease of molecular As a rule, renal hemodynamics are either normal or super-
structure, “a molecular disease” based on one point mutation. It normal in patients with Hb SS and who are less than 30 years
is most fascinating that one substitution in the gene encoding, of age. The filtration fraction (glomerular filtration rate/effec-
with the resulting replacement of 6 glutamic acid by valine, tive renal plasma flow) has been found to be decreased (mean,
leads to the protean and devastating clinical manifestations of 14% to 18%; normal, 19% to 22%). It has been suggested that
sickle cell disease. The structural and functional abnormalities in selective damage of the juxtamedullary glomeruli might result
the kidneys of patients with sickle cell disease, all resulting from in a lower filtration fraction because these nephrons appear to
that one point mutation, are described and discussed. have the highest filtration fractions. Microradioangiographic
When sickle hemoglobin (Hb S) is deoxygenated the replace- studies lend support to this suggestion [5].
ment of 6 glutamic acid with valine has as a consequence a Speculation exists as to the possible mechanisms responsi-
hydrophobic interaction with another hemoglobin molecule ble for the decline in renal hemodynamics with age, some-
(reproduced schematically in Fig. 4-3). One of the two sub- times ending in renal failure with shrunken end-stage kidneys.
units forms a hydrophobic contact with an acceptor site on a This decline could be the result of the loss of medullary circu-
subunit of a neighboring chain. An aggregation into large lation, as suggested by the microradioangiographic studies.
polymers is triggered. The twisted ropelike structure to the right Another possible mechanism is the relationship between
is a polymer composed of 14 strands. supernormal hemodynamics, hyperfiltration, and glomeru-
In a concentrated solution of deoxygenated Hb S, large poly- losclerosis [6].
mers and free tetramers are demonstrated readily. However, An inability to achieve maximally concentrated urine has
species of intermediate size cannot be detected. This means been the most consistent feature of sickle cell nephropathy.
Sickle Cell Disease 4.3
Molecular Pathogenic Mechanisms and Sickling

FIGURE 4-1
EF1
EF Three-dimensional drawing of a hemoglo-
bin molecule. Shown are the interrelation-
F'
β2 F1 β1 ship of the two and two chains, local-
ization of the helices, amino acids in the
A9 H23 chains, and iron molecules in the porphyria
F E' A'
A
H15
structure. Of the 1 and 2 chains the heli-
F8 cal and nonhelical segments can be identi-
H H'
B1
fied easily. The individual amino acids are
B E7
H9 FG3
FG4 marked as circles and connected to each
G9 C3
G C3
G1 G' C B14 other. The dark rectangles represent the
C4 C6 CD5 heme group, and within their center is the
G19 E C'
E1 iron molecule. These heme groups are local-
B11 G3 C7 B9
E1 C6 ized between the E and F helices. The helices
CD5 G' C5 G1
C C3 G2 G
G9
G19 in a hemoglobin molecule are designated by
FG5
C5 FG4
letters from A to H, starting from the
FG3
F'
H9 E7 B amino end. The whole molecule has a
E E7 spherical form with a three-dimensional
D1 F8
H' FG4 H
F measurement of 64 by 55 by 50 Å.
H15 A12
E' A
(Adapted from Dickerson and Geis [7];
with permission.)
α2 A' A1 α1
EF EF1
Respiratory Movement of the Hemoglobin Molecule

Shift of
FIGURE 4-2
β chains Respiratory movement of a hemoglobin
molecule. From a functional point of view
F F the so-called respiratory movement of the
β1 E β2 β1 B' E β2 hemoglobin molecule is of great impor-
A A
F'
B' H' A' tance. When the four oxygen atoms bind to
F'
H' oxyhemoglobin, the firmly bound 1-1
H H
and 1-2 move away from each other
G G slightly. After full oxygenation the heme
GH GH
C B C B groups of the chains are 7 Å closer to
C G' C
G
G'
B G each other (R configuration). After deoxy-
B D D
E E genation the opposite occurs (T configura-
GH GH tion). This “respiratory movement” (R indi-
H H
F' cates the relaxed and T the tense configura-
α1 F' α2 α1 α2
A A tion) is of great importance in our
F F understanding of the pathogenesis of sick-
ling: polymerization occurs when the T
configuration takes place. (Adapted from
Oxyhemoglobin Deoxyhemoglobin Dickerson and Geis [7]; with permission.)
FIGURE 4-3
Schematic representation of the interactions
β α α β of sickle red cells. Sickle red cells (dark circles)
traverse the microcirculation, releasing oxy-
β α α β gen from oxyhemoglobin, and change into
O2 deoxyhemoglobin (light circles).
Deoxygenation of hemoglobin S induces a
change in conformation in which the sub-
units move away from each other. The
β hydrophobic patch at the site of the 6
α
β where the valine replacement has occurred
β α (shown as a projection) can bind to a com-
α
β plementary hydrophobic site of the 6 valine
α β replacement (shown as an indentation). This
α mechanism is important for the formation of
β
β α a polymer (see Fig. 4-4). The diagram to the
α
right shows the assembly of deoxyhemoglo-
β
α β bin S into a helical 14-strand fiber: a poly-
α mer is formed (see Fig. 4-5). As the deoxyhe-
β
β α moglobin S polymerizes and fibers align, the
α erythrocyte is transformed into a “sickle”
β shape, observed at the bottom by scanning
α
electron micrography. (Adapted from Bunn
[4]; with permission).
Cell
Polymer
FIGURE 4-4
Nucleation 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 erythro-
cytes that causes elevation of the intracellular hemoglobin concentration. This mechanism
Alignment Growth 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].
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. B–D, 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.)
A B C D
Polymerization of Hemoglobin S
A B
FIGURE 4-6
Polymerization of hemoglobin S. Polymerization of deoxygenated on the localization of the polymers in the cell. A collection of electron
hemoglobin S is the primary event in the molecular pathogenesis of microscopy scans of sickle cells undergoing intracellular polymeriza-
sickle cell disease, resulting in a distortion of the shape of the erythro- tion is shown here. The slides were created in different laboratories.
cyte and a marked decrease in its deformability. These rigid cells are A, Characteristic peripheral blood smear from a patient with sickle cell
responsible for the vaso-occlusive phenomena that are the hallmark of anemia. Extreme sickled forms and target cells are seen. B, Electron
the disease [4]. Interesting shapes of variable forms result depending microscopy scan of normal erythrocytes.
C D E
F G
H I J
C, Electron microscopy scan of a normal
erythrocyte and a sickle cell. D–L, This
series of sickle cells show many possible
formations of sickled erythrocytes. The
variety of shapes results from the intracellu-
lar localization of the polymers. In banana-
or sickle-shaped cells the polymers have
formed bundles of fibers oriented along the
long axis of the cell. In cells with a holly-
leaf shape (panel E), the hemoglobin fibers
point in different directions.
K L
Types of Sickle Cells and Released Membrane Structures
A B
C D
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 present-
ed evidence of enhanced trans-bilayer movement of phosphatidyl-
choline 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 irre-
versibly 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, explain-
E ing 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 for-
mation 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.)
Penetration and Deconstruction

of the Erythrocyte Membrane
Spicule formation in sickled erythrocyte Spicule formation in

sickled erythrocyte
FIGURE 4-8
Penetration and destruction of the erythrocyte membrane. A, The
membrane is penetrated and destroyed by the intracellular forma-
tion 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 ten-
dency toward coagulation of sickle cell blood (prethrombotic
Band 3 Actin Band 4.1 Spectrin Ankyrin
state). C, The relationship between the protein skeleton of the
C erythrocyte and lipid membrane is shown. (Adapted from Franck
C E
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 radiat-
ing 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.)
Renal Concentrating Mechanism in a Normal Person

Juxtamedullary nephron
1200
Urine osmolality, mosmol/kg
600
Cortex
400
0
1 5 10 50 100 500
A Urine arginine vasopressin, pg min–1 C –1osm
FIGURE 4-10
A–H, Models to demonstrate the principle of countercurrent multi-
Thin
plier in creating high urine concentration. The first panel illustrates
segment
Medulla
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 Vasa
population but are necessary for producing concentrated urine recta
[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 collect-
ing ducts results in production of highly concentrated urine.
B
Urine concentration and dilution: countercurrent multiplier FIGURE 4-10 (Continued)
285 285 285 185 285 185 285 285
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
1 2 3 4
Urine concentration and dilution: countercurrent multiplier
Loop of Henle
Descending Ascending Collecting

limb limb duct
285 100
285 100 285
ADH
H 2O
Na+Cl– Urea
300 300 300 100 300 300 300 Urea 100 300 300
H 2O
ADH
H 2O
Na+Cl– Urea
525 525 525 325 525 525 525 Urea 325 525 525
H 2O
ADH
H 2O
Na+Cl– Urea
750 750 750 550 750 750 750 Urea 550 750 750
H 2O
ADH
H 2O
Na+Cl– Urea
975 975 975 775 975 975 975 Urea 775 975 975
H 2O
1200 Na+Cl– ADH
Urea
H 2O H 2O
1200 Urea
1200 1200 1000 1200 1200 1000 1200 1200
Urine
5 6
D
Urine concentration and dilution: countercurrent diffusion (exchange) FIGURE 4-10 (Continued)
285 100
285 315 300
Na+Cl– Na+Cl–
300 300 Urea 100 300 Urea
H 2O H 2O Na+Cl–
300 Urea
H 2O
Na+Cl– Na+Cl– 525 525

525 525 Urea 325 525 Urea
H 2O H 2O Na+Cl–
Urea
525 H 2O
Na+Cl– Na+Cl–
Urea 750 750
750 750 Urea 550 750
H 2O H 2O
Na+Cl–
Urea
H 2O
750
Na+Cl–
Na+ Cl–
Urea 975 975
975 975 Urea 775 975 H 2O
H 2O
Na+Cl–
Na+Cl– Urea
975 H 2O
Urea
H 2O Na+Cl–
1200 Urea
1200 1200 1000 H 2O 1200 1200
Loop of Henle Vasa recta

(countercurrent multiplier system) (countercurrent exchange system)
E
Urine concentration and dilution: countercurrent diffusion (exchange)
285 285 315
300 Solute Solute 300 300 Solute Solute 300

H 2O H 2O H 2O H 2O
300 300
525
H 2O H 2O H 2O H 2O
525
525
750
H 2O H 2O H 2O H 2O
750
750
975 Solute Solute 975 975 Solute 975 Solute 950

H 2O H 2O H 2O H 2O
975
1200 Solute Solute 1200 1200 Solute 1200

H 2O H 2O H 2O
1200
1 2
F

Urine concentration and dilution: diluting kidney
280 280
% of fil
0
28
Na+Cl–H O Urea 20
trat
Na+Cl–
Cortex
2 100
e
H 2O
Urea
280 280
Na+Cl–
10
H 2O
0% of
Urea
280 280 lt r a 100 280
i f
te
280
2 5 % of filtrate
3 0 % of filtrate
300
280
100
280 280
Na+Cl– Na+Cl–
Na+Cl–
H 2O
300
325
H 2O
Na+Cl– H 2O
H 2O Na+Cl–
300 300 100 100 300
Na+Cl– Na+Cl– H 2O
H 2O H 2O Na+Cl– Na+Cl–
Na+Cl–
Medulla
325
350
325 325 125 325

H 2O
Na+Cl– Na+Cl– 100
H 2O
Na+Cl– 150 H 2O
H 2O Na+Cl– Na+Cl–
350 350 350
Na+Cl–
350
375
H 2O
Na+ Cl –
H 2O Na+Cl– H 2O
H 2O Na+Cl– 100
375 375 175 375

Na+Cl– Na+Cl–
H 2O
375
Na+Cl–
te 400
H 2O
400 400 tra 400
2 0 % o f f il 100
10% of
filtrate
G

Urine concentration and dilution: concentrating kidney
285 285
% of fil
5
28
Na+Cl–H O Urea 20
trat
Na+Cl–
Cortex
2 100
e
H 2O
Urea H 2O
285 285
Na+Cl–
10
H 2O 200
0% of
Urea H 2O ADH
285 285 lt r a 100 285
i f
te
285
2 5 % of filtrate
3 0 % of filtrate
375
225
285
300 Na+Cl– Urea 300

Urea + – H 2O ADH
H 2O 100 Na Cl
Urea
H 2O
300
Na+Cl– ADH Na+Cl–

525
Urea Na+Cl–
H 2O Na+ Cl –
H 2O
Urea Urea
H 2O Na+Cl–
525 525 325 Urea 525
525
H 2O
525
Na+Cl–
Urea Na+Cl– Na+Cl– ADH
Medulla
H 2O
750
H 2O
Na+Cl– Urea
750 750 Urea 550 Na+Cl– 750
H 2O Urea
H 2O 750
750
Na+Cl–
Urea Na+Cl– ADH Na+Cl–
H 2O
Na+ –
975
Cl
Urea H 2O
975 975 H 2O 775 Na+Cl– Urea 975
Urea
H 2O 975
Na+Cl–
Urea Na+Cl–
H 2O ADH
Na+Cl–
975
+ –
120 Na Cl 0 H 2O
1200 0 100 120
0
Urea 1200
25% of f iltrate 1200
1% of
filtrate
H
Relationship Between Maximal Urinary Osmolality and Age

Hemoglobin AA AS SS SC ACo CCo heterozygotous hemoglobin disease (Hb AS),
1400 sickle cell hemoglobin C disease (SC), hemo-
Maximum osmolality, mosm/kg H2O
globin C trait (AC), and hemoglobin C disease

1200 (Hb CC). Normal persons have a mean maxi-
1000 mal urinary osmolality of 1058 ±SD 128
mOsm/kg H2O. The most marked impairment
800 in concentrating capacity occurs in Hb SS dis-
ease. Maximal urinary osmolality decreases
600
significantly in the first decade of life and sta-
400 bilizes in patients over 10 years of age at a
mean of 434 ±SD 21 mOsm/kg H2O. The
200 measurement has been designated the fixed
0 maximum of sickle cell nephropathy. In
0 20 40 60 0 20 40 60 0 20 40 60 0 20 40 60 0 20 40 60 80 patients with Hb AS and Hb SC, a progressive
Age, y decrease in maximal urinary osmolality can be
observed with age. C hemoglobin alone (AC
or CC) does not impair the concentrating abil-
FIGURE 4-11 ity of the kidneys. The renal concentrating
Relationship between maximal urinary osmolality and age in normal subjects and in patients capacity of the heterozygote (Hb AS) also is
with hemoglobinopathies. Results of an investigation into a large group of normal persons and affected, but only later in life. (Adapted from
those with homozygotous hemoglobin disease (Hb SS; Hb SS + Hb F), van Eps et al. [13]; with permission.)
Relationship Between Nephron with Long

Loops and Those with Short Loops of Henle
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
Cortex
medullary zone. These nephrons may be largely responsible for achiev-
ing 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
Subcortex
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 originat-
ing in the juxtamedullary cortex. In such animal preparations, a severe
Outer medulla 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 resul-
Inner medulla tant 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 nor-
mal circulation through the vasa recta, preventing both active and pas-
sive accumulation of solute in the papillae necessary to achieve maxi-
mally 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.
Relationship Between Concentrating

Capacity and Patient Age
FIGURE 4-13
Aug. Sept. Oct. Nov. Dec. Jan Feb Mar.
31 10 20 30 10 20 30 10 20 30 10 17 20 30 10 20 1 A–E, Relationship between concentrating
W.J. 4 y. capacity and patient age. Over a prolonged
Red blood cell- period, we investigated the effect of multi-
suspension ple transfusions of hemoglobin A erythro-
175 mL cytes into children and adults with sickle
20 cell anemia (4, 7, 11, 15, and 40 years). In
content,
the first panel, the effects of multiple trans-

g%
Hemoglobin, Hb
5 fusions of normal blood given to a 4-year-

old boy with homozygotic sickle cell ane-
100 mia. A significant improvement in concen-
%
0 trating capacity can be observed. This

A S F diminishes in older patients.
CInuline , CCreatinine , Urine osmolality,

mL/min mL/min mosm/kg H2O
900
700
500
200
50
200
50
1500
mL/min
CPAH ,
1000
500
fraction, %
Filtration
15
5
A
June July Aug. Sept.

May June July Aug. Sept. Jan. Mar. 10 20 30 10 20 30 10 20 30 10 20
31 10 20 30 10 20 30 10 20 30 10 6 3 M.V. 11 y.
F.A. 7 y.
Red blood cell-
Red blood cell- suspension
suspension 350 mL
350 mL
content,
15
g%
CCreatinine , Urine osmolality, Hemoglobin, Hb
content,
15
g%
Hemoglobin, Hb
5
5
100
%
100
%
0
0 A S F
A S F
mosm/kg H2O
CInuline , CCreatinine , Urine osmolality,
800
mL/min mL/min mosm/kg H2O
1100 600
900 400
700
mL/min
200 200
50 50
200 200
mL/min
CInuline ,
50 50
1500 2000
mL/min
mL/min
CPAH ,
CPAH ,
1000 1500
500 1000
fraction, %
Filtration
fraction, %
Filtration
20 15
10 10
5
B C


Dec. Feb.
'62 '65 Apr. May June July Aug. Sept. Oct. Nov.
29 25 22 30 10 20 30 10 20 30 10 20 30 10 20 30 10 20 30 10 20 30 10 20
M.K. 15 y.
Red blood cell-
suspension
350 mL
content,
15
g%
Urine osmolality, Hemoglobin, Hb
100 A
S
%
F
0
mosm/kg H2O
800
600
400
CCreatinine ,
200
mL/min
50
200
mL/min
CInuline ,
50
1500
mL/min
CPAH ,
1000
500
Filtration
fraction,
20
%
10
May June July Aug.

1 10 20 30 10 20 30 10 20 30 10 20
A.P. 40 y.
Red blood cell-
suspension
300 mL
content,
15
g%
CInuline , CCreatinine , Urine osmolality, Hemoglobin, Hb
5
100 A
%
S
F
0
mL/min mosm/kg H2O
800
600
400
200
50
200
mL/min
50
1500
mL/min
CPAH ,
1000
500
Filtration
fraction,
20
%
10
E
Relationship Between Age and Ability to Reverse the

Defect in Urinary Concentration by Blood Transfusions
FIGURE 4-14
1100 8 patients; van Eps [12] 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
Maximal urinary osmolality, mosm
6 patients; Keitel [13]

achieved before transfusion (lower point of each vertical line) and after multiple transfu-
sions with normal blood (upper point of each vertical line) in 14 patients with sickle cell
800 disease, ranging in age from 2 to 40 years. B, The percentage of increase in maximal uri-
nary osmolality resulting from transfusion. Maximal urinary osmolality before transfusion
is depressed at all ages; significant improvement after transfusion occurs only in children
500 and adolescents. (From van Eps et al. [13]; with permission.)
200
A
100
Increase in maximal urinary osmolality, %
80
60
40
20
0
0 10 20 30 40 50
B Time, y
Length of the Loops of Henle in Animals

Correlated with Kidney Concentrating Capacity
FIGURE 4-15
Normal kidney Sickle cell kidney
14% juxtamedullary Beaver kidney Length of the loops of Henle in animals
nephrons with long loops Long loops of Henle correlated with kidney concentrating capac-
not functioning ity. A, Investigations of animal species [14]
Cortex Medulla or absent with different lengths of the loops of Henle
and correlation with the concentrating
Outer
Inner
zone
capacity of their kidneys reveal their rela-

Sickle cell trait: tionship. B, Desert animals with very long
Progressive loss in 70 y of loops of Henle can produce highly concen-
inner medullary trated urine; in contrast, beavers living in
concentrating function
water-rich surroundings have only short
loops of Henle and cannot produce urine
Sickle cell anemia: concentrate over 450 mOsm.
A. Up to about 15 y: reversible
concentrating defect (Continued on next page)
B. Over 15 y: complete and irreversible
loss of inner medullary
concentrating function
A
B Beaver Rabbit Psammomys

In sickle cell disease the long loop of Henle has been obliterated 400 mosm, much as in beavers. An overview has been reproduced.
and the concentrating capacity of the kidney is not higher than (From van Eps and De Jong [15]; with permission.)
Urinary Acidification
FIGURE 4-16
SS Anemia
A, Urinary acidification. Patients with
75 70
Ammonium chloride Ammonium chloride hemoglobin SS or SC demonstrate an
incomplete form of renal tubular acidosis.
T.A., µ-equiv/min/1.73 m2
In response to a short-duration acid load,

74 50 all of the patients studied by Goossens and
Blood pH
coworkers [16] with otherwise normal renal

function were unable to decrease urine pH
30 below 5.3, whereas normal persons achieve
73 a urinary pH of 5.0 or lower. Titrateable
acid (TA) and total hydrogen ion excretion
10 are lower in patients with Hb SS or Hb SC;
72 however, in most cases, ammonia excretion
2 4 6 8 10 2 4 6 8 10 is appropriate for the coexisting urine pH.
The acidification defect has been classified
Ammonium chloride
90
Ammonium chloride as distal rather than proximal, because no
7.0
associated wasting of bicarbonate occurs,
and the acidification defect is characterized
by failure to achieve a normal minimal uri-
NH4+, µ-equiv/min/1.73 m2
70
nary pH during acid loading. Investigators
from several centers have found no evi-
Urinary pH
6.0
dence of metabolic acidosis in the absence
50
of a sickle cell crisis; however, they have
found changes consistent with mild chronic
respiratory alkalosis [15].
5.0 30
10
4.0
2 4 6 8 10 2 4 6 8 10
A Time, h Time, h

Normals SC B, Relationship between renal concentrating and acidifying capacity
AS SS in Hb AS, SC, and SS and in normal persons [16].
1200
Maximal urinary osmolality
1000
800
600
400
4.4 4.6 4.8 5.0 5.2 5.4 5.6 5.8 6.0

B Minimal urinary pH
Tubular Reabsorption of Phosphate

in Sickle Cell Nephropathy
FIGURE 4-17
0.50 0.50
Relationship between Cp/glomerular filtration rate and serum phos-
phate. Closed circles represent values for patients who had fasted
0.40 0.60
TmP/GFR 2.5–4.2 from food and drink; open circles are values obtained when UpV
was 0.032 mmol/min. The continuous line shows the mean of the
0.30 0.70 values in patients with sickle cell anemia, and the hatched area
T.R.P.
UV/L
indicates the range for normal persons. Cp—clearance of phos-

0.20 0.80 phate; TmP/GFR—tubular maximum reabsorption of phosphate/
+ glomerular filtration rate. (Adapted from De Jong and coworkers
0.10 0.90 [17]; with permission.)
+
0 1.00
0 1 2 3 4 5 6 7 8
Phosphate, mg/100 mL
Blood Pressure in Sickle Cell Disease

FIGURE 4-18
Male Female Blood pressure and sickle cell anemia. Mean standard deviation of
180
ns ns ns ns <0.05 <0.01 ns P
systolic and diastolic blood pressure in control subjects (dotted
lines) and patients with sickle cell anemia (closed lines) who are
160 matched for age and gender. (From De Jong and van Eps [20].)
Systolic
140
120
mm Hg
100
80 Diastolic
60
<0.01 <0.01 ns ns <0.02 <0.05 <0.05 P
15–24 25–34 35–44 45–54 15–24 25–34 35–44 45–54

Age, y
References
1. Herrick JB: Peculiar elongated and sickle shaped red blood corpuscles 11. Frank PFH: Studies on the phospolid organization in membranes of
in a case of severe anemia. Arch Intern Med 1910, 6:517. abnormal erythrocytes [PhD thesis]. Utrecht: State University of
2. Pauling L, et al.: Sickling cell anemia, molecular disease. Science 1949, Utrecht; 1984.
110:543. 12. Statius van Eps LW, Schouten H, Ter Haar Romeny Wachter CCh, la
Porte-Wijsman LW: The relation between age and renal concentrating
3. Ingram VM: Gene mutations in human hemoglobin: the chemical
capacity in sickle cell disease and hemoglobin C disease. Clin Chim
difference between normal and sickle cell hemoglobin. Nature 1959,
Acta 1970, 27:501.
180:326.
13. Statius van Eps LW, Schouten H, la Porte-Wijsman LW, Struyker
4. Bunn HF: Mechanisms of disease: pathogenesis and treatment of sick- Boudier AM: The influence of red blood cell transfusions on the
le cell disease. N Engl J Med 1997, 337:762–769. hyposthenuria and renal hemodynamics of sickle cell anemia. Clin
5. Statius van Eps LW, Pinedo Veels C, De Vries H, De Koning J: Nature Chim Acta 1967, 17:449.
of concentrating defect in sickle cell nephropathy, microradioangio- 14. Schmidt-Nielsen B, O’Dell R: Structure and concentrating mechanism
graphic studies. Lancet 1970, 1:450. in the mammalian kidney. Am J Physiol 1961, 200:1119.
6. Hostetter TH, et al.: Hyperfiltration in remnant nephrons: a potential- 15. Keitel HG, et al.: Hyposthenuria in sickle cell anemia: a reversible
ly adverse response to renal ablation. Am J Physiol 1981, 241:F85. renal defect. J Clin Invest 1956, 35:998.
7. Dickerson RE, Geis I: The Structure and Action of Proteins. New 16. Statius van Eps LW, De Jong PE: Sickle cell disease. In Diseases of the
York: Harper and Row, 1969, 1971. Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little,
8. Perillie PE, Epstein, FH: Sickling phenomenon produced by hyperton- Brown; 1997:2201.
ic solutions: a possible explanation for the hyposthenuria of sicklemia. 17. Goossens JP, Statius van Eps LW, Schouten H, Gieterson AL:
J Clin Invest 1963, 42:570. Incomplete renal tubular acidosis in sickle cell disease. Clin Chim
9. Edelstein SJ: Structure of the fibers of hemoglobin S: human hemoglo- Acta 1972, 41:149.
bins and hemoglobinopathies: a review to 1981. Galveston: University 18. De Jong PE, et al.: The tubular reabsorption of phosphate in sickle
of Texas; 1981. cell nephropathy. Clin Sci 1978, 55:429.
10. Franck PF, Bevers EM, Lubin BH, et al.: Uncoupling of the membrane 19. De Jong PE, Landman H, Statius van Eps LW: Blood pressure in sickle
skeleton from the lipid bilayer: the cause of accelerated phospholipid cell disease. Arch Intern Med 1982, 142:1239.
flip-flop leading to an enhanced procoagulant activity of sickled cells. 20. De Jong PE, Statius van Eps LW: Sickle cell nephropathy: new insights
J Clin Invest 1985, 75:183–190. into its pathophysiology. Editorial review. Kidney Int 1985, 27:711.
Renal Involvement
in Malignancy
Richard E. Rieselbach
A. Vishnu Moorthy
Marc B. Garnick
P
atients with malignancy are particularly vulnerable to development
of renal abnormalities [1]. Additionally, patients with renal abnor-
malities 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, how-
ever, 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 neo-
plasms 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 pro-
ducing obstruction of urine flow via extrinsic compression of the urinary
tract. This occurs most often with gynecologic and other pelvic neo-
plasms in women and with prostatic cancer in men.
Systemic manifestations of cancer may involve the kidney via forma-
tion 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 hyper-
calcemia and hyperuricemia, may impair renal function.
Finally, a high percentage of cancer patients are candidates for aggres-
CHAPTER
sive chemotherapy or radiation therapy, or both. Nephrotoxicity due to
5
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 pro-
duce significant renal damage.
FIGURE 5-1
CLINICAL SYNDROMES OF RENAL Clinical syndromes of renal involvement in malignancy. Renal
INVOLVEMENT IN MALIGNANCY 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
Acute renal failure malignancy may directly involve the transplanted kidney.
Prerenal
Intrinsic
Postrenal
Hematuria and/or nephrotic syndrome
Specific tubular dysfunction and associated fluid and electrolyte disorders
Malignancy in the renal transplant patient
Prerenal Acute Renal Failure

caused by excessive loss from the gastroin-
testinal tract due to vomiting or diarrhea
CAUSES OF PRERENAL ACUTE RENAL FAILURE
induced by cancer or its therapy. Also, hypov-
olemia may occur owing to internal fluid loss
due to translocation of ECF volume with
Clinical syndrome Cause sequestration in third spaces, as seen in peri-
ECF volume contraction (hypovolemia) External fluid loss (skin, gastrointestinal, renal, hemorrhage) tonitis, bowel obstruction, malignant effusion,
Internal fluid loss (peritonitis, bowel obstruction, acute pancreatitis, or interleukin-2 therapy [8].
hemorrhage, malignant effusion) A decrease in effective intravascular volume
Peripheral vasodilation Sepsis may occur owing to peripheral vasodilation,
Anaphylaxis as frequently noted in sepsis. A decrease in
Anesthesia cardiac output due to cardiac tamponade sec-
Drug overdose ondary to malignant pericardial disease also
Impaired cardiac function Myocardial infarct, failure may produce prerenal ARF. Hepatobiliary dis-
Arrhythmia ease may cause alterations in intrarenal hemo-
Pericardial tamponade dynamics with resultant hepatorenal syn-
Pulmonary embolus drome, as seen in hepatic veno-occlusive dis-
Bilateral extrarenal vascular occlusion Arterial ease following bone marrow transplantation
Venous
(see Fig. 5-3). The administration of nons-
teroidal anti-inflammatory agents for analge-
Functional disorders of intrarenal circulation Hepatorenal syndrome
sia in the cancer patient may lead to ARF by
Drugs that inhibit prostaglandin synthesis
elimination of the prostaglandin-mediated
intrarenal vasodilatation. This homeostatic
mechanism represents a critical hemodynamic
adjustment necessary for maintaining
FIGURE 5-2 glomerular filtration rate in a patient with
Causes of prerenal failure (ARF). Prerenal ARF is encountered frequently in the cancer patient, cancer in whom renal blood flow may be
particularly in association with depletion of the extracellular fluid (ECF) volume, which is decreased owing to a variety of causes.
Renal Involvement in Malignancy 5.3
60
ic-uremic syndrome (HUS) can be observed. As noted, the greatest
risk for development of ARF occurs 10 to 21 days after BMT, with
50 the usual cause at this time being prerenal acute renal failure due to
Azotemia hepatic veno-occlusive disease. This causes a syndrome very similar to
40 the hepatorenal syndrome (HRS). There are five clinical similarities
Patients, %
between the two syndromes: 1) jaundice and portal hypertension pre-

30
Tumor Stored cede the onset of ARF, 2) a very low fractional excretion of sodium
20
lysis marrow always occurs, 3) the blood urea nitrogen (BUN)/creatinine ratio is
syndrome toxicity HUS
ARF CSA very high, 4) mild hyponatremia and a decrease in systemic arterial
10 blood pressure are usually present, and 5) postmortem examination
of patients dying of this syndrome fails to reveal any structural or
0 morphologic basis for ARF, suggesting a hemodynamic cause [9].
–10 0 7 14 21 28 1y In contrast to the very high incidence of hepatic VOD in patients
Conditioning Time, d 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
FIGURE 5-3 and autologous hematopoietic support for high-risk breast cancer
Time distribution and frequency of renal syndromes in the setting of revealed a frequency of hepatic VOD of 4.7 %, as compared with a
bone marrow transplantation (BMT). The solid line depicts the reported incidence ranging from 22% to 53% in various series of
approximate frequency of renal insufficiency, as defined by at least a patients undergoing allogeneic bone marrow transplantation [10]. In
doubling of the baseline serum creatinine concentration (azotemia); this series of autologous transplants, 21% of patients developed
the dotted line represents the frequency of dialysis required because of severe renal dysfunction, which correlated most significantly with sep-
acute renal failure (ARF). During the period of conditioning, tumor sis, liver, and pulmonary disease. The major incidence of renal failure
lysis syndrome and stored marrow-infusion toxicity are most com- occurred during chemotherapy, before the initiation of hematopoietic
mon; 10 to 28 days after transplantation, the peak incidence of ARF cell support, thereby primarily incriminating the cytoreductive thera-
is observed, most notably due to a hepatorenal-like syndrome associ- py rather than hematopoietic cell support [10]. CSA—cell surface
ated with veno-occlusive disease (VOD). After 1 month, the hemolyt- antigen. (From Zager [9]; with permission.)
lonephritis. Although immune-complex–mediated glomerular disease is

not uncommon in patients with cancer [11], glomerular disease caus-
CAUSES OF INTRINSIC ACUTE RENAL FAILURE
ing 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
Glomerular abnormalities Glomerulonephritis
patients with disseminated malignancy or after chemotherapy
Hemolytic-uremic syndrome for malignancy.
Tubular abnormalities Ischemic acute tubular necrosis (ATN) With respect to tubular abnormalities, ARF may arise either on the
Exogenous nephrotoxins basis of ischemia or as a result of exposure to exogenous or endoge-
Antineoplastic agents nous nephrotoxins. Renal ischemia is usually the initiating factor when
Antimicrobials ATN follows sepsis or shock or when it arises as a postsurgical com-
Radiocontrast media plication. Cancer patients are particularly vulnerable to ARF induced
Anesthetic agents by exogenous nephrotoxins in view of their frequent exposure to a
Endogenous nephrotoxins wide variety of nephrotoxic drugs. The indicated nephrotoxins of
Myoglobin endogenous origin are encountered with increasing frequency in the
Hemoglobin cancer patient.
Immunoglobulins and light chains The most frequent cause of interstitial abnormalities is acute tubu-
Calcium and phosphorus lointerstitial nephritis, which may be induced in cancer patients via
Uric acid and xanthine hypersensitivity to various drugs. These patients frequently receive the
Interstitial abnormalities Drug-induced acute tubulointerstitial nephritis analgesics and antimicrobials associated with this form of ARF.
Acute pyelonephritis Immunosuppressed cancer patients may be particularly vulnerable to
Tumor infiltration severe acute bacterial pyelonephritis. ARF may occur in this setting,
Radiation nephropathy even in the absence of urinary tract obstruction or another underlying
Abnormalities of intrarenal blood Disseminated intravascular coagulation renal disease [13]. Tumor infiltration of the kidney may involve the
vessels Hemolytic-uremic syndrome
interstitium but rarely causes ARF [14]. Finally, radiation nephropathy
may occur following radiation therapy for cancer and has been associ-
Malignant hypertension
ated with ARF [15], although when it occurs, it more frequently pro-
Vasculitis
duces 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
FIGURE 5-4 the cancer patient is more often older, atheroembolic disease or malig-
The four major causes of malignancy-associated intrinsic acute renal nant hypertension must be considered as a possible cause of intrarenal
failure (ARF). With glomerular abnormalities, the pathologic process vascular occlusion in the presence of ARF. Finally, vasculitis is a consid-
most frequently involves diffuse proliferative or crescentic glomeru- eration, particularly in the presence of hepatitis B antigenemia.
A B
Hemolytic-uremic syndrome (HUS). A 46-year-old woman with agents. The risk of developing mitomycin C–induced HUS is 2% to
metastatic carcinoma of the lung and congestive heart failure devel- 10%, and cumulative doses larger than 60 mg are often associated
oped renal insufficiency over a 12-week period. A percutaneous with the disease [19]. The patients with cancer are often in remis-
renal biopsy revealed that several glomeruli had the acute changes sion at the time of diagnosis. The mortality rate has been as high
of swelling and detachment of endothelial cells and luminal occlu- as 70%, usually in the first 2 months, and is related to renal failure
sion (panel A, periodic acid–Schiff stain). The arterioles and arter- and sepsis.
ies showed intimal cellular swelling and hyperplasia and fibrin The diagnosis of HUS should be considered in the clinical setting
deposition. Immunofluorescence microscopy revealed glomerular of acute renal failure associated with thrombocytopenia and
fibrin deposition (panel B). microangiopathic hemolytic anemia with schistocytes (seen on a
Hemolytic-uremic syndrome is a thrombotic microangiopathy peripheral blood smear). The renal biopsy results show a variety of
presenting as an acute illness characterized by renal failure, throm- glomerular and vascular changes, such as endothelial cell swelling,
bocytopenia, and microangiopathic hemolytic anemia. Vascular detachment of thrombi, and thrombotic occlusion of the lumen.
and endothelial cell injury leads to microvascular thrombosis and Fibrin is noted in the walls of blood vessels of glomeruli on
ischemic organ damage. HUS can occur in diverse clinical settings, immunofluorescence microscopy. On electron microscopy, endothe-
including metastatic carcinoma, particularly of the stomach, breast, lial cell swelling and detachment from the basement membrane,
or lung [17]. The initiating factor is presumably tumor emboli. subendothelial granular material, and luminal thrombi may be seen
These patients have an extremely poor prognosis and often die in the glomeruli. Treatment is generally supportive, including dialy-
within a few weeks of diagnosis [18]. HUS also has been reported sis. Hemolytic-uremic syndrome with vascular endothelial injury
after chemotherapy for cancer. This form of chemotherapy-related both in the glomeruli and in the intrarenal blood vessels may occur
HUS is mainly associated with mitomycin C but has also been in patients with disseminated malignancy or after chemotherapy
noted after therapy with bleomycin and platinum-containing for malignancy.
(ARF) is dose related, nonoliguric, and usually reversible. The

serum creatinine level may increase immediately after administra-
tion 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
FIGURE 5-6 reabsorptive defect [22]. Magnesium wasting may be present for
Renal changes in humans following cisplatin administration. The many months but usually remits when cisplatin is discontinued.
proximal convoluted tubules are dilated and show coagulation Associated hypocalcemia and hypokalemia may persist unless hypo-
necrosis of the epithelium and epithelial nuclear atypia. The tubu- magnesemia has been corrected. In recent years in some settings, cis-
lar lumens contain eosinophilic material [20]. platin has been replaced with carboplatin, which is not nephrotoxic
Cisplatin is the most frequently used antineoplastic agent for the in usual doses (400 to 600 mg/m2). Transient ARF has been noted
treatment of solid tumors, and the pathogenesis of its nephrotoxici- in patients receiving very high doses (1600 to 2400 mg/m2),
ty has been studied extensively. Cisplatin-induced acute renal failure however. (From Rieselbach and Garnick [1]; with permission.)
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 maintain-
ing a high urinary volume and pH was realized, renal toxicity was
noted in approximately 30% of treatment courses and was responsi-
ble for 20% of drug-related deaths during high-dose MTX-leucov-
orin 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 follow-
ing 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.
FIGURE 5-7 The 7-OH metabolite of MTX also may precipitate within the
Methotrexate (MTX) nephrotoxicity. Renal biopsy specimen from a nephrons. This metabolite may account for as much as 7% to 33%
patient treated with 3 g/m2 of MTX followed by leucovorin who of the MTX appearing in the urine 24 to 48 hours after intravenous
became dehydrated and developed acute renal failure. Precipitated administration; its solubility is only 25% of that observed for MTX
material in the tubules (arrow) strongly reacted with a fluorescinated [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
CAUSES OF RENAL FAILURE IN MULTIPLE MYELOMA
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
Cause Pathogenesis disorders, including Fanconi’s syndrome, the intratubular precipita-
Light-chain cast nephropathy Intratubular precipitation of light chains tion of these proteins causes light-chain cast nephropathy and
AL amyloidosis Deposition of amyloid fibers composed acute renal failure. The light chains (usually lambda) may be trans-
of light chains (Congo red positive) formed into Congo-red–positive amyloid fibrils and deposited dif-
Light-chain deposition disease Nodular glomerulosclerosis with granular fusely throughout the body [29]. Deposition of amyloid in renal
deposits (Congo red negative) of light tissue results in the nephrotic syndrome and, often, renal failure.
chains along the basement membrane Biopsy of the kidney, abdominal fat pad, or rectal mucosa is useful
Plasma cell infiltration of the kidney Often incidental finding at autopsy in the diagnosis of AL amyloidosis. Light chains may also be
Rare cause of renal dysfunction deposited in a granular pattern along the basement membranes of
Fanconi’s syndrome and other tubular Tubular toxicity of light chains blood vessels in a variety of organs. In the kidney, these deposits
dysfunction are noted in the glomeruli, causing an expansion of the
Hypercalcemic nephropathy Bone resorption causing hypercalcemia mesangium, and appear as nodular glomerulosclerosis. This condi-
Acute uric acid nephropathy Renal tubular precipitation of uric acid tion is referred to as light-chain deposition disease (LCDD) [30].
following tumor lysis Other causes of renal failure in a patient with multiple myeloma
Radiocontrast nephropathy Interaction between light chains and include metabolic disturbances such as hypercalcemia and hyper-
radiocontrast agents uricemia. 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
FIGURE 5-8 and tubular precipitation, thereby causing acute renal failure. The
Renal failure in multiple myeloma. The patient with multiple prognosis for recovery from acute renal failure in a patient with
myeloma is at increased risk for the development of acute renal multiple myeloma is generally poor unless reversible factors such as
failure [27]. In up to 25% of patients with multiple myeloma, hypercalcemia or dehydration are responsible [27].
FIGURE 5-9
Light-chain cast nephropathy. The kidney at autopsy of a 68-year-
old 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 hema-
toxylinophilic 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 reab-
sorption is most often responsible owing to bone metastases or to the release of humoral
substances such as parathyroid hormone–like 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 irre-
versible damage can occur with long-standing hypercalcemia [35]. Recovery of the glomeru-
lar 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 precipita-
tion in collecting ducts produces severe tubular dilatation (DeGalantha stain). This patient,
who received chemotherapy for acute lymphocytic leukemia before allopurinol was avail-
able, 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 aggres-
sive 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 hyper-
uricemia. 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 charac-
teristic 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 lym-
phoma 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].
FIGURE 5-12
PROPHYLAXIS AND TREATMENT OF ACUTE URIC ACID Prevention and management of acute uric
NEPHROPATHY AND ACUTE TUMOR LYSIS SYNDROME acid nephropathy (AUAN) and the acute
tumor lysis syndrome (ATLS). The metabol-
ic consequences of rapid malignant cell lysis
Prophylaxis are many, ranging from moderate hyper-
A. Patients presenting (before chemotherapy) with evidence of large, rapidly proliferating tumor burden and uricemia to death from hyperkalemia. The
hyperuricemia measures employed for prevention and
1. Correct initial electrolyte and fluid imbalance, and azotemia, if possible; dialysis as indicated for established renal management vary according to the type and
failure or unresponsive electrolyte or metabolic abnormalities extent of the tumor and whether cytolytic
2. Maintain adequate hydration and urine output (>3 L/d). May require 4 to 5 L/24 h of intravenous hypotonic therapy has been initiated.
saline or bicarbonate; diuretics as indicated In recent years, with appropriate prophy-
3. Give Allopurinol* (300 mg/m2) at least 3 days before therapy if possible laxis and dialytic therapy, AUAN and ATLS
4. Alkalinize urine to pH >7.0 (hypotonic NaHCO3 infusion; Diamox if necessary) rarely represent life-threatening problems.
5. Postpone chemotherapy (if possible) until uric acid and electrolytes are reasonably normalized When acute renal failure (ARF) does occur,
6. Continuous-flow leukapheresis might be indicated for patients with a high circulating blast count (white cell prognosis is excellent. The approach to
count >100,000/mm3) AUAN and ATLS is divided into two
B. Patients presenting (before chemotherapy) with normouricemia, but still at risk stages. The first is to prevent or minimize
1. Allopurinol* 300 mg/m2; at least 2 days before therapy if possible the metabolic consequences, and the second
2. 4 to 5 L/d of intravenous fluid as described above involves treatment if prophylaxis has not
3. Urinary alkalinization as described above been successful. The approach to both pro-
Treatment phylaxis and treatment includes inhibition
C. Patients presenting (usually after chemotherapy) with renal failure of xanthine oxidase, forced diuresis, and
1. Same as for patients with tumor and hyperuricemia if sufficient renal function remains. If dialysis is necessary,
urinary alkalinization. If treatment is not
continuous hemodialysis or hemofiltration may be preferable if severe hyperuricemia or hyperkalemia is present successful and ARF develops, these patients
2. Discontinue urine alkalinization when uric acid homeostasis is achieved (to avoid Ca3[PO412]precipitation) respond very well to hemodialysis, with
3. Treat symptomatic hypocalcemia after correction of hyperphosphatemia morbidity and mortality usually related to
the underlying disease process [39].
*Allopurinol dosage must be adjusted for level of renal function.
metabolism and pharmacology must be con-

OH OH OH sidered to avoid life-threatening toxicity [40].
Allopurinol is a structural analogue of
C N C N C N hypoxanthine. The product of the enzymatic
N C N C N C
C–H Xanthine C–H Xanthine C–OH oxidation of allopurinol is the xanthine ana-
oxidase oxidase logue oxypurinol. Both allopurinol and oxy-
C C C C C C
H N N HO N N HO N N purinol act as xanthine oxidase inhibitors.
H H H Allopurinol is rapidly absorbed from the gas-
Hypoxanthine Xanthine Uric acid trointestinal tract and is not protein bound.
It has a half-life of just 2 to 3 hours because
OH OH it has a clearance equal to the glomerular fil-
H H tration rate and is rapidly converted to oxy-
C C C C purinol via enzymatic oxidation. By contrast,
N C N C oxypurinol has a half-life of 18 to 30 hours
N Xanthine N
oxidase because it undergoes extensive tubular reab-
C C C C sorption and is dependent on renal excretion
H N N HO N N
for elimination. Thus, allopurinol dosage
H H
must be modified according to renal func-
Allopurinol Oxypurinol (Alloxanthine)
tion. Serious toxicity may occur in the pres-
(4-Hydroxypyrazolo pyrimidine) (4,6-Dihydroxypyrazolo pyrimidine)
ence of a sustained increase in oxypurinol
concentration. Oxypurinol may be removed
FIGURE 5-13 effectively with dialysis, since it is not pro-
Allopurinol structure and metabolism. Allopurinol is a crucial component of therapy for the pre- tein bound. (From Rieselbach and Garnick
vention and management of acute uric acid nephropathy and acute tumor lysis syndrome. Its [1]; with permission.)
throughout the cortex of the kidney. The pelvic and parenchymal

hemorrhages are secondary to severe thrombocytopenia.
Microscopically, many myeloblasts are seen in the interstitial infil-
trates. 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 exami-
nation. The differential diagnosis in this setting includes obstruc-
tion 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 respon-
siveness of the tumor to radiation or chemotherapy. A rapid reduc-
FIGURE 5-14 tion in renal size and return of renal function toward the baseline
Interstitial tumor infiltration due to leukemia. Leukemic infiltrates level may be seen within a few days with responsive tumors. (From
in this case of acute myelocytic leukemia are diffusely present Skarin [31]; with permission.)
B
tration or occasionally by the presence of a large solitary tumor.
A Renal failure due to parenchymal infiltration by lymphoma cells is
extremely rare. In one large series, uremia resulting from lym-
FIGURE 5-15 phomatous replacement of kidney tissue was the cause of death in
Renal involvement in lymphoma. A, Renal involvement in a patient only 0.7% of patients [42]. As with leukemia, when lymphoma has
with diffuse large cell lymphoma. There is little remaining parenchy- caused renal failure, chemotherapy and radiation therapy have led
ma in this specimen, which exhibits many large, gray-white nodules to improvement in kidney function.
of tumor. Although primary renal lymphoma is rare, 5% to 10% of B, Lymphoma with renal infiltration. A 65-year-old-man present-
patients with disseminated lymphoma exhibit clinically detectable ed with left flank pain and microscopic hematuria of 6 weeks’
renal involvement. At autopsy, the incidence of renal involvement duration. He had a left renal mass demonstrable on abdominal
by lymphoma has been estimated by several series to be more than ultrasound. Left renal perihilar and retroperitoneal lymph node
30% [41]. The incidence was higher in patients with lymphosarco- enlargement was noted on a CT scan. He was normotensive and
ma or histiocytic lymphoma than in those having Hodgkin’s disease, had a serum creatinine level of 1.2 mg/dL. A needle biopsy of the
with its occurrence in mycosis fungoides being intermediate in fre- renal mass, under CT guidance, revealed renal parenchymal infil-
quency. The majority of patients had involvement of both kidneys. tration with lymphoid cells with neoplastic characteristics. (Panel A
Lymphoma may involve the kidney by multinodular or diffuse infil- from Skarin [31]; with permission.)
Postrenal Acute Renal Failure

FIGURE 5-16
CAUSES OF POSTRENAL ACUTE RENAL FAILURE The etiology of postrenal failure involves obstruction at various
anatomic sites by tumors of the urinary tract or surrounding tis-
sues. Some of the more common causes of bladder neck obstruc-
Anatomic site Cause tion in the cancer patient include prostatic hypertrophy [43] and
prostatic or bladder cancer [44]. Postrenal acute renal failure may
Urethral obstruction Prostatic hypertrophy also be produced by bilateral obstruction of both ureters (or unilat-
Bladder neck obstruction Prostatic or bladder cancer eral ureteral obstruction in the presence of a single kidney). This
Functional: neuropathy or drugs may be caused by invasion of the ureters by bladder neoplasms or,
Bilateral ureteral obstruction Extraureteral more commonly, by retroperitoneal spread of malignancies, partic-
(or unilateral obstruction with Cancer of prostate or uterine cervix ularly of colon, prostate, bronchus, or breast origin.
single kidney) Periureteral fibrosis
Accidental ureteral ligation during
pelvic surgery for cancer
Intraureteral
Uric acid crystals or stones
Blood clots
Pyogenic debris
Edema
Necrotizing papillitis
FIGURE 5-17
Urinary tract obstruction. Obstruction is a prominent feature of
Uterus urinary tract involvement in gynecologic cancers [45]. The ureters
Nodal
obstruction 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 blad-
der may be subject to direct extension of tumor with occlusion of
ureteral orifices. In this figure, the anterior wall of the bladder is
Bladder
ulceration cut away to illustrate these as well as other forms of urinary tract
Stricture involvement by gynecologic cancers. In this setting, obstruction
Uretovaginal may produce either acute or chronic renal failure depending on the
fistula
location of the obstruction and the rapidity of tumor growth.
(Adapted from Rieselbach and Garnick [1].)
Bladder
Vesicovaginal
fistula
Vagina
Diagnostic approach to acute renal failure ment is suggestive of

glomerulonephritis, while
STEP I eosinophiluria is indica-
tive of acute interstitial
ACUTE CHRONIC nephritis. Step IV
Normal recent function Prior renal dysfunction involves obtaining blood
Normal renal size on ultrasound Small kidneys on ultrasound
Normal HCT Anemia chemistries and other
blood studies, abnormali-
STEP II
ties that may strongly
History, physical exam support a given diagno-
Prerenal Intrinsic renal Postrenal sis. Step V is employed in
Edema Hypotension Distended bladder the presence of oliguric
CHF Nephrotoxins Pelvic mass ( )
Cirrhosis Systemic symptoms Enlarged kidney(s) acute renal failure.
ECFV contraction Trauma/surgery Flank pain Urinary diagnostic
Drugs Prostatism ( )
indices are used to distin-
STEP III
guish between prerenal
Urinalysis acute renal failure and
Dipstick- Orthotolidine glomerulonephritis, as
RBC casts and/or Epithelial cells Uric acid
Eosinophils dysmorphic RBCs negative Granular, pigmented casts crystals Benign positive on dipstick but opposed to acute tubular
proteinuria RBC negative in sediment
necrosis or acute obstruc-
tion. Evaluation of the
Acute tubulointerstitial Glomerulonephritis Light-chain Acute uric Prerenal urine is also helpful in
nephritis or vasculitis cast nephropathy acid or detecting the presence of
nephropathy postrenal
Acute tubular necrosis light chains of
Gallium Renal UPE Myoglobin immunoglobulins, which
scan biopsy Bone marrow STEP IV Hemoglobun
biopsy may be diagnostic of
multiple myeloma-
Blood chemistries Other blood studies
induced acute renal fail-
↑BUN/creatinine ratio SPE→M spike ure. Also, an increased
↑Calcium ↓ C3/C4 (complement)
↑Uric acid ↓ Haptoglobin
urinary uric acid/creati-
↑Phoshorus Eosinophilia nine ratio may indicate
↑CPK, aldolase
acute uric acid nephropa-
thy. In the patient who is
STEP V
anuric (<50 mL of urine
Urinary diagnostic indicies per day), it is particularly
Prerenal or Acute uric acid ATN or
important to rule out
Light chain
glomerulonephritis nephropathy nephropathy obstruction obstruction. Bilateral cor-
UNA<20, FENA<1% Urine uric acid/ UNA>40, FENA>3%
tical necrosis or glomeru-
Urine positive
UOSM>500 creatinine >1.0 for light chains UOSM<350 lonephritis must be con-
Anuria
sidered in this setting; a
renal biopsy may be nec-
essary for definitive diag-
Renal biopsy Glomerulonephritis Obstruction Exclude obstruction nosis. If bilateral renal
Ultrasound
CT scan artery or vein occlusion
Bilateral cortical necrosis
Retrograde pyelogram is a consideration,
Bilateral renal artery or vein occlusion angiography may be indi-
cated. ATN—acute tubu-
Magnetic resonance angiography lar necrosis; BUN—
Duplex ultrasonography blood urea nitrogen;
Digital subtraction angiography
Renal arteriography/venography CHF—congestive heart
failure; CPK—creatine
phosphokinase; ECFV—
extracellular fluid vol-
FIGURE 5-18 ume; FENa—fractional
Diagnostic approach to acute renal failure. Acute renal failure developing in a patient with malignancy may be due extraction of sodium;
to diverse causes. It is important to employ an organized diagnostic approach to define the specific cause in a cost- Hct—hematocrit; SPE—
effective manner. The approach outlined in this figure involves five steps. Step I addresses the distinction between serum protein elec-
acute and chronic renal failure, and step II lists the various causes of prerenal, intrinsic, and postrenal acute renal trophoresis; Una—urine
failure (see Figs. 5-2, 5-4, and 5-16) according to data obtained from the history and physical examination. sodium; Uosm—urine
Urinalysis is very useful in the workup of a patient with acute renal failure, particularly due to intrinsic renal osmolality; UPE—urine
disease, as outlined in step III. The presence of red blood cell (RBC) casts or dysmorphic RBCs in the urine sedi- protein electrophoresis.
Hematuria and/or the Nephrotic Syndrome

FIGURE 5-19
CAUSES OF HEMATURIA AND/OR Causes of hematuria and/or the nephrotic syndrome. Hematuria
THE NEPHROTIC SYNDROME and/or the nephrotic syndrome may occur in association with malig-
nancy without causing acute or chronic renal failure. Causes may
include one of the many paraneoplastic types of glomerulonephritis,
Paraneoplastic glomerulonephritis with proteinuria and often the nephrotic syndrome resulting from
Membranous glomerulonephritis the glomerular injury; hematuria is also noted in some cases. In con-
Minimal change nephrotic syndrome
trast, isolated hematuria is the predominant feature when primary
or metastatic renal cancer erodes the intrarenal vasculature.
Crescentic glomerulonephritis
Proteinuria, and in some cases the nephrotic syndrome, may be the
Membranoproliferative glomerulonephritis
presenting nephrotoxicity of cancer chemotherapy agents.
Primary or metastatic renal cancer
Chemotherapy agents causing nephrotic syndrome
Mitomycin C
Gemcitabine
Interferon
A B
FIGURE 5-20
Membranous glomerulonephritis and the nephrotic syndrome in a chest mass. He died 10 months later. Membranous glomeru-
patient with bronchogenic carcinoma. A 76-year-old veteran pre- lonephritis and bronchogenic carcinoma were diagnosed at autopsy.
sented with ankle edema and weight gain of 8 weeks’ duration. He A, Light microscopic study of the kidney of this patient. Note the
was noted to have the nephrotic syndrome with 5 grams of protein- thickening of capillary walls and spikes (PAM stain). B, Immuno-
uria per day. A chest radiograph revealed a perihilar mass. A bron- fluorescence microscopy of renal tissue showing peripheral
choscopic biopsy of the mass was diagnostic of malignancy. He was glomerular capillary deposition of IgG in a granular pattern indica-
managed conservatively with diuretics and radiotherapy for the tive of immune-complex-mediated glomerulonephritis.
C D
C, Electron microscopy of the glomerulus showing subepithelial of cases [5]. Although a variety of malignancies have been observed
electron-dense deposits along the capillary walls. There is efface- to be associated with membranous glomerulonephritis, the most
ment of the epithelial cell foot processes, which is a common find- common sites are the breast, the lung, and the colon. In some
ing in patients with nephrotic syndrome. D, Bronchogenic carcino- instances, the tumor antigen or antitumor antibodies have been
ma noted at autopsy in this patient (hematoxylin and eosin stain). detected in the glomeruli. Development of the nephrotic syndrome
Membranous glomerulonephritis is an immune-complex–mediat- has been temporally related to the malignancy in several instances,
ed glomerular disease, often resulting in nephrotic syndrome as a and successful cure of the malignancy has led to a remission in the
clinical manifestation. In adults older than the age of 50, a coexist- nephrotic syndrome. Relapses have been associated with reappear-
ing malignancy, usually a carcinoma, may be present in up to 10% ance of proteinuria [46].
A B
FIGURE 5-21
Minimal change nephrotic syndrome in Hodgkin’s disease. A, Light occurrence of glomerular diseases has been noted [5,46]. Several his-
microscopic study of a renal biopsy specimen from a 57-year-old tologic types of glomerular diseases have been documented in these
man with nephrotic syndrome of 3 months’ duration. Urine protein instances; the most common type has been minimal change nephrotic
excretion was 7.1 g/d. The serum creatinine concentration was 1.3 syndrome [47]. The glomeruli of these patients are normal on light
mg/dL. The patient also had cervical lymphadenopathy, biopsy of microscopic study and are devoid of hypercellularity or capillary
which revealed Hodgkin’s disease of the mixed cellularity type. He wall thickening. No immunoglobulins are noted in the glomeruli on
was treated with irradiation to the upper mantle region with reso- immunofluorescence microscopy. On electron microscopy, efface-
lution of the lymphadenopathy. Proteinuria also declined to 2 g/d ment of the epithelial cell foot processes is the only abnormality pre-
in 2 weeks and was absent in 8 weeks. The glomerulus was normo- sent. Proteinuria has been noted to remit with cure of lymphoma
cellular with delicate capillary walls diagnostic of minimal change (with use of surgery, radiotherapy, or chemotherapy) in some cases;
nephrotic syndrome (PAM stain). relapses in nephrotic syndrome occur with recurrence of the tumor.
B, Electron microscopy of a glomerulus from the same patient This has been documented to occur several times in some patients
showing glomerular capillaries with extensive effacement of the [47]. The pathogenesis of minimal change nephrotic syndrome in
epithelial foot processes but without electron-dense deposits. patients with malignancy remains unknown. It is possible that a
In patients with Hodgkin’s disease and other malignancies arising cytokine or tumor cell product may be responsible for the increase in
from lymph nodes as well as different types of chronic leukemias, the glomerular permeability with resultant proteinuria [48].
A. COMPARISON OF PARAPROTEINEMIAS
Diagnosis Frequency* Clinical Findings Renal Lesions Diagnostic Means

Multiple myeloma Yes Proteinuria (light chain) Light-chain cast nephropathy Immunoelectrophoresis or bone marrow
Acute renal failure Acute tubular necrosis Light chains in urine
Hypercalcemia
AL amyloidosis Yes Proteinuria Deposits of amyloid fibrils in the kidney Renal or rectal biopsy
Nephrotic syndrome Immunoelectrophoresis
Light-chain deposition disease No Proteinuria Nodular glomerulosclerosis with granular deposition Renal biopsy
Nephrotic syndrome of light chains along the glomerular and tubular Bone marrow biopsy
Chronic renal failure basement and membrane; usually kappa light Immunoelectrophoresis
chains
Waldenström’s macroglobulinemia Rarely No renal symptoms or Intraglomerular “coagula” of IgM Immunoelectrophoresis
minimal proteinuria Bone marrow biopsy
Monoclonal gammopathy of Rarely Proteinuria Proliferative glomerulonephritis in some case Immunoelectrophoresis
unknown significance (MGUS) Nephrotic syndrome Bone marrow biopsy
Renal biopsy
* Frequency of renal involvement.
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 Waldenström’s
macroglobulinemia. Renal dysfunction is uncommon in this condi-
tion [49]. Hyperviscosity is present. On rare occasions, thrombi com-
posed 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 condi-
B tion is referred to as monoclonal gammopathy of unknown signifi-
cance (MGUS) and may on occasion progress to multiple myeloma
FIGURE 5-22 (see Color Plate) or amyloidosis [50].
A, Paraprotein abnormalities as a cause of nephrotic syndrome. This B, Light-chain deposition disease (LCDD) in a patient with mul-
table compares the characteristics of various paraproteinemias. tiple myeloma. A light microscopic study of a renal biopsy speci-
Paraproteins are abnormal immunoglobulins or abnormal men from a 65-year-old man with recently diagnosed multiple
immunoglobulin fragments produced by B lymphocytes. They are mon- myeloma who was found to have an elevated serum creatinine con-
oclonal, appear in the serum or urine (or both), and cause renal damage centration (2.6 mg/dL) and proteinuria of 3 g/d. Note the nodular
by several different mechanisms. Paraproteinemias comprise a group of mesangial lesions, capillary wall thickening, and hypercellularity
disorders characterized by overproduction of different paraproteins. resembling diabetic nodular glomerulosclerosis.
Multiple myeloma is a common type of paraproteinemia. The Immunofluorescence staining was positive for kappa light chains
overproduction of immunoglobulins or light chains, or both, causes but negative for lambda light chains.
because of the myriad paraneoplastic signs and symptoms, now

renal cancer is often termed “the radiologist’s 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 expo-
sure 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 transloca-
FIGURE 5-23 tion between the short arm of chromosome 3 and either chromosome
Renal cell carcinoma. With massive invasion by tumor, the renal 6 or 8. Other abnormalities have been reported as well [52].
vein may become occluded by adherent tumor thrombus. Renal It should be noted that other primary tumors of the kidneys in
adenocarcinoma is the most common tumor of the kidney [51]. In the adult include transitional cell carcinoma of the renal pelvis
the past, many of these tumors achieved large sizes before being and other neoplasms, such as angiomyolipoma and oncocytoma.
detected and hence were advanced in their stage and limited in Metastatic lesions of the kidney include those arising from the
their curability by surgical resection. Today, many renal cancers common epithelial cancers such as breast, lung, colon, and infil-
are often detected with routine abdominal computed tomography trative lesions secondary to lymphoma and leukemias. (From
for nonrelated indications. Once called “the internist’s tumor” Skarin [31]; with permission.)
FIGURE 5-24
PRESENTING SIGNS AND SYMPTOMS Presenting signs and symptoms of renal cell carcinoma. Patients
OF RENAL CELL CARCINOMA with renal cell cancer present with symptoms produced by the
local neoplasm, with signs and symptoms of paraneoplastic phe-
nomena, or with other aspects of systemic disease. Alternatively,
Feature Frequency, % the patient may be totally asymptomatic and may be diagnosed
from a radiologic abnormality detected on ultrasound or abdomi-
Hematuria 40–65 nal CT scanning. Fewer than 10% of patients present with the
Pain 20–50 classic triad of hematuria, abdominal mass, and flank pain. The
Flank or abdominal mass 20–40 most common features include hematuria (70%), flank pain
Weight loss 30 (50%), palpable mass (20%), fever (15%), and erythrocytosis
Symptoms from distant metastatic spread 10 (infrequent). Other features may include acute onset of lower
Fever 15–20 extremity edema, or, in males, the presence of a left-sided varico-
Classic triad (pain, hematuria, mass) 10 cele, indicating obstruction of the left gonadal vein at its point
Polycythemia <5 of entry into the left renal vein by a tumor thrombus [53,54].
Acute varicocele <5
FIGURE 5-25
FREQUENCY OF SYSTEMIC EFFECTS IN PATIENTS Frequency of systemic effects. The most frequent systemic manifes-
WITH RENAL CELL CARCINOMA tations 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
Symptom Incidence, % secretion of substances such as prostaglandins, renin, glucocorti-
coids, and cytokines (eg, interleukin-6). At presentation, a small
Elevated ESR 362/6.51 (55.6) percentage of tumors are bilateral, while nearly a third of patients
Anemia 409/991 (41.3) have demonstrable metastatic disease, which may occur in virtually
Hypertension 89/237 (37.6) any organ. Most common sites of metastases include lung, bone,
Cachexia 338/979 (34.5) liver, and brain. ESR—erythrocyte sedimentation rate. (From
Pyrexia 164/954 (17.2) Chisholm and Roy [55]; with permission.)
Abnormal liver function 60/400 (15.0)
Elevated alkaline phosphatase 64/434 (14.7)
Hypercalcemia 33/577 (5.7)
Polycythemia 33/903 (3.7)
Neuromyopathy 13/400 (3.3)
Amyloidosis 12/573 (2.1)
FIGURE 5-26
Stage I Stage III 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 repre-
Vena cava Aorta sents cancer that is confined to the kidney capsule; stage II indi-
cates invasion through the renal capsule, but not beyond Gerota’s
Stage II Stage IV
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 carcino-
mas were classified according to cell type and growth pattern. The
former included clear cell, spindle cell, and oncocytic carcinoma,
Stage I: Confined to kidney while the latter included acinar, papillary, and sarcomatoid vari-
Stage II: Including renal vein involvement eties. Recently, this classification has undergone a transformation
Stage III: Lymph node and caval involvement to reflect more accurately the morphologic, histochemical, and
Stage IV: Adjacent organ metastases molecular basis of differing types of adenocarcinoma [58]. Based
on these studies, five distinct types of carcinoma have been identi-
fied: clear cell, chromophilic, chromophobic, oncocytic, and col-
lecting duct. Each of these types has a unique growth pattern, cell
of origin, and cytogenetic characteristics [59,60]. (From Brenner
and Rector [56].)
360 Dialysate
Serum
Osmolality, mOsm/L
340
Osmotic
320 equilibrium
300
0 1 2 3 4
C 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 If the sonographic criteria for a simple cyst are not met or the
cancer—an algorithm for diagnosis and management of a renal intravenous pyelogram suggests a solid or complex mass, a CT scan
mass. The discovery of evidence during the history or physical should be performed. If a renal neoplasm is demonstrated on CT
examination that suggests a renal abnormality should be followed scanning, renal vein or vena caval involvement should be assessed
by either an intravenous pyelogram or an abdominal ultrasound. with CT scanning or magnetic resonance imaging. Although used
With increasing frequency, however, evidence of a space-occupying frequently in the past, selective renal arteriography has assumed a
lesion in the kidney is found incidentally during radiographic testing more limited use, mainly in further evaluating the renal vasculature
for other unrelated conditions. Renal ultrasonography may help dis- in patients who are to undergo partial nephrectomy (nephron-spar-
tinguish simple cysts from more complex abnormalities. A simple ing surgery). CT scanning is also very helpful in determining the
cyst is defined sonographically by the lack of internal echoes, the presence of lymphadenopathy.
presence of smooth borders, and the transmission of the ultrasound The differential diagnosis of a renal mass detected on CT scanning
wave. If these three features are present, the cyst is most likely includes primary renal cancers, metastatic lesions of the kidney, and
benign. At one time, cyst puncture was used, but it seems to be benign lesions. The latter include angiomyolipomas (renal hamar-
unnecessary today in the asymptomatic patient without hematuria. tomas), oncocytomas, and other rare or unusual growths. If a renal
Periodic repetition of the ultrasound is suggested for follow-up. If a cancer is considered based on the radiographic studies of the kidney,
change in the lesion occurs, cyst puncture, needle aspiration, or CT the patient should undergo a preoperative staging evaluation to
scanning should be considered to evaluate the lesion further. assess the presence of metastases in the lung, bone, or brain.
(Continued) The operative and diagnostic approach is dictated considered for nephrectomy following the response, however.
according to the preoperative stage of the patient. For example, the Finally, since many renal tumors can become quite large, considera-
patient who presents with stage IV disease by virtue of a positive tion should be given to palliative nephrectomy (in the setting of
bone scan may need only a needle biopsy of either the kidney lesion metastatic disease), especially if the patient experiences uncontrol-
or the bone lesion to establish the tissue diagnosis and thus avoid lable hematuria or pain or is catabolic secondary to the sheer mass
more extensive surgery on the kidney. In contrast, a patient with an of the tumor.
isolated pulmonary lesion may be considered for both nephrectomy The medical management of patients with either locally advanced
and pulmonary nodulectomy at one operative intervention. renal cancer or metastatic disease provides a great challenge to physi-
The standard therapy for localized renal cell carcinoma is radical cians and clinical investigators. Although chemotherapy and hor-
nephrectomy, which includes removal of the kidney, Gerota’s fascia, monal treatments have been studied extensively in patients with
the ipsilateral adrenal gland, and regional hilar lymph nodes. The metastatic renal cancer, no single treatment protocol or program has
value of an extended hilar lymphadenectomy seems to be its ability been uniformly effective. Therefore, most physicians treating the dis-
to provide prognostic information, since there is rarely a therapeutic ease usually rely on novel modalities of treatment, including biologic
reason for performing this portion of the operation. In the past, the response modifiers, investigational anticancer agents, differentiation
removal of the ipsilateral adrenal gland was done routinely; today, agents (such as retinoic acid), vaccines, and gene therapy. Interferon
most data suggest that it is involved less than 5% of the time, more therapy with interferon-, -, or - has led to responses in approxi-
frequently with large upper-pole lesions. Thus, today, ipsilateral mately 15% to 20% of treated patients [64]. Interferons demonstrate
adrenalectomy is reserved for those patients with abnormal-appear- antiproliferative activity against renal cell cancers in vitro, stimulate
ing glands or enlarged glands on CT scan or those with large upper- immune cell function, and can modulate the expression of major his-
pole lesions, in which the probability of direct extension of the tocompatibility complex molecules. Although responses have been
tumor to the adrenal gland is more likely [61]. seen in cancers involving many different anatomic areas, patients
Partial nephrectomy (nephron-sparing surgery) has become more who have had a prior nephrectomy with isolated pulmonary metas-
popular, especially for patients with small tumors, for those at risk for tases and who are otherwise well may enjoy a higher response rate
developing bilateral tumors, or for patients in whom the contralateral [65]. Duration of response is usually less than 2 years; longer lasting
kidney is at risk for other systemic diseases, such as diabetes or hyper- remissions have been noted in a few selected patients. Interferons
tension [62]. The main concern associated with partial nephrectomy have been combined with other immune modifiers as well as with
is the likelihood of tumor recurrence in the operated kidney, since chemotherapy agents with no real improvement in patient outcome
many renal cancers may be multicentric. Local recurrence rates of 4% in larger-scale trials. Several smaller trials have combined interferon
to 10% have been reported; lower rates have been reported when with interleukin-2 or chemotherapy agents (eg, 5-fluorouracil) with
partial nephrectomy was performed for smaller lesions (< 3 cm) with some encouraging preliminary results.
a normal contralateral kidney. Lesions that are centrally located, how- Interleukin 2 (Il-2) has received a great deal of attention as a
ever, still require radical nephrectomy. Frequent follow-up, usually potential advance in the treatment of renal cell cancer. This agent
with CT scanning or ultrasonography, will be necessary in those enhances both proliferation and functioning of lymphocytes involved
patients who undergo partial nephrectomy. Inferior vena caval in antigen recognition and tumor elimination. Initial studies used
involvement with renal cancer occurs more frequently with right- very high doses of Il-2 in association with ex vivo populations of
sided tumors and is usually associated with metastases in nearly 50% lymphoid cells grown and matured under the influence of Il-2 [66].
of patients. Vena caval obstruction may lead to the diagnosis; it may These programs resulted in substantial toxicity, including patient
present with abdominal distention from ascites, hepatic dysfunction, deaths, but nevertheless had early and encouraging therapeutic
nephrotic syndrome, abdominal wall venous collaterals, varicocele, results. Unfortunately, the initial encouraging results were not consis-
malabsorption, or pulmonary embolus. The anatomic location of the tently observed in larger-scale trials. Efforts are now directed at
caval thrombus is important prognostically; supradiaphragmatic selectively manipulating the immune-enhancing features of the treat-
lesions, which may involve the heart, can be resected, but the progno- ment, with modification of the toxic effects. In several recent studies,
sis is poor. Subdiaphragmatic lesions enjoy a better 5-year survival, the use of lower doses of Il-2 without the cellular components has
but the survival rate is usually less than 50% [63]. In the surgical resulted in comparable results with less toxicity.
management of these patients, a team of specialists is required, espe- The toxicity of Il-2 is related to alterations in vascular permeabil-
cially if a cardiac tumor thrombectomy is contemplated. ity, leading to a capillary leak type of syndrome. Although the drug
The role of surgery in the management of metastatic disease either is approved by the Food and Drug Administration for the manage-
at initial presentation or later remains controversial. Although most ment of patients with metastatic renal cell cancer, its use should be
data that support nephrectomy plus metastatectomy are anecdotal, restricted to those patients who can tolerate the side effect profile
many patients with synchronous renal cell cancer and an isolated and those patients with acceptable cardiac, renal, pulmonary, and
pulmonary nodule may be considered for surgical resection of both hepatic function.
lesions. Likewise, patients who develop an isolated lesion in the liver Investigational therapies continue to be studied for renal cell cancer.
or lung some time following the removal of the kidney also may be These include novel cytokines such as interleukin-12, combinations of
considered for surgical removal of the metastasis. Nevertheless, even biologics with or without chemotherapeutic agents, circadian timing of
when such vigorous surgery is carried out, most patients do poorly. chemotherapy administration, vaccine therapy, various forms of cellular
Additional controversy surrounds the practice of performing therapy, and gene therapy [67]. Although all these approaches have a
nephrectomy in patients with widespread metastatic disease as a solid scientific preclinical rationale, none, unfortunately, can be consid-
means of potentially improving their response to systemic therapy. ered standard treatment. The sobering fact still remains that nearly
Many investigative programs require such resection, but at this writ- 50% of all patients diagnosed with renal cell cancer die of their disease
ing, the practice should be considered investigational. A patient who within 5 years of diagnosis, and a substantial proportion have advanced
does experience an excellent response to systemic therapy should be stages of cancer spread at initial presentation.
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

FIGURE 5-29
CAUSES OF CHRONIC RENAL FAILURE Causes of chronic renal failure. The glomerular abnormalities listed
may be associated with cancer but most often do not cause a sig-
nificant degree of chronic renal failure; their clinical expression
Glomerular abnormalities Glomerulonephritis most often involves hematuria or the nephrotic syndrome.
Amyloidosis Disordered immunoglobulin production associated with multiple
Primary renal cancer
myeloma is a frequent cause of interstitial abnormalities, producing
chronic renal failure in association with cancer. Renal failure has
Antineoplastic agents
been reported to develop in up to half of patients with myeloma at
Tubulointerstitial abnormalities Immunoglobulins or light chains
some time during their illness and is associated with a significantly
Radiation nephropathy
worse prognosis [71]. The multiple causes of renal failure in myelo-
Leukemic infiltration
ma have been previously reviewed (see Fig. 5-8). Radiation
Lymphomatous infiltration
nephropathy may produce chronic renal failure owing to interstitial
Metastatic infiltration abnormalities and may be associated with severe hypertension.
Chronic pyelonephritis Interstitial involvement by metastatic infiltration of the kidneys or
Antineoplastic agents by hematologic neoplasms may rarely cause chronic renal failure.
Renovascular disease Hypertension due to malignancy The immunosuppressed status of many cancer patients serves to
Peripheral vascular involvement by renal increase their susceptibility to bacterial and fungal invasion of the
or nonrenal cancer renal interstitium. Thus, chronic pyelonephritis may be a cause of
Renal vein thrombosis chronic renal failure in the cancer patient, particularly in associa-
Obstruction Hemolytic-uremic syndrome tion with chronic obstruction.
Cancer With regard to renal vascular disease, hypertension due to malig-
Prostate nancy may produce nephrosclerosis. Hypertension may be associat-
Cervix ed with the hypercalcemia of malignancy and is observed frequent-
Bladder ly in patients with renal carcinoma. Perirenal vascular involvement
Retroperitoneal lymphoma may be observed with primary renal cancer or nonrenal cancer;
Primary renal renal vein thrombosis or occlusion may occur because of external
Uric acid or calcium stones compression by tumor or direct extension of tumor. When obstruc-
Periureteral fibrosis tion is present at any level of the urinary tract, the continued pro-
duction 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 associa-
tion with cancer are similar to those noted in Figure 5-16 in the
production of postrenal acute renal failure.

Amyloidosis. A, Light microscopic study of a renal biopsy speci-
men from a patient with multiple myeloma and AL amyloidosis
showing eosinophilic, fluffy amyloid deposits in the glomerulus.
(Periodic acid–Schiff stain.) B, When stained with Congo red and
viewed under polarized light, the amyloid deposits show apple-
green 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 pro-
teins 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
A with the nephrotic syndrome and renal insufficiency. There is no
specific therapy for renal amyloidosis. Some patients have experi-
enced 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].
C
POTENTIALLY NEPHROTOXIC CHEMOTHERAPEUTIC AGENTS
Risk Type of renal failure Time Course

Drug High Intermediate Low Acute Chronic Specific tubular damage Immediate Delayed
Alkylating agents
Cisplatin X X X X X X
Carboplatin X X X X X X
Cyclophosphamide X X X
Ifosfamide X X X X
Streptozotocin X X X X
Semistine (methyl-CCAU) X X X
Carmustine (BCNU) X X X
Antimetabolites
Methotrexate† X X X
Cytosine arabinoside (Ara-A) X X X
5-Fluorouracil (5-FU)‡ X X X X
5-Azacitidine X X X X
6-Thiognanine X X X
Antitumor antibiotics
Mitomycin§ X X X
Mithramycin¶ X X X
Doxorubicin X X X
Biologic agents
Interferons X X X X X
Interleukin-2 X X X
*Fanconi’s 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 may induce nephrotoxicity soon after initiation of therapy or
agents may result in chronic renal failure but also may manifest only after long-term administration. The risk of nephrotoxicity
as acute renal failure, specific tubular dysfunction, or the varies with each agent. This table summarizes the risk of
nephrotic syndrome. Nephrotoxicity has been observed with use nephrotoxicity, time of onset, and type of functional impairment
of alkylating agents, antimetabolites, antitumor antibiotics, and produced by each agent. (From Massry and Glassock [73];
biologic agents, as outlined in the table. These neoplastic agents with permission.)
FIGURE 5-32
Semustine nephropathy. A, Photomicrograph of the late stages of
semustine nephrotoxicity in a specimen obtained at autopsy.
A

B, Photomicrograph of a renal biopsy specimen from a patient with
advanced semustine nephrotoxicity. Semustine (methyl-CCNU) is a lipid-
soluble 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 nephro-
toxic 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 fig-
ure, toxicity involves glomerulosclerosis, focal tubular atrophy, and vary-
ing degrees of interstitial fibrosis on light microscopic examination.
B (From Harmon and coworkers [74]; with permission.)
A B
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 bor-
der 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 prac-
ticed 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, prolifera-
tion of fibrous tissue, and disruption of the renal capillaries and arterioles. FIGURE 5-34
Clinically, the disease manifests predominantly with renal dysfunction and hypertension. Bilateral ureteral obstruction by diffuse
Hematuria, oliguria, fatigue, and gradually developing renal atrophy are common manifes- large-cell lymphoma. Extensive retroperi-
tations. The chronic form of radiation nephropathy may occur 10 to 15 years after the toneal involvement is evident. Confluent
radiation treatments. (From Rieselbach and Garnick [1]; with permission.) adenopathy of retroperitoneal lymph nodes
has led to bilateral encasement and com-
pression of the ureters by pink-tan, fleshy
tumor. This may produce chronic renal fail-
ure if tumor involvement is slowly progres-
sive or involves predominantly one ureter.
(From Skarin [31]; with permission.)
Specific Renal Tubular Dysfunction and

Associated Fluid and Electrolyte Disorders
to mineralocorticoid deficiency and affecting
tubular transport at the same site.
RENAL TUBULAR DYSFUNCTION IN MALIGNANCY
Hypercalcemia is the most common setting
in which tumor products or metabolites can
cause specific tubular defects. In this case,
Cause Clinical presentation profound tubular dysfunction is observed
Tumor-induced inappropriate hormone concentrations involving impairment of bicarbonate or sodi-
PTH-like substances Hypercalcemia um transport, urinary concentration, hydro-
Hypophosphatemia gen ion secretion, or the renal handling of
Excess ADH Hyponatremia (SIADH) potassium, phosphorus, or magnesium [35].
Deficient ADH Hypernatremia (central DI) Massive lysozymuria may be associated with
Adrenocortical excess Hypokalemia renal damage, leading to kaliuresis and
Adrenocortical insufficiency Hyperkalemia hypokalemia [78]. Elevations of lysozyme lev-
Tumor products or metabolites els are seen with acute myelogenous leukemia.
Lysozyme (AML) Hypokalemia
In this setting, proximal tubular defects in
urate, phosphate, and amino acid reabsorp-
Fanconi’s syndrome
tion have also been noted [79]. Isolated
Immunoglobulin light chains (MM) Renal tubular acidosis
hypouricemia has been reported in patients
Fanconi’s syndrome
with advanced Hodgkin’s disease; these
Hypercalcemia (MM, osseous metastases) Urinary concentrating defect
patients have increased renal clearance of
Multiple transport defects
urate despite decreased serum urate levels.
Reabsorptive urate transport inhibitor (Hodgkin’s, solid tumors) Hypouricemia Abnormal urate clearance was corrected by
Intrinsic successful treatment of the underlying
Amyloid deposits in collecting ducts (MM) Nephrogenic DI Hodgkin’s disease, suggesting a humoral basis
Partial intrarenal obstruction (MM cast nephropathy) Nephrogenic DI for this tubular defect. Hypouricemia, in asso-
Antineoplastic agents ciation with other types of proximal tubular
Cyclophosphamide SIADH dysfunction, has been associated with a vari-
Ifosfamide Fanconi’s syndrome ety of solid tumors. In multiple myeloma, the
Vincristine SIADH proliferation of abnormal plasma cells pro-
Cisplatin Hypomagnesemia duces large quantities of a variety of
Streptozocin Renal tubular acidosis immunoglobulins. These may produce
Hypophosphatemia changes in tubular function, which result
Fanconi’s syndrome from tubular reabsorption of the freely fil-
tered low-molecular-weight tumor products.
These in turn interfere with normal metabo-
lism of proximal tubular cells after their reab-
sorption. This toxicity produces Fanconi’s
FIGURE 5-35 syndrome, which is a complex proximal tubu-
Renal tubular dysfunction. Specific tubular dysfunction may be encountered in association lopathy associated with multiple reabsorption
with the four major causes listed. defects, and renal tubular acidosis, which may
Normal renal tubular function is controlled by a delicate balance of humoral mediators. be of the proximal or distal variety.
Thus, a tumor-induced inappropriate concentration of a hormone that normally contributes Intrinsic renal lesions produced by cancer
to the modulation of this balance may result in a profound disturbance of tubular function, may cause nephrogenic diabetes insipidus, in
thereby causing impairment of fluid and electrolyte balance as well as other homeostatic which the kidney is unresponsive to the action
defects. A tumor product appears to be the basis for renal phosphate loss in some cases, in of antidiuretic hormone (ADH), with resul-
that the resultant hypophosphatemia regresses when the tumor is removed [75]. tant formation of inappropriately dilute urine.
Hyponatremia occurs frequently in the patient with cancer; it is frequently caused by the This may be seen in multiple myeloma, in
syndrome of inappropriate antidiuretic hormone secretion (SIADH). Bronchogenic carcino- which causative intrinsic lesions could include
ma is the most frequent cause of this syndrome. A number of other tumors have also been intratubular obstruction by myeloma proteins
reported to cause SIADH. Disappearance of the syndrome on removal of the tumor or or amyloid deposition in collecting ducts.
improvement following successful chemotherapy has been observed frequently [76]. Cancer Various antineoplastic agents produce a
is a common cause of central diabetes insipidus; metastatic lesions have been reported to wide array of tubular dysfunction, with
cause 5% to 20% of all cases, with breast cancer being the primary malignancy in more defective reabsorptive transport of magne-
than half the cases reported [77]. Adrenocortical steroid excess may be associated with sium constituting the defect of greatest clini-
malignancies and often manifests with hypokalemia and metabolic alkalosis due to exces- cal significance. AML—acute myelogenous
sive mineralocorticoid effect in the distal nephron. Adrenal insufficiency may develop owing leukemia; DI—diabetes insipidus; MM—mul-
to metastatic lesions of the adrenal glands, producing hyperkalemia and hyponatremia due tiple myeloma; PTH—parathyroid hormone.
Malignancy in the Renal Transplant Patient

FIGURE 5-36
MALIGNANCY IN THE RENAL TRANSPLANT PATIENT 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 com-
Cancer of the skin and lips mon form of malignancy is skin cancer. Its incidence may be as high as
Squamous cell carcinoma 24% in countries such as Australia where excessive exposure to the sun
Basal cell carcinoma
occurs. Other forms of cancer also occur with increased incidence in the
transplant recipient. Malignant lymphoma, especially at extranodal sites
Malignant melanoma
(such as the central nervous system), occurs with increased frequency.
Malignant lymphoma
Women with renal transplants have been observed to have an increased
Non-Hodgkin’s lymphoma
incidence of cervical cancer. Kaposi’s sarcoma can account for 5% to
Reticulum cell sarcoma
10% of posttransplant neoplasms. This tumor may be confined to the
B-cell lymphoproliferative syndromes (Epstein-Barr virus)
skin or may involve the viscera.
Kaposi’s sarcoma Several factors contribute to the increased risk of cancer in the
Cutaneous form immunosuppressed renal transplant recipient. These include loss of
Visceral and cutaneous form immune surveillance, chronic antigenic stimulation, oncogenic potential
Genitourinary cancer of the immunosuppressant agents, and viral infections leading to neo-
Carcinoma of the native kidney (acquired cystic kidney disease) plasia. Epstein-Barr virus has been implicated in the polyclonal B-cell
Carcinoma of the transplanted kidney lymphoproliferative disease in these patients. Lymphoproliferative disor-
Renal cell carcinoma ders have been noted to occur after a median period of 56 months
Malignant melanoma when azathioprine and prednisone are used as immunosuppressive ther-
Carcinoma of the urinary bladder (cyclophosphamide associated) apy. After the introduction of cyclosporine, lymphoproliferative disor-
Uroepithelial tumors (associated with analgesic abuse) ders develop sooner, with a median interval of only 6 months [81].
Gynecologic cancer The prognosis for patients with skin cancer remains good. Preventive
Carcinoma of the cervix measures such as avoiding sun exposure, utilization of sun-blocking
Ovarian cancer creams, and careful periodic skin examinations are important. Patients
with Kaposi’s sarcoma confined to the skin may have remission rates of
up to 50% with cessation of immunosuppression or with chemothera-
py. Patients with Kaposi’s 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 pred-
nisone, azathioprine, and antilymphocyte globulin (ALG). The allo-
graft functioned poorly despite therapy a week later with OKT3.
Results of a percutaneous renal biopsy were suspicious for a lym-
phoproliferative 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 poly-
clonal in nature, and the patient’s serologic testing was positive for
Epstein-Barr virus. Immunosuppression was stopped, and therapy
with ganciclovir was started.
References
1. Rieselbach RE, Garnick MB (eds): Cancer and the Kidney. 23. Garnick MB, Mayer RJ: Management of acute renal failure associated
Philadelphia: Lea & Febiger, 1982. with neoplastic disease. Oncologic Emergencies. Edited by Yarbo J,
2. Marple JT, MacDougall M: Development of malignancy in the end- Bornstein R. New York: Grune and Stratton; 1981:247.
stage renal disease patient. Semin Nephrol 1993, 13:306–314. 24. Von Hoff DD, Penta JS, Helman LJ, Slavik M: Incidence of drug-
3. Flombaum C: Electrolyte and renal abnormalities. In Critical Care of related deaths secondary to high-dose methotrexate and citrovorum
the Cancer Patient, edn 2. Edited by Groeger JS. St. Louis: Mosby factor administration. Cancer Treat Rep 1977, 61:745.
Year Book; 1991:140–164. 25. Hande KR, Donehower RC, Chabner BA: Pharmacology and pharmo-
4. Garnick MB, Richie JP: Primary neoplasms of the kidney and renal kinetics of high dose methotrexate in man. In Clinical Pharmacology
pelvis. In Diseases of the Kidney, edn 6. Edited by Schrier RW, of Antineoplastic Drugs. Edited by Pinedo HM. New York:
Gottschalk CW. Boston: Little, Brown; 1997:779–802. Elsevier/North Holland; 1978.
5. Norris SH: Paraneoplastic glomerulopathies. Semin Nephrol 1993, 26. Jacobs SA, Stoller RG, Chabner BA, Johns DG: 7-Hydroxy
13:258–272. methotrexate as a urinary metabolite in human subjects and rhesus
monkeys receiving high dose methotrexate. J Clin Invest 1976,
6. Sanders PW, Herrera GA: Monoclonal immunoglobulin light chain-
57:534.
related renal disorders. Semin Nephrol 1993, 13:324–341.
27. Johnson WJ, Kyle RA, Pineda AA, et al.: Treatment of renal failure
7. Safirstein RL: Renal diseases induced by antineoplastic agents. In
associated with multiple myeloma. Arch Intern Med 1990,
Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW.
50:863–869.
Boston: Little, Brown; 1996:1153–1165.
28. Solomon A, Weiss DT, Kattine AA: Nephrotoxic potential of Bence-
8. Guleria AS, Yang JC, Topalian SL, et al.: Renal dysfunction associated
Jones proteins. N Engl J Med 1991, 324:1845–1851.
with the administration of high-dose interleukin-2 in 199 consecutive
patients with metastatic melanoma or renal cell carcinoma. J Clin 29. Kyle RA, Gertz MA: Systemic amyloidosis. Crit Rev Oncol Hematol
Oncol 1994, 12:2714–2722. 1990, 10:49–87.
9. Zager RA: Acute renal failure in the setting of bone marrow trans- 30. Preud’homme JL, Aucouturier P, Striker L: Monoclonal immunoglob-
plantation. Kidney Int 1994, 46:1443–1458. ulin deposition disease (Randall type): relationship with structural
abnormalities of immunoglobulin chains. Kidney Int 1994,
10. Merouani A, Shpall EJ, Jones RB, et al.: Renal function in high dose
46:965–972.
chemotherapy and autologous hematopoietic cell support treatment
for breast cancer. Kidney lnt 1996, 50:1026–1031. 31. Skarin AT: Atlas of Diagnostic Oncology. New York: Gower Medical
Publishing; 1991.
11. Zimmerman SW, Moorthy AV, Burkholder PM, Jenkins PG:
Glomerulopathies associated with neoplastic disease. In Cancer and 32. Rosol TJ, Capen CC: Mechanisms of cancer-induced hypercalcemia.
the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea Lab Invest 1992, 67:680–702.
& Febiger; 1982. 33. Seymour JF, Gagel RF: Calcitriol: the major humoral mediator of
12. Jenkins PG, Rieselbach RE: Acute renal failure: diagnosis, clinical hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas.
spectrum, and management. In Cancer and the Kidney. Edited by Blood 1993, 82:1383–1394.
Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 34. Benabe JE, Martinez-Maldonado M: Hypercalcemic nephropathy.
13. Baker LRJ, Cattell WR, Fry IK, Mallison WJ: Acute renal failure due Arch Intern Med 1978, 138:777–779.
to bacterial pyelonephritis. Q J Med 1979, 48:603. 35. Coe FL, Favus MJ, Kathpalia SC, et al.: Calcium and phosphorus
14. Mayer RJ: Infiltrative and metastatic disease of the kidney. In Cancer metabolism in cancer: hypercalcemic nephropathy. In Cancer and the
and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea &
Lea & Febiger; 1982. Febiger; 1982.
15. Greenberger JS, Weichselbaum RR, Cassady JR: Radiation nephropa- 36. Rieselbach RE, Sorensen LB: Uric acid metabolism in cancer: hyper-
thy. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. uricemic nephropathy. In Cancer and the Kidney. Edited by
Philadelphia: Lea & Febiger; 1982. Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982.
16. Lodish JR, Boxer RJ: Urinary tract hemorrhage. In Cancer and the 37. Bishop MR, Coccia PF: Tumor lysis syndrome. In Clinical Oncology.
Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Edited by Abeloff MD, Armitage JO, Lichter AS, Niederhuber JR.
Febiger; 1982. New York: Churchill Livingstone; 1995:557–561.
17. Murgo AJ: Thrombotic microangiopathy in the cancer patient includ- 38. Band PR, Silverberg DS, Henderson JF, et al.: Xanthine nephropathy
ing those induced by chemotherapeutic agents. Semin Hematol 1987, in a patient with lymphosarcoma treated with allopurinol. N Engl J
24:161–174. Med 1970, 2283:354.
18. D’Elia JA, Aslani M, Schermer S, et al.: Hemolytic-uremic syndrome 39. Pichette V, Leblanc M, Bonnardeaux A, et al.: High dialysate flow
and acute renal failure in metastatic adenocarcinoma treated with mit- rate continuous arteriovenous hemodialysis: a new approach for the
omycin: case report and literature review. Renal Failure 1987, treatment of acute renal failure and tumor lysis syndrome. Am J
170:107–113. Kidney Dis 1994, 23:591.
19. Remuzzi G, Ruggenenti P: The hemolytic-uremic syndrome. Kidney 40. Hande KR, Noone RM, Stone WJ: Severe allopurinol toxicity:
Int 1995, 47:2–19. Description and guidelines for prevention in patients with renal insuf-
20. Gonzalez-Vitale JC, et al.: The renal pathology in clinical trials of cis- ficiency. Am J Med 1984, 76:47–56.
platinum (II) diamminedichloride. Cancer 1977, 39:1362.21. 41. Obrador GT, Price B, O’Meara Y, Salant DJ: Acute renal failure due
Bhuchar VK, Lanzotti VJ: High-dose cisplatin for lung cancer. Cancer to lymphomatous infiltration of the kidneys. J Am Soc Nephrol 1997,
Treat Rep 1982, 66:375. 8:1348–1354.
21. Bhuchar VK, Lanzotti VJ: High-dose cisplatin for lung cancer. Cancer 42. Richmond J, Sherman RS, Diamond HD, Craver LF: Renal lesions
Treat Rep 1982, 66:375. associated with malignant lymphomas. Am J Med 1962, 32:184–207.
22. Schilsky RL, Anderson T: Hypomagnesemia and renal magnesium
wasting in patients receiving cisplatin. Ann Intern Med 1979, 90:929.
43. Gutmann FD, Boxer RJ: Pathophysiology and management of urinary 64. Nanus DM, Pfeffer LM, Bander NH, et al.: Antiproliferative and anti-
tract obstruction. In Cancer and the Kidney. Edited by Rieselbach RE, tumor effects of alpha-interferon in renal cell carcinomas: correlation
Garnick MB. Philadelphia: Lea & Febiger; 1982. with the expression of a kidney-associated differentiation glycopro-
44. Boxer RJ, Garnick MB, Anderson T: Extrarenal cancer of the geni- tein. Cancer Res 1990, 50:4190–4194.
tourinary tract. In Cancer and the Kidney. Edited by Rieselbach RE, 65. Minasian LM, Motzer RJ, Gluck L, et al.: Interferon alfa-2a in
Garnick MB. Philadelphia: Lea & Febiger; 1982. advanced renal cell carcinoma: treatment results and survival in 159
45. Kearney GP, Knapp RC: Genitourinary complications of gynecologic patients with long-term follow-up. J Clin Oncol 1993, 11:1368–1375.
cancers. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick 66. Law TM, Motzer RJ, Mazumdar M, et al.: Phase III randomized trial
MB. Philadelphia: Lea & Febiger; 1982. of interleukin-2 with or without lymphokine activated killer cells in
46. Eagen JW, Lewis EJ: Glomerulopathies of neoplasia. Kidney Int 1977, the treatment of patients with advanced renal cell carcinoma. Cancer
11:297–306. 1995, 76:824–832.
47. Moorthy AV, Zimmerman SW, Burkholder PM: Nephrotic syndrome 67. Wigginton JM, Komschlies KL, Back TC, et al.: Administration of
in Hodgkin’s disease: evidence for pathogenesis alternative to immune interleukin-12 with pulse interleukin-2 and the rapid and complete
complex deposition. Am J Med 1976, 61:471–477. eradication of murine renal carcinoma. J Natl Cancer Inst 1996,
88:38–43.
48. Shalhoub RJ: Pathogenesis of lipoid nephrosis: a disorder of T-cell
function. Lancet 1974, 2:556–560. 68. Manning EC, Belenko MI, Frauenhoffer EE, Ahsan N: Acute renal
failure secondary to solid tumor renal metastases: case report and
49. Tsuji M, Ochiai S, Taka T, et al.: Nonamyloidotic nephrotic syndrome
review of the literature. Am J Kidney Dis 1996, 27:284–291.
in Waldenstrom’s macroglobulinemia. Nephron 1990, 54:176–178.
69. Wagle DG, Moore RH, Murphy GP: Secondary carcinomas of the
50. Kyle RA: “Benign” monoclonal gammopathy—after 20-35 years of
kidney. J Urol 1975, l 14:30–32.
follow-up. Mayo Clin Proc 1993, 68:26–36.
70. Wilson RE, Hager EB, Hampers CL, et al.: Immunologic rejection of
51. Garnick MB: Bladder, renal and testicular cancer. Scientif Am Med
human cancer transplanted with a renal allograft. N Engl J Med
1995: 12:ixB 1–5.
1968, 278:479–483.
52. Shapiro CL, Garnick MB, Kantoff PW: Tumors of the kidney, ureter,
71. Sharland A, Snowdon L, Joshua DE, et al.: Hemodialysis: an appro-
and bladder. In Cecil Textbook of Medicine, edn 20. Edited by
priate therapy in myeloma-induced renal failure. Am J Kidney Dis
Bennett JC. Philadelphia: WB Saunders; 1996:867.
1997, 30:786–792.
53. McDougal WS, Garnick MB: Clinical signs and symptoms of kidney
cancer. In Comprehensive Textbook of Genitourinary Oncology. 72. Gertz MA, Kyle RA, Greipp PR: Response rates and survival in pri-
Edited by Vogeizang NJ, Scardino PT, Shipley WU, et al. Baltimore: mary systemic amyloidosis. Blood 1991, 77:257–262.
Williams & Wilkins; 1996:P546. 73. Massry, Glassock: Textbook of Nephrology, edn 3. Baltimore:
54. Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Williams & Wilkins; 1995.
Med 1996, 335:8665–8875. 74. Harmon WC, Cohen HJ, Schneeberger E, et al.: Chronic renal failure
55. Chisholm GD, Roy RR: The systemic effects of malignant renal in children treated with methyl CCNU. N Engl J Med 1979,
tumors. Br J Urol 1971, 43:687–700. 300:1200–1203.
56. Brenner B, Rector F: The Kidney, edn 5. Philadelphia: WB Saunders 75. Daniels RA, Weisenfeld I: Tumorous phosphaturic osteomalacia:
Co.; 1996. report of a case associated with multiple hemangiomas of bone. Am J
Med 1979, 67:155–159.
57. Beahrs OH, Henson DE, Hutter RVP, et al.: Handbook for the
Staging of Cancer: From the Manual for Staging Cancer, edn 4. 1993, 76. Simpson DP, Wen SF, Chesney RW: Fluid and electrolyte abnormalities
Philadelphia: J.B. Lippincott; 1993. due to tumors, their products, or metabolites. In Cancer and the
Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea &
58. Storkel S, van den Berg E: Morphologic classification of renal cancer. Febiger; 1982.
World J Urol 1995, 13:153–158.
77. Hauck WA, Olson KB, Horton J: Clinical features of tumor metastasis
59. Latif F, Tory K, Gnarra J, et al.: Identification of the von Hippel- to the pituitary. Cancer 1970, 26:656.
Lindau tumor suppressor gene. Science 1993, 260:1317–1320.
78. Pickering TG, Catovsky D: Hypokalemia and raised lysozyme level in
60. Storkel S, Stearata PV, Drenckhain D, Thoenes W: The human chro- acute myeloid leukemia: Q J Med 1973, 42:677–682.
mophobe cell renal carcinoma: its probable relation to intercalated
cells of the collecting duct. Virchows Arch B Cell Pathol 1989, 79. Bennett JS, et al.: Hypouricemia in Hodgkin’s disease. Ann Intern
56:237–245. Med 1972, 76:751–756.
61. Shalev M, Cipolia B, Guille F, et al.: Is ipsilateral adrenalectomy a 80. Chan L, Kam I, Spees EK: Outcome and complications of renal trans-
necessary component of radical nephrectomy? J Urol 1995, plantation. In Diseases of the Kidney, edn 6. Edited by Schrier RW,
153:1415–1417. Gottschalk CW. Boston: Little, Brown; 1997:2713–2769.
62. Licht MR, Novick AC, Goormastic M: Nephron sparing surgery in 81. Stone RM, Mark EJ, Ferry JA: Case records of the Massachusetts
incidental versus suspected renal cell carcinoma. J Urol 1994, General Hospital: Weekly clinicopathological exercises. A 67-year-old
152:39–42. renal-transplant recipient with anemia, leukopenia, and pulmorary
lesions. N Engl J Med 1997, 337:1065–1074.
63. Thrasher JB, Paulson DF: Prognostic factors in renal cancer. Urol Clin
North Am 1993, 20:247–262.
Renal Involvement in
Tropical Diseases
Rashad S. Barsoum
Magdi R. Francis
Visith Sitprija
T
ropical nephrology is no longer a regional issue. With the enor-
mous 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 [1–3].
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 [4–7].
The so-called typical tropical nephropathies are broadly classified as
infective or toxic. Infective nephropathies include renal diseases associat-
ed 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 ori-
gin, such as certain mushrooms and the djenkol bean [3].
Tropical bacterial infections often are associated with renal complica-
tions 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, CHAPTER
cholera, tetanus, scrub typhus, and diphtheria [8–16]. Renal involvement
in mycobacterial infections such as tuberculosis and leprosy usually pur-
6
sues a subacute or chronic course [17–19].
The clinical spectrum of renal involvement extends all the way Mycotic infections are described in detail elsewhere.
from asymptomatic proteinuria or urinary sediment abnormalities Discussed here is a fairly common mycotic infection, mucormy-
to fatal acute renal failure. The respective renal pathologies include cosis, which occurs in underdeveloped tropical regions, partic-
glomerular, microvascular, and tubulointerstitial lesions. ularly among immunocompromised patients. Also described is
The pathogenesis of renal complications in tropical bacterial ochratoxin, a fungal toxin often incriminated in the pathogen-
infections is multifactorial. The principal factors are direct tis- esis of Balkan nephropathy. Ochratoxin also contributes to pro-
sue invasion by the causative organisms and remote cellular and gressive interstitial nephropathy in Africa [20].
humoral effects of bacterial antigens and endotoxins. The rela- Three ways exist by which parasitic infections cause renal
tive significance of the different pathogenetic mechanisms disease: 1) direct physical invasion of the kidneys or urinary
varies with the causative organism. tract, as in schistosomiasis, echinococcosis, and filariasis; 2)
In tropical zones many viral nephropathies are endemic, such renal injury as a consequence of the acute systemic effects of
as those associated with human immunodeficiency virus and parasitic infection, eg, falciparum malaria; and 3) immune-
hepatitis A, B, and C viruses. These are addressed in Chapter 7. mediated renal injury resulting from the concomitant host-par-
Here the focus is on an important viral disease endemic in asite interaction, eg, schistosomiasis, malaria, filariasis, leish-
Southeast Asia that often causes minor epidemics in Africa and maniasis, trichinosis, echinococcosis, toxoplasmosis, and try-
other tropical countries, dengue hemorrhagic fever. panosomiasis [21–32].
Infective Tropical Nephropathies

Bacterial Infections
CLINICAL MANIFESTATIONS OF TROPICAL BACTERIAL NEPHROPATHIES
Disease Abnormal sediment Proteinuria ARF CRF HUS Hemolysis DIC Jaundice Commonly associated features
Salmonellosis +++ ++++ + - + + + + Gastrointestinal
Shigellosis + - ++* + + + Neurologic†
Leptospirosis ++++ ++++ ++++ - + + + ++++ Hemorrhagic tendency
Polyuria‡
Melioidosis +++++ + ++ - Hyponatremia§
Cholera + - Hypokalemia, acidosis
Tetanus + ++++ +++ - Sympathetic overflow
Scrub typhus + ++ + - + +
Diphtheria + + + - Myocarditis, polyneuritis
Tuberculosis ++ +/+++ + Retroperitoneal nodes
Leprosy ++ +++ + + 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].
ARF—acute renal failure; CRF—chronic renal failure; DIC—disseminated intravascular coagulation; HUS—hemolytic 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 [33–35].
Renal Involvement in Tropical Diseases 6.3
SPECTRUM OF RENAL PATHOLOGY IN TROPICAL BACTERIAL INFECTIONS
Other tubular
Disease Glomerulonephritis Vasculitis AIN ATN changes
Deposits of
immunoglobulins,
complement,
MPGN EXGN MCGN MN NG CGN Amyloid and antigen
Salmonellosis ++ ++* G,M,A,C3,Ag† ++ + Cloudy swelling
Shigellosis + + + Cloudy swelling
Leptospirosis + + M,C3 + ++ +++
Melioidosis + +++ + Cloudy swelling
Cholera ++ Vacuolation‡
Tetanus ++
Scrub typhus + + + Cloudy swelling
Diphtheria ++ +/++ Degeneration§
Tuberculosis + +
Leprosy +/+++ + + +¶ + G,M,A,C3 + +/+++** 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].

AIN—acute interstitial nephritis; ATN—acute tubular necrosis; CGN—crescentic glomerulonephritis; EXGN—exudative glomeru-
lonephritis; MCGN—mesangiocapillary glomerulonephritis; MN—membranous glomerulopathy; NG—necrotizing glomerulitis;
+—<10%; ++—10%–24%; +++—25%–50%.
FIGURE 6-2
Spectrum of renal pathology in tropical bacterial infections [36–38].
A B
FIGURE 6-3
Glomerular lesions associated with tropical bacterial patient with shigellosis. B, Exudative glomerulonephritis in a
infections. A, Simple proliferative glomerulonephritis in a patient with salmonellosis.
C D
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 leptospiro-
sis. (Hematoxylin-eosin stain 250.)
B, Cortical necrosis in a child with severe
shigellosis and hemolytic uremic syndrome.
A B
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.)
A B
C D
FIGURE 6-7
Interstitial lesions associated with bacterial infections. stain 100.) C, Renal abscess in a patient with septicemic
A, Acute interstitial nephritis in a patient with diphtheria. melioidosis. (Hematoxylin-eosin stain 75.) D, Micro-
(Hematoxylin-eosin stain 100.) B, Perivenular monocytic abscesses in a patient with typhoid fever [40]. (Hematoxylin-
infiltration in a patient with scrub typhus. (Hematoxylin-eosin eosin stain 75.)

Low-power electron micrograph. Here leptospires (arrow) in the Renal tuberculosis. Seen here are multiple tuberculous granulomata
peritubular cortical interstitial space are seen in a patient with with Langhans’ giant cells. Diffuse interstitial tuberculosis without
leptospirosis. (Magnification 12,000.) definite granulomatous formation also has been described.
Bacterial infection
Direct invasion Monocyte activation Endothelial injury Nonspecific

inflammatory effects
T-cell response Monokines Humoral Hematologic
B-cell response IL-1,6 Complement/coagulation

TNF-α
NO
Antibodies ROM Platelets Erythrocytes
Adhesion molecules
Immune complexes Endothelin DIC Hemolysis
Abscess Renal ischemia

Hypovolemia Cholestasis
Glomerulonephritis Interstitial nephritis 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 host’s 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. ATN—acute tubular necrosis; DIC—disseminated intravascular coagulation;
IL—interleukin; NO—nitric oxide; ROM—reactive oxygen molecules; TNF-—tumor necrosis factor-.
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
90
Clinical manifestations of renal involvement in dengue hemorrhag-
80 ic fever. Note that proteinuria and abnormal urinary sediment are
70 the most common manifestations. Also note the high incidence of
60 hyponatremia, like with many other tropical infections [40,41].
Incidence, %
50
40
30
20
10
0
Urinary Proteinuria Hyponatremia Lactic Acute renal
sediment acidosis failure
abnormalities
Selected important features
FIGURE 6-13
Renal lesions in a patient with dengue hem-
orrhagic fever. A, Mesangial proliferative
glomerulonephritis, which usually is associ-
ated with deposits of immunoglobulins G
and M and complement 3. (Hematoxylin-
eosin stain 200.) B, Acute tubular necro-
sis, which is associated with interstitial
edema and mononuclear cell infiltration.
A B
Mycotic Infections

Section from a patient with mucormycosis, showing extensive tissue Ochratoxin-A–induced interstitial fibrosis, showing marked inter-
necrosis, weak inflammatory cellular infiltration, and fungal hyphae tubular scarring with patchy atrophy and collapse of tubules. This
branching at right angles. (Hematoxylin-eosin stain 150.) patient’s 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.)
Parasitic Infections
FIGURE 6-16
Schistosoma hemalobium Global distribution of important parasitic
Schistosoma mansoni
nephropathies. Note the high prevalence of
schistosomal, malarial, filarial, and
echinococcal renal complications in Africa;
Echinococcosis S. mansoni and hydatid in South America;
Plasmodium falciparum malaria and filariasis in South
Quartan falciparum East Asia and filariasis in India [3].
malaria
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 hypersensi-
tivity 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. (Hematoxylin-
eosin stain 300.)
A B
A B C
FIGURE 6-18
Cystoscopic appearances of different bladder lesions associated with Schistosoma haema-
tobium 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.)

Postmortem specimen Filariasis of the
showing advanced abdominal lymphat-
bilharzial involvement ics. Lymphangio-
of the urinary tract. gram shows the
Note the dirty blad- dilated retroperi-
der mucosa, fibrosed toneal lymphatics in
muscle layer, and neo- a patient with filari-
plastic growth (histo- al chyluria.
logically a squamous
cell carcinoma) cut
through transversely.
The ureters are dilat-
ed, with a clear stric-
ture 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 consid-
erable scarring, with
the right kidney also
showing chronic back
pressure changes.
Antigens
Merozoites
Erythrocyte
Monocyte
Hemolysis
Cell membrane
changes TH1 TH2
TNF-α CIC
Platalet
CD8+ B Immunoglobulins
Endothelial activation
Hemodynamic changes Acute inflammatory Immune complex disease

FIGURE 6-22
Acute Tubulointerstitial Acute Proliferative Erythrocyte knobs in a patient with falci-
tubular nephropathy glomerulonephritis glomerulonephritis parum malaria [43]. These erythrocyte
necrosis
knobs contain novel proteins, mainly
Plasmodium falciparum erythrocyte mem-
brane protein (PfEMP), histidine-rich pro-
FIGURE 6-21
tein 1, and histidine-rich protein 2, that are
The pathogenesis of falciparum malarial renal complications. Note the infection triggers synthesized under the influence of the DNA
two initially independent pathways: red cell parasitization and monocyte activation. These of the parasite [44–46]. These proteins con-
subsequently interact, as the infected red cells express abnormal proteins that induce an stitute the sticky points (arrows) by which
immune reaction by their own right, in addition to providing sticky points (knobs) for parasitized erythrocytes aggregate and
clumping and adherence to platelets and capillary endothelium. TNF- released from the adhere to blood platelets and endothelial
activated monocytes shares in the endothelial activation. As both pathways proceed and cells [47,48]. EN—electron microphoto-
interact, a variety of renal complications develop, including acute tubular necrosis, acute graph. (Magnification 12,000.)
interstitial nephritis and acute glomerulonephritis. B—B-lymphocyte; CD8—cytotoxic T
cell; CIC—circulating immune complexes; TH—T-helper cells (1 and 2); TNF-—tumor
necrosis factor-.
B
FIGURE 6-23
Renal lesions in a patient with falciparum malaria. A, Proliferative
and exudative glomerulonephritis, an immune-complex–mediated
lesion that may lead to an acute nephritic syndrome, which usually
is reversible by antimalarial treatment. (Hematoxylin-eosin stain
A 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.)

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.)
FIGURE 6-24
The broad lines of the immune response to
+
CDCT parasitic infections. Note the pivotal role of
ACDC the monocyte, activated by exposure to para-
ADCC
– sitic antigens, in stimulating both T-helper 1
Parasite (TH1) and T-helper 2 (TH2) cells. The differ-
Eosinophil –
+ ent cytokine mediators and parasite elimina-
+ + + + Neutrophil tion mechanisms are shown. B—B-lympho-
cyte; -IFN—-interferon; CIC—circulating
Complement
Antigen immune complexes; GM-CSF—granulocyte-
CIC + macrophage colony-stimulating factor;
IL-5,13 IL-2 IgM,E,G,A Ig—immunoglobulin; IL—interleukin.
IL-1,6,12
GM-CSF
+
B
TH2 TH1 + +
γ-IFN
IL-2
IL-4,5,10
FIGURE 6-25
The T-helper1–T-helper 2 (TH1-TH2) cell balance that determines
the clinical expression of different parasitic nephropathies. TH1
predominance leads to either reversible acute proliferative glomeru-
lonephritis or acute interstitial nephritis. TH2 predominance tends
to lessen the severity of the lesions and may lead to chronic
Active monocytes Inactive monocytes
TH2, CD8 cells TH2 ,CD8 cells glomerulonephritis in the presence of copathogenic factors such as
IgG1,2,3 IgM,IgG4,IgA concomitant infection (malaria, schistosomiasis), autoimmunity
IL-1,6;+γIFN IL-4,5,10 (malaria, filariasis, schistosomiasis), or immunoglobulin A (IgA)
switching (Schistosoma mansoni) [7, 9, 49–52]. CD4—T-helper
cells; CD8—cytotoxic cells; -INF—-interferon; IL—interleukin.
Initial events Late events

FIGURE 6-26
Leishmaniasis. A, Amastigotes in peripheral
blood monocytes. Amastigotes downregu-
late the host cells that show no attempt at
eradicating the parasite. (Hematoxylin-
eosin stain 450.) B, Interstitial nephritis
representing a TH1 predominant state,
which is self-limited owing to the parasite-
induced monocyte inhibition [53].
A B
FIGURE 6-27
Trichinosis. A, Here Trichinella spiralis is
encysted in the muscle tissue of a patient.
(Hematoxylin-eosin stain 75.) B, Asso-
ciated proliferative glomerulopathy in a
patient. This lesion usually is subclinical
but may be manifested as an acute nephritic
syndrome that can be resolved with anti-
parasitic treatment. This lesion represents a
TH1 predominant state. (Hematoxylin-
eosin stain 150.)
A B
A
FIGURE 6-28
Echinococcosis. A, Mesangiocapillary type
III glomerulonephritis. (Hematoxylin-eosin
stain 200.) B, Electron micrograph
showing subepithelial deposits. (Hema-
toxylin-eosin stain 25,000.) C, Peri-
pheral part of a hydatid cyst showing the
daughter cysts in a patient. (Hematoxylin-
eosin stain 75.) C
FIGURE 6-29
Onchocercosis. A, The parasite Onchocerca
volvulus deposits lesions in tissues. (Hema-
toxylin-eosin stain 150.) B, Associated
mesangial proliferative lesion. This lesion rep-
resents a TH1 predominant state. Some
patients, however, develop an autoimmune
reaction that leads to progressive glomeru-
lonephritis. (Hematoxylin-eosin stain 175.)
A B
FIGURE 6-30
Quartan malarial nephropathy. A, Prolifer-
ative glomerulonephritis with capillary wall
thickening. (Hematoxylin-eosin stain
200.) B, Subendothelial deposits with split-
ting 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.
A B
A B
Intestinal schistosomiasis. A, Pair of adult Schistosoma mansoni worms in colonic mucosa. Patient with hepatosplenic schistosomiasis,
(Hematoxylin-eosin stain 75.) B, Colonic granuloma around a viable ovum. (Hema- complicating intestinal mansoniasis. Note
toxylin-eosin stain 150.) 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].
FIGURE 6-33
Early glomerular lesion in a patient with
schistosomiasis. A, Mesangial proliferation.
(Hematoxylin-eosin stain 200.) B, Sch-
istosomal gut antigen deposits in the
mesangium. Other immunofluorescent
deposits at this stage include immunoglobu-
lins 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 necessari-
ly progress any further. (Hematoxylin-eosin
stain 300.)
A B
A B
C D
FIGURE 6-34
Histologic lesions in a patient with progressive Schistosoma segmental glomerulosclerosis. (Masson trichrome stain 150.)
mansoni glomerulopathy. A, Mesangial proliferative glomeru- The two lesions in panels C and D are associated with advanced
lonephritis. (Hematoxylin-eosin stain 150.) B, Exudative hepatic fibrosis, impaired macrophage function, and predomi-
glomerulonephritis, often encountered with concomitant nant immunoglobulin A mesangial deposits [7,55]. The lesions
Salmonella paratyphi A infection [9]. (Hematoxylin-eosin stain shown are categorized, respectively, as classes I to IV schistoso-
150.) C, Mesangial proliferation with areas of mesangiocapil- mal glomerulopathy according to the classification system of the
lary changes. (Hematoxylin-eosin stain 150.) D, Focal and African Association of Nephrology [54].
Pathogenesis of S. mansoni glomerulotherapy FIGURE 6-35

Pathogenesis of Schistosoma mansoni
Adult worms in glomerulopathy. Note the crucial role of
the portal vein hepatic fibrosis, which 1) induces glomeru-
lar hemodynamic changes; 2) permits schis-
Egg granulomata Egg granulomata tosomal antigens to escape into the systemic
in the portal tracts in the colonic mucosa circulation, subsequently depositing in the
glomerular mesangium; and 3) impairs
clearance of immunoglobulin A (IgA),
Mucosal
Autoimmunity Antigens breach
Switching which apparently is responsible for progres-
sion of the glomerular lesions. IgA synthesis
seems to be augmented through B-lympho-
cyte switching under the influence of inter-
IgG,M,E Immune complexes IgA leukin-10, a major factor in late schistoso-
mal lesions [7].
Impaired macrophage function
Periportal fibrosis Portosystemic collaterals
Glomerular deposits
A C
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 haematobi-
um 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.)
FIGURE 6-37
Pathogenesis of schistoma-associated amyloidosis
Pathogenesis of schistosoma-associated amyloidosis. The monocyte
Interleukin-1,6 Hepatocyte continues to release interleukin-1 and interleukin-6 under the influ-
+
Antigen ence of schistosomal antigens. These antigens stimulate the hepato-
cytes to release AA protein, which has a distinct chemoattractant
function. The monocyte is the normal scavenger of serum AA pro-
Uptake
tein, a function that is impaired in hepatosplenic schistosomiasis.
AA protein Serum AA protein accumulates and tends to deposit in tissue.
Matrix adhesion
Tissue deposition Chemoattraction
Toxic Tropical Nephropathies

Toxins of Animal Origin
FIGURE 6-38
NEPHROPATHIES ASSOCIATED WITH EXPOSURE TO ANIMAL TOXINS Nephropathies associated with exposure to
toxins of animal origin. Note that acute
renal failure is the most common and
Acute renal failure Vasculitis Subnephrotic proteinuria Nephrotic syndrome important renal complication. Vascular and
glomerular lesions are occasionally encoun-
Snake bite +++ + + (MPGN) tered with specific exposures [56–62].
Scorpion sting +
Insect stings + ++ (MCD, MPGN, MN)
Jelly fish sting +
Spider bite +
Centipede bite +
Raw carp bile ++
MCD—minimal change disease; MN—membranous glomerulonephritis; MPGN—mesangial proliferative glomeru-

lonephritis; +—<10%; ++—10%–24%; +++—25%–50%.
FIGURE 6-39
Pathogenetic mechanisms in snake venom nephrotoxicity
Pathogenetic mechanisms in snake venom
nephrotoxicity. The immediate effect of
Snake venom
exposure is attributed to direct hematologic
toxicity involving the coagulation system
Direct toxicity Immunologic
reaction and red cell membranes. The massive
release of cytokines and rhabdomyolysis
also contribute. Late effects may be encoun-
Disseminated Hemolysis Cytokines tered as a consequence of the immune
intravascular Rhabdomyolysis Mediators Mesangiolysis response to the injected antigens.
coagulation
Hemodynamic
Vasculitis
changes
Renal ischemia
Acute Acute tubular

Glomerulonephritis
glomerulonephritis necrosis
Toxins of Plant Origin

FIGURE 6-40
NEPHROPATHIES ASSOCIATED WITH EXPOSURE TO PLANT TOXINS Nephropathies associated with exposure to
toxins of plant origin. Note that with the
exception of Djenkol bean nephrotoxicity,
Acute renal failure Hypertension Proteinuria Hematuria most plant toxins lead to acute renal failure
due to hemodynamic effects [63–66].
Djenkol bean +++ ++ +++ ++++
Mushroom poisoning + +
Callilepis laureola +++
Semecarpus anacardium +
+—<10%; ++—10%–24%; +++—25%–49%; ++++—50%–80%.
Acknowledgment
The authors acknowledge the help of Professor Amani Amin University, for providing very valuable material included in
Soliman, Chairperson of the Parasitology Department, Cairo this work.
References
1. Giacomini T, Toledano D, Baledent F: The severity of airport malaria. 4. Prina E, Lang T, Glaichenhaus N, et al.: Presentation of the protective
Bull Soc Pathol Exot Faliales 1988, 81:345–350. parasite antigen LACK by Leishmania-infected macrophages. J
2. Vanherweghem JL: A new form of nephropathy secondary to the Immunol 1996, 156: 4318–4327.
absorption of Chinese herbs. Bull Mem Acad R Med Belg 1994, 5. Persat F, Vincent C, Schmitt D, et al.: Inhibition of human peripheral
149:128–135. blood mononuclear cell proliferative response by glycosphingolipids
3. Barsoum R, Sitprija V: Tropical nephrology. In Diseases of the from metacestodes of Echinococcus multilocularis. Infect Immun
Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, 1996, 64:3682–3687.
Brown and Company; 1997:2221–2268.
6. Clark IA: Suggested importance of monokines in pathophysiology 31. Ginsburg BE, Wasserman J, Huldt G, et al.: A case of glomeru-
of endotoxin shock and malaria. Klin Wochenschr 1982, lonephritis associated with acute toxoplasmosis. Br Med J 1974,
60:756–758. 3:664–665.
7. Barsoum RS, Nabil M, Saady G, et al.: Immunoglobulin A and the 32. Lindsley HB, Nagle RB, Werner PA, et al.: Variable severity of
pathogenesis of schistosomal glomerulopathy. Kidney Int 1996, glomerulonephritis in inbred rats infected with Trypanosoma rhode-
50:920–928. siense: correlation with immunoglobulin class-specific antibody
8. Khajehdehi P, Tastegar A, Karazmi A: Immunological and clinical responses to trypanosomal antigens and total IgM levels. Am J Trop
aspects of kidney disease in typhoid fever in Iran. Q J Med 1984, Med Hyg 1980, 29:348–357.
209:101–107. 33. Srivastava RN, Mocedgil A, Bagga A, et al.: Hemolytic uremic syn-
9. Bassily S, Farid Z, Barsoum RS, et al.: Renal biopsy in schistosoma- drome in children in northern India. Pediatr Nephrol 1991,
salmonella associated nephrotic syndrome. J Trop Med Hyg 1976, 5:284–288.
79:256–258. 34. O’Riordan T, Kavanagh P, Mellotte G, et al.: Haemolytic uraemic syn-
10. Benish ML, Harris JR, Wojtyniak BJ , et al.: Death in shigellosis: inci- drome in shigella. Irish Med J 1990, 83:72–73.
dence and risk factors in hospitalized patients. J Infect Dis 1990, 35. Magaldi AJ, Yasuda PN, Kudo LH, et al.: Renal involvement in lep-
161:500–506. tospirosis: a pathophysiologic study. Nephron 1992, 62:332–339.
11. Sitprija V: Leptospirosis. Med Int 1992, 106:4476–4479. 36. Sinniah R, Churg J, Sobin LH (eds.): Renal Disease: Classification and
12. Susaengrat W, Dhiensiri T, Sinavatana P, et al.: Renal failure in melioi- Atlas of Infectious and Tropical Diseases. Chicago: ASCP Press; 1988.
dosis. Nephron 1987, 46:167–169. 37. Melby EI, Jacobsen J, Olsnes S, et al.: Entry of protein toxins in
13. World Health Organization: Cholera in Africa. WHO Weekly polarized epithelial cells. Cancer Res 1993, 53:1753–1760.
Epidemiol Rec 1997, 72:89–92. 38. Nigam P, Pant KC, Kapoor KK, et al.: Histo-functional status of kid-
ney in leprosy. Indian J Lepr 1986, 58:567–575.
14. Martinelli R, Matos CM, Rocha H: Tetanus as a cause of acute renal
failure: possible role of rhabdomyolysis. Rev Soc Bras Med Trop 39. American Society of Clinical Pathologists: Renal Disease:
1993, 26:1–4. Classification and Atlas of Infection and Tropical Diseases. Edited by
Sinniah R, Chugh J, Sobin LH. Chicago: ASCP Press; 1988:137.
15. Hsu GJ, Young T, Peng MY, et al.: Acute renal failure associated with
scrub typhus, report of a case. J Formosan Med Assoc 1993, 40. Baker NM, Mills AE, Rachman I, et al.: Hemolytic uremic syndrome
92:475–477. in typhoid fever. Br Med J 1974, 2:84–87.
16. Singh M, Saidali A, Bakhtiar A: et al.: Diphtheria in Afghanistan: 41. Sitprija V, Boonpucknavig W: The kidney in dengue. Proceedings of
review of 155 cases. J Trop Med Hyg 1985, 88:373–376. the 11th Asian Colloquium of Nephrology. Singapore; 1996:260–265.
17. Latimer JK: Renal tuberculosis. N Engl J Med 1975, 273:208–214. 42. Boonpucknavig V, Bhamarapravati N, Boonpucknavig E, et al.:
Glomerular changes in dengue hemorrhagic fever. Arch Pathol Lab
18. Chugh KS, Damle PB, Kaur S: Renal lesions in leprosy amongst North
Med 1976, 100:206–212.
Indian patients. Postgrad Med J 1983, 59:707–711.
43. Kilejian A, Abati A, Trager W: Plasmodium falciparum and
19. Madiwale CV, Mittal BV, Dixit M , et al.: Acute renal failure due to
Plasmodium coatney: immunogenicity of knoblike protrusions on
crescentic glomerulonephritis complicating leprosy. Nephrol Dial
infected erythrocyte membrane. Exp Parasitol 1977, 42:157.
Transplant 1994, 9:178–179.
44. Kojima S: Molecular biology of malaria. XIV International Congress
20. Saadi MG, Abdulla E, Fadel F, et al.: Prevalence of ochratoxin-A (OT-
on Nephrology, Sydney; 1997:S5.
A) among Egyptian children and adults with different renal diseases
[abstract]. Second International Congress on Geographic Nephrology, 45. Leech JH, Barnwell JW, Aikawa M, et al.: Plasmodium falciparum
Hurghada, Egypt; 1993:22. malaria: association of knobs on the surface of infected erythrocytes
with a histidine-rich protein and the erythrocyte skeleton. J Cell Biol
21. Barsoum RS: Schistosomiasis. In Oxford Textbook of Clinical
1984, 98:1256.
Nephrology. Oxford: Oxford University Press; Edited by Cameron S,
Davidson A, Grunfeld JP, et al. 1992:1729–1741. 46. Parra ME, Evans CB, Taylor DW: Identification of Plasmodium falci-
parum histidine-rich protein 2 in the plasma of humans with malaria.
22. Beyribey S, Cetinkaya M, Adsan O, et al.: Treatment of renal hydatid J Clin Microbiol 1991, 29:1629–1634.
disease by pedicled omentoplasty. J Urol 1995, 154:25–27.
47. Butthep P, Bunyaratvej A: An unusual adhesion between red cells and
23. Addiss DG, Dimock KA, Eberhard ML, et al.: Clinical, parasitologic platelets in falciparum malaria. J Med Assoc Thai 1992, 75(suppl
and immunologic observations of patients with hydrocele and ele- 1):195–202.
phantiasis in an area with endemic lymphatic filariasis. J Infect Dis
1995, 171:755–758. 48. Udeinya IJ, Schmidt JA, Aikawa M, et al.: Falciparum malaria infect-
ed erythrocytes specifically bind to cultured human endothelial cells.
24. Sitprija V: Nephrology forum: nephropathy in falciparum malaria. Science 1981, 213:555.
Kidney Int 1988, 34:867–877.
49. Wedderburn N, Ochs HD, Clark EA, et al.: Glomerulonephritis in
25. Sobh M, Moustafa F, El-Arbagy A, et al.: Nephropathy in asympto- common marmosets infected with Plasmodium brazilianum and
matic patients with active Schistosoma mansoni infection. Int Urol Epstein-Barr virus. J Infect Dis 1988, 148:289.
Nephrol 1990, 22:37–43.
50. Yahya TM, Benedict S, Shalabi A, et al.: Antineutrophil cytoplasmic
26. Hendrickse RG, Adeniyi A: Quartan malarial nephrotic syndrome in antibody (ANCA) in malaria is directed against cathepsin G. Clin Exp
children. Kidney Int 1979, 16:64–74. Immunol 1997, 110:41–44.
27. Waugh DA, Alexander JH, Ibels LH: Filarial chyluria–associated 51. Meilof JF, Van der Lelij A, Rokeach LA, et al.: Autoimmunity and
glomerulonephritis and therapeutic consideration in the chyluric filariasis: autoantibodies against cytoplasmic cellular proteins in sera
patient. Aust N Z J Med 1980, 10:559–562. of patients with onchocerciasis. J Immunol 1993, 151:5800–5809.
28. Ayachi R, Ben Dhia N, Guediche N, et al.: The nephrotic syndrome in 52. Thomas MA, Frampton G, Isenberg DA, et al.: A common anti-DNA
kala-azar. Arch Fr Pediatr 1988, 45:493–495. antibody idiotype and anti-phospholipid antibodies in sera from
29. Sitprija V, Keoplung M, Boonpucknavig V, et al.: Renal involvement patients with schistosomiasis and filariasis with and without nephritis.
in human trichinosis. Arch Intern Med 1980, 140:544–546. J Autoimmune 1989, 2:803–811.
30. Okelo GBA, Kyobe J: A three-year review of human hydatid disease 53. Prina E, Lang T, Glaichenhaus N, et al.: Presentation of the protective
seen at Kenyata National Hospital. East Afr Med J 1981, parasite antigen LACK by Leishmania-infected macrophages. J
58:695–701. Immunol 1996, 156:4318–4327.
54. Barsoum RS: Schistosomal glomerulopathies. Kidney Int 1993, 61. Logan JL, Ogden DA: Rhabdomyolysis and acute renal failure follow-
44:1–12. ing the bite of the giant desert centipede, Scolopendra heros. West J
55. Barsoum RS, Sersawy G, Haddad S, et al.: Hepatic macrophage Med 1985, 142:549.
function in schistosomal glomerulopathy. Nephrol Dial Transplant 62. Lin CT, Huang PC, Yen TS, et al.: Partial purification and some
1988, 3:612–616. characteristic nature of a toxic fraction of the grass carp bile. Clin
56. Chugh KS: Snake bite induced renal failure in India. Kidney Int Biochem Soc 1977, 6:1.
1989, 194. 63. Eiam-Ong S, Sitprija V, Saetang P, et al.: Djenkol bean nephrotoxicity
57. Waterman J: Some notes on scorpion poisoning in Trinidad. Trans R in Southern Thailand. Proceedings of the First Asia Pacific Congress
Soc Trop Med Hyg 1993, 32:607. on Animal, Plant and Microbial Toxins. Singapore; 1989:628.
58. Barss P: Renal failure and death after multiple stings in Papua New 64. McClain JL, Hause DW, Clark MA: Amanita phalloides mushroom
Guinea. Ecology, prevention and management of attacks by vespid poisoning: a cluster of four fatalities. J Forensic Sci 1989, 34:83.
wasps. Med J Aust 1989, 151:659. 65. Bye BN, Coetzer TH, Dutton MF: An enzyme immunoassay for
59. Spielman FJ, Bowe EA, et al.: Acute renal failure as a result of atractyloside, the nephrotoxin of Callilepis laureola (Impila).
Physalia physalis sting. South Med J 1982, 75:1425. Toxicology 1990, 28:997.
60. Kibukamusoke JW, Chugh KS, Sakhuja V: Renal effects of envenoma- 66. Matthai TP, Date A: Renal cortical necrosis following exposure to sap
tion. In Tropical Nephrology. Edited by Kibukamusoke JW. Canberra, of the marking nut tree (Semecarpus anacardium). Am J Trop Med
Australia: Citforge Pty; 1984:170. Hyg 1979, 28:773.
Renal Disease in
Patients Infected with
Hepatitis and Human
Immunodeficiency Virus
Jacques J. Bourgoignie
T.K. Sreepada Rao
David Roth
I
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 dis-
covery of the disease, deaths are decreasing. Nevertheless, in the CHAPTER
United States, as of June 30, 1997, there were over 600,000 cumula-
tive cases of HIV infection, with over 400,000 deaths. Worldwide,
7
the HIV epidemic continues to spread; an estimated 20 million per-
sons are infected with HIV. Recent advances in the clinical manage-
ment of these patients result from better understanding of the repli-
cation kinetics of HIV, assays to measure viral load, availability of
new effective drugs against HIV, and demonstration that with HIV infection now is common. The incidence of renal
aggressive protocols combining antiviral drugs substantially complications in this population is expected to increase further
reduce HIV replication. Thus, prolonged survival of patients as patients live longer.
Hepatitis B and C Virus

FIGURE 7-1
RENAL DISEASE ASSOCIATED WITH Renal disease associated with hepatitis B. Infection with
HEPATITIS B VIRUS INFECTION hepatitis B virus (HBV) may be associated with a variety of
renal diseases [1,2]. Many patients are asymptomatic, with plas-
ma serology positive for hepatitis B surface antigen (HBsAg),
hepatitis B core antibody (HBcAb), and hepatitis B antigen
Lesion Clinical presentations Pathogenesis
(HBeAg). The pathogenetic role of HBV in these processes has
Membranous nephropathy Nephrotic syndrome Deposition of HBeAg been documented primarily by demonstration of hepatitis B anti-
with anti-HBeAb gen-antibody complexes in the renal lesions [1,3,4]. Three major
Polyarteritis nodosa Vasculitis, nephritic Deposition of circulating forms of renal disease have been described in HBV infection. In
antigen-antibody membranous nephropathy, it is proposed that deposition of
complexes HBeAg and anti-HBe antibody forms the classic subepithelial
Membranoproliferative Nephrotic, nephritic Deposition of complexes immune deposits [1,3–5]. Polyarteritis nodosa is a medium-sized
glomerulonephritis containing HBsAg and
vessel vasculitis in which antibody-antigen complexes may be
HBeAg
deposited in vessel walls [1,2]. Finally, membranoproliferative
glomerulonephritis is characterized by deposits of circulating
HBeAg—hepatitis B antigen; HBsAg—hepatitis B surface antigen. 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 anti-
RENAL DISEASE ASSOCIATED WITH
HEPATITIS C VIRUS INFECTION bodies; polyclonal immunoglobulin G anti-HCV antibodies within
the cryoprecipitate; and HCV RNA in the plasma and cryoprecipi-
tate [6,7]. Furthermore, evidence exists suggesting direct involve-
ment of HCV-containing immune complexes in the pathogenesis of
Disease Renal manifestations Serologic testing
this renal disease [6]. Sansono and colleagues [12] demonstrated
Mixed cryoglobulinemia Hematuria, proteinuria Positive cryoglobulins; HCV-related proteins in the kidneys of eight of 12 patients with
[6–11] (often nephrotic), rheumatoid factor cryoglobulinemia and membranoproliferative glomerulonephritis
variable renal insufficiency often present (MPGN) by indirect immunohistochemistry. Convincing clinical
Membranoproliferative Hematuria, proteinuria Hypocomplementemia; data exist suggesting that HCV is responsible for some cases of
glomerulonephritis [13] (often nephrotic) rheumatoid factor and
cryoglobulins may be
MPGN and possibly membranous nephropathy [13–15]. In one
present report of eight patients with MPGN, purpura and arthralgias were
Membranous Proteinuria Complement levels normal; uncommon and cryoglobulinemia was absent in three patients [13].
nephropathy [14,15] (often nephrotic) rheumatoid factor Circulating anti-HCV antibody and HCV RNA along with elevated
negative 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
FIGURE 7-2 that demonstrate a beneficial response to chronic antiviral therapy
Renal disease associated with hepatitis C. Hepatitis C virus (HCV) with -interferon [6,13,16,17]. Even more compelling evidence for
infection is associated with parenchymal renal disease. Chronic a beneficial effect of -interferon in HCV-induced mixed cryoglob-
HCV infection has been associated with three different types of ulinemia was demonstrated in a randomized prospective trial of 53
renal disease. Type II or essential mixed cryoglobulinemia has been patients given either conventional therapy alone or in combination
strongly linked with HCV infection in almost all patients with this with -interferon [18]. Because of the likely recurrence of viremia
disorder [6–11]. The clinical manifestations of this renal disease and cryoglobulinemia with cessation of -interferon therapy after
include hematuria, proteinuria that is often in the nephrotic range, conventional treatment (3 106 U three times weekly for 6 mo),
and a variable degree of renal insufficiency. Essential mixed cryo- extended courses of therapy (up to 18 mo) and higher dosing regi-
globulinemia had been considered an idiopathic disease; however, mens are being studied [19–21].
Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus 7.3

Membranoproliferative glomerulonephritis with hepatitis C. Electron microscopy of membranoproliferative glomerulonephritis
Micrograph of a biopsy showing membranoproliferative glomeru- from the biopsy specimen shown in Figure 7-3. Mesangial cell
lonephritis (MPGN) in a patient with hepatitis C virus (HCV) infec- interposition is noted with increased mesangial matrix. Abundant
tion. A lobulated glomerulus with mesangial proliferation and an subendothelial immunocomplex deposits are noted. Fusion of the
increase in the mesangial matrix are seen. Although still an idiopath- epithelial cell foot processes also is seen.
ic 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 Protein WORLDWIDE PREVALENCE OF ANTI–HEPATITIS C

Capsid glycoproteins helicase Replicase AMONG PATIENTS ON DIALYSIS
341 Nucleotides
Open-reading C E1 E2 NS2 NS3 NS4a NS4b NS5a NS5b
frame
5-1-1
RIBA2 Continent ELISA-1 positive, %
North America [25–29] 8–36
C200 Epitope South America [30] 39
2
ELISA Europe [31–41] 1–54
SA2 RIBA
ELI BA2 2
RI ELISA Asia [42–49] 17–51
C22-3 C33c C100-3 RIBA1+2 New Zealand and Australia [50,51] 1.2–10
Epitope Epitope Epitope 2
3000 Amino acids

Genomic HCV RNA ELISA-1—enzyme-linked immunosorbent assay-1.
5' 3'
FIGURE 7-6
FIGURE 7-5 Prevalence of anti-HCV among dialysis patients. Patients receiving
Diagnostic tests for HCV infection. In 1989, hepatitis C virus (HCV) dialysis clearly are at greater risk for acquiring hepatitis C virus
was cloned and identified as the major cause of parenterally transmit- (HCV) infection than are healthy subjects, based on the seropreva-
ted non-A, non-B hepatitis [22]. The first serologic test for HCV lence of anti-HCV antibodies among patients with end-stage renal
employed an enzyme-linked immunosorbent assay (ELISA-1) that disease. These results of ELISA-1 testing likely underestimate true
detected a nonneutralizing antibody (anti-HCV) to a single recombi- positivity because studies have demonstrated a nearly twofold
nant antigen. Limitations of the sensitivity and specificity of this test increase in seropositivity when screening dialysis patients with the
led to development of second-generation tests, ELISA-2 and a recom- ELISA-2 assay [52]. Additional studies have demonstrated that
binant immunoblot assay (RIBA-2) [23]. The standard for identifying most patients receiving dialysis who have anti-HCV seropositive
active HCV infection remains the detection of HCV RNA by reverse test results have circulating HCV RNA by polymerase chain reac-
transcriptase polymerase chain reaction. (Adapted from Roth [24].) tion analysis, indicating active viral replication.
FIGURE 7-7
RISK FACTORS IN THE Risk of HCV in the ESRD population. Numerous studies have demonstrated a strong
POPULATION WITH END-STAGE association between the prevalence of hepatitis C virus (HCV) infection among patients
RENAL DISEASE AND HEPATITIS receiving dialysis and both the number of transfusions received and duration of dialysis
C VIRUS INFECTION [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 dialy-
Transfusions [24,27,30,32,54–57] sis consistently have a lower prevalence of anti-HCV antibody [60–70]. Moreover, units
Duration of end-stage renal disease with a low prevalence of anti-HCV have been shown to have a lower seroconversion rate
[29,30,32,35,37,53–61] [71]. The latter two observations coupled with the independent association of duration of
Mode of dialysis [60–70] dialysis with seropositivity argue in favor of nosocomial transmission of HCV in hemo-
Prevalence of hepatitis C virus infection dialysis units. This conclusion is further supported by data showing a decreased incidence
in the dialysis unit [71,72] 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 HEPATITIS C Transmission of HCV during dialysis. Convincing data are available that demonstrate an
VIRUS IN HEMODIALYSIS UNITS 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 adja-
cent to that of a patient testing positive for anti-HCV [71–75]. Units using dedicated
Breakdown in universal precautions [73,74] machines have shown a decreased incidence of seroconversion [51]. The literature provides
Dialysis adjacent to an infected patient [71,75] conflicting data on the likelihood of passage of HCV RNA into dialysis ultrafiltrate and
Dialysis equipment [46,60]
the risk of contamination by reprocessing filters [71,72,76–78]. At this time the Centers
for Disease Control does not recommend that patients who are HCV positive be isolated
Type of dialyzer membrane [76–78]
or dialyzed on dedicated machines and has no official policy concerning reuse of machines
Reuse [71,72]
in these patients [79].
FIGURE 7-9
Liver disease among anti-HCV–positive dialysis patients. Serum
alanine aminotransferase levels are elevated in only 24% to 67%
Chronic active of dialysis patients who test positive for the anti-hepatitis C virus
Cirrhosis hepatitis (HCV) [80]. Caramelo and colleagues [81] evaluated liver biopsies
Pericentral 9% 42% from 33 patients on hemodialysis who tested positive using ELISA-2
fibrosis and found a variety of histologic patterns; however, over 50% of
3%
these patients had chronic hepatitis or cirrhosis. No correlation has
been found between mean levels of serum aminotransferase and
Other Hemosiderosis severity of liver disease [81]. At this time, liver biopsy is the only
6% 15% Reactive reliable method to determine the extent of hepatic injury in patients
hepatitis Chronic with end-stage renal disease infected with HCV. Liver function tests
18% persistent
hepatitis
and HCV serology testing may help identify patients who are at risk
6% for liver disease. However, a liver biopsy should be obtained before
initiating therapy or as part of the evaluation before transplanta-
tion. 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
PREVALENCE OF LIVER DISEASE AFTER Liver disease after kidney transplant. Biochemical abnormalities
KIDNEY TRANSPLANTATION reflecting liver injury have been reported in 7% to 34% of kidney
recipients in the early period after transplantation [23,82–86].
Morbidity and mortality associated with liver disease, however, are
First decade, % Second decade, % rarely seen until the second decade after transplantation [87]. Liver
dysfunction can be secondary to viral infections, such as hepatitis B
Acute liver disease: 5–65 Chronic liver disease: 5–40 and C, herpes simplex virus, Epstein-Barr virus, and cyto-
Chronic liver disease: 5–15 Death from liver failure: 10–30 megalovirus, in addition to the hepatotoxicity associated with several
immunosuppressive agents (azathioprine, tacrolimus, and cyclo-
sporine) [88]. However, hepatitis C virus infection has been demon-
strated convincingly to be the primary cause of posttransplantation
liver disease in renal allograft recipients [89,90].
FIGURE 7-11
TRANSMISSION OF HEPATITIS C VIRUS INFECTION Organ donor hepatitis C virus (HCV) transmission. Most recipients
BY CADAVERIC DONOR ORGANS of a kidney from a donor positive for hepatitis C virus RNA will
become infected with HCV if the organ is preserved in ice. ELISA-
1 testing of serum samples from 711 cadaveric organ donors iden-
Posttransplantation HCV infection status tified 13 donors positive for anti-HCV infection; 29 recipients of
organs from these donors were followed [91,92]. The prevalence of
Reference Anti-HCV, n/n (%) HCV RNA, n/n (%) HCV RNA in these allograft recipients increased from 27% before
Pereira et al. [91,92] 16/24(67) 23/24(96) transplantation to 96% after transplantation. In contrast, studies
Roth et al. [93] 10/31(32) Not available from centers using pulsatile perfusion of the kidney during preser-
Tesi et al. [94] 15/43(35) 21/37(57) vation have confirmed transmission of HCV in only about 56% of
Vincente et al. [95] 1/7(14) 1/7(14) cases [93,94]. Several factors might explain the discrepancy in
Wreghtt et al. [96] 6/15(40) 12/14(86) transmission rates. One possibility may involve differences in organ
preservation. Zucker and colleagues [97] demonstrated that pul-
satile 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 varia-
tion 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
Recipient 3a (Donor 1a) Recipient strain
5 a kidney from a positive donor into a positive recipient. In a simple
Donor strain
Both strains
but important study, Widell and colleagues [98] demonstrated three
Recipient 1b (Donor 1a) differing virologic patterns of HCV infection emerging after kidney
4
transplantation from a donor infected with HCV into a recipient
Patient, n
Recipient 2b (Donor 3a)

infected with HCV. Superinfection with the donor strain, persis-
3
tence of the recipient strain, or long-term co-infection with both
Recipient 2b (Donor 3a) the donor and recipient strain may result. The clinical significance
2
of infection with more than one HCV strain has not been deter-
Recipient 2b (Donor 3a) mined in the transplantation recipient with immunosuppression,
1 although no data exist to suggest that co-infection confers a worse
outcome. For this reason, many centers will transplant a kidney
Pretransplant 0 3 6 9 12 15 18 21 24 27 from a donor who was infected with HCV into a recipient infected
Months after transplant with HCV rather than discard the organ. (Data from Widell and
colleagues [98]; with permission.)
FIGURE 7-13
IMPACT ON OUTCOME OF HEPATITIS C VIRUS INFECTION Pretransplant HCV infection effect on out-
CONTRACTED BEFORE TRANSPLANTATION come. Reports have varied from different
centers concerning the impact of pretrans-
plantation hepatitis C virus (HCV) infection
After transplantation* on outcome after transplantation. Patient
survival and graft survival were significant-
Anti–hepatitis C ly worse among patients with anti-HCV
Reference virus infection Actuarial graft survival, % Actuarial patient survival, % infection in some studies [99,100]; in other
Fritche et al. [99] ELISA-2 positive 32(10) 58(8) studies a measurable impact could not be
ELISA-2 negative 53(10) 82(8) detected [90,101]. Some of these differences
Pereira et al. [100] ELISA-2 positive 50 59 could be attributed to geographic variation
ELISA-2 negative 59 85 in the prevalence of various HCV genotypes,
Roth et al. [90] RIBA-2 positive 81(5) 63(5) differing immunosuppressive protocols, and
RIBA-2 negative 80(5) 63(5) length of follow-up after transplantation.
Ynares et al. [101] ELISA-1 positive 33(10) 53(10)
ELISA-1 negative 25(10) 54(10)
ELISA—enzyme-linked immunosorbent assay; RIBA—recombinant immunoblot assay.

*Numbers in parentheses indicate years after transplatation.
[102–106]. From a cohort of 98 renal allo-

graft recipients with HCV, Roth and col-
GLOMERULAR DISEASE IN KIDNEY RECIPIENTS
leagues [105] detected de novo membra-
INFECTED WITH HEPATITIS C VIRUS
noproliferative glomerulonephritis in the
biopsies of five of eight patients with pro-
teinuria of over 1 g/24 h [105]. Compared
Number of anti–HCV- Histologic diagnosis with a control group of nonproteinuric kid-
Reference positive patients MGN MPGN DPGN CGN Total cases of GN ney recipients infected with HCV, patients
Cockfield and 51 – – – – 11* with MPGN had viral particles present in
Prieksaitis [102] greater amounts in the high-density frac-
Huraib et al. [103] 30 0 5 1 1 7 tions of sucrose density gradients associated
Morales et al. [104] 166 7 0 0 0 7 with significant amounts of IgG and IgM.
Roth et al. [105] 98 0 5 0 0 5 Thus, deposition of immune complexes con-
Morales et al. [106] 409 15 0 0 0 15 taining HCV genomic material may be
involved in the pathogenesis of this form of
CGN—crescentic glomerulonephritis; DPGN—diffuse proliferative GN; MGN—membranous GN; MPGN. The differential diagnosis for signif-
MPGN—membranoproliferative GN. icant proteinuria in a patient infected with
*No specific diagnosis. HCV after transplantation should include
immune-complex glomerulonephritis.
Similarly, if the renal allograft biopsy shows
FIGURE 7-14 immune-complex glomerulonephritis, the
Glomerular disease in HCV positive recipients. Chronic hepatitis C virus (HCV) infection patient should be tested for HCV infection
has been associated with several different immune-complex–mediated diseases in the renal without regard to serum alanine amino-
allograft, including membranous and membranoproliferative glomerulonephritis (MPGN) transferase levels.
FIGURE 7-15
INTERFERON THERAPY FOR PATIENTS IN END-STAGE Interferon in HCV-positive end-stage renal
RENAL DISEASE WITH HEPATITIS C VIRUS INFECTION disease (ESRD) and transplant patients. -
Interferon therapy in patients infected with
hepatitis C virus (HCV) who have ESRD
Reference Study population Patients, n Clearing of HCV RNA, % Comments has been studied in both patients receiving
dialysis and transplantation recipients.
Pol et al. [107] HD 19 53 Some studies have reported encouraging
Casanovas et al. HD 10 10 early responses [107–111]. Relapses are
[108] common after cessation of treatment, how-
Koenig et al. [109] HD 37 65 ever, and many transplantation recipients
Duarte et al. [110] HD 5 NA have experienced deterioration in allograft
function [112–116]. Based on the poor out-
Raptopoulou-Gigi HD 19 77
et al. [111] comes reported in transplantation recipi-
ents, additional studies are needed. These
Magnone et al. [112] TX 7 NA 6/7 (86%) rejection
studies would evaluate the long-term bene-
Rostaing et al. [113] TX 16 33 6/16 (37%) acute renal failure fits of a strategy in which infected patients
Harihara et al. [114] TX 3 0 3/3(100%) renal failure who have ESRD are treated with -interfer-
Thervet et al. [115] TX 13 0 2/3 (67%) acute renal failure on while on dialysis in an effort to clear
Izopet et al. [116] TX 15 0 5/15 (33%) acute renal failure
viremia before the planned transplantation.
Further study of protocols using extended
Ozgur et al. [117] TX 5 NA All with improved liver histology
treatment periods coupled with differing
dosing regimens are necessary to determine
HD—hemodialysis; NA—not available; TX—transplantation. the optimal therapy for the patient infected
with HCV who has ESRD.
Human Immunodeficiency Virus

FIGURE 7-16
RENAL COMPLICATIONS OF HUMAN Renal complications of HIV. Renal complications are frequent, and
IMMUNODEFICIENCY VIRUS INFECTION 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
Acid-base and electrolyte disturbances infections and tumors. The renal diseases include a variety of acid-
Acute renal failure base and electrolyte disturbances, acute renal failure having various
Human immunodeficiency virus–associated nephropathies
causes, specific HIV-associated nephropathies, and renal infections
and tumors.
Renal infections and tumors
FIGURE 7-17
PATHOGENESIS OF HYPONATREMIA IN PATIENTS Hyponatremia pathogenesis in AIDS. Single and mixed acid-base
WITH ACQUIRED IMMUNODEFICIENCY SYNDROME 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
Hypovolemia follow pharmacologic interventions and usually are not associated
Tubular dysfunction with structural lesions in the kidneys unless renal failure also is
Mineralocorticoid deficiency
present. Hyponatremia is the most prevalent electrolyte abnormality,
occurring in 36% to 56% of patients hospitalized with AIDS
Syndrome of inappropriate antidiuretic hormone
[118–122]. In the absence of an evident source of fluid loss, volume
Hemodilution
depletion may be related to renal sodium wasting as a result of
Addison’s disease or hyporeninemic hypoaldosteronism [123–125].
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].
foscarnet, pentamidine, cidofovir, rifampin, and amphotericin B),

other organ toxicity (didanosine, foscarnet, and rifampin), or
ELECTROLYTE COMPLICATIONS OF DRUGS USED TO
interference with uric acid metabolism. Hypernatremia may be
TREAT ACQUIRED IMMUNODEFICIENCY SYNDROME
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
Hypernatremia: foscarnet, rifampin, amphotericin B nephrotoxicity. Hypocalcemia may result from urinary losses of
Hyperkalemia: pentamidine, ketoconazole, trimethoprim magnesium and hypomagnesemia (pentamidine and amphotericin B)
Hypokalemia: rifampin, didanosine, amphotericin B, foscarnet or from drug-induced pancreatitis (pentamidine, didanosine, and
Hypomagnesemia: pentamidine, amphotericin B foscarnet). Hypercalcemia occurs in association with granulomatous
Hypocalcemia: foscarnet, pentamidine, didanosine disorders, disseminated cytomegalovirus infection, lymphoma,
Hypercalcemia: foscarnet human T-cell leukemia (HTLV) related to HTLV-I infection or
Hypouricemia: rifampin foscarnet administration. Hypouricemia was described in 22% of
Hyperuricemia: didanosine, pyranzinamide, ethambutol patients as a result of an intrinsic tubular defect in urate transport
Tubular acidosis: amphotericin B, trimethoprim, cidofovir, rifampin, foscarnet 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
FIGURE 7-18 or electrolyte disturbances, a careful review of the pharmacopeia
Drugs causing electrolyte complications. A number of drugs used used to treat patients with HIV infection is mandated. Extensive
in the treatment of patients with AIDS can induce acid-base or reviews of the complications associated with drugs are available
electrolyte abnormalities from direct renal toxicity (didanosine, [127,128].
30%, most often in patients with AIDS and prerenal azotemia from hypovolemia, hypotension,
severe hypoalbuminemia, superimposed sepsis, or drug nephrotoxicity (radiocontrast dyes, fos-
CAUSES OF ACUTE RENAL FAILURE
carnet, acyclovir, pentamidine, cidofovir, amphotericin B, nonsteroidal anti-inflammatory drugs,
and antibiotics) [129–138]. The clinical presentation, laboratory findings, and course of acute
tubular necrosis do not differ in patients with AIDS and those in other clinical settings.
Prerenal azotemia, acute tubular necrosis Prevention includes correction of fluid and electrolyte abnormalities and dosage adjustments of
Allergic interstitial nephritis potentially nephrotic drugs. Identification and withdrawal of the offending agents usually result
Obstructive nephropathy in recovery of renal function. Dialysis may be needed before renal function improves. Less
Rhabdomyolysis, myoglobinuric acute renal failure frequent causes of acute renal failure include allergic acute interstitial nephritis; complicating
Thrombotic thrombocytopenic purpura, hemolytic treatments with trimethoprim and sulfamethoxazole, rifampin, or acyclovir; and acute
uremic syndrome obstructive nephropathy, resulting from the intrarenal precipitation of crystals of sulfadiazine,
Rapidly progressive glomerulonephritis acyclovir, urate, or protease inhibitors [134,139–146]. Obstructive uropathy without
hydronephrosis also may develop in patients with lymphoma as a result of lymphomatous
ureteropelvic infiltration or retroperitoneal fibrosis [147–149]. Rhabdomyolysis with myoglo-
binuric acute renal failure usually occurs in the setting of cocaine use [150]. Instances of acute
FIGURE 7-19 renal failure associated with intravascular coagulation related to thrombotic thrombocytopenic
Causes of acute renal failure. Acute renal purpura (TTP) or hemolytic uremic syndrome (HUS) have been reported (vide infra). Rare
failure is related to complications of AIDS, its causes of acute renal failure include disseminated microsporidian infection or histoplasmosis
treatment, or the use of diagnostic agents in [151,152]. A clinical presentation of acute renal failure also can be seen in patients with acute
about 20% of patients [129,130]. Acute tubu- immunocomplex postinfectious glomerulonephritis, crescentic glomerulonephritis, or fulminant
lar necrosis occurs with a prevalence of 8% to HIV-associated glomerulosclerosis.
FIGURE 7-20
Acyclovir, g/d IV
2.4 Acyclovir nephrotoxicity. Drugs may induce acute renal failure by

1.4 more than one mechanism. For instance, acute renal failure may
0.4 complicate the use of acyclovir as a result of intrarenal precipitation
-0.6 of acyclovir crystals, acute interstitial nephritis, or acute tubular
necrosis [139,144,153]. An example of nonoliguric acute tubular
7 7 necrosis associated with administration of large doses of intravenous
6 6 acyclovir is illustrated, which was readily reversible on decreasing
Urine volume, L/d
Serum creatinine,
5 5 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
mg/dL
4 4
3 3 kidneys. Renal biopsy is useful for diagnostic and prognostic purpos-
2 2 es when the cause of acute renal failure is not clinically evident. In a
1 1 recent study of 60 patients with acute renal failure, a percutaneous
0 0 renal biopsy yielded a pathologic diagnosis in 13% that was not
1 2 3 4 5 6 7 8 expected clinically [154].
Day
FIGURE 7-21
MANAGEMENT OF SEVERE Acute renal failure management. Rao and Friedman [155] compared the course of 146
ACUTE RENAL FAILURE 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
HIV Non-HIV 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
Conservative 20 (14%) 42 (14%) recovered renal function when conservative therapy alone was sufficient. When dialysis
Recovered 85% 83% NS intervention was needed, it was not initiated more often in the group with HIV than in the
Needing dialysis 126 264 control group (42% and 24%, respectively; P<0.003). In those patients in whom dialysis
Not initiated 42% 22% 0.003 was initiated, recovery occurred in about half in each group. Overall, the mortality in
Initiated 73 207 patients with severe acute renal failure was not significantly different in those with HIV
Recovered 56% 47% NS 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.
FIGURE 7-22
NEPHROPATHIES Nephropathies associated with HIV. The literature refers to the glomerulosclerosis associated
ASSOCIATED WITH with human immunodeficiency virus (HIV) as HIV-associated nephropathy. However, HIV-
HUMAN IMMUNODEFICIENCY associated nephropathies may include a spectrum of renal diseases, including HIV-associated
VIRUS INFECTION 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
Focal segmental or global glomerulosclerosis mesangial hyperplasia and minimal change disease also may be associated with HIV, particu-
Diffuse and global mesangial hyperplasia
larly in children. Therefore, the nomenclature of HIV-associated nephropathies should be
amended to list the associated qualifying histologic feature [156]. All types of glomeru-
Minimal change disease
lopathies have been observed in patients with HIV-infection. Their prevalence and severity
Others:
vary with the population studied. Focal segmental or global glomerulosclerosis is most preva-
Immune-complex glomerulopathies
lent in black adults. In whites, proliferative and other types of glomerulonephritis predomi-
Hemolytic uremic syndrome, thrombotic
nate. In children with perinatal acquired immunodeficiency syndrome, glomerulosclerosis,
thrombocytopenic purpura
diffuse mesangial hyperplasia, and proliferative glomerulonephritis are equally prevalent.
largely black intravenous (IV) drug abusers, a group of patients in

100 whom heroin nephropathy was prevalent. Thus, concern existed
Glomerulosclerosis that this entity merely represented the older heroin nephropathy
Diff. mesangial hyperplasia
Other now seen in HIV-infected IV drug abusers. However, in a Miami-
75 based 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,
Percent
50 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 glomeru-
25
losclerosis. These morphologic differences were reflected in more
severe clinical presentations, with blacks more likely to manifest
0
proteinuria in the nephrotic range (>3.5 g/24 h) and renal insuffi-
ciency (serum creatinine concentration (>3 mg/dL). Whites often had
Caribbean blacks American blacks Whites
(n=22) (n=11) (n=12) 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, homo-
FIGURE 7-23 sexuals, patients exposed to heterosexual transmission or to contami-
Glomerulosclerosis associated with HIV. In the United States, HIV- nated blood products, and children infected perinatally [163,164].
associated focal segmental or global glomerulosclerosis was Subsequent reports confirmed the unique clinical and histopatho-
described originally in 1984 in large East Coast cities, particularly logic manifestations of HIV-associated glomerulosclerosis and its
New York and Miami [157–159]. This entity initially was consid- striking predominance in blacks independent of IV drug abuse
ered with skepticism because it was not seen in San Francisco, [165]. Racial factors explain the absence of HIV-associated
where most patients testing seropositive were white homosexuals glomerulosclerosis in whites and Asians. The cause of this strong
[160,161]. In New York, patients with glomerulosclerosis were racial predilection is unknown.
FIGURE 7-24
TWO CASE HISTORIES OF PATIENTS WITH HUMAN IMMUNODEFICIENCY These two patients illustrate typical presenting
VIRUS INFECTION ASSOCIATED WITH GLOMERULOSCLEROSIS features of HIV-associated glomerulosclerosis,
ie, proteinuria, usually in the nephrotic range;
normal-sized or large echogenic kidney; and
renal insufficiency rapidly progressing to end-
41-year-old black Jamaican woman 28-year-old black Haitian man
stage renal disease (ESRD). The onset of the
October 1985: A dockworker until 3 months before admission, when nephropathy is often abrupt, with uremia and
Viral syndrome. 135 lbs; proteinuria, 1+; serum creati- fevers began to occur. No identifiable risk factor. He massive nonselective proteinuria (sometimes
nine, 0.5 mg/dL; blood pressure, 130/70 mm Hg presented with a blood pressure of 110/80 mm Hg, in excess of 20 g/24 h). These fulminant
December 1986: periorbital and trace ankle edema, interstitial pneu-
monia, and diffuse adenopathies. Serum creatinine
lesions may present as acute renal failure in
Fever, fatigue, cough. 120 lbs; proteinuria, 1+; interstitial
increased from 5.3 to 9 mg/dL in 6 days; albumin, 1.6 patients who were well only a few weeks or
pneumonia; serum creatinine, 1.5 mg/dL; ex-husband months before hospitalization. In other
g/dL; proteinuria, 6.9 g/24 h; 15-cm, echogenic kid-
used intravenous drugs; 11-cm, echogenic kidneys patients, minimal proteinuria and azotemia at
neys. Renal biopsy showed focal segmental glomeru-
February 1987: losclerosis. Lymph node biopsy showed presentation increase insidiously over a period
3+ edema. 116 lbs; proteinura, 12.7 g/24 h; serum crea- Mycobacterium gordonae. This patient returned to of several months until a nephrotic syndrome
tinine, 11.4 mg/dL; albumin, 2.5 g/dL; blood pressure, Haiti after six hemodialyses. becomes evident, with rapid evolution there-
150/86; renal biopsy showed focal segmental
after to uremia and ESRD. Hypertension and
glomerulosclerosis
peripheral edema may be absent even in the
May 1987:
context of advanced renal insufficiency or
100 lbs; patient died after 3 months of hemodialysis
severe nephrotic syndrome. The status of the
from sepsis and cryptococcal meningitis
patient’s HIV infection rather than the pres-
ence 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 7-26
Pathologic features of glomerulosclerosis. None of the features list-
FIGURE 7-25 ed is pathognomonic. The concomitant presence of glomerular and
Ultrasonography of a hyperechogenic 15-cm kidney in a patient tubular lesions with tubuloreticular inclusions in the glomerular
with HIV-associated glomerulosclerosis, nephrotic syndrome, and and peritubular capillary endothelial cells, however, is highly sug-
renal failure. gestive of glomerulosclerosis associated with human immunodefi-
ciency virus infection [134,166–171].
FIGURE 7-28
More advanced glomerulosclerosis. Micrograph of a more
FIGURE 7-27 advanced stage of glomerulosclerosis with large hyperplastic viscer-
Glomerulosclerosis. Micrograph of segmental glomerulosclerosis al epithelial cells loaded with hyaline protein droplets, interstitial
with hyperplastic visceral epithelial cells (arrows). infiltrate, and tubules filled with proteinaceous material.

Collapsing glomerulosclerosis. Micrograph of global collapsing Dilated microcystic tubules. Micrograph of massively dilated micro-
glomerulosclerosis. No patent capillary lumina are present. In the cystic tubules filled with variegated protein casts adjacent to nor-
same patient, normal glomeruli, glomeruli with segmental sclerosis, mal-sized glomeruli. These casts contain all plasma proteins. The
and glomeruli with global sclerosis may be found [172]. 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.
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 protein-
uria. The characteristic microcystic tubular dilations and the kidney
enlargement of glomerulosclerosis associated with human immun-
odeficiency virus infection are absent in patients with diffuse mesan-
gial 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 immunofluo-
rescent 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].
FIGURE 7-33
HIV infection 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
HIV in glomerular, tubular HIV in lymphocytes, before opportunistic infections develop. HIV-associated glomeru-
epithelial cells monocytes losclerosis 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
Cytopathic HIV gene Cytokines,
conclusively and systematically; injury by HIV gene products; or injury
effects products growth factors
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
Glomerular epithelial cell proliferation
Tubular epithelial cell apoptosis and proliferation glomerulosclerosis also suggests that unique viral-host interactions
may be necessary for expression of the nephropathy
[132,156,166,173–175].
Glomerulosclerosis Tubular microcysts

Transplantation of kidneys between normal mice TREATMENT OPTIONS OF GLOMERULOSCLEROSIS

and mice transgenic of noninfectious HIV
ASSOCIATED WITH HUMAN IMMUNODEFICIENCY
VIRUS INFECTION
Transgenic kidney Normal kidney
in in
normal mouse transgenic mouse Antiretroviral therapy
Corticosteroids
Cyclosporine
Kidney develops Kidney remains Angiotensin-converting enzyme inhibitors
glomerulosclerosis disease-free Dialysis
FIGURE 7-34
HIV proteins in glomerulosclerosis. HIV-associated glomerulosclero- FIGURE 7-35
sis has been viewed as a complication that occurs either as a direct Treatment of glomerulosclerosis. There have been no prospective
cellular effect of HIV infection or HIV gene products in the kidney, controlled randomized trials of any therapy in patients with nephropa-
as an indirect effect of the dysregulated cytokine milieu existing in thy associated with HIV infection. Thus, the optimal treatment is
patients with acquired immunodeficiency syndrome, or both. Studies unknown. Individual case reports and studies, often retrospective,
involving reciprocal transplantation of kidneys between normal and on a small number of patients suggest a beneficial effect of
mice transgenic of noninfectious HIV clearly show that the patho- monotherapy with azidothymidine (AZT) on progression of renal
genesis of HIV-glomerulosclerosis is intrinsic to the kidney [176]. In disease [177–179]. No reports exist on the effects of double or
these studies, HIV-glomerulosclerosis developed in kidneys of trans- triple antiretroviral therapy on the incidence or progression of
genic mice transplanted into nontransgenic littermates, whereas kid- renal disease in patients with HIV who have modest proteinuria or
neys from normal mice remained disease-free when transplanted into nephrotic syndrome. The incidence of HIV-associated glomeruloscle-
HIV-transgenic mice [176]. These findings suggest that HIV gene rosis may be declining as a result of prophylaxis with AZT,
proteins, rather than infective HIV, may induce the nephropathy trimethoprim and sulfamethoxazole, or other drugs. Using logistic
either through direct effects on target cells or indirectly through the regression analysis, Kimmel and colleagues [180] demonstrated an
release of cytokines and growth factors. 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 pro-
teinuria 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.
FIGURE 7-36
4.0 Effect of angiotensin-converting enzyme (ACE) inhibitors on pro-
P=0.006
3.5 Fosinopril gression of glomerulosclerosis associated with HIV infection. Serum
Control ACE levels are increased in patients with HIV infection [184]. Kimmel
4.0
and colleagues [180], using captopril, and Burns and colleagues [185],
3.5
using fosinopril, demonstrated a renoprotective effect of ACE
3.0
inhibitors in patients with biopsy-proven HIV-associated glomeru-
2.5 losclerosis. In the former study, the median time to end-stage renal
2.0 disease was increased from 30 to 74 days in nine patients given
1.5 6.25 to 25 mg captopril three times a day. In the latter study, 10
1.0
mg of fosinopril was given once a day to 11 patients with early
renal insufficiency (serum creatinine <2 mg/dL). Serum creatinine
0.5 and proteinuria remained stable during 6 months of treatment with
0 fosinopril. In contrast, patients not treated with fosinopril exhibited
0 4 8 12 16 20 24 progressive and rapid increases in serum creatinine and proteinuria.
Week Similar outcomes prevailed in patients with proteinuria in the
9 nephrotic range and serum creatinine levels less than 2 mg/dL.
P=0.006 Captopril also is beneficial to the progression of the nephropathy
8 Fosinopril
Control
in HIV-transgenic mice [186]. The mechanism(s) of the renoprotective
7
effects of ACE inhibitors are unclear and may include hemodynamic
Urinary protein, g/24 h
6 effects, decreased expression of growth factors, or an effect on HIV

5 protease activity. Renal biopsy early in the course of the disease is
4
important to define the renal lesion and guide therapeutic intervention.
3
2
1
0
0 4 8 12 16 20 24
Week
FIGURE 7-37
SURVIVAL OF PATIENTS WITH HUMAN Survival rates in dialysis patients. Once end-stage renal disease
IMMUNODEFICIENCY VIRUS INFECTION (ESRD) develops and supportive maintenance dialysis is needed, the
RECEIVING CHRONIC HEMODIALYSIS 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
Reference Year Patients Mean survival, mo
also may develop malnutrition, wasting, and failure to thrive that are
Rao et al. [187] 1987 79 AIDS <3 unresponsive to intensive nutritional support [131]. Recent studies,
Ortiz et al. [188] 1988 17 AIDS 3 however, show that the survival of patients with AIDS maintained on
12 carriers 16 chronic hemodialysis is improving. Enhanced survival has been
Feinfeld et al. [189] 1989 5 AIDS 13 attributed to antiviral drugs, better prophylaxis, and aggressive treat-
10 carriers 16 ment of opportunistic infections. We have seen four patients with
Ribot et al. [190] 1990 8 AIDS 88% <12 HIV infection survive for more than 10 years on hemodialysis.
28 carriers 96% >12 Chronic hemodialysis and chronic ambulatory peritoneal dialysis are
Schrivastava et al. [191] 1992 44 AIDS 41% >15 equally appropriate treatments for patients with HIV infection and
Kimmel et al. [192] 1993 23 AIDS 14.7 ESRD. Universal precautions should be used for peritoneal dialysis
Ifudu et al. [193] 1997 34 AIDS 57 and hemodialysis alike, because infectious HIV is present in peri-
toneal effluent and blood.
FIGURE 7-38
PREDICTORS OF SURVIVAL OF PATIENTS WITH Predictors of survival. Perinbasekar and colleagues [194] analyzed
HUMAN IMMUNODEFICIENCY VIRUS INFECTION those factors associated with better survival in patients infected
RECEIVING CHRONIC HEMODIALYSIS 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
R P are associated with decreased survival.
CD4 0.668 <0.001

Blood pressure, systolic 0.496 <0.02
Infection rate 0.519 <0.01
Proteinuria 0.537 <0.02
Edema +/ 14.5 vs 6.1 mo <0.01
Antiretroviral therapy +/- 15.2 vs 62. mo <0.01
FIGURE 7-39
RECOMMENDED ANTI- Antiretroviral therapy. Recommended antiretroviral therapy for patients with HIV infection
RETROVIRAL THERAPY 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,
Combination of two reverse transcriptase inhibitors asymptomatic patients with CD4 counts under 500/µL, and asymptomatic patients with
Aggressive triple therapy, including a protease CD4 counts over 500/µL and plasma HIV RNA levels over 20,000 copies/mL [195].
inhibitor for patients who are Reduced dosages are required for reverse transcriptase inhibitors in renal insufficiency.
Symptomatic of acquired immunodeficiency Although the clearance information on these drugs is limited, additional dosing is not
syndrome necessary in patients receiving maintenance dialysis. No dosage reduction is needed for
Asymptomatic with CD4 <500 cells/µL protease inhibitors.
Asymptomatic with CD4 >500 cells/µL but viral
load > 20,000
Proliferative glomerulonephritides represent instances of postinfectious glomerulonephritis

or manifestations of hepatitis C co-infection [196–199]. Alternatively, proliferative
OTHER NEPHROPATHIES
glomerulonephritides may result from renal depository of preformed circulating immune
ASSOCIATED WITH HUMAN
complexes with specificity for HIV proteins and are HIV-associated [199]. In patients
IMMUNODEFICIENCY VIRUS
infected with HIV, membranous glomerulonephritis has been associated with hepatitis B,
INFECTION
hepatitis C, syphilis, and systemic lupus erythematosus [198,200–203]. Lupus-like nephritis
has been reported in children and adults with HIV infection in association with membra-
nous, mesangial, and intracapillary proliferative glomerular lesions [204]. IgA nephropathy
Immune-complex glomerulopathies has been reported in association with HIV infection. The occurrence of IgA nephropathy
Proliferative glomerulonephritis may not be coincidental and is HIV-associated. Indeed, circulating immune complexes com-
Membranous glomerulonephritis posed of idiotypic IgA antibody reactive with anti-HIV IgG or IgM were identified in two
Lupus-like nephropathy patients, and the identical immune complex was eluted from the renal biopsy tissue of one
Immunoglobulin A nephropathy patient studied [199,205]. Unlike HIV-associated glomerulosclerosis, HIV-associated IgA
Hemolytic uremic syndrome, thrombotic nephropathy has been reported exclusively in white patients with early HIV infection
thrombocytopenic purpura 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 syn-
FIGURE 7-40 drome/thrombotic thrombocytopenic purpura (HUS/TTP) in patients infected with HIV is
Other nephropathies associated with HIV. unknown. Plasma tissue plasminogen activator is increased in patients infected with HIV
A variety of immune-complex-mediated who have thrombotic microangiopathy [207]. There is no association with Escherichia coli
glomerulopathies have been documented in 0154:H7 infection, and intercurrent infections have been demonstrated in only one third of
patients with HIV infection. Some represent patients. Renal involvement in TTP usually is minimal, whereas vascular and glomerular
glomerular diseases associated with HIV involvement are more frequent and extensive in HUS and can lead to renal cortical necrosis.
infection, whereas others may be incidental Therapy with plasmapheresis, using fresh frozen plasma replacement, should be instituted
or manifestations of associated diseases. as soon as the diagnosis of HIV-related HUS/TTP is made [208].
FIGURE 7-41
RENAL INFECTIONS AND TUMORS ASSOCIATED WITH Other renal findings in patients with AIDS include infections and
HUMAN IMMUNODEFICIENCY VIRUS INFECTION 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
Pathogens Neoplasms they are found at autopsy. Cytomegalovirus infection is the most
common [209]. Referrals to a urologist are reported for renal and
Cytomegalovirus Kaposi’s sarcoma perirenal abscesses with uncommon organisms (Candida, Mucor
Candida Carcinoma mycosis, Aspergillus, and Nocardia). Nephrocalcinosis can occur in
Nocardia Lymphoma association with pulmonary granulomatosis, Mycobacterium
Cryptococcus Myeloma avium–intracellulare infection, or as a manifestation of extrapul-
Pneumocystis monary pneumocystis infection. Renal tuberculosis is a manifestation
Mycobacterium of miliary disease. Non-Hodgkin’s lymphoma and Kaposi’s sarcoma
Toxoplasma are the most frequently found renal neoplasms in patients with
Histoplasma AIDS, usually as a manifestation of disseminated involvement.
Aspergillus
Herpes
References
1. Johnson RJ, Couser WG: Hepatitis B infection and renal disease: 16. Johnson RJ, Willson R, Yamabe H, et al.: Renal manifestations of
clinical, immunopathogenetic and therapeutic considerations. Kidney hepatitis C virus infection. Kidney Int 1994, 46:1255.
Int 1990, 37:663. 17. Johnson RJ, Gretch DR, Couser WG, et al.: Hepatitis C virus associ-
2. Lai KN, Lai FM: Clinical features and natural history of hepatitis B ated glomerulonephritis: effect of -interferon therapy. Kidney Int
virus–related glomerulopathy in adults. Kidney Int 1991, 35(suppl):S40. 1994, 46:1700.
3. Takekoshi Y, Tochimaru H, Nagatta Y, Itami N: 18. Misiani R, Bellavita P, Fenili D, et al.: Interferon--2a therapy in
Immunopathogenetic mechanisms of hepatitis B virus–related cryoglobulinemia associated with hepatitis C virus. N Engl J Med
glomerulopathy. Kidney Int 1991, 35(suppl):S34. 1994, 330:751.
4. Lai KN, Li PK, Lui SF, et al.: Membranous nephropathy related to 19. Poynard T, Bedossa P, Chevallier M, et al.: A comparison of three
hepatitis B virus in adults. N Engl J Med 1991, 324:1457. interferon--2b regimens for the long-term treatment of chronic non-
5. Lin CY: Clinical features and natural course of HBV-related glomeru- A, non-B hepatitis. N Engl J Med 1995, 332:1457.
lopathy in children. Kidney Int 1991, 35(suppl):S46. 20. Poynard T, Leroy V, Cohard M, et al.: Meta-analysis of interferon
6. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infec- randomized trials in the treatment of viral hepatitis C: effects of dose
tion in type II cryoglobulinemia. N Engl J Med 1992, 327:1490–1495. and duration. Hepatology 1996, 24:778.
7. Misiani R, Bellavita P, Fenili D, et al.: Hepatitis C virus infection in 21. Sarac E, Bastacky S, Johnson JP: Response to high-dose interferon-
patients with essential mixed cryoglobulinemia. Ann Intern Med after failure of standard therapy in MPGN associated with hepatitis
1992, 117:573–577. C virus infection. Am J Kidney Dis 1997, 30:113.
8. Disdier P, Harle JR, Weiller PJ: Cryoglobulinemia and hepatitis C 22. Choo Q, Kuo G, Weiner AJ, et al.: Isolation of a cDNA clone derived
infection. Lancet 1991, 338:1151–1152. from a blood-borne non-A, non-B viral hepatitis genome. Science
1989, 244:358–362.
9. Dammacco F, Sansono D: Antibodies to hepatitis C virus in essential
mixed cryoglobulinemia. Clin Exp Immunol 1992, 87:352–356. 23. Pereira BJG: Hepatitis C infection and post-transplantation liver dis-
ease. Nephrol Dial Transplant 1995, 10(suppl 1):58–67.
10. Galli M, Monti G, Monteverde A: Hepatitis C virus and mixed cryo-
globulinemias. Lancet 1992, 1:989. 24. Roth D: Hepatitis C virus: The nephrologist’s view. Am J Kidney Dis
1995, 25:3–16.
11. Ferri C, Greco F, Longobardo G: Antibodies to hepatitis C virus in
patients with mixed cryoglobulinemia. Arthritis Rheum 1991, 25. Zeldis JB, Depner TA, Kuramoto IK, et al.: The prevalence of hepatitis
34:1606–1610. C virus antibodies among hemodialysis patients. Ann Intern Med 1990,
112:958–960.
12. Sansono D, Gesualdo L, Mano C, et al.: Hepatitis C virus related
proteins in kidney tissue from hepatitis C virus–infected patients 26. Hardy NM, Sandroni S, Danielson S, Wilson WJ: Antibody to hepatitis
with cryoglobulinemic membranoproliferative glomerulonephritis. C virus increases with time on dialysis. Clin Nephrol 1992, 38:44–48.
Hepatology 1997, 25:1237–1244. 27. Jeffers LJ, Perez GO, de Medina MD, et al.: Hepatitis C infection in
13. Johnson RJ, Gretch DR, Yamabe H, et al.: Membranoproliferative two urban hemodialysis units. Kidney Int 1990, 38:320–322.
glomerulonephritis associated with hepatitis C virus infection. N Engl 28. Getzung T, Lindsay K, Brezina M, et al.: Hepatitis C virus antibody
J Med 1993, 328:465–470. in hemodialysis patients: prevalence and risk factors. Lancet 1990,
14. Rollino C, Roccatello D, Giachino O, et al.: Hepatitis C virus infec- 335:A589.
tion and membranous glomerulonephritis. Nephron 1991, 29. Niu MT, Coleman PJ, Alter MJ: Multicenter study of hepatitis C
59:319–320. virus infection in chronic hemodialysis patients and hemodialysis cen-
15. Davda R, Peterson J, Weiner R, et al.: Membranous glomerulonephri- ter staff members. Am J Kidney Dis 1993, 22:568–573.
tis in association with hepatitis C virus infection. Am J Kidney Dis 30. Muller GY, Zabaleta ME, Arminio A, et al.: Risk factors for dialysis-
1993, 22:452–455. associated hepatitis C in Venezuela. Kidney Int 1992, 41:1055–1058.
31. Esteban JI, Esteban RK, Viladomiu L, et al.: Hepatitis C virus anti- 56. Mosconi G, Campieri C, Miniero R, et al.: Epidemiology of hepatitis C
bodies among risk groups in Spain. Lancet 1989, ii:294–296. in a population of hemodialysis patients. Nephron 1992, 61:298–299.
32. Mondelli MU, Smedile V, Piazza V, et al.: Abnormal alanine amino- 57. Scotto G, Savastano AM, Forcella M, et al.: HCV infections in dialysis
transferase activity reflects exposure to hepatitis C virus in hemodialy- patients. Nephron 1992, 61:320–321.
sis patients. Nephrol Dial Transplant 1991, 6:480–483. 58. Ponz E, Campistol JM, Barrera JM, et al.: Hepatitis C virus antibodies
33. Mortimer PP, Cohen BJ, Litton PA, et al.: Hepatitis C virus antibody. in patients on hemodialysis and after transplantation. Transplant
Lancet 1989, 2:798. Proc 1991, 23:1371–1372.
34. Roggendorf M, Deinhard F, Rasshofer R, et al.: Antibodies to hepatitis 59. Yamaguchi K, Nishimura Y, Fukuoka N, et al.: Hepatitis C virus
C virus. Lancet 1989, 2:324–335. antibodies in hemodialysis patients. Lancet 1990, 335:1409–1410.
35. Schlipkoter U, Roggendorf M, Ernst G, et al.: Hepatitis C virus anti- 60. Brugnano R, Francisci D, Quintaliani G, et al.: Antibodies against
bodies in hemodialysis patients. Lancet 1990, 335:1409. hepatitis C virus in hemodialysis patients in the central Italian region of
36. Kallinowski B, Theilmann L, Gmelin K, et al.: Prevalence of antibod- Umbria: evaluation of some risk factors. Nephron 1992, 61:263–265.
ies to hepatitis C virus in hemodialysis patients. Nephron 1991, 61. Cantu P, Mangano S, Masini M, et al.: Prevalence of antibodies
59:236–238. against hepatitis C virus in a dialysis unit. Nephron 1992,
37. Elisa M, Tsianos E, Mavridis M, et al.: Antibodies against hepatitis C 61:337–338.
virus (anti-HCV) in hemodialysis patients: association with hepatitis 62. Cendoroglo-Neto M, Draibe SA, Silva AE, et al.: Incidence of and
B serological markers. Nephrol Dial Transplant 1991, 6:476–479. risk factors for hepatitis B virus and hepatitis C infection among
38. Conway M, Catterall AP, Brown EA, et al.: Prevalence of antibodies to hemodialysis and CAPD patients: evidence for environmental trans-
hepatitis C in dialysis patients and transplant recipients with possible mission. Nephrol Dial Transplant 1995, 102:240–246.
routes of transmission. Nephrol Dial Transplant 1992, 7:1226–1229. 63. Selgas R, Martinez-Zapico R, Bajo MA, et al.: Prevalence of hepatitis
39. Malaguti M, Capece R, Marciano M, et al.: Antibodies to hepatitis C C antibodies (HCV) in a dialysis population at one center. Perit Dial
virus (anti-HCV): prevalence in the same geographical area in dialysis Int 1992, 12:28–30.
patients, staff members, and blood donors. Nephron 1992, 61:346. 64. Chan TM, Lok ASF, Cheng IKP: Hepatitis C infection among dialysis
40. Mondelli MU, Cristina G, Pazza V, et al.: High prevalence of antibod- patients: a comparison between patients on maintenance hemodialysis
ies to hepatitis C virus in hemodialysis units using a second genera- and continuous ambulatory peritoneal dialysis. Nephrol Dial
tion assay. Nephron 1992, 61:350–351. Transplant 1991, 6:944–947.
41. Chauveau P, Courouce AM, Lemarec N, et al.: Antibodies to hepatitis 65. Dussol B, Berthezene P, Brunet P, et al.: Hepatitis C virus infection
C virus by second generation test in hemodialyzed patients. Kidney among chronic dialysis patients in the south-east of France. Nephrol
Int 1993, 46(suppl 43):S149–S152. Dial Transplant 1995, 10:477–478.
42. Sheu JC, Lee SH, Wang JT, et al.: Prevalence of anti-HCV and HCV 66. McIntyre PG, McCrudden EA, Dow BC, et al.: Hepatitis C virus
viremia in hemodialysis patients in Taiwan. J Med Virol 1992, infection in renal dialysis patients in Glasgow. Nephrol Dial
37:108–112. Transplant 1994, 9:291–295.
43. Ayoola EA, Huraib S, Arif M, et al.: Prevalence and significance of 67. Huang CC, Wu MS, Lin DY, et al.: The prevalence of hepatitis C
antibodies to hepatitis C virus among Saudi hemodialysis patients. antibodies in patients treated with continuous ambulatory peritoneal
J Med Virol 1991, 35:155–159. dialysis. Perit Dial Int 1992, 12:31–33.
44. Korksal I, Biberoglu K, Biberoglu S, et al.: Hepatitis C virus antibodies 68. Jonas MM, Zilleruelo GE, Larue SI, et al.: Hepatitis C infection in a
among risk groups in Turkey. Infection 1991, 19:228–229. pediatric dialysis population. Pediatrics 1992, 89:707–709.
45. Bahakim H, Bakir TMF, Arif M, et al.: Hepatitis C virus antibodies 69. Barril G, Traver JA: Prevalence of hepatitis C virus in dialysis patients
in high-risk Saudi groups. Vox Sang 1991, 60:162–164. in Spain. Nephrol Dial Transplant 1995, 10(suppl 6):78–80.
46. Mitwalli A, Al-Mohaya S, Al Wakeel J, et al.: Hepatitis C in chronic 70. Yoshida CFT, Takahashi C, Gaspar AMC, et al.: Hepatitis C virus in
renal failure patients. Am J Nephrol 1992, 12:228–291. chronic hemodialysis patients with non-A, non-B hepatitis. Nephron
47. Alfuray O, Sobh M, Buali AR, et al.: Hepatitis C virus infection in 1992, 60:150–153.
chronic hemodialysis patients, a clinicopathologic study. Nephrol 71. Jadoul M, Cornu C, Van Ypersele de Strihou C, et al.: Incidence and
Dial Transplant 1992, 7:327–332. risk factors for hepatitis C seroconversion in hemodialysis: a prospec-
48. Oguchi H, Miyassaka M, Tokunaga S, et al.: Hepatitis virus infection tive study. Kidney Int 1993, 44:1322–1326.
(HBV and HCV) in eleven Japanese hemodialysis units. Clin Nephrol 72. Pinto dos Santos J, Loureiro A, Cendoroglo Meto M, et al.: Impact
1992, 38:36–43. of dialysis room and reuse strategies on the incidence of HCV infec-
49. Lin DY, Lin HH, Huang CC, et al.: High incidence of hepatitis C tion in HD units. Nephrol Dial Transplant 1996, 11:7017–7022.
virus infection in hemodialysis patients in Taiwan. Am J Kidney Dis 73. Gilli P, Moretti M, Soffritti S, et al.: Non-A, non-B hepatitis and anti-
1993, 21:288–291. HCV antibodies in dialysis patients. Int J Artif Organs 1990,
50. Blackmore TK, Maddocks P, Stace NH, et al.: Prevalence of antibodies 13:737–741.
to hepatitis C virus in patients receiving renal replacement therapy, 74. Okuda K, Hayashi H, Yokozeki KEA: Mode of nosocomial HCV
and in the staff caring for them. Aust N Z J Med 1992, 22:353–357. infection among chronic hemodialysis patients and its prevention.
51. Roger SD, Cunningham A, Crewe E, et al.: Hepatitis C virus infec- Hepatology 1994, 19:293.
tion in heamodialysis patients. Aust N Z J Med 1991, 21:22–24. 75. Da Porto A, Adami A, Susanna F, et al.: Hepatitis C virus in dialysis
53. Natov SN, Pereira BJG: Hepatitis C infection in patients on dialysis. units: a multicenter study. Nephron 1992, 61:309–310.
Semin Dial 1994, 7:360–368. 76. Hubmann R, Zazgornik J, Gabriel C, et al.: Hepatitis C virus: Does it
54. Dussol B, Chicheporttiche C, Cantaloube JF, et al.: Detection of hepati- penetrate the hemodialysis membrane? PCR analysis of hemodialysis
tis C infection by polymerase chain reaction among hemodialysis ultrafiltrate and whole blood. Nephrol Dial Transplant 1995,
patients. Am J Kidney Dis 1993, 22:574–580. 10:541–542.
55. Kundsen F, Wantzin P, Rasmussen K, et al.: Hepatitis C in dialysis 77. Caramelo C, Navas S, Alberola ML, et al.: Evidence against transmis-
patients: relationship to blood transfusions, dialysis and liver disease. sion of hepatitis C virus though hemodialysis ultrafiltrate and peritoneal
Kidney Int 1993, 43:1353–1356. fluid. Nephron 1994, 66:470–473.
55. Dentico, P, Buongiorno R, Volpe A, et al.: Prevalence and incidence 78. Lombardi M, Cerrai T, Dattolo P, et al.: Is the dialysis membrane a
of hepatitis C virus (HCV) in hemodialysis patients: study of risk fac- safe barrier against HCV infection? Nephrol Dial Transplant 1995,
tors. Clin Nephrol 1992, 61:49–52. 10:578–579.
79. Alter MJ, Favero MS, Moyer LA, et al.: National surveillance of dialy- 104. Morales JM, Fernandez-Zatarain G, Munoz MA, et al.: Clinical pic-
sis-associated diseases in the United States, 1989. ASAIO Trans 1991, ture and outcome allograft membranous glomerulonephritis in renal
37:97–109. transplant patients with hepatitis C virus infection. J Am Soc Nephrol
80. Natov SN, Pereira BJG: Hepatitis C infection in patients on dialysis. 1995, 6:1107.
Semin Dial 1994, 7:360–368. 105. Roth D, Cirocco R, Zucker K, et al.: De novo membranoproliferative
81. Caramelo C, Ortiz A, Aguilera B, et al.: Liver disease patterns in glomerulonephritis in hepatitis C virus-infected renal allograft recipients.
hemodialysis patients with antibodies to hepatitis C virus. Am J Transplantation 1995, 59:1676–1682.
Kidney Dis 1993, 22:822–823. 106. Morales JM, Capdevila JP, Campistol JM, et al.: Membranous
82. LaQuaglia MP, Tolkoff-Rubin NE, Dienstag JL, et al.: Impact of glomerulonephritis associated with hepatitis C virus infection in renal
hepatitis on renal transplantation. Transplantation 1981, 32:504–507. transplant patients. Transplantation 1997, 63:1634–1639.
83. Boyce NW, Hodsworth SR, Hooke D, et al.: Nonhepatitis B-associated 107. Pol S, Thiers V, Carnot F, et al.: Efficacy and tolerance of -2b inter-
liver disease in a renal transplant population. Am J Kidney Dis 1988, feron therapy on HCV infection of hemodialyzed patients. Kidney Int
11:307–312. 1985, 47:1412–1418.
84. Weir MR, Kirkman RL, Strom TB, et al.: Liver disease in recipients 108. Casanovas TT, Baliellas C, Sese E, et al.: Interferon may be useful in
of long-functioning renal allografts. Kidney Int 1985, 28:839–844. hemodialysis patients with hepatitis C virus chronic infection who are
85. Ware AJ, Luby JP, Hollinger B, et al.: Etiology of liver disease in candidates for kidney transplant. Transplant Proc 1995, 27:2229–2230.
renal-transplant patients. Ann Intern Med 1979, 91:364–371. 109. Koenig P, Vogel W, Umlauft F, et al.: Interferon treatment for chronic
86. Debure A, Degos F, Pol S, et al.: Liver diseases and hepatic complica- hepatitis C virus infection in the uremic patient. Kidney Int 1994,
tions in renal transplant patients. Adv Nephrol 1988, 17:375–400. 45:1507–1509.
87. Mahony JF: Long term results and complications of transplantation: 110. Duarte R, Huraib S, Said R, et al.: Interferon- facilities renal trans-
the kidney. Transplant Proc 1989, 21:1433–1434. plantation in hemodialysis patients with chronic viral hepatitis. Am J
88. Rao KV, Anderson WR, Kasiske BL, et al.: Value of liver biopsy in the Kidney Dis 1995, 25:40–45.
evaluation and management of chronic liver disease in renal transplant 111. Raptopoulou-Gigi M, Spaia S, Garifallos A, et al.: Interferon--2b
recipients. Am J Med 1993, 94:241–250.
treatment of chronic hepatitis C in hemodialysis patients. Nephrol
89. Pereira BJG, Wright TL, Schmid CH, et al.: The impact of pretrans- Dial Transplant 1995, 10:1834–1837.
plantation hepatitis C infection on the outcome of renal transplanta-
112. Magnone M, Hollet JL, Shapiro R, et al.: Interferon- induced acute
tion. Transplantation 1995, 60:799–805.
renal allograft rejection. Transplantation 1995, 59:1068.
90. Roth D, Zucker K, Cirocco R, et al.: The impact of hepatitis C virus
infection on renal allograft recipients. Kidney Int 1994, 45:238–244. 113. Rostaing L, Izopet J, Baron E, et al.: Preliminary results of treatment
of chronic hepatitis C with recombinant interferon- in renal trans-
91. Pereira BJG, Milford EL, Kirkman RL, et al.: Prevalence of hepatitis plant patients. Nephrol Dial Transplant 1995, 10:93–96.
C virus RNA in organ donors positive for hepatitis C antibody and in
the recipients of their organs. N Engl J Med 1992, 327:910–915. 114. Harihara Y, Kurooka Y, Yanagisawa T, et al.: Interferon therapy in
renal allograft recipients with chronic hepatitis C. Transplant Proc
92. Pereira BJG, Wright TL, Schmid CH, et al.: A controlled study of hepati-
tis C transmission by organ transplantation. Lancet 1995, 345:484–487. 1994, 26:2075.
93. Roth D, Fernandez JA, Babischkin S, et al.: Detection of hepatitis C 115. Thervet E, Pol S, Legendre C, et al.: Low dose recombinant leukocyte
virus infection among cadaver organ donors: evidence for low trans- interferon alpha treatment of hepatitis C viral infection in renal trans-
mission of disease. Ann Intern Med 1992, 117:470. plant recipients. Transplantation 1994, 58:625.
94. Tesi RJ, Waller K, Morgan CJ, et al.: Transmission of hepatitis C virus 116. Izopet J, Rostaing L, Cazabet M, et al.: Failure of HCV RNA clear-
by kidney transplantation: the risks. Transplantation 1994, 57:826. ance in kidney transplant recipients treated with -interferon. J Am
Soc Nephrol 1994, 5:1013A.
95. Vincente F, Lake J, Wright T, et al.: Nontransmission of hepatitis C
from cadaver organ donors to transplant recipients. Transplantation 117. Ozgur O, Boyacioglu S, Telatar H, et al.: Recombinant -interferon
1993, 55:674–675. in renal allograft recipients with chronic hepatitis C. Nephrol Dial
96. Wreghtt TG, Gray JJ, Allain JP, et al.: Transmission of hepatitis C Transplant 1995, 10:2104–2106.
virus by organ transplantation in the United Kingdom. J Hepatol 118. Glassock RJ, Cohen Ah, Danovitch G, et al.: Human immunodeficien-
1994, 20:768–772. cy virus (HIV) infection and the kidney. Ann Intern Med 1990,
97. Zucker K, Cirocco R, Roth D, et al.: Depletion of hepatitis C virus 112:35–49.
from procured kidneys using pulsatile perfusion preservation. 119. Seney FD Jr, Burns DK, Silva FG: Acquired immunodeficiency syndrome
Transplantation 1994, 54:832. and the kidney. Am J Kidney Dis 1990, 16:1–13.
98. Widell A, Mansson S, Persson NH, et al.: Hepatitis C superinfection 120. Vitting KE, Gardenswartz MH, Zabetakis PM, et al.: Frequency of
in hepatitis C virus (HCV)-infected patients transplanted with an hyponatremia and nonosmolar vasopressin release in the acquired
HCV-infected kidney. Transplantation 1995, 60:642–647. immunodeficiency syndrome. JAMA 1990, 263:973–976.
99. Fritsche C, Brandes JC, Delaney SR, et al.: Hepatitis C is a poor 121. Agarwal A, Soni A, Ciechanowsky M, et al.: Hyponatremia in
prognostic indicator in black kidney transplant recipients. patients with the acquired immunodeficiency syndrome. Nephron
Transplantation 1993, 55:1283–1287.
1989, 53:317–321.
100. Pereira BJG, Wright TL, Schmid CH, et al. for the New England Organ
122. Tang WW, Kapstein, EM, Feinstein EI, et al.: Hyponatremia in hospi-
Bank Hepatitis C Study Group: the impact of pretransplantation
talized patients with acquired immune deficiency syndrome and the
hepatitis C infection on the outcome of renal transplantation.
Transplantation 1995, 60:799–805. AIDS related complex. Am J Med 1993, 94:169–174.
101. Ynares C, Johnson HK, Kerlin T, et al.: Impact of pretransplant hepatitis 123. Greene LW, Cole W, Greene JB, et al.: Adrenal insufficiency as a com-
C antibody status upon long-term patient and renal allograft survival: a plication of the acquired immunodeficiency syndrome. Ann Intern
5- and 10-year follow-up. Transplant Proc 1993, 25:1466–1468. Med 1984, 101:497–498.
102. Cockfield SM, Prieksaitis JK: Infection with hepatitis C virus increas- 124. Kalin G, Torensky L, Seras DS, et al.: Hyporeninemic hypoaldostero-
es the risk of de novo glomerulonephritis in renal transplant recipi- nism associated with the acquired immunodeficiency syndrome. Am J
ents. J Am Soc Nephrol 1995, 6:1078. Med 1987, 82:1035–1038.
103. Huraib S, Al Khudair W, Abu Romeh S, et al.: Pattern and prevalence 125. Guenthner EE, Rabinowe SL, Van Niel A, et al.: Primary Addison’s
of glomerulonephritis in renal transplant hepatitis C (HCV ) patients disease in a patient with the acquired immunodeficiency syndrome.
(PTS). J Am Soc Nephrol 1995, 6:1093. Ann Intern Med 1984, 100:847–848.
126. Santos GI, Garcia PI, del Arco GC, et al.: Sindrome de secrecion 150. Roth D, Alarcon FJ, Fernandez JA, et al.: Acute rhabdomyolysis asso-
inapropiada asociado con el sindrome de immunodeficiencia adquirida. ciated with cocaine intoxication. N Engl J Med 1988, 319:673–677.
Rev Clin Esp 1991, 188:120–122. 151. Aarons EJ, Woodrow D, Hollister WS, et al.: Reversible renal failure
127. Berns JS, Cohen RM, Stumacher RJ, et al.: Renal aspects of therapy caused by a microsporidian infection. AIDS 1994, 8:1119–1121.
for human immunodeficiency virus and associated opportunistic 152. Clinicopathologic Conference: Fever and acute renal failure in a
infections. J Am Soc Nephrol 1991, 1:1061–1080. 31-year-old male with AIDS. Am J Med 1997, 102:310–315.
128. Berns JS, Cohen RM, Rudnick MR, et al.: Renal aspects of antimicro- 153. Becker BN, Fall P, Hall C, et al.: Rapidly progressive acute renal
bial therapy for HIV infection. In Renal and Urologic Aspects of HIV failure due to acyclovir: case report and review of the literature.
Infection. Comtemp Issues Nephrol 1996, 29:195–235. Am J Kidney Dis 1993, 22:611–615.
129. Valeri A, Neusy AJ: Acute and chronic renal disease in hospitalized 154. Peraldi MN, Ovali N, Rondeau E, et al.: Is biopsy useful in HIVJ-
AIDS patients. Clin Nephrol 1991, 35:110–118. infected patients with acute renal failure? A retrooperative study.
130. Genderini A, Bertoli S, Scorza D, et al.: Acute renal failure in patients J Am Soc Nephrol 1997, 8:130A.
with acquired immune deficiency syndrome. J Nephrol 1991, 1:45–47. 155. Rao TK, Friedman EA: Outcome of severe acute renal failure in patients
131. Rao TK, Friedman EA: Renal syndromes in the acquired immunode- with acquired immunodeficiency syndrome. Am J Kidney Dis 1995,
ficiency syndrome (AIDS): lessons learned from analysis over 5 years. 25:390–398.
Artif Organs 1988, 12:206–209. 156. Bourgoignie J: Glomerulosclerosis associated with HIV infection.
132. Bourgoignie JJ: Renal complications of human immunodeficiency Contemp Issues Nephrol 1996, 29:59–75.
virus type 1. Kidney Int 1990, 37:1571–1584. 157. Rao TK, Filippone EJ, Nicastri AD, et al.: Associated focal and segmen-
133. Cantor ES, Kimmel PL, Bosch JP: Effect of race on expression of tal glomerulosclerosis in the acquired immunodeficiency syndrome. N
acquired immunodeficiency syndrome–associated nephropathy. Arch Engl J Med 1984, 310:669–673.
Intern Med 1991, 151:125–128. 158. Pardo V, Aldana M, Colton RM, et al.: Glomerular lesions in the
134. D’Agati V, Cheng JI, Carbone L, et al.: The pathology of HIV- acquired immunodeficiency syndrome. Ann Intern Med 1984,
nephropathy: a detailed morphologic and comparative study. Kidney 101:429–434.
Int 1989, 35:1358–1370. 159. Gardenswartz MH, Lerner CW, Seligson GR, et al.: Renal disease in
135. Polis MA, Spooner KM, Baird BF, et al.: Anticytomegaloviral activity patients with AIDS: a clinicopathologic study. Clin Nephrol 1984,
and safety of cidofovir in patients with human immunodeficiency 21:197–204.
virus infection and cytomegalovirus viruria. Antimicrob Agents 160. Mazbar SA, Schoenfeld PY, Humphreys MH: Renal involvement in
Chemother 1995, 39:882–886. patients infected with HIV: experience at San Francisco General
136. Seidel EA, Koenig S, Polis MA: A dose escalation study to determine Hospital. Kidney Int 1990, 37:1325–1332.
the toxicity and maximally tolerated dose of foscarnet. AIDS 1993, 161. Humphreys MH: Human immunodeficiency virus–associated
7:941–945. nephropathy: east is east and west is west? Arch Intern Med 1990,
137. Rao TKS, Berns JS: Acute renal failure in patients with HIV infections. 150:253–255.
Contemp Issues Nephrol 1996, 29:41–57. 162. Bourgoignie JJ, Ortiz-Interian C, Green DF, et al.: The epidemiology
138. Jabs DA, David MD, Kuriniji et al.: Parenteral cidofovir for cyto- of human immunodeficiency virus–associated nephropathy. In
megalovirus retinitis in patients with AIDS: the HPMC peripheral Nephrology, vol 1. Edited by Hatano M. Tokyo: Springer-Verlag;
cytomegalovirus retinitis trial. A randomized controlled trial. Ann 1991:484–492.
Intern Med 1997, 126:264–275. 163. Pardo V, Meneses R, Ossa L, et al.: AIDS-related glomerulopathy:
139. Rashed A, Azadeh B, Abu Romeh SH: Acyclovir-induced acute tubu- occurrence in specific risk groups. Kidney Int 1989, 31:1167–1173.
lo-interstitial nephritis. Nephron 1990, 56:436–438. 164. Strauss J, Abitbol C, Zilleruelo G, et al.: Renal disease in children
140. Christin S, Baumelou A, Bahri S, et al.: Acute renal failure due to with the acquired immunodeficiency syndrome. N Engl J Med 1989,
sulfadiazine in patients with AIDS. Nephron 1990, 55:233–234. 321:625–630.
141. Carbone LG, Bendixen B, Appel GB: Sulfadiazine-associated obstruc- 165. Nochy D, Gotz D, Dosquet P, et al.: Renal disease associated with
tive nephropathy occurring in a patient with the acquired immunodefi- HIV infection: a multicentric study of 60 patients from Paris hospitals.
ciency syndrome. Am J Kidney Dis 1988, 12:72–75. Nephrol Dial Transplant 1993, 8:11–19.
142. Molina JM, Belenfant X, Doco-Lecompte T, et al.: Sulfadiazine- 166. D’Agati V, Appel GB: HIV infection and the kidney. J Am Soc
induced crystalluria in AIDS patients with toxoplasma encephalitis. Nephrol 1997, 8:138–152.
AIDS 1991, 5:587–589. 167. Cohen AH, Nast CC: HIV-associated nephropathy: a unique com-
143. Becker K, Jablonowski H, Haussinger D: Sulfadiazine-associated bined glomerular, tubular and interstitial lesion. Modern Pathol
nephrotoxicity in patients with the acquired immunodeficiency 1988, 1:87–97.
syndrome. Medicine 1996, 75:185–194. 168. Soni A, Agarwal A, Chander P, et al.: Evidence for an HIV-related
144. Sawyer MH, Webb DE, Balow JE, et al.: Acyclovir-induced acute renal rephropathy: a clinicopathological study. Clin Nephrol 1989, 31:12–17.
failure. clinical course and histology. Am J Med 1988, 84:1067–1071. 169. Bourgoignie JJ, Pardo V: The nephropathology in human immuno-
145. Tashima KT, Horowitz JD, Rosen S: Indinavir nephropathy [letter]. deficiency virus (HIV-1) infection. Kidney Int 1991, 35:S19–S23.
N Engl J Med 1997, 336:138–139. 170. Cohen AH: Renal pathology of HIV-associated nephropathy.
146. Kopp JB, Miller KD, Micam JAM, et al.: Crystoalluria and urinary Contemp Issues Nephrol 1996, 27:155–180.
tract abnormalities associated with Indinovir. Ann Intern Med 1997, 171. Pardo V, Strauss J, Abitbol C: Renal disease in children with HIV
127:119–125. infection. Contemp Issues Nephrology 1996, 29:135–154.
147. Spector DA, Katz RS, Fuller H, et al.: Acute non-dilating obstructive 172. Langs C, Gallo GR, Schacht RG, et al.: Rapid renal failure in AIDS-
renal failure in a patient with AIDS. Am J Nephrol 1989, 9:129–132. associated focal glomerulosclerosis. Arch Intern Med 1990,
148. Comiter S, Glasser J, Al-Askari S: Ureteral obstruction in a patient 150:287–292.
with Burkitt’s lymphoma. Urology 1992, 39:277–289. 173. Humphreys MH: Human immunodeficiency virus–associated
149. Kuhlman JE, Browne D, Shermak M, et al.: Retroperitoneal and glomerulosclerosis. Kidney Int 1995, 48:311–320.
pelvic CT of patients with AIDS: primary and secondary involvement 174. Shuka RR, Kimmel PL, Jumar A: Molecular biology of HIV-1 and
of the genitourinary tract. Radiographics 1991, 11:473–483. kidney disease. Contemp Issues Nephrol 1996, 29:329–389.
175. Barisoni L, Bruggeman L, Schwartz E, et al.: Pathogenesis of HIV-asso- 192. Kimmel PL, Umana WO, Simmens SJ, et al.: Continuous ambulatory
ciated nephropathy in transgenic mice. J Am Soc Nephrol 1997, peritoneal dialysis and survival of HIV infected patients with end-
8:492A. stage renal disease. Kidney Int 1993, 44:373–378.
176. Bruggeman LA, Dikman S. Meng C, et al.: Nephropathy in human 193. Ifudu O, Mayers JD, Matthew JJ, et al.: Uremia therapy in patients with
immunodeficiency virus-1 transgenic mice is due to renal transgene end-stage renal disease and human immunodeficiency virus infection:
expression. J Clin Invest 1997, 100:84–92. Has the outcome changed in the 1990s? Am J Kidney Dis 1997,
29:549–552.
177. Babut-Gay ML, Echard M, Kleinknecht D, et al.: Zidovudine and
nephropathy with human immunodeficiency virus (HIV) infection 194. Perinbasekar S, Brod-Miller S, Pal S, et al.: Predictors of survival in
[letter]. Ann Intern Med 1989, 111:856–857. HIV-infected patients on hemodialysis. Am J Nephrol 1996,
16:280–286.
178. Harrer T, Hunzelmann N, Stoll R, et al.: Therapy for HIV-1 related
nephritis with zidovudine. AIDS 1990, 4:815–817. 195. Carpenter C, Fischl M, Hammer S, et al.: Antiretroviral therapy for
HIV infection in 1996. JAMA 1996, 276:146–154.
179. Ifudu O, Rao TK, Tan CC, et al.: Zidoudine is beneficial in human
immunodeficiency virus associated nephropathy. Am J Nephrol 1995, 196. Casanova S, Mazzucco G, Barbiano di Belgiojoso G, et al.: Pattern of
15:217–221. glomerular involvement in human immunodeficiency virus-infected
patients: an Italian study. Am J Kidney Dis 1995, 26:446–453.
180. Kimmel PL, Mishkin GJ, Umana WO: Captopril and renal survival in
patients with human immunodeficiency virus nephropathy. Am J 197. Korbet SM, Schwartz MM: Human immunodeficiency virus infection
Kidney Dis: 1996, 28:202–208. and nephrotic syndrome. Am J Kidney Dis 1992, 20:97–103.
198. Stokes MB, Chawla H, Brody RI, et al.: Immune complex glomeru-
181. Smith MC, Austen JL, Carey JT, et al.: Prednisone improves renal
lonephritis in patients co-infected with human immunodeficiency
function and proteinuria in human immunodeficiency virus-associat-
virus and hepatitis C virus. Am J Kidney Dis 1997, 29:514–525.
ed nephropathy. Am J Med 1996, 101:41–48.
199. Kimmel PL, Phillips TM: Immune-complex glomerulonephritis associ-
182. Watterson MK, Detwiler RD, Bolin P Jr: Clinical response to pro-
ated with HIV infection. Contemp Issues Nephrol 1996, 29:77–110.
longed corticosteroids in a patient with human immunodeficiency
virus-associated nephropathy. Am J Kidney Dis 1997, 29:624–626. 200. Guerra IL, Abraham AA, Kimmel PL, et al.: Nephrotic syndrome
associated with chronic persistent hepatitis B in an HIV antibody
183. Ingulli E, Tejani A, Fikrig S, et al.: Nephrotic syndrome associated positive patient. Am J Kidney Dis: 1987, 10:385–388.
with acquired immunodeficiency syndrome in children. J Pediatr
1991, 119:710–716. 201. Schectman JM, Kimmel PL: Remission of hepatitis B–associated mem-
branous glomerulonephritis in human immunodeficiency virus infection.
184. Ouelette DR, Kelly JW, Anders JT: Serum angiotensin converting Am J Kidney Dis 1991, 17:716–718.
enzyme level is elevated in patients with HIV-infection. Arch Intern
202. Kusner DJ, Ellner JJ: Syphilis, a reversible cause of nephrotic syn-
Med 1992, 152:321–324.
drome in HIV infection [letter]. N Engl J Med 1991, 324:341–342.
185. Burns G, Paul SK, Sivak SL, et al.: Effect of angiotensin-converting
203. D’Agati V, Seigle R: Coexistence of AIDS and lupus nephritis: a case
enzyme inhibition in HIV-associated nephropathy. J Am Soc Nephrol
report. Am J Nephrol 1990, 10:243–247.
1997, 8:1140–1146.
204. Contreras G, Green DF, Pardo V, et al.: Systemic lupus erythematosus
186. Bird JE, Kopp JB, Gitlitz P, et al.: Captopril intervention is of benefit in two adults with human immunodeficiency virus. Am J Kidney Dis
in HIV-transgenic mice. J Am Soc Nephrol 1997, 8:611A. 1996, 28:292–295.
187. Rao TKS, Friedman EA, Micastri AD: The types of renal disease in 205. Kimmel PL, Phillips TM, Farkas-Szallasi T, et al.: Idiotypic IgA
human acquired immunodeficiency syndrome. N Engl J Med 1987, nephropathy in patients with HIV infection. N Engl J Med 1992,
316:1062–1068. 327:702–706.
188. Ortiz C, Meneses R, Jaffe D, et al.: Outcome of patients with human 206. Bourgoignie JJ, Pardo V: Human immunodeficiency virus: associated
immunodeficiency virus on maintenance hemodialysis. Kidney Int nephropathies [editorial]. N Engl J Med 1992, 327:729–730.
1988, 34:248–253.
207. Peraldi MN, Berrou J, Flahaut A, et al.: Elevated plasma tissue type
189. Feinfeld DA, Kaplan R, Dressler R, et al.: Survival of human plasminogen activator (tPA) in HIV-infected patients with thrombotic
immunodeficiency virus infected patients on maintenance dialysis. microangiopathy [abstract]. J Am Soc Nephrol 1996, 7:1377.
Clin Nephrol 1989, 32:221–224. 208. Berns JS: Hemolytic uremic syndrome and thrombotic thrombocy-
190. Ribot S, Dean D, Goldblat M, et al.: Prognosis of HIV positive dialysis topenic purpura associated with HIV infection. Contemp Issues
patients [abstract]. Kidney Int 1990, 37:315. Nephrol 1996, 29:111–133.
191. Schrivastava D, Delano BG, Lundin P, et al.: Factors affecting survival 209. Nadasdy T, Miller KW, Johnson LD, et al.: Is cytomegalovirus associ-
of HIV+ patients undergoing maintenance hemodialysis [abstract]. ated with renal disease in AIDS patients? Modern Pathol 1992,
J Am Soc Nephrol 1992, 3:320. 5:277–282.
Renal Involvement
in Sarcoidosis
Garabed Eknoyan
S
arcoidosis is a clinicopathologic syndrome resulting from dis-
persed organ involvement by a noncaseating granulomatous
process of unknown cause. The clinical manifestations of sar-
coidosis 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 remis-
sions 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 sea-
sonal 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 sug-
gests 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 sar-
coidosis. Elevated levels of calcitriol are consequent to the capacity of
the infiltrating macrophages of the granulomas to synthesize calcitriol. CHAPTER
Elevated levels of ACE are consequent to that of the multinucleated
giant and epithelioid cells that ultimately develop in the granulomas,
8
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
and are of limited value in diagnosis; however, they can be use- the active granulomatous lesions. Close monitoring of patients
ful in follow-up of the course of the disease and patient response is essential during tapering and after discontinuation of steroid
to treatment. therapy, because 25% of treated patients experience relapse.
In symptomatic cases, steroids are highly effective in sup- Other drugs that have been used in cases unresponsive to
pressing the cellular inflammatory reaction of sarcoidosis and steroids are methotrexate, chloroquine, azathioprine, and
in reversing most forms of organ dysfunction caused by granu- cyclophosphamide. Of these, methotrexate seems to be more
lomatous infiltration. Therapy with prednisone (30 to 40 mg/d) effective.
for 8 to 12 weeks, with gradual tapering of the dose (10 to The prognosis is worse in blacks, the elderly, and those
20 mg/d) over 6 to 12 months, is usually sufficient. Persistent patients who fail to respond to steroids or have extensive multi-
dysfunction can result from residual fibrosis after reversal of organ involvement.
Pathophysiology and Diagnosis
A B
C D
Pathology of granulomatous lesions in lungs affected by sarcoidosis. teristic of sarcoidosis are shown. (Hematoxylin-eosin stain 10.)
The diagnosis of sarcoidosis depends on demonstration of the charac- C and D, Lesions in the lung are illustrated, showing their course from
teristic lesion of noncaseating granulomas within the affected organs. a cellular inflammatory response, which may be asymptomatic (panel
As with other epithelioid granulomas, the more commonly involved C), to that of the fibrotic resolution (panel D). The fibrotic response
organs are the lungs and liver. A, A section of a normal lung is shown. usually accounts for the permanent loss of normal parenchyma and
(Pentachrome stain 10.) B, Multiple noncaseating granulomas and organ function. (Hematoxylin-eosin stain 10 and pentachrome
areas of mononuclear cell infiltration of the lung interstitium charac- 10, respectively.) (From Newman et al. [1]; with permission.)
Renal Involvement in Sarcoidosis 8.3
FIGURE 8-2
Pathogenesis of granulomatous
lesions Pathogenesis of granulomatous lesions. Mononuclear cell infiltra-
tion is the initial step in the sequence of events that leads to granu-
loma formation. Recruited macrophages then differentiate into
Mononuclear cell infiltration 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 colla-
Macrophage aggregation ↑ Synthesis of 1,25-dihydroxy-vitamin D3 gen 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
Epithelioid and multinucleated ↑ Synthesis of angiotensin-converting
giant cells the infiltrating macrophages and is not unique to sarcoidosis but a
enzyme
feature of most other granulomatous disorders. Although lacking
in specificity to be of diagnostic merit, radioactive gallium scans
Encapsulating rim can be used as noninvasive methods of assessing the activity of sar-
CD4>CD8 (except in rare cases) coid granulomas. The uptake of radioactive gallium by the
B cells, few macrophages and lymphocytes reflects the activity of the infiltrat-
Fibroblasts ing cells in affected organs.
Mast cells
FIGURE 8-4
CYTOKINES IMPLICATED IN SARCOIDOSIS FREQUENCY OF ORGAN INVOLVEMENT Frequency of organ
PERPETUATING GRANULOMAS involvement.
Sarcoidosis is a
Patients, % multisystem disease.
Interferon- Parenchymal
Thoracic 90–100 involvement by
Interleukin-2, 6, and 1
Stage I: hilar adenopathy granulomatous
Chemoattractants
Stage II: hilar adenopathy plus lesions is most
Adhesion molecules pulmonary infiltration common in the
Tumor necrosis factor- Stage III: pulmonary infiltration lungs, whereas that
Dermatologic 25 of renal involvement
Erythema nodosum, lupus pernio, papules, macules, plaques is relatively rare.
Ophthalmic 25
FIGURE 8-3 Uveitis, iritis, conjunctivitis
Cytokines implicated in perpetuating granu- Nervous system 10
lomas. Cytokines released by the infiltrating Peripheral neuropathy, Bell’s palsy
mononuclear cells and T-cell lymphocytes Central nervous system
initiate the cascade of inflammatory reaction Gastrointestinal 40–70
that results in subsequent formation of the Liver
noncaseating granulomas that characterize Spleen
sarcoidosis. It is the loss of the otherwise
Cardiac 5–10
balanced ability of cytokines to modulate
Renal 1–20
the inflammatory response that accounts for
Musculoskeletal 10–15
the progression of the initial inflammatory
Polyarthritis, lower > upper
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.
FIGURE 8-5
DIFFERENTIAL DIAGNOSIS OF Differential diagnosis of pulmonary sarcoidosis. The lungs are the principal organs involved
PULMONARY SARCOIDOSIS in sarcoidosis. Pulmonary involvement may or may not be associated with hilar lym-
phadenopathy. 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 radi-
Sarcoidosis ographs. Pulmonary symptoms develop when the disease is in its late fibrotic phase and are
Beryllium exposure associated with airway obstruction.
Hypersensitivity pneumonitis
Idiopathic pulmonary fibrosis
Mycobacterial infection
Fungal infections
Methotrexate-induced pneumonitis
Wegener’s granulomatosis
FIGURE 8-6
LABORATORY FINDINGS Laboratory findings in sarcoidosis. The diagnosis of sarcoidosis depends on the demon-
IN SARCOIDOSIS stration 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,
Hyperglobulinemia being present in two thirds of cases. About half of patients have liver involvement, with
Abnormal liver function tests some abnormality of liver function tests; anergy is present in about half of patients;
Anergy leukopenia is present in 25% to 30%. Hypercalciuria is common because of increased lev-
Leukopenia els of calcitriol. In 50% to 60% of patients levels of angiotensin-converting enzymes are
Hyperuricemia elevated. Fever is present in about one third of patients.
Hypercalciuria
Hypercalcemia
Elevated calcitriol (1,25-dihydroxy-vitamin D3)
Elevated angiotensin-converting enzyme
Cryoglobulinemia
FIGURE 8-7
RENAL INVOLVEMENT IN SARCOIDOSIS 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
Patients, % increased synthesis of 1,25-dihydroxy-vitamin D3 by the
macrophages of the granulomatous lesions. The consequent
Calcium metabolism increased calcium absorption from the gastrointestinal tract results
Hypercalciuria 50–60 in the hypercalciuria that can be detected in more than half of
Hypercalcemia 10–20 patients. The frequency of hypercalciuria depends on the extent of
Nephrolithiasis ≈10 granulomatous lesions and on the time of the year, being more
Nephrocalcinosis 5–10 common in spring and summer when exposure to the sun is great-
Tubulointerstitial nephritis est. Hypercalcemia is less common and usually depends on coexis-
Granulomatous 15–40 tent deterioration of renal function when the capacity of the kidney
Fibrotic 10–20 to excrete calcium is compromised. In most patients, hypercalciuria
Glomerulopathy Rare is asymptomatic. Its principal manifestations are inability to con-
Membranous centrate the urine and polyuria. Nephrolithiasis occurs in about
Proliferative 10% of patients; another 10% develop nephrocalcinosis.
Focal segmental glomerulosclerosis
Arteritis Rare
Granulomatous angiitis
Obstructive nephropathy Rare
Retroperitoneal lymphadenopathy
Retroperitoneal fibrosis
tomatic, and the disease may go undetected.

Abnormal calcium metabolism and
pathophysiology of renal involvement in sarcoidosis Polyuria and a reduced capacity to concen-
trate the urine are its main manifestations.
Sarcoid Either of these two features may be the result
granulomas of tubulointerstitial nephritis caused by sar-
coidosis, and can be present in the absence of
any altered calcium metabolism.
↓ Parathyroid hormone Nephrocalcinosis also may be asymptomatic.
secretion ↑ Levels of calcitriol
In contrast, nephrolithiasis presents as renal
colic or hematuria. Hypercalcemia develops
only when the load of calcium to be excreted
↑ Intestinal calcium absorption exceeds the ability of the kidneys to excrete
and ↑ bone resorption the calcium load, either because of reduced
renal function or, less commonly, when the
↓ Tubular calcium ↑ Calcium load for amount of calcium absorbed is excessive. The
absorption renal excretion magnitude of hypercalcemia determines its
symptomatology. The circulating level of
parathyroid hormone should be determined
Renal calcium ↓Renal in patients with hypercalcemia. An increase
deposition Function
in the prevalence of parathyroid adenomas
seems to occur in sarcoidosis. In hypercal-
↓ Total calcium cemia caused by elevated levels of calcitriol
Outflow tract parenchymal
excretion and by reduced renal excretion of calcium,
parathyroid hormone levels should be negligi-
ble. Detection of elevated levels of parathy-
Hypercalciuria Nephrolithiasis Nephrocalcinosis Hypercalcemia
roid hormone should lead to the search for
an adenoma. Patient management is directed
at reducing calcitriol synthesis by treating the
FIGURE 8-8 granulomatous lesions with steroids. Equally
Abnormal calcium metabolism and pathophysiology of renal involvement in sarcoidosis. important measures in the management of
Increased synthesis of calcitriol (1,25-dihydroxy-vitamin D3) by the macrophages of the such patients are restriction of calcium
granulomatous lesions of sarcoidosis are at the core of the abnormal calcium metabolism intake, avoidance of dietary supplements that
that accounts for the principal manifestations of renal involvement of sarcoidosis (gray contain vitamin D, shunning exposure to
boxes). Patients with hypercalciuria, which by far is the most common, may remain asymp- 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 abnormal-
ity. 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.
FIGURE 8-10
DIFFERENTIAL DIAGNOSIS OF Differential diagnosis of granulomatous lesions in renal sarcoidosis. Once considered rare,
GRANULOMATOUS LESIONS granulomatous interstitial nephritis is now observed in 10% of kidney biopsy results. Most
IN RENAL SARCOIDOSIS of these are seen in cases of drug hypersensitivity. The commonly implicated drugs are anti-
biotics and nonsteroidal anti-inflammatory drugs. Sarcoidosis and Wegener’s granulomatosis
each account for 5% to 10% of cases observed on kidney biopsy. Other less common and
Lesion Patients, % 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.
Drug-induced 55–70
Sarcoid 5–10
Wegener’s granulomatosis 5–10
Other (less common):
Tuberculosis
Brucellosis
Vasculitis
Systemic lupus
erythematosus
Idiopathic 15–20
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 pro-
gressive 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.
FIGURE 8-12
8 Pre-R R Clinical course of granulomatous nephritis. Extensive granulomatous
infiltration of the kidneys can result in acute renal failure as a pre-
Serum creatinine, mg/100mL
7
senting clinical feature of sarcoidosis in the absence of any evidence
6
of other organ involvement. As a rule, improvement in renal func-
5 tion occurs after steroid therapy (R), as shown here, in the clinical
4 course of one such patient. (From Bolton et al. [2]; with permission.)
3
2
1
60
50
40
30
20
10
40
30
Hematocrit, %
20
10
60
Prednisone
qod, mg 30
September October Nov. Dec. Jan. Feb. Mar. April May June July
Time, mo
FIGURE 8-13
CASE REPORT OF A PATIENT WITH SARCOIDOSIS Obstructive nephropathy due to sarcoidosis. Acute deterioration of
HAVING RETROPERITONEAL FIBROSIS renal function in sarcoidosis very rarely results from obstructive
nephropathy caused by intrarenal granulomatous infiltrates or
from extensive retroperitoneal lymphadenopathy or fibrosis caus-
Patient profile ing obstruction of the renal vasculature or ureteral outflow [3,4].
(From Grodin et al. [3]; with permission.)
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
CASE REPORT OF A PATIENT WITH SARCOIDOSIS CASE REPORT OF A PATIENT WITH RECURRENT
HAVING GLOMERULOPATHY GRANULOMATOUS SARCOID NEPHRITIS IN A
TRANSPLANTED KIDNEY
Patient profile
Aged 13 y Sarcoidosis with pulmonary, hepatic, and ophthalmic symptoms
A man aged 57 years with 3 months’ history of progressive edema
Responded to steroids
Past history: pulmonary sarcoidosis, treated with steroids for 10 years, on 5 mg 4 times Steroids discontinued due to cataract and hypertension
a day on admission
Aged 19 y Renal involvement progressive to end-stage renal disease
Physical examination: blood pressure, 180/95 mm Hg; peripheral edema Cadaveric transplantation after 3 months of dialysis
Laboratory test results: blood urea nitrogen, 32 mg/dL; creatinine, 4.3 mg/dL; albumin, Medications: azathioprine, 75 mg per day; prednisone tapered to
2.9 g/dL; cholesterol, 543 mg/dL; urinalysis, 6–8 erythrocyte/high-power field, 3 + 15 mg 4 times a day
protein; 24-h urine protein, 1.5 g Aged 26 y Creatinine, 3.1 mg/dL; creatinine clearance, 20 mL/min;
Kidney biopsy: membranous glomerulopathy; no granulomas 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 8-14
Sarcoid-associated glomerulopathy. Whereas renal involvement in
sarcoidosis primarily is due to abnormalities of calcium metabolism
and tubulointerstitial nephritis, rare cases of glomerulopathy have FIGURE 8-15
been associated with sarcoidosis. The detection of an abnormal urine Recurrent granulomatous sarcoid nephritis in a transplanted kid-
sediment and proteinuria in a patient with sarcoidosis should always ney. In patients with sarcoidosis having renal involvement whose
lead to consideration of glomerular disease. A variety of glomerular renal failure has progressed to end-stage renal disease, kidney
lesions have been reported in patients with sarcoidosis, including transplantation can be successful. However, due consideration
membranous glomerulopathy, minimal change disease, membrano- should be given to the fact that recurrence of sarcoidosis in renal
proliferative glomerulonephritis, focal glomerulosclerosis, immuno- allografts have been reported. Conversely, documented cases exist
globulin A nephropathy, and crescentic glomerulonephritis. Of these, in which sarcoidosis was transmitted by cardiac or bone marrow
membranous glomerulopathy is more common. These rare cases may transplantation. This observation has been taken as evidence of an
represent a chance coexistence of two separate diseases; however, infectious or transmissible cause of sarcoidosis that highlights the
their occurrence in a disease of altered immunity may reflect a problem of transplantation in patients with sarcoidosis. (From
causative association. Mesangial deposits of C3 have been observed Shen et al. [6]; with permission.)
in cases of sarcoid granulomatous nephritis in the absence of any clin-
ical 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.)
References
1. Newman LS, Rose CS, Maier LA: Sarcoidosis. N Engl J Med 1997, 4. Cuppage FE, Emmott DF, Duncan KA: Renal failure secondary to sar-
336:1224–1234. coidosis. Am J Kidney Dis 1990, 11:519–521.
2. Bolton WK, Atuk NO, Rametta C, et al.: Reversible renal failure from 5. Taylor RG, Fisher C, Hoffbrand BI: Sarcoidosis and membranous
isolated granulomatous renal sarcoidosis. Clin Nephrol 1976, glomerulonephritis: a significant association. Br Med J 1982,
5:88–92. 284:1297–1298.
3. Grodin M, Filastre JP, Ducastelle T, et al.: Sarcoidosis retroperitoneal 6 Shen SY, Hall-Craggs M, Posner JN, Shalozz B: Recurrent sarcoid
fibrosis, renal arterial involvement and unilateral focal glomeruloscle- granulomatous nephritis and reactive tuberculin test in a renal trans-
rosis. Arch Intern Med 1980, 140:1240–1242. plant recipient. Am J Med 1986, 80:699–702.
Casella FJ, Allon M: The kidney in sarcoidosis. J Am Soc Nephrol Fuss M, Pepersack T, Gillet C, et al.: Calcium and vitamin D metabo-
1993, 3:1555–1562. lism in granulomatous diseases. Clin Rheumatol 1992, 11:28–36.
Romer FK: Renal manifestations and abnormal calcium metabolism in Hanedouche T, Grateau G, Noel LH, et al.: Renal granulomatous sar-
sarcoidosis. Quart J Med 1980, 49:233–247. coidosis: Report of 6 cases. Nephrol Dial Transplant 1990, 5: 18–24.
Essential Mixed
Cryoglobulinemia
Giuseppe D’Amico
Franco Ferrario
U
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 hav-
ing essential mixed cryoglobulinemia. Essential mixed cryoglobuline-
mia 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 vas-
cular involvement of the kidney occur. The most frequent histologic pic-
ture, especially in the acute stages, is a membranoproliferative glomeru-
lonephritis (MPGN) with subendothelial deposits, with some character-
izing 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 dis-
ease, being characterized by periods of temporary reactivation CHAPTER
(nephritic or nephrotic syndrome, sometimes with rapidly occurring
renal insufficiency) and long-lasting periods of partial remission. Only
9
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.
During acute flare-ups, antiviral treatment (interferon-) is insuf- ized events might induce the shift to abnormal proliferation of
ficient to control the renal disease, even when it reduces viremia. a clone of B cells, producing a monoclonal IgM rheumatoid fac-
Steroids, usually associated with immunosuppressive drugs tor. Thus, a type II MC is induced that can be considered a lym-
(cyclophosphamide), are then necessary to control renal disease. phoproliferative disorder. It has been suggested that the IgMk
Hepatitis C virus can infect B lymphocytes and stimulate produced by this permanent clone of B cells has affinity for the
them to synthesize the cryoprecipitating polyclonal rheumatoid glomerular matrix and can deposit, in the glomerulus together
factors responsible for type III MC. In some patients with this with the IgG to which it binds in the blood, IgG that probably
polyclonal B-cell activation, additional but as yet uncharacter- acts as an anti-HCV antigen antibody.
CLASSIFICATION OF CRYOGLOBULINEMIAS AND ASSOCIATED DISEASES
Type I: single monoclonal IgA, Type II: polyclonal IgG bound to

IgG, or IgM monoclonal anti-IgG rheumatoid factor* Type III: polyclonal IgG bound to polyclonal anti-IgG rheumatoid factor*
Multiple myeloma B-lymphocytic neoplasm Autoimmune diseases: SLE, polyarteritis nodosa, rheumatoid arthritis, scleroderma,
Sjögren’s syndrome, and Henöch-Schonlein purpura
Waldenström’s macroglobulinemia Diffuse lymphoma Infections diseases: mononucleosis, cytomegalovirus, hepatitis B, subacute bacterial
endocarditis, leprosy, malaria, schistosomiasis, toxoplasmosis, AIDS
Chronic lymphocytic leukemia Chronic lymphocytic leukemia Miscellaneous diseases: primary proliferative glomerulonephritis, lymphoma, chronic
hepatitis, biliary cirrhosis
Idiopathic monoclonal gammopathy Sjögren’s syndrome Essential
Essential
*Usually IgM.
From Brouet and coworkers [1]; with permission.
FIGURE 9-1
Classification of cryoglobulinemias and associated diseases as proposed not clear, and this group of mixed cryoglobulinemias was called essential
by Brouet and coworkers in 1974 [1]. Up to the end of the 1980s, the [2,3]. As indicated in Figure 9-4, it now is evident that most essential
cause of about 30% of both types II and III mixed cryoglobulins was mixed cryoglobulinemias are associated with hepatitis C virus infection.
FIGURE 9-2
DETECTION OF CIRCULATING CRYOGLOBULINS AND Correct methodology for detecting circulating cryoglobulins.
DETERMINATION OF CRYOPRECIPITATE Cryoglobulins are immunoglobulins that precipitate reversibly from
cooled serum.
Prewarm syringe, needle, and tubes at 37°C

Take 20 mL of whole blood and put it immediately at 37°C
Incubate for 2 h at 37°C to allow clotting
Centrifuge twice at 1700 g X 10 at 37°C to discard platelets and erythrocytes
Cryoglobulins precipitate reversibly from cooled serum
Keep serum at 4°C in a conical graduate tube
Look at the serum after 7 d
Centrifuge serum at 400 g X 10 at 4°C and calculate the cryocrit as the percentage of
packed cryoglobulins and serum ratio
Renal Involvement in Essential Mixed Cryoglobulinemia 9.3
ed at least four times. Next, the cryopre-

cipitate is solubilized in three volumes of
phospate-buffered saline at 37°C before
gel electrophoresis is performed.
A, Example of type II mixed cryoglobu-
A B lin; the immunoglobulin M rheumatoid fac-
tor contains but not light chains and
FIGURE 9-3 (see Color Plate) therefore is monoclonal. B, Example of
Immunoglobulin composition and clonality of mixed cryoglobulins characterized by type III mixed cryoglobulin; the immuno-
immunofixation. The cryoglobulins (isolated, as indicated in Fig. 9-2) are resuspended in globulin M rheumatoid factor contains
three volumes of cold phosphate-buffered saline at 4°C and then washed by centrifuging both and light chains and therefore is
at 1700 g for 10 minutes at 4°C; the supernatant is discarded. This procedure is repeat- 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 Serum HCV antibodies Serum HCV RNA
Patients tested, n Positive patients, % Patients tested, n Positive patients, %
Ferri et al. [5] II and III EMC 52 54
Galli et al. [6] II and III EMC 129 80
63 70
Pechère-Bertschi et al. [7] II and III EMC 15 87 7 71
Agnello et al. [8] II EMC 19 42 19 84
Misiani et al. [9] II EMC 75 96 28 93
Pasquariello et al. [10] II EMC with GN 26 100 7 100
Cacoub et al. [11] II and III EMC 63 52 16 63
SMC 52 27
Bichard et al. [12] II and III EMC — — 15 93
D’Amico, Unpublished data II EMC 41 95 41 95
II EMC wtih GN 28 93 28 93
III EMC 13 77 13 77
*According to published data [4].

EMC—essential mixed cryoglobulinemia; GN—glomerulonephritis; HCV—hepatitis C virus; SMC—secondary mixed cryoglobulinemia.
FIGURE 9-4
Second-generation enzyme-linked immunosorbent assay has antibodies. The prevalence of positivity of HCV RNA
been used by all the authors listed here (with the exception in the 15 patients studied by Bichard and coworkers [12]
of Agnello and coworkers [9], who used a recombinant increased from 60% to 93% when cryoprecipitate from
immunoblot assay) to measure anti–hepatitic C virus (HCV) serum was tested.
FREQUENT EXTRARENAL SIGNS IN PATIENTS WITH

TYPES II AND III MIXED CRYOGLOBULINEMIA
Signs and symptoms Prevalence during course of disease, %

Cutaneous purpura ≈ 95
Arthralgias ≈ 85
Fever ≈ 60
Hepatosplenomegaly ≈ 95
Neuropathy ≈ 40
Abdominal pain ≈ 30

Extrarenal signs frequently present in patients with types II and III A purpuric rash of the legs in a patient with mixed cryoglobuline-
mixed cryoglobulinemia, either essential or due to hepatitis C virus mia associated with hepatitis C virus infection.
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 9-7
DISTINCTIVE FEATURES OF MEMBRANOPROLIFERATIVE The distinctive features of the membra-
GLOMERULONEPHRITIS, OR CRYOGLOBULINEMIC GLOMERULONEPHRITIS noproliferative glomerulonephritis. This dis-
order, called cryoglobulinemic glomeru-
lonephritis, occurs only in patients with
Exudative component type II mixed cryoglobulinemia, especially
The major constituent of intracapillary proliferation is an infiltration of leukocytes, mainly monocytes, that in the acute stage of the disease [4,14]. In
sometimes is massive. about 20% of patients with type II mixed
Intraluminal thrombi cryoglobulinemia, a less distinctive picture
Huge deposits of cryoglobulins called intraluminal thrombi sometimes fill the capillary lumen. of lobular membranoproliferation is found,
Interposition of monocytes in the double contour of the capillary wall whereas an additional 20% exhibit mild
Monocytes, in close contact with the subendothelial deposits of cryoglobulins, are interposed between the glomerular
mesangial proliferation. These various types
basement membrane and the newly formed membranelike material, to give the double-contoured appearance of the of histologic lesions can be found by repeat
capillary wall, whereas peripheral interposition of mesangial matrix and cells is moderate. biopsies in the same patient during different
Structured crystalloid deposits on electron microscopy stages of the disease.
Intraluminal and subendothelial deposits of cryoglobulins sometimes show a specific fibrillar structure on
electron microscopy.
Vasculitis of small and medium-sized arteries
Necrotizing arteritis, without concomitant features of segmental necrotizing glomerulonephritis, is found in one
third of patients.

Membranoproliferative exudative glomerulonephritis in patients Immunohistochemical staining with anti–monocyte-macrophage
with type II mixed cryoglobulinemia. The marked endocapillary antibody (CD68). This reaction confirms that the intracapillary
hypercellularity also is due to massive intraglomerular infiltration of hypercellularity is due mainly to accumulation of these mononu-
mononuclear leukocytes, mainly monocytes (Fig. 9-9). Mesangial clear leukocytes. Their average number in acute stages of cryoglob-
cell proliferation and mesangial matrix expansion are mild. Many ulinemic glomerulonephritis is four times greater than in severe
loops show a thickened glomerular capillary wall, with frequent proliferative lupus nephritis [15]. (Immunoperoxidase 250.)
double-contoured basement membrane. (Trichrome stain 250.)

Monocyte in close contact with a massive endocapillary deposit showing phagocytic activity.
(Uranyl acetate–lead 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 Waldenström macroglobu-
linemia. The glomerulus shows morphologic lesions similar to
those seen in Figure 9-8, characterized by marked endocapillary
hypercellularity mainly a result of mononuclear leukocyte accumu-
lation. 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 cryo-
globulins. (Trichrome stain 250.)
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-µm long, with a hollow axis, appear-
ing in cross-sections as annular bodies [16]. (Uranyl acetate–lead citrate 22,000.)
(Courtesy of Department of Pathology, San Carlo Borromeo Hospital, Milan, Italy.)

Silver stain showing the double-contoured appearance of the base- Interposition of monocytes in cryoglobulinemic glomerulnephritis.
ment membrane. This morphologic aspect is diffuse and more Two monocytes containing lysosomes are interposed, together with
clearly visible than in idiopathic membranoproliferative glomeru- electron-dense subendothelial deposits, between the glomerular base-
lonephritis or lupus nephritis. (Silver stain 250.) ment membrane and the newly formed basement-membrane–like
material of the double-contoured capillary wall. The interposition of
monocytes is a distinctive feature of cryoglobulinemic glomerulnephri-
tis [17,18]. Mesangial matrix and mesangial cell interposition, howev-
er, usually are less evident than in idiopathic membranoproliferative
glomerulonephritis, as is glomerular sclerosis. (Uranyl acetate-lead cit-
rate 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 prolif-
eration 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 infiltra-
tion. (Trichrome 250.)
FIGURE 9-16
The glomerulus showing only mild mesangial proliferation and
mesangial matrix expansion. Thickening of the glomerular base-
ment 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 membranoprolif-
erative 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.)
A 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 distribu-
tion. (Immunoglobulin 250.) The components of mixed cryo-
globulinemia immunoglobulin M and G, usually associated with
C3, are the most frequently found immunoreactants.
C

Interstitial infiltrates having different degrees of intensity and diffu- Arteritis of small and medium-sized arteries. In about one third of
sion. When present, these infiltrates are composed not only of T lym- cases an arteritis of small and medium-size arteries also is present.
phocytes and monocyte macrophages, as in most glomerular diseases, The artery shows diffuse fibrinoid necrosis of the vessel wall (in
but also of B lymphocytes. (Periodic acid–Schiff reaction 100.) 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
antibody–associated). This finding suggets that the vasculitic dam-
age is limited to arterial vessels of larger size. (Trichrome 100.)
FIGURE 9-20
RENAL SYNDROME AT PRESENTATION IN PATIENTS Renal syndrome at presentation in patients
WITH CRYOGLOBULINEMIC GLOMERULONEPHRITIS with cryoglobulinemic glomerulonephritis
AND ASSOCIATED HISTOLOGIC LESION and associated histologic lesion. During the
course of this disease, both the systemic and
renal signs may vary remarkably, with peri-
Renal syndrome Patients, % Frequent histologic features ods of exacerbation alternating with peri-
ods of quiescence. Very often, exacerbation
Isolated proteinuria with microscopic hema- ≈55 Membranoproliferative glomerulonephritis of the extrarenal signs is associated with
turia, sometimes associated with moderate (MPGN), with moderate infiltration of monocytes exacerbation of renal disease (recurrent
chronic renal insufficiency Lobular MPGN episodes of nephritic or nephrotic syn-
Mesangioproliferative glomerulonephritis drome); however, a flare-up of renal disease
Acute nephritic syndrome, sometimes com- ≈25 MPGN with leukocytic infiltration, or intraluminal may occur even in the absence of exacerba-
plicated by acute oliguric renal failure thrombi owing to abrupt massive precipitation tion of the extrarenal signs. Partial or total
of cryoglobulins, usually associated with renal
and systemic vasculitis, or both
prolonged remission occurs spontaneously
or after treatment in 10% to 15% of
Nephrotic syndrome ≈20 MPGN, frequently of lobular type, with some
infiltration of monocytes patients. Arterial hypertension frequently is
severe and is present in most patients with
cryoglobulinemic nephropathy.
LABORATORY ABNORMALITIES IN CLINICAL OUTCOMES OF 105 PATIENTS STUDIED

ESSENTIAL MIXED CRYOGLOBULINEMIA IN THREE MILAN HOSPITALS FROM 1966 TO 1990
Circulating cryoglobulins 49% cumulative 10-year probability of survival, without renal failure
Cryocrits ranging from 2% to 70%, with large variations during the course of the disease 40% of patients died, mostly from cardiovascular diseases, liver failure, or infections
Hypocomplementemia 14% of patients progressed to chronic renal failure and required dialysis
Very low levels of early C components (C1q and C4) and CH50; slightly low levels of 14% of patients achieved complete and prolonged remission of renal symptoms
C3; and high levels of late C components, C5 and C9
FIGURE 9-22
FIGURE 9-21 The clinical outcomes in 105 patients studied in three hospitals in
Relevant laboratory abnormalities in “essential” mixed cryoglobu- Milan, Italy, between 1966 and 1990. The medial total follow-up
linemia. During the course of this disease, cryoglobulins may tem- time from clinical onset was approximately 11 years [19].
porarily become undetectable. Low levels of serum C4 cannot be
corrected by treatment. Low levels of C3 frequently are found dur-
ing clinical flare-ups and can be corrected by treatment.
FIGURE 9-23
TREATMENT OF ACUTE RENAL EXACERBATIONS This approach to treatment of the acute renal exacerbations of
OF CRYOGLOBULINEMIC GLOMERULONEPHRITIS cryoglobulinemia and vasculitis used previously when the viral
AND VASCULITIS 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 complica-
Steriods are used to control inflammatory renal and systemic involvement tions in the acute stage of the disease [20].
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
FIGURE 9-24
PROPOSED TREATMENT FOR MIXED The proposed treatment for mixed cryoglobulinemia associated with
CRYOGLOBULINEMIA ASSOCIATED WITH HEPATITIS hepatitis C virus infection in the presence of severe acute signs of
C VIRUS INFECTION renal involvement, ie, glomerulonephritis and vascultits. Plasma
exchange is used only when acute renal insufficiency caused by mas-
sive precipitation of cryoglobulins is present. Interferon- is given
Drug Dosage Duration for more than 6 months only when negation of hepatitis C virus
RNA is achieved in the first months, suggesting a beneficial effect
Interferon- 3.0–6.0 MU, 3 times weekly 6–12 mo on the viremia. Only the antiviral treatment with interferon- even-
Steriods Methylprednisolone, 0.75–1.0 g/d, intravenously 3d tually associated with low doses of steriods to conrol the systemic
Prednisone, 0.5 mg/kg of body weight tapered 6 mo signs of mixed cryoglobulinemias should be given if renal involve-
over a few weeks until maintenance dose of ment is mild. The association of interferon- with another antiviral
10–15 mg/d is achieved
agent ribavirin, 0.6 to 1.0 g/d orally, now is being tested in patients
Cyclophosphamide 2 mg/kg of body weight 3–4 mo
with hepatitis C virus infection, with promising results [20].
Plasmapheresis Exchanges of 3 L of plasma, 3 times weekly 2–3 wk
FIGURE 9-25
– Infection by HCV The mechanisms of renal complications induced by hepatitis C virus
– Emergence of a B lymphocyte (HCV) infection, with or without associated mixed cryoglobulinemia,
permanent clone
producing IgMk RF 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
IgMk RF
HCV IgG Ab
infected by HCV. It is unknown whether the IgM RF deposits in the
Serum glomerulus alone, with subsequent in situ binding of IgG (perhaps
bound already to viral antigens, or as a complex composed of HCV
HCV-IgG HCV-IgG-IgMk antigens, IgG anti-HCV antibodies, and IgMk RF). Only recently
have specific HCV-related proteins been detected in glomerular struc-
tures using indirect immunochemistry. As depicted on the left, it is
Deposition of anti-HCV Precipitation of In situ binding of possible that in a minority of cases immune complexes composed of
immune complexes the circulating HCV-IgG Ab to HCV antigens and anti-HCV IgG antibodies can deposit directly in
type II cryo predeposited IgMk Glomerulus the glomerular structures, in the absence of a concomitant type II MC
MPGN without with a monoclonal IgM RF. This deposition induces an immune-com-
cryoglobulinemia Cryoglobulinemic GN
plex glomerulonephritis similar to that described in patients infected
with the hepatitis B virus. (Adapted from D’Amico [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
1. Brouet JC, Clauvel JP, Danon F, et al.: Biological and clinical significance 13. D’Amico G, Ferrario F, Colasanti G, Bucci A: Glomerulonephritis in
of cryoglobulins: a report of 86 cases. Am J Med 1974, 57:775–778. essential mixed cryoglobulinemia (EMC). In Proceedings of the XXI
2. Meltzer M, Franklin EC, Elias K, et al.: Cryoglobulinemia: a clinical Congress of the European Dialysis and Transplant Association. Edited
and laboratory study. II. Cryoglobulins with rheumatoid factor by Davison PJ, Guillou PJ. London: Pitman; 1985:527–547.
activity. Am J Med 1966, 40:837–856. 14. D’Amico G, Colasanti G, Ferrario F, Sinico RA: Renal involvement in
3. Gorevic PD, Kassab HJ, Levo Y, et al.: Mixed cryoglobulinemia: essential mixed cryoglobulinemia. Kidney Int 1989, 35:1004–1014.
clinical aspects and long-term follow-up of 40 patients. Am J Med 15. Castiglione A, Bucci A, Fellin G, et al.: The relationship of infiltrating
1980, 69:287–308. renal leukocytes to disease activity in lupus and cryoglobulinemic
4. D’Amico G: Cryoglobulinemic glomerulonephritis: a membranoprolif- glomerulonephritis. Nephron 1988, 50:14–23.
erative glomerulo-nephritis induced by hepatitis C virus. Am J Kidney 16. Cordonnier D, Martin H, Groslambert P, et al.: Mixed IgG-IgM cryo-
Dis 1995, 25:361–369. globulinemia with glomerulonephritis. Immunochemical fluorescent
5. Ferri C, Greco F, Longobardo G: Antibodies to hepatitis C virus in patients and ultrastructural study of kidney and in vitro cryoprecipitate. Am J
with mixed cryoglobulinemia. Arthritis Rheum 1991, 34:1606–1610. Med 1975, 59:867–872.
6. Galli M, Monti G, Munteverde A: Hepatitis C virus and mixed cryo- 17. Mazzucco G, Monga G, Casanova S, Cagnoli L: Cell interposition in
globulinemias. Lancet 1992, 1:989. glomerular capillary walls in cryoglobulinemic glomerulonephritis:
ultrastructural investigation of 23 cases. Ultrastruct Pathol 1986,
7. Pechère-Bertschi A, Perrin L, De Sassure P, et al.: Hepatitis C: a 10:355–361.
possible etiology for cryoglobulinemia type II. Clin Exp Immunol
1992, 89:419–422. 18. D’Amico G, Colasanti G, Ferrario F et al.: L’atteinte rénale dans la
cryoglobulinémie mixte essentielle: un type particulier de néphropathie
8. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection à médiation immunologique. In Actualités Néphrologiques. Edited by
in type II cryoglobulinemia. N Engl J Med 1992, 327:1490–1495. Flammarion Médecine Sciences; 1987:201–219.
9. Misiani R, Bellavita P, Fenili D: Hepatitis C virus and cryoglobuline- 19. Tarantino A, Campise M, Banfi G, et al.: Long-term predictors of sur-
mia [letter]. N Engl J Med 1993, 328:1121. vival in essential mixed cryoglobulinemic glomerulonephritis. Kidney
10. Pasquariello A, Ferri C, Moriconi L, et al.: Cryoglobulinemic Int 1995, 47:618–623.
membranoproliferative glomerulonephritis associated with hepatis C 20. D’Amico G, Fornasieri A: Cryoglobulinemia. In Current Therapy in
virus [letter]. Am J Nephrol 1993, 13:300–304. Nephrology and Hypertension: A Companion to Brenner and Rector’s
11. Cacoub P, Lunel Fabiani F, Musset L, et al.: Mixed cryoglobulinemia the Kidney. Edited by Brady HR, Wilcox CS. Philadelphia: WB
and hepatitis C virus. Am J Med 1994, 96:124–132. Saunders Company; 1998 (in press).
12. Bichard P, Ounanian A, Girard M, et al.: High prevalence of hepatitis C virus 21. D’Amico G: Is type II mixed cryoglobulinaemia an essential part of
RNA in the supernatant and the cryoprecipitate of patients with essential and hepatitis C virus (HCV)-associated glomerulonephritis? Nephrol Dial
secondary type II mixed cryoglobulinemia. J Hepatol 1994, 21:58–63. Transplant 1995, 1279–1282.
Kidney Disease and
Hypertension in Pregnancy
Phyllis August
K
idney disease and hypertensive disorders in pregnancy are dis-
cussed. 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 manifes-
tations of preeclampsia; however, the cause of this disease remains
unknown. The diagnostic categories of hypertension in pregnancy,
pathophysiology of preeclampsia, and important principles of preven-
tion and treatment also are reviewed.
CHAPTER
10
Anatomic Changes in the Kidney During Pregnancy

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
Increased kidney size 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 demon-
strate the iliac sign in which ureteral dilation terminates at the level of
the pelvic brim where the ureter crosses the iliac artery. Ureteral dila-
Increased renal blood flow
tion and urinary stasis contribute to the increased incidence of asymp-
Increased glomerular filtration rate tomatic bacteriuria and pyelonephritis in pregnancy.
Dilation of urinary tract
Changes in Renal Function During Pregnancy

FIGURE 10-2
↓ Uric acid reabsorption Changes in renal function during pregnancy. Marked renal hemo-
dynamic changes are apparent by the end of the first trimester.
Both the glomerular filtration rate (GFR) and effective renal plas-
↑ Renin ma 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 ani-
mals 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
Renal vasodilation ↑ Aldosterone
women than in those who are not pregnant (0.5 mg/d and 9
↑ Glomerular filtration rate ↑ Sodium reabsorption
mg/dL, respectively). The increased filtered load also results in
↑ Renal blood flow ↑ Water reabsorption
↑ Urinary calcium
increased urinary protein excretion, glucosuria, and aminoaciduria.
↓ Serum creatinine
↑ Glucosuria The uric acid clearance rates increase to a greater extent than does
↑ Urinary protein
↑ Aminoaciduria 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 stimu-
lated 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].
Kidney Disease and Hypertension in Pregnancy 10.3
Serum Electrolytes in Pregnancy

FIGURE 10-3
A Altered osmoregulation: B Serum chloride levels are Serum electrolytes in pregnancy. A, During normal gestation, serum
↓ Serum sodium and ↓ Posm unchanged compared with
osmolality decreases by 10 mosm/L and serum sodium (Na+) decreases
with ↓ Osmotic Threshold women who are not pregnant
by 5 mEq/L. A resetting of the osmoreceptor system occurs, with
for the argenine vasopressin
release and thirst 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
Na+ Cl-
136 mEq/L 104 mEq/L either normal or, on average, 0.3 mEq/L lower than are values in
women who are not pregnant [4]. The ability to conserve potassi-
3.7 mEq/L 20 mEq/L
um may be a result of the elevated progesterone in pregnancy [5].
K+ HCO3
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
C Mild hypokalemia may be D Mild respiratory alkalosis is decrease by about 4 mEq/L [6].
observed due to ↑ glomerular associated with small decreases
filtration rate, ↑ urine flow, in plasma bicarbonate
and ↑ aldosterone
Blood Pressure and the Renin-Aldosterone

System in Pregnancy
PRA
120 Postpartum angiotensinogen values
14
110
12 *
Blood pressure, mmHg
PRA, ng/mL/h
100 10
90 Sitting 8
Standing
80 6
*
70 4 **
**
*
60 2 * *
(N) (7) (16) (18) (18) (18) (19) (18) (18)(15) (19)
50 0
4 8 12 16 20 24 28 32 36 40 PP 4 8 12 16 20 24 28 32 36 38 PP
A Gestation, wk B Gestation, wk
FIGURE 10-4
Blood pressure and the renin-aldosterone system in pregnancy. pregnancy and often approaches prepregnancy levels at term.
Normal pregnancy is associated with profound alterations in B, Despite the decrease in blood pressure, plasma renin activity
cardiovascular and renal physiology. These alterations are (PRA) increases during the first few weeks of pregnancy; on
accompanied by striking adjustments of the renin-angiotensin- average, close to a fourfold increase in PRA occurs by the end of
aldosterone system. A, Blood pressure and peripheral vascular the first trimester, with additional increases until at least 20
resistance decrease during normal gestation. The decrease in weeks. The source of the increased renin is thought to be the
blood pressure is apparent by the end of the first trimester of maternal renal release of renin.
Urine aldosterone Urine sodium

Plasma aldosterone 200 Urine potassium
120
150
24-hr Na+ and K+, mEq

100 100
Plasma aldosterone, ng/100mL

Urine aldosterone, µg/d
100
80 80
60 60
50
40 40
0
20 20
8 12 16 20 24 28 32 36 38 PP
C 0 0 D Gestation, wk

C, Changes in renin are associated with commensurate changes in increases in late gestation to a greater degree than does plasma
the secretory rate of aldosterone. Although a correlation exists aldosterone, which may reflect an increased production of the
between the increase in renin and that of aldosterone, the latter 3-oxo conjugate measured in urine. D, Despite the marked increas-
increases to a greater degree in late pregnancy. This observation es in aldosterone during pregnancy, 24-hour urinary sodium and
suggests that other factors may regulate secretion to a greater degree potassium excretion remain in the normal range. PP— postpartum.
than does angiotensin II in late gestation. Urinary aldosterone (From Wilson and coworkers [7]; with permission.)
Functional Significance of the Stimulated

Renin-Angiotensin System in Pregnancy
Pregnant (n = 9) FIGURE 10-5
Nonpregnant (n = 8) Functional significance of the stimulated renin-angiotensin system
85 25 (RAS) in pregnancy. We determine whether changes in the RAS in
pregnancy are primary, and the cause of the increase in plasma vol-
80 20 ume, or whether these changes are secondary to the vasodilation
and changes in blood pressure. To do so, we administered a single
PRA, mg/mL/h
MAP, mm Hg
*
75 15 P < .05 dose of captopril to normotensive pregnant women in their first
and second trimesters and age-matched normotensive women who
70 10 were not pregnant. We then measured mean arterial pressure (MAP)
P < 0.005 and plasma renin activity (PRA) before and 60 minutes after the dose.
65 5
* A, Despite similar baseline blood pressures, blood pressure decreased
60 0 more in pregnant women compared with those who were not preg-
T=0 T = 60 T=0 T = 60 nant in response to captopril. This observation suggests that the
A B RAS plays a greater role in supporting blood pressure in pregnan-
cy. 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. T—time. (From August and coworkers [8]; with permission.)
Pregnancy and the Course of Renal Disease
FIGURE 10-6
INTERRELATIONSHIPS BETWEEN Pregnancy may influence the course of renal disease. Some women
PREGNANCY AND RENAL DISEASE 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
Impact of pregnancy on renal disease Impact of renal disease on pregnancy deteriorates, the ability to sustain a healthy pregnancy decreases. The
Hemodynamic changes → hyperfiltration Increased risk of preeclampsia
presence of hypertension greatly increases the likelihood of renal
deterioration [2]. Although hyperfiltration (increased glomerular
Increased proteinuria Increased incidence of prematurity,
intrauterine growth retardation filtration rate) is a feature of normal pregnancy, increased intra-
Intercurrent pregnancy-related illness,
eg, preeclampsia glomerular pressure is not a major concern because the filtration
Possibility of permanent loss
fraction decreases. Possible factors related to the pregnancy-related
of renal function 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

FIGURE 10-7
RENAL DISEASE CAUSED Diabetes mellitus is a common disorder in pregnant women. Patients with overt nephropathy
BY SYSTEMIC ILLNESS 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.)
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%
Pregnancy and Systemic Lupus Erythematosus

FIGURE 10-8
RENAL DISEASE ASSOCIATED WITH SYSTEMIC ILLNESS Patients with systemic lupus erythematosus
(SLE) often are women in their childbearing
years. Pregnancies in women with evidence
Pregnancy and SLE* Antiphospholipid antibody syndrome in pregnancy of nephritis are potentially hazardous, partic-
ularly if active disease is present at the time
Poor outcome is associated with the following: Increased fetal loss of conception or if the disease first develops
Active disease at conception Arterial and venous thromboses during pregnancy. When hypertension and
Disease first appearing during pregnancy Renal vasculitis, thrombotic microangiopathy azotemia are present at the time of concep-
Hypertension, azotemia in the first trimester Preeclampsia tion the risk of complications increases, as it
High titers of antiphospholipid antibodies or Treatment: heparin and aspirin? does with other nephropathies [10–14]. The
lupus anticoagulant presence of high titers of antiphospholipid
antibodies also is associated with poor preg-
*Systemic lupus erythematosus (SLE) is unpredictable during pregnancy. nancy outcome [15]. The presence of anti-
phospholipid antibodies or the lupus anti-
coagulant is associated with increased fetal
loss, particularly in the second trimester;
increased risk of arterial and venous throm-
bosis; manifestations of vasculitis such as
thrombotic microangiopathy; and an
increased risk of preeclampsia. Treatment
consists of anticoagulation with heparin
and aspirin.
Lupus Versus Preeclampsia

FIGURE 10-9
LUPUS FLARE-UP VERSUS PREECLAMPSIA 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,
SLE PE whereas the appropriate treatment of preeclampsia is delivery. Thus,
it is important to accurately distinguish these entities. Preeclampsia
Proteinuria + + is rare before 24 weeks’ gestation. Erythrocyte casts and hypocom-
Hypertension + + plementemia are more likely to be a manifestation of lupus, whereas
Erythrocyte casts + - abnormal liver function test results are seen in preeclampsia and not
Azotemia + + usually in lupus.
Low C3, C4 + -
Abnormal liver function test results - +/-
Low platelet count + +/-
Low leukocyte count + -
C—complement; minus sign—absent; plus sign—present; PE—preeclampsia;

SLE—systemic lupus erythematosus.
Chronic Primary Renal Disease in Pregnancy

FIGURE 10-10
CAUSES OF CHRONIC PRIMARY Primary renal disease in pregnancy that is chronic (ie, preceded pregnancy) may result
RENAL DISEASE IN PREGNANCY 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
FIGURE 10-11
POLYCYSTIC KIDNEY DISEASE Although advanced renal disease caused by polycystic kidney disease (PKD) usually devel-
AND PREGNANCY ops 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
Increased incidence of urinary tract infection more severe in women with PKD. The presence of maternal hypertension has been shown
Maternal hypertension associated with poor outcome to be associated with adverse pregnancy outcomes [16]. Pregnancy has been reported to be
Extrarenal complications: subarachnoid hemorrhage,
associated with increased size and number of liver cysts owing to estrogen stimulation.
liver cysts Women with intracranial aneurysms may be at increased risk of subarachnoid hemorrhage
during labor.
Management of Chronic Renal Disease During Pregnancy

FIGURE 10-12
MANAGEMENT OF CHRONIC RENAL Management of chronic renal disease during pregnancy is best
DISEASE DURING PREGNANCY accomplished with a multidisciplinary team of specialists.
Preconception counseling permits the explanation of risks involved
with pregnancy. Patients should understand the need for frequent
Preconception counseling monitoring of blood pressure and renal function. Protein restriction
Multidisciplinary approach is not advisable during gestation. Salt intake should not be severely
Frequent monitoring of blood pressure (every 1–2 wk) and renal function (every mo)
restricted. When renal function is impaired, modest salt restriction
may help control blood pressure. Blood pressure should be main-
Balanced diet (moderate sodium, protein)
tained at a level at which the risk of maternal complications owing
Maintain blood pressure at 120–140/80–90 mm Hg
to elevated blood pressure is low. Patients should be monitored
Monitor for signs of preeclampsia
closely for signs of preeclampsia, particularly in the third trimester.
Renal Disease During Pregnancy

FIGURE 10-13
MOST COMMON CAUSES OF DE NOVO Renal disease may develop de novo during pregnancy. The usual
RENAL DISEASE IN PREGNANCY 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
Glomerulonephritis Interstitial nephritis increased in size during pregnancy.
Lupus nephritis Obstructive uropathy
Acute renal failure
Investigation of the Cause of Renal Disease During Pregnancy

FIGURE 10-14
RENAL EVALUATION Investigation of the cause of renal disease during pregnancy can be conducted with serolog-
DURING PREGNANCY ic, functional, and ultrasonographic testing. Renal biopsy is rarely performed during gesta-
tion. Renal biopsy usually is reserved for situations in which renal function suddenly deteri-
orates without apparent cause or when symptomatic nephrotic syndrome occurs, particular-
Serology ly when azotemia is present. Almost no role exists for renal biopsy after gestational week
Function 32 because at this stage the fetus will likely be delivered, independent of biopsy results [17].
Ultrasonography
Biopsy: <32 wk
Deteriorating function
Morbid nephrotic syndrome
New-Onset Azotemia, Proteinuria, and Hypertension

Occurring in the Second Half of Pregnancy
FIGURE 10-15
INTRINSIC RENAL DISEASE VERSUS PREECLAMPSIA New-onset azotemia, proteinuria, and hypertension occurring in
the second half of pregnancy should be distinguished from pre-
eclampsia. Most cases of preeclampsia are associated with only
Renal disease Preeclampsia mild azotemia; significant azotemia is more suggestive of renal dis-
ease. Azotemia in the absence of proteinuria or hypertension would
Serum creatinine >1.0 mg/dL 0.8–1.2 mg/dL be unusual in preeclampsia, and thus, would be more suggestive of
Urinary protein Variable >300 mg/d intrinsic renal disease. Thrombocytopenia, elevated liver function
Uric acid Variable >5.5 mg/dL test results, and significant anemia are not typical features of renal
Blood pressure Variable >140/90 mm Hg disease (except for thrombotic microangiopathic syndromes) and
Liver function test results Normal May be increased are features of the variant of preeclampsia known as the hemolysis,
Platelet count Normal May be decreased elevated liver enzymes, and low platelet count (HELLP) syndrome.
Urine analysis Variable Protein, with or without
erythrocytes, leukocytes
Acute Tubular Necrosis and Pregnancy

FIGURE 10-16
ACUTE RENAL FAILURE Most pregnant women with acute renal failure have acute tubular necrosis secondary to
IN PREGNANCY 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 tubular necrosis; hemodynamic factors, toxins, acute fatty liver of pregnancy, a disorder that occurs late in gestation characterized by
serious infection, and so on jaundice and severe hepatic dysfunction. This syndrome has features that overlap with the
Acute interstitial nephritis hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome variant of
Acute fatty liver of pregnancy preeclampsia as well as microangiopathic syndromes (eg, hemolytic uremic syndrome and
Preeclampsia-HELLP syndrome thrombotic thrombocytopenic purpura).
Microangiopathic syndromes
Acute cortical necrosis: obstetric hemorrhage
HELLP—hemolysis, elevated liver enzymes, and low

platelet count.
HELLP Syndrome, AFLP, TTP, and HUS

FIGURE 10-17
DIFFERENTIAL DIAGNOSIS OF MICROANGIOPATHIC Hemolysis, elevated liver enzymes, and low
SYNDROMES DURING PREGNANCY platelet count (HELLP) syndrome; acute
fatty liver of pregnancy (AFLP); thrombotic
thrombocytopenic purpura (TTP); and
HELLP AFLP TTP HUS hemolytic uremic syndrome (HUS) have sim-
ilar clinical and laboratory features [18,19].
Hypertension 80% 25–50% Occasional Present The subtle differences are summarized.
Renal insufficiency Mild to moderate Moderate Mild to moderate Severe (Adapted from Saltiel and coworkers [18].)
Fever, neurologic 0 0 ++ 0
symptoms
Onset 3rd trimester 3rd trimester Any time Postpartum
Platelet count Low to very low Low to very low Low to very low Low to very low
Liver function test High to very high High to extremely Usually normal Usually normal
results high
Partial thromboplastin Normal to high High Normal Normal
time
Antithrombin III Low Low Normal Normal
AFLP—acute fatty liver of pregnancy; HELLP—hemolysis, elevated liver enzymes, and low platelet count;
HUS–hemolytic uremic syndrome; TTP—thrombotic thrombocytopenic purpura.
Adapted from Saltiel et al. [18].
Fertility in Women in End-Stage Renal Disease

FIGURE 10-18
DIALYSIS AND PREGNANCY 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 suc-
cessful, with the chances of success increasing when residual renal function exists [20]. The
Successful outcome, 20–30% overall strategy should be to maintain blood chemistry levels as close as possible to normal
High incidence of prematurity by increasing the number of hours of dialysis to 20 or more. Erythropoietin may be used
Outcome related to residual maternal renal function
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 peri-
Management:
toneal dialysis compared with hemodialysis. The incidence of worsening maternal hyper-
Increased hours on dialysis
tension and subsequent premature delivery is high.
Erythropoietin therapy
Blood pressure control
Therapy with low doses of heparin
Continuous ambulatory peritoneal dialysis versus
hemodialysis ?
Fertility and Renal Transplantation

FIGURE 10-19
RENAL TRANSPLANTATION AND PREGNANCY 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 trans-
Prognosis depends on blood pressure and baseline renal function plantation before pregnancy so that renal function is stable and
(<1.5–2 mg/dL; normal blood pressure) doses of immunosuppressants are lowest [21]. Cyclosporine, pred-
Controversy over whether pregnancy accelerates graft loss nisone, and azathioprine are safe during pregnancy and are not
Patients are advised to wait 2 y after transplantation before pregnancy associated with fetal abnormalities. Limited experience exists with
mycophenolate mofetil during pregnancy.
Hypertensive Disorders in Pregnancy

FIGURE 10-20
Developing nations Developed nations Mortality and hypertension. Worldwide, hypertensive disorders are a
Sepsis major cause of maternal mortality, accounting for almost 20% of mater-
8% nal deaths. Most deaths occur in women with eclampsia and severe
Hemorrhage
20% hypertension (HTN) and are due to intracerebral hemorrhage [22].
Embolism
Sepsis 20%
Other
40% 25%
HTN Abortion
15% 17%
Other HTN
25% 17%
Hemorrhage
13%
100–800/100,000 12/100,000
(deaths, births) (deaths, births)
FETAL CONSEQUENCES OF CLASSIFICATION OF CLINICAL FEATURES

MATERNAL HYPERTENSION HYPERTENSIVE DISORDERS OF PREECLAMPSIA
DURING PREGNANCY IN PREGNANCY
Historical:
3- to 6-fold increase in stillbirths Preeclampsia, eclampsia Nulliparity
5- to 15-fold increase in intrauterine growth restriction Chronic hypertension Multiple gestations
Family history
Premature delivery Chronic hypertension with superimposed preeclampsia
Preexisting renal or vascular decrease
Long-term developmental and neurologic problems Transient hypertension
Hypertension:
140/90 mm Hg after 20 wk or
30 mm Hg increase in systolic pressure or
15 mm Hg increase in diastolic pressure
FIGURE 10-21 FIGURE 10-22 Sudden appearance of edema,
Hypertensive disorders in pregnancy are Several classification systems exist for hyper- especially in hands and face
associated with increased incidences of still- tensive disorders of pregnancy. The one used Rapid weight gain
birth, fetal growth restriction, premature most commonly in the United States is that Headache, visual disturbances,
delivery, and long-term developmental prob- proposed in 1972 by the American College abdominal or chest pain
lems secondary to prematurity. These com- of Obstetricians and Gynecologists and
plications are more frequent when hyperten- endorsed by the National High Blood
sion is due to preeclampsia. Pressure Education Program. The distinction
is made between the pregnancy-specific FIGURE 10-23
hypertensive disorder (preeclampsia, and the The diagnosis of preeclampsia is strength-
convulsive form, eclampsia) and chronic ened when one or more of the risk factors
hypertension that precedes pregnancy, which are present. Hypertension develops after 20
usually is due to essential hypertension. weeks, with normal blood pressures in the
Women with chronic hypertension are at first half of pregnancy. Although edema is a
greater risk for preeclampsia (20–25%). feature of many normal pregnancies, its
Transient hypertension refers to late preg- sudden appearance in the face and hands in
nancy elevations in blood pressure, without association with a rapid weight gain, is sug-
any of the laboratory or clinical features of gestive of preeclampsia. Headache, visual
preeclampsia. This disorder may recur with disturbances, and abdominal or chest pain
each pregnancy (in contrast to preeclampsia, are signs of impending eclampsia.
which usually is a disease of first pregnancy)
and usually indicates a genetic predisposition
to essential hypertension.
FIGURE 10-24
CLINICAL FEATURES OF CHRONIC Women with chronic hypertension are usually older and may be
HYPERTENSION IN PREGNANCY 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
Women are older, more likely to be multiparous stage 1 or 2 hypertension may have normal blood pressures by
Hypertension: present before 20 wk, or documented previous pregnancy the time of their first antepartum visit. The risk of preeclampsia
Blood pressure may be significantly lower or normal in mid pregnancy
is substantially increased in women with chronic hypertension.
Risk of superimposed preeclampsia of 15–30%
FIGURE 10-25
LABORATORY ABNORMALITIES IN PREECLAMPSIA Laboratory tests are helpful in making the diagnosis of preeclampsia.
AND CHRONIC HYPERTENSION In addition to proteinuria, which may occur late in the course of the
disease, hyperuricemia, mild azotemia, hemoconcentration, and hypo-
calciuria are observed commonly. Some women with preeclampsia
Chronic hypertension Preeclampsia may develop a microangiopathic syndrome with hemolysis, elevated
liver enzymes, and low platelet counts (HELLP). The presence of the
Renal: HELLP syndrome usually reflects severe disease and is considered an
Creatinine Normal Increased; increased indication for delivery. Women with uncomplicated chronic hyperten-
blood urea nitrogen, sion have normal laboratory test results unless superimposed
creatinine
preeclampsia or underlying renal disease exists.
Uric acid Normal Increased (>5.5 mg/dL)
Urinary protein <300 mg/d >300 mg/d
Urinary calcium >200 mg/d <150 mg/d
Heme:
Hematocrit Normal Increased (>38%)
Platelets Normal Decreased
Liver function tests:
Aspartate aminotransferase Normal Increased
Alanine aminotransferase Normal Increased
Albumin Normal Decreased
FIGURE 10-26
Pathophysiology of preeclampsia Preeclampsia is a syndrome with both maternal and fetal manifes-
tations. Current evidence suggests that an underlying genetic pre-
disposition leads to abnormalities in placental adaptation to the
maternal spiral arteries that supply blood to the developing feto-
Fetal placental unit. These abnormalities in the maternal spiral arteries
syndrome
(IUGR, IUD, prematurity) lead to inadequate perfusion of the placenta and may be the earli-
est changes responsible for the maternal disease. The maternal dis-
ease is characterized by widespread vascular endothelial cell dys-
function, resulting in vasospasm and intravascular coagulation and,
ultimately, in hypertension (HTN), renal, hepatic, and central ner-
Maternal vous system (CNS) abnormalities. The fetal syndrome is a conse-
syndrome quence of inadequate placental circulation and is characterized by
(HTN, renal, CNS)
growth restriction and, rarely, demise. Premature delivery may
occur in an attempt to ameliorate the maternal condition. IUD—
intrauterine death; IUGR—intrauterine growth retardation.
Placental disease Maternal disease

Abdominal implantation Vasoplasm
Placental vascular lesions Intravascular coagulation
Endothelial dysfunction
Genetic susceptibility
(maternal x fetal)
FIGURE 10-27
GENETICS OF PREECLAMPSIA A positive family history is a risk factor for preeclampsia, and the incidence is approxi-
mately 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
Increased incidence observed in mothers, daughters, 10 instances in which the disease occurred in one but not the other monozygotic twin.
granddaughters of probands These data raise the possibility of paternal or fetal genetic influence [24]. The mode of
Mode of inheritance unknown: inheritance of preeclampsia is not known. Several possibilities have been suggested, includ-
Single recessive gene ? ing a recessive gene with the possibility of a maternal-fetal genotype-by-genotype interac-
Shared maternal-fetal recessive gene ? tion or a dominant maternal gene with incomplete penetrance.
Dominant gene with incomplete penetrance ?
Normal pregnancy Preeclampsia Fetus Mother

A B (placenta) (uterus)
Cell column of
Spiral arteries anchoring villus
Myometrium Cytotrophoblast
stem cells
Decidua
AV Fetal Uterine
Basement stroma blood
membrane vessels
Syncytiotrophoblast
Maternal
blood
FV space
Invasion
Zone I Zone II and III Zone IV Zone V

A
Umbilical artery
Villus
Intervillus space Umbilical vein FIGURE 10-29
(containing fetal
arteriole and venule) (maternal blood) Transformation of the spiral arteries. A, The process by which the
maternal spiral arteries are transformed into dilated vessels in preg-
nancy is believed to involve invasion of the spiral arterial walls by
FIGURE 10-28 endovascular trophoblastic cells. These cells migrate in retrograde
Uteroplacental circulation in normal pregnancy and preeclampsia. fashion, involving first the decidual and then the myometrial seg-
A, Normal placentation involves the transformation of the branches ments of the arteries and then causing considerable disruption at
of the maternal uterine arteries—the spiral arteries—from thick- all layers of the vessel wall. The mechanisms involved in this com-
walled muscular arteries into saclike flaccid vessels that permit plex process are only beginning to be elucidated. These mecha-
delivery of greater volumes of blood to the uteroplacental unit. nisms involve alterations in the adhesion molecules of the invading
B, Evidence exits that in women with preeclampsia this process is trophoblast cells, such that they acquire an invasive phenotype and
incomplete, resulting in relatively narrowed spiral arteries and mimic vascular endothelial cells [26].
decreased perfusion of the placenta [25].

(b) B, In women destined to develop preeclampsia, trophoblastic inva-
sion of the spiral arteries is incomplete; it may occur in the decid-
(a) CTBs ual but not the myometrial segments of the artery, and in some ves-
Endothelium sels the process does not occur at all. The arteries, therefore,
(c) remain thick-walled and muscular, the diameters in the myometrial
Tunica
media 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 neces-
sary for normal remodeling of the maternal spiral arteries [27].
This failure of cytotrophoblast invasion of the spiral arteries is con-
sidered to be the morphologic basis for decreased placental perfu-
Fully modified Partially modified Unmodified sion in preeclampsia. (a)—fully modified regions. (b)—partially
region region region modified vessel segments. (c)—unmodified vessel segments in the
myometrium. AV–anchoring villus; CTBs—cytotrophoblast cells;
Decidua Myometrium
B FV—floating villi. (From Zhou and coworkers [27]; with permission.)
FIGURE 10-30
Placental
ischemia Pathophysiology of preeclampsia. A major unresolved issue in the
Lipid peroxides
Cytokines pathophysiology of preeclampsia is the mechanism whereby abnor-
malities in placental modulation of the maternal circulation lead to
maternal systemic disease. The current schema, which is a hypothe-
Endothelial cell damage Platelet aggregation sis, 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
Thromboxane A2 ↑ systemic vasospasm, intravascular coagulation and decreased organ
Serotonin, PDGF ↑
flow that are characteristic of preeclampsia. NO—nitric oxide;
PGI2 ↓ Systemic PDGF—platelet-derived growth factor; PGI2—prostacyclin 2.
NO ↓ vasoplasm
Thrombin ↑
Endothelin ↑
Mitogenic factors↑
(eg, PDGF) ↓ Organ flow
Intravascular
coagulation
Central nervous sytem
Visual disturbances
Seizures
Hyperemia, focal anemia Cardiac
Thrombosis, hemorrhage
↓ Cardiac output
↓ Plasma volume
↑ Atrial natriuretic factor
Pulmonary edema
Hepatic
Vasospasm
Reduced flow
Periportal hemorrhagic necrosis Intravascular coagulation
Subcapsular hematoma
↑ Aspartate aminotransferase Vascular
↑ Alanine aminotransferase
↑ Systemic vascular resistance
↑ Blood pressure
↑ Angiotensin II sensitivity
Renal Endotheliosis
Proteinuria
↓ Glomerular filtration rate
↓ 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.
of vasoconstrictors
The endothelium such as endothelin (ET).
and platelet-vessel Compensatory suppres-
wall interaction
↓ Placental hormones Platelets sion of the renin-
+
Endothelial Thr angiotensin system
(eg, estrogen, progesterone) +
cells PThr occurs, suggesting that
cGMP excess angiotensin II
− TXA2 (AII) does not play a
↑ Circulating endothelial toxins
5-HT 5-HT Compensatory major role in preeclamptic
AII
responses: hypertension (HT).
A ↓ Plasma renin Finally, sodium retention
S
NO/PGl2 1 ↓ Aldosterone
Endothelin owing to renal vasocon-
Relaxation Contraction
Proliferation
striction may further
↑ Sympathetic nervous system Antiproliferation
S2 increase blood pressure.
cGMP/cAMP TX ET cAMP—cyclic adenosine
Vascular smooth
muscle cells monophosphate; cGMP—
cyclic guanosine
monophosphate; 5-HT—
serotonin; PThr—
parathyroid hormone;
FIGURE 10-32
S2—serotonergic receptors;
Hypertension in preeclampsia. Although the mechanism of the increased blood pressure in preeclampsia is Thr—thombin TX—
not established, evidence suggests it may involve multiple processes. A possible scenario involves the following: thromboxane; TXA2—
decreased placental production of estrogen and progesterone, both of which have hemodynamic effects; thromboxane A2.
increased circulating endothelial toxins, possibly released from a poorly perfused placenta; and increased (Adapted from Lüscher
activity of the sympathetic nervous system. These processes may then result in alterations in platelet– vascular and Dubey [28];
endothelial cell function, with decrease in vasodilators such as nitric oxide and prostacyclin and increased production with permission.)
↓ Renin
↑ Proteinuria ↓ Urinary calcium

Hypocalciuria
↓ Renal vasodilation
↓ Glomerular filtration rate ↓ Urate excretion
↓ Renal blood flow

Light microscopy of the renal lesion of preeclampsia: glomerular Functional renal alterations in preeclampsia. The functional conse-
endotheliosis. On light microscopy, the glomeruli from preeclamp- quences of glomerular endotheliosis and of the hormonal alter-
tic women are characterized by swelling of the endothelial and ations in preeclampsia are summarized in this schematic diagram
mesangial cells. This swelling results in obliteration of the capillary of the nephron in preeclampsia. Suppression of the renin-
lumina, giving the appearance of a bloodless glomerulus. On occa- angiotensin system occurs, probably in response to vasoconstric-
sion, the mesangium, severely affected, may expand. Thrombosis tion and elevated blood pressure. The glomerular lesion leads to
and fibrinlike material and foam cells may be present, and epithe- proteinuria, which may be heavy. Renal hemodynamic changes
lial crescents have been described in rare instances [2]. include modest decreases in the glomerular filtration rate (GFR)
and renal blood flow (RBF). Decreased sodium and uric acid excre-
tion may be caused by increased proximal tubular reabsorption.
The mechanism for the marked hypocalciuria is not known.
FIGURE 10-35
Trial Number of trials Antiplatelet Control Odds ratio and 95% Cl (horizontal line) Prevention of preeclampsia with low-dose
therapy therapy (antiplatelet: placebo)
aspirin. Investigators have sought methods
to prevent preeclampsia (eg, salt restriction,
prophylactic diuretics, and high-protein
Smaller studies 11 10/319 50/284
(<200 women) (3.1%) (17.6%) diets). One approach that has been exten-
sively investigated in the last 10 years is
Larger studies: therapy with low-dose aspirin. It was
EPHREDA (1990) 5/156 8/74 hypothesized that such therapy reversed the
Hauth (1993) 5/303 17/303
Italian (1993) 12/565 9/477
imbalance between prostacyclin and throm-
Sibai (1993) 69/1570 94/1565 boxane that may be responsible for some of
Viinikka (1993) 9/103) 11/105) the manifestations of the disease. Several
CLASP (1994) 313/4659 352/4650 large trials now have been completed, and
All larger trials 6 413/7356 491/7174
Odds ratio most have had negative results. Shown here
Overall results
is an overview of the effects of aspirin on
25% SD 6 proteinuric preeclampsia reported from all
All trials 17 423/7675 541/7458 odds reduction
(5.5%) (7.3%) (2p = 0.00002) trials of antiplatelet therapy (through 1994)
as analyzed by the Collaborative Low-dose
0 0.5 1.0 1.5 Aspirin in Pregnancy (CLASP) Collaborative
Antiplatelet Antiplatelet
Group [28]. Odds ratios (area proportional
therapy therapy to amount of information contributed) and
better worse 99% confidence interval (CI) are plotted for
various trials. A black square to the left of
the solid vertical line suggests a benefit (how-
ever, this indication is significant at 2p >0.01
only if the entire CI is to the left of solid ver-
tical line). (From CLASP Collaborative
Group [29]; with permission.)
FIGURE 10-36
Prevention of preeclampsia using calcium
Study
Favors calcium Favors control supplementation. Another preventive strategy
that has been extensively investigated, with
Marya et al.,1987 0.65 (0.31–1.38)
Villar et al.,1987 0.43 (0.06–3.14) conflicting outcomes, is calcium supplemen-
Lopez-Jaramillo et al.,1989 0.03 (0.002–0.49) tation. The rationale for this approach is
Lopez-Jaramillo et al.,1990 0.07 (0.004–1.27) based on the observations that low dietary
Montanaro et al.,1990 0.25 (0.06–1.03) calcium intake may increase the risk for
Villar and Repke,1990 0.13 (0.007–2.65) preeclampsia, and that preeclampsia is charac-
Belizan et al.,1991 0.66 (0.34–1.27) terized by abnormalities in calcium metabolism
Cong et al.,1993 0.19 (0.009–4.10)
that suggest a calcium deficit, eg, decreased
Sanchez-Ramos et al.,1994 0.22 (0.07–0.74)
Pooled estimate 0.38 (0.22–0.65) vitamin D and hypocalciuria [31]. A recent
meta-analysis of 14 trials of calcium supple-
0.001 0.01 0.1 1.0 10.0 mentation in pregnancy concluded that calci-
um supplementation during pregnancy leads
OR to reductions in blood pressure and a lower
incidence of preeclampsia. In contrast, a
large randomized trial of calcium supple-
mentation in 4589 low-risk women failed to
demonstrate a benefit of calcium therapy
[31]. CI—confidence interval; OR—odds
ratio. (From Bucher and coworkers [30];
with permission.)
FIGURE 10-37
TREATMENT OF PREECLAMPSIA Treatment of preeclampsia requires close monitoring of both the maternal and fetal condi-
tion 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.
Close monitoring of maternal and fetal conditions Maternal hypertension should be treated to avoid cerebrovascular and cardiovascular
Hospitalization in most cases complications. Magnesium sulfate is the treatment of choice for seizure prophylaxis and
Lower blood pressure for maternal safety
usually is instituted immediately after delivery. When the fetus is mature, delivery is indi-
cated in all cases. When the fetus is immature, the decision to deliver is made after careful-
Seizure prophylaxis with magnesium sulfate
ly assessing both the maternal and fetal condition. When maternal health is in jeopardy,
Timely delivery
delivery is necessary, even with a premature fetus.
FIGURE 10-38
ANTIHYPERTENSIVE THERAPY Some controversy exists regarding when to institute antihypertensive therapy in women
IN PREECLAMPSIA 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
Decreased uteroplacental blood flow and placental fetal distress. Furthermore, lowering maternal blood pressure does not cure preeclampsia.
ischemia are central to the pathogenesis of Thus, antihypertensive therapy is instituted when the blood pressure reaches a level at
preeclampsia. which the physician considers the maternal condition to be in danger from hypertension.
Lowering blood pressure does not prevent or cure For most physicians, this treatment threshold is at approximately 150/100 mm Hg.
preeclampsia and does not benefit the fetus unless Aggressive lowering of blood pressure is not advisable.
delivery can be safely postponed.
Lowering blood pressure is appropriate for maternal safety:
maintain blood pressure at 130–150/85–100 mm Hg.
FIGURE 10-39
ANTIHYPERTENSIVE THERAPY IN PREECLAMPSIA 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
Imminent delivery Delivery postponed agents for pregnant women, and both have been used successfully
in preeclampsia. Calcium channel blockers should be used with
Hydralazine (intravenous, intramuscular) Methyldopa caution because they may act synergistically with magnesium sul-
Labetalol (intravenous) Labetalol, other blockers fate, resulting in precipitous decreases in blood pressure. Rarely,
Calcium channel blockers Calcium channel blockers agents such as diazoxide may be needed; however, when hyperten-
Diazoxide (intravenous) Hydralazine sion is severe, maternal safety takes priority over pregnancy status.
blockers When delivery can be postponed safely for several days, an oral
Clonidine agent is indicated. Methyldopa is one of the safest drugs in preg-
nancy and has been used extensively with excellent maternal and
fetal outcome. Labetalol and other blockers have been used suc-
cessfully 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 cloni-
dine, although anecdotal reports suggest these agents are safe.
Treatment alogrithm for chronic hypertension

150
Preconception
140
Systolic
Screen for secondary hypertension (pheo, renovascular hypertension)

130 Counseling: Increased risk of preeclampsia (25%)

Lifestyle adjustments: increase rest, decrease exercise
120 Adjust medications: discontinue ACE inhibitors
110
100 First trimester
90 Diastolic BP, mm Hg
Diastolic
<90 90–100 ≥ 100

80
70 Consider careful Adjust medications: Increase medication
decrease in Stop ACE and
60 BP medication angiotensin II β blockers
Decrease diuretic dose
Pre- 10 20 28 32 38
pregnancy Baseline evaluation for secondary hypertension if clinically suspected
Gestation, wk
Second trimester
FIGURE 10-40 Nonpharmacologic treatment
❑ Home BP monitoring
Blood pressure changes during pregnancy in women with chronic ❑ Adequate rest
hypertension. Women with preexisting or chronic hypertension
Diastolic BP, mm Hg
during pregnancy have a favorable prognosis, unless preeclampsia
<90 90–100 ≥ 100
develops. The risk of superimposed preeclampsia is about 25%.
Women with this complication are at greater risk for fetal compli- Consider careful Continue treatment Indicates significant
cations during pregnancy, including premature delivery, growth decrease in hypertension:
BP medication consider stopping work;
restriction, and perinatal mortality. close surveillance
Women with chronic hypertension experience a decrease in blood for preeclampsia
pressure during pregnancy that may permit withdrawal of some or
all antihypertensive medication. In those women with uncomplicat- Third trimester
ed chronic hypertension (solid line), blood pressure decreases in the Increased surveillance for preeclampsia
first trimester, then may decrease even further in the second trimester. Check BP every 2 weeks
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 FIGURE 10-41
(broken lines), blood pressure often decreases in the first trimester.
Treatment algorithm for chronic hypertension. Ideally, patients
There is often a failure to decrease further in the second trimester,
with chronic hypertension should be evaluated before pregnancy so
however, and blood pressures may actually begin to increase slightly.
that secondary hypertension can be diagnosed and treated appro-
Blood pressure then increases significantly when preeclampsia
priately. Women can be counseled regarding the need for possible
develops [33].
life-style adjustments, and medications can be adjusted. Blood pres-
sure (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 diag-
nosed before it progresses to a severe stage.
FIGURE 10-42
ANTIHYPERTENSIVE THERAPY The overall treatment goals of chronic hypertension in pregnancy are to ensure a success-
FOR CHRONIC HYPERTENSION ful full-term delivery of a healthy infant without jeopardizing maternal well-being. The
DURING PREGNANCY 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 ben-
efits to the mother (for the duration of pregnancy) of having a normal blood pressure.
Methyldopa Most antihypertensive agents have been evaluated only sporadically during gestation, and
blockers (labetalol) careful follow-up of children exposed in utero to many of the agents is lacking. The only
Calcium channel blockers
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
Hydralazine
to be one of the safest drugs during pregnancy. blockers and calcium channel blockers
Diuretics
are acceptable second- and third-line agents. Diuretics can be used at low doses, particu-
larly in salt-sensitive hypertensive patients on chronic diuretic therapy. Angiotensin-con-
verting 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.
References
1. Baylis C: Glomerular filtration and volume regulation in gravid animal 19. Sibai BM, Kustermann L, Velasco J: Current understanding of severe
models. Clin Obstet Gynaecol 1987, 1:789. preeclampsia, pregnancy-associated hemolytic uremic syndrome,
2. Lindheimer MD, Katz AI: The kidney and hypertension in pregnancy. thrombotic thrombocytopenic purpura, hemolysis, elevated liver
In The Kidney, edn 4. Edited by Brenner BM, Rector FC. Philadelphia: enzymes, and low platelet syndrome, and postpartum acute renal
WB Saunders Co; 1991:1551–1595. failure: different clinical syndromes or just different names? Curr
Opinion Nephrol Hypertens 1994, 3:436–445.
3. Davison JM, Shiells EA, Philips PR, Lindheimer MD: Serial evaluation
20. Hou S: Peritoneal dialysis and hemodialysis in pregnancy. Clin Obstet
of vasopressin release and thirst in human pregnancy: role of chorionic
Gynaecol (Balliere) 1994, 8:491–510.
gonadotropin in the osmoregulatory changes of gestation. J Clin
Invest 1988, 81:798. 21. Davison JM: Pregnancy in renal allograft recipients: problems, prognosis,
and practicalities. Clinc Obstet Gynaecol (Balliere) 1994, 8:511–535.
4. Lindheimer MD, Richardson DA, Ehrlich EN, Katz AI: Potassium
homeostasis in pregnancy. J Reprod Med 1987, 32:517. 22. Douglas KA, Redman CW: Eclampsia in the United Kingdom. BMJ
1994, 309:1395–1400.
5. Brown MA, Sinosich MJ, Saunders DM, Gallery EDM: Potassium
regulation and progesterone-aldosterone interrelationships in human 23. Chesley LC, Annitto JE, Cosgrove RA: Pregnancy in the sisters and
pregnancy. A prospective study. Am J Obstet Gynecol 1986, 155:349. daughters of eclamptic women. Pathol Microbiol 1961, 24:662.
24. Cooper DW, Brenneckes SP, Wilton AN: Genetics of pre-eclampsia.
6. Lim VS, Katz AI, Lindheimer MD: Acid-base regulation in pregnancy.
Hypertens Preg 1993, 12:1.
Am J Physiol 1976, 231:1764.
25. Khong TY, WF De, Robertson WB, Brosens I: Inadequate maternal
7. Wilson M, Morganti AA, Zervoudakis I, et al.: Blood pressure, the renin-
vascular response to placentation in pregnancies complicated by
aldosterone system and sex steroids throughout normal pregnancy. Am J
preeclampsia and small for gestational age infants. Br J Obstet
Med 1980, 68:97. Gynaecol 1986, 93:1049–1059.
8. August P, Mueller FB, Sealey JE, Edersheim TG: Role of renin- 26. Zhou Y, Fisher SJ, Janatpour M: Human cytotrophoblasts adopt a
angiotensin system in blood pressure regulation in pregnancy. vascular phenotype as they differentiate. A strategy for successful
Lancet 1995, 345:896–897. endovascular invasion? J Clin Invest 1997, 99:2139–2151.
9. Diabetic nephropathy. Pregnancy performance and fetal-maternal 27. Zhou Y, Damsky CH, Fisher SJ: Preeclampsia is associated with failure
outcome. Am J Obstet Gynecol 1988, 159:56. of human cytotrophoblasts to mimic a vascular adhesion phenotype.
10. Hayslett JP, Lynn RI: Effect of pregnancy in patients with lupus One cause of defective endovascular invasion in this syndrome? J Clin
nephropathy. Kidney Int 18:207, 1980. Invest 1997, 99:2152–2164.
11. Houser MT, Fish AJ, Tagatz GE, et al.: Pregnancy and systemic lupus 28. Lüscher TF, Dubey RK: Endothelium and platelet=derived vasoactive
erythematosus. Am J Obstet Gynecol 1980, 138:409. substances: role in the regulation of vascular tone and growth. In
Hypertension: Pathophysiology, Diagnosis and Management, edn 2.
12. Fine LG, Barnett EV, Danovitch GM, et al.: Systemic lupus erythematosus
New York: Raven Press; 1995: 609–630.
in pregnancy. Ann Intern Med 1981, 94:667.
29. CLASP Collaborative Group. CLASP: A randomized trial of low-dose
13. Imbasciati E, Surian M, Bottino S, et al: Lupus nephropathy and
aspirin for the prevention and treatment of preeclampsia among 9364
pregnancy. A study of 26 pregnancies in patients with systemic pregnant women. Lancet 1994, 343:619–629.
lupus erythematosus and nephritis. Nephron 1984, 36:46.
30. Bucher HC, Guyatt GH, Cook RJ, et al.: Effect of calcium supplemen-
14. Jungers P, Dougodos M, Pelissier C, et al.: Lupus nephropathy and tation on pregnancy-induced hypertension and preeclampsia: a meta-
pregnancy. Report of 104 cases in 36 patients. Arch Intern Med 1982, analysis of randomized controlled trials. JAMA 1996,
142:771. 275:1113–1117.
15. Lockshin MD, Druzin MC, Goel S, et al.: Antibody to cardiolipin as a 31. Hojo M, August P: Calcium metabolism in normal and hypertensive
predictor of fetal distress on death in pregnant patients with systemic pregnancy. Semin Nephrol 1995, 15:504–511.
lupus erythematosus. N Engl J Med 1985, 313:152.
32. Levine RJ, Hauth JC, Curet LB, et al.: Trial of calcium to prevent
16. Chapman AB, Johnson AM, Gabow PA: Pregnancy outcome and its preeclampsia. N Engl J Med 1997, 337:69–76.
relationship to progression of renal failure in autosomal dominant 33. August P, Lenz T, Ales KL, et al.: Longitudinal study of the renin
polycystic kidney disease. J Am Soc Nephrol 1994, 5:1178–1185. angiotensin system in hypertensive women: deviations related to the
17: Lindheimer MD, Davison JM. Renal biopsy during pregnancy: development of superimposed preeclampsia. Am J Obstet Gynecol
“To b... or not to b...” Br J Obstet Gynecol 1987, 94:932. 1990, 163:1612–1621.
18. Saltiel C, Legendre, Grunfeld JP, et al.: Hemolytic uremic syndrome in
association with pregnancy. In Hemolytic Uremic Syndrome and
Thrombotic Thrombocytopenic Purpura. Edited by Kaplan BS,
Trompeter RS, Moake JL. New York: Marcel Dekker; 1992:241–254.
Collagen Vascular Diseases
and Dysproteinemias
Jo H.M. Berden
Karel J.M. Assmann
R
enal involvement in systemic lupus erythematosus (SLE), dys-
proteinemias, and certain rheumatic diseases, namely rheuma-
toid arthritis, Sjögren’s 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 charac-
terized 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 recent-
ly by identification of the nucleosome as the major driving autoanti-
gen in SLE and the possible role of disturbances in apoptosis in dis-
ease 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 assess-
ment of kidney biopsies. The therapeutic options for treatment of
lupus nephritis are discussed as are the results of treatment of end-
stage 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 speci-
CHAPTER
men to reveal clues for the diagnosis. On immunofluorescence, the
distribution of the light or heavy chain isotype, or both, can be detect-
11
ed in the tissue deposits, whereas electron microscopy can define the
ultrastructural organization. Incidence and types of renal involve-
ment, the pathogenesis and risk factors for the various types of renal
lesions, the histology of the different renal manifestations, and an
overview of the therapy are given. The renal manifestations of The third part of this chapter presents a concise review of
cryoglobulinemias and fibrillary and immunotactoid glomeru- renal involvement in rheumatoid arthritis, Sjögren’s syndrome,
lonephritis also are discussed. and scleroderma.
Systemic Lupus Erythematosus
CUMULATIVE INCIDENCE OF CLINICAL SYMPTOMS EPIDEMIOLOGIC AND GENETIC CHARACTERISTICS

AND AUTOANTIBODY FORMATION IN SYSTEMIC OF SYSTEMIC LUPUS ERYTHEMATOSUS
LUPUS ERYTHEMATOSUS
Epidemiology Genetics
Percent Prevalence: between 25 and 250 per 100,000 Concordancy in twins
Frequency of major clinical symptoms persons, depending on racial and geographic Monozygotic: 50–60%
Musculoarticular symptoms 60–95 background Dizygotic: 5–10%
Cutaneous manifestations 55–80 Race: more prevalent in Asians and blacks Familial aggregation in 10%
Renal involvement 40–55 Gender: female preponderance; gender ratio Association with the following:
Neuropsychiatric disease 30–60 between 20 and 40 years; male:female, 1:9 HLA: B7, B8, DR2, DR3, DQW1
Pulmonary and cardiac disease 20–40
Age: onset mainly between 20–40 y Complement:
Hematologic abnormalities 60–85 C4A Q0
Occurrence of major autoantibody specificities C1q or C4 deficiency
Antinuclear autoantibody 95 Fc receptor IIA low-affinity
Anti–double-stranded DNA 60–75 phenotype
Antihistone 50–70 X chromosome ?
Antinucleosome Up to 80
Anti-Sm 10–30
Anti-ribonucleoprotein (RNP) 10–30
Anti–Sjögren’s syndrome (SS-A) (Ro) 20–60
Anti-SS-B (La) 15–40 FIGURE 11-2
Anticardiolipin 10–30 The major epidemiologic characteristics of systemic lupus erythe-
Antierythrocyte 50–60 matosus are listed. The prevalence of the disease depends on ethnic
Antilymphocyte 50–70 background. The highest prevalence is seen in Asians and Blacks.
Antithrombocyte 10–30
As in other systemic autoimmune diseases, there is a striking prepon-
derance in women, especially during childbearing age. This prepon-
derance is related to hormonal status. Animal studies have shown
that estrogens have a facilitating effect on disease expression, where-
FIGURE 11-1 as androgens have a suppressive effect. The importance of estrogens
This overview of the major clinical symptoms illustrates the systemic is further substantiated by the fact that changes in the hormonal
character of lupus erythematosus. Depending on patient selection, homeostasis (eg, at onset of puberty, during use of oral anticontra-
renal involvement occurs in up to half of patients. In almost all ceptives, and during pregnancy and puerperium) are associated with
patients, antibodies are formed against nuclear antigens, as detected an increased frequency of lupus onset and disease flare-up. The
by antinuclear antibody (ANA) testing. These ANAs are either directed genetic susceptibility is illustrated by the concordance of the disease
against nucleic acids (DNA), nuclear proteins (histones, Sm, ribonu- in twins, occurrence of familial aggregation, and association with
cleoprotein, Sjögren’s syndrome-A [SS-A], and SS-B) or nucleosomes certain genes, mainly human leukocyte antigens (HLA).
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 autoan-
tibodies 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.
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.3
ANA test
THE 1982 REVISED AMERICAN RHEUMATISM
ASSOCIATION CRITERIA FOR CLASSIFICATION
OF SYSTEMIC LUPUS ERYTHEMATOSUS Negative Positive
No further evaluation
unless strong clinical
suspicion
Criterion Sensitivity, %* Specificity, %*
1. Malar rash 57 96
?
2. Discoid rash 18 99 Western blot test
Negative Crithidia lucillae
3. Photosensitivity 43 96 on nuclear extracts
4. Oral ulcers 27 96 ?
5. Arthritis (two or more joints) 86 37
anti-ENA Positive
6. Serositis: 56 86
Pleuritis or pericarditis Ouchterlony
7. Renal disorder: 51 94 immunodiffusion
Proteinuria > 0.5 g/24 h or cellular casts (red, using ENAs Farr assay
hemoglobin, granular, tubular, or mixed)
8. Neurologic disorder:
Seizures or psychosis 20 98
9. Hematologic disorder:
FIGURE 11-4
Hemolytic anemia or leukopenia (<4 59 89 Algorithm for analysis of antinuclear antibodies (ANA) in systemic
109/L) or lymphopenia (<1.5 109/L) lupus erythematosus. To demonstrate the presence of antinuclear
or thrombopenia (<100 109/L) antibodies the ANA test is used as a screening procedure. Details
10. Immunologic disorder: 85 93 of this ANA test and the different ANA patterns are given in Figure
Positive LE cell test result or positive
anti–double-stranded DNA or positive
11-5. A positive ANA test result indicates the presence of antinuclear
anti-Sm or false-positive TPI/VDRL test antibodies. Although the pattern of ANA can give an indication
11. Antinuclear antibody 99 49 about the specificity of the antinuclear antibody, additional tests
are needed to define this specificity. Antibody specificity to double-
stranded DNA (dsDNA) can be identified by the Crithidia assay
*The sensitivity was calculated as the percentage of patients with SLE who were positive (Fig. 11-6), in which a single-celled organism is used that has pure-
for this criterion over those in whom this criterion was analyzed. The specificity was
ly dsDNA in the kinetoplast. When this test result is positive, the
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. titer of anti-dsDNA antibodies can be determined using the Farr
TPI—treponemal immobilization; VDRL—Venereal Disease Research Laboratory.
assay (Fig. 11-7). When these anti-dsDNA test results are negative,
ANA positivity is most likely caused by antibodies directed against
Data from Tan et al. [1].
nuclear proteins. Autoantibodies can be analyzed by the Western
blot test on nuclear extracts (Fig. 11-8). The advantage of this
FIGURE 11-3 technique over the Ouchterlony technique using extractable nuclear
These criteria were selected for their sensitivity and specificity in antigens (ENA), is that the Western blot test allows identification
classifying patients with systemic lupus erythematosus (SLE). In the of a large number of autoantibody specificities in one test, although
selection process, these criteria were analyzed in 177 patients with both tests do not completely overlap.
SLE and 162 patients in the control group matched for age, gender,
and race. Patients in the control group had a nontraumatic nondegen-
erative 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.
FIGURE 11-5
Patterns of antinuclear antibody (ANA)
staining. The ANA test is carried out by incu-
bation of the serum with either preparations
of cultured cells (eg, human cervical carcino-
ma 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;
A B (Continued on next page)


C, speckled; and D, nucleolar. Although not
conclusive, these patterns can give an indica-
tion about the autoantibody specificity caus-
ing the nuclear staining. The homogeneous
and peripheral patterns mainly are caused
by autoantibodies directed against the nucle-
osome (histone–DNA complex) or double-
stranded DNA. The speckled pattern can
be observed in antibodies against the nuclear
proteins Sm, ribonucleoprotein, Sjögren’s syn-
drome-A [SS-A] (Ro), SS-B (La), Jo-1, topoi-
C D somerase I, and anticentromere antibodies.
The nucleolar staining is associated with anti-
bodies against nucleolus-specific RNA, as
seen in certain limited forms of scleroderma.
(From Maddison [2]; with permission.)
FIGURE 11-6
Nucleus + Screening for anti–doubled-stranded DNA (dsDNA) antibodies
+
Mitochondrion using the Crithidia assay. The hemoflagellate Crithidia luciliae con-
tains in its kinetoplast pure dsDNA, not complexed to proteins [3].
Kinetoplast Anti-dsDNA Fluorescent Serially diluted serum samples are added to the slide carrying
+ dsDNA labeled Crithidia cells. Binding of antibodies is visualized by fluorescinated
Crithidia luciliae antihuman anti–immunoglobulin G antibodies. Antibodies to dsDNA are
immunoglobulin almost pathognomonic for systemic lupus erythematosus and there-
fore can be regarded as marker antibodies [4]. (From Klippel and
Croft [5]; with permission.)
Fluorescence of kinetoplast
FIGURE 11-7
Farr assay for quantitative measurement of anti-double-e-stranded DNA (dsDNA) anti-
bodies. The serum to be tested is added to a tube containing radiolabeled dsDNA. When
Test serum containing anti-dsDNA 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 dis-
ease 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.)
Radiolabeled dsDNA added
DNA–anti-DNA complexes precipitated

by ammonium sulphate
Radioactivity in precipitate measured

FIGURE 11-8
Western blot test of autoantibodies on nuclear extracts. Nuclear pro-
Topo I Scl-55 teins extracted from human cervical carcinoma cells (HeLa cells) are
RNP 70,000 separated on polyacrylamide gel and transferred to nitrocellulose.
Subsequently, identical strips of the blot are incubated with various
SS-B SS-50 patient sera. Binding of autoantibodies can be visualized with peroxi-
dase or alkaline phosphatase–labeled antihuman immunoglobulin.
Lane 1: anti-ribonucleoprotein (RNP)
A and centromere (CR-17) activity
B Lane 2: anti-Sm (B/B-D)
Sm
B’ Lane 3: anti-RNP and anti-Sm
C Lane 4: anti–Sjögren’s syndrome (SS-B) (La)
Lane 5: anticentromere
Centromere CR-17 Lane 6: antitopoisomerase I (Topo I)
D
Antibodies against Sm are rather specific for systemic lupus ery-
thematosus (SLE) and can be used as marker antibody, anti-ribonu-
cleoprotein for mixed connective tissue disease (MCTD), cen-
1 2 3 4 5 6 tromere (CR17) for the limited variant of scleroderma, SS-B for
Sjögren’s syndrome and SLE, and topoisomerase I for systemic scle-
roderma. The Western blot test is a simplified version of the cur-
rently available technique, which allows identification of autoanti-
bodies 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];

Persistence of autoreactive T cells
the only way to generate these oligonucleosomes is by the process of
Dysregulation of apoptosis
apoptosis. Presently, ample evidence exists that the autoimmune
Decreased response in SLE is T-cell–dependent and autoantigen-driven [14].
phagocytosis However, dsDNA is very poorly immunogenic, which is in line with
the fact that antigen-presenting cells cannot present DNA-derived
Quantitative and qualitative oligonucleotides to T cells by way of their major histocompatibility
Antinucleosome Ab, anti-DNA Ab complex class II molecules. However, recently it has become evident
changes in nucleosomes
that the nucleosome is the driving autoantigen in SLE.
In murine lupus, T cells specific for nucleosomes have been identi-
fied. These T cells not only drive the formation of nucleosome-spe-
In situ binding of Deposition of circulating
nucleosomes to GBM (HS?) nucleosome-Ab complex
cific autoantibodies (ie, antibodies that react with the intact nucleo-
some but not with its constituent DNA and histones) but also the
formation of anti-DNA and antihistone antibodies [15]. The his-
Nucleosome-mediated Ab-binding to GBM tone-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
Activation of complement, glomerulonephritis 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 [18–20].
FIGURE 11-9 Figure 11-11 illustrates the central role of the nucleosome in the gen-
Hypothesis for the pathophysiology of lupus nephritis. In recent eration of the antinuclear autoantibody repertoire. These antinucleo-
years, evidence has emerged that the process of apoptosis is disturbed some and anti-DNA antibodies, after complex formation with the
in systemic lupus erythematosus (SLE). The first indication was found nucleosome, can localize in the glomerular basement membrane
in the MRL/l lupus mouse model, in which a deficiency of the Fas (GBM) by way of binding to heparan sulfate (HS). This binding occurs
receptor was identified [9]. Activation of this Fas receptor induces through binding of the cationic histone part of the nucleosome to the
apoptosis. Transgenic correction of the Fas-receptor defect prevents anionic HS, as demonstrated by in vivo perfusion studies [21]. The rel-
development of lupus [10]. In human SLE, Fas receptor expression is evance of this binding mechanism for lupus nephritis was shown by
normal; however, a number of other observations indicate abnormali- the elution of nucleosome-specific autoantibodies from glomeruli,
ties in apoptosis [11,12] (Fig. 11-10). Alterations in apoptosis can identification of nucleosome deposits in glomeruli of patients with
lead to the persistence of autoreactive T and B cells, because apopto- lupus nephritis, and presence of nucleosome–antinucleosome antibody
sis is the major mechanism for the elimination of autoreactive cells. In complexes in the glomerular capillary wall in patients with lupus
addition, these alterations can lead to quantitative and qualitative dif- nephritis [18,22–25]. The pathophysiologic significance of this nucleo-
ferences in the release of nucleosomes (Fig. 11-10). some-mediated binding to the GBM was illustrated by the observation
Nucleosomes are the basic structures of chromatin. They consist of that heparin could prevent this binding and inhibit the glomerular
pairs of the core histones H2A, H2B, H3, and H4 around which dou- inflammation and proteinuria in lupus mice [26]. References 11 and
ble-stranded DNA (dsDNA) is wrapped twice. DNA in the circulation 14 provide a more detailed description of these mechanisms.
FIGURE 11-10
INDICATIONS FOR A DISTURBED APOPTOSIS IN On the one hand, indications exist that apoptosis is increased in
HUMAN SYSTEMIC LUPUS ERYTHEMATOSUS human systemic lupus erythematosus (SLE) (eg, increased Fas expres-
sion and increased in vitro apoptosis). On the other hand, some find-
ings suggest that apoptosis is decreased (eg, increased levels of solu-
Finding Study ble Fas, increased bcl-2 expression, and decreased anti-CD3–induced
apoptosis). Bcl-2 is a physiologic inhibitor of apoptosis, and trans-
Increased expression of Fas receptor Mysler et al. [28], Lorenz et al. [29] genic induction of bcl-2 overexpression leads to lupuslike autoimmu-
Circulating levels of soluble Fas nity [27]. Although presently it is difficult to reconcile these findings,
Increased Cheng et al. [30] it is clear that changes in the delicate balances governing apoptosis
Normal Goel et al. [31], Knipping et al. [32] can lead to apoptosis at the wrong moment (too late) or at the
Increased in vitro apoptosis of lymphocytes Lorenz et al. [29], Emlen et al. [33] wrong place (systemically instead of locally).
Abnormal anti-CD3–induced apoptosis Kovacs et al. [34]
Apoptosis-induced alterations of autoantigens
Proteolysis Casciola-Rosen et al. [35],
Casiano et al. [36],
Rosen and Casciola-Rosen [37],
Casiano [38]
Phosphorylation Utz et al. [39]
Reactive oxygen species–mediated damage Cooke et al. [40]
Apoptosis-induced surface expression Casciola-Rosen et al. [41],
of autoantigens Jordan and Kuebler [42]
Decreased phagocytosis of apoptotic cell Herrmann et al. [43]
FIGURE 11-11
Chromatin Central role of T cells specific for nucleosomal histone peptides in
the generation of the antinuclear autoantibody repertoire in sys-
temic 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 pep-
Anti-HMG
Anti-DNA B cell
tides to T cells. After activation of the T cell, it provides help to the
B cell 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
MHC II-Peptide antigen-processing by these B cells, can generate additional antinu-
clear autoantibody responses (anti–doubled-stranded DNA, antihis-
Histone-
peptide TCR tone, and anti-HMG). This intramolecular antigen-spreading owing
Th cell to different endosomal antigen-processing revealing cryptic neoepi-
CD40L topes, is now known for a number of autoimmune responses [44].
Anti-nucleosome
B cell MHC—major histocompatibility complex; TCR—T-cell receptor.
CD40 (From Datta and Kaliyaperumal [45]; with permission.)
Anti-Histone CD4
B cell
along the capillary loops. Dependent on the severity of the morpho-

logic damage, the extent of immune deposits, and whether less or
WORLD HEALTH ORGANIZATION MORPHOLOGIC
more than half of glomeruli are affected, this form of proliferative
CLASSIFICATION OF LUPUS NEPHRITIS
lupus nephritis was divided into focal segmental glomerulonephritis
(1995 REVISED VERSION)
(class III) and diffuse glomerulonephritis (class IV). The distinction
between class III and class IV, however, is arbitrary; it also is unreli-
able in clinical practice. Therefore, the recent modification of the
Class WHO classification (1995) proposes a new definition of classes III
I. Normal glomeruli and IV lupus nephritis.
A. Nil (by all techniques) All more severe forms of proliferative lupus nephritis are included
B. Normal on light microscopy but deposits seen on electron or immunofluores- in class IV and specified as mild, moderate, or severe, depending
cence microscopy on the severity on the glomerular damage. In active lesions there
II. Pure mesangial alterations (mesangiopathy) occurs a large increase in mesangial cells; an influx of monocytes
A. Mesangial widening, mild hypercellularity, or both or granulocytes; so-called hyaline thrombi in the capillary lumina;
B. Moderate hypercellularity and necrosis of the capillary loops, defined as severe mesangial
III. Focal segmental glomerulonephritis (associated with mild or moderate proliferative or endocapillary proliferative glomerulonephritis, and
mesangial alterations) sometimes with varying degrees of extracapillary proliferation. In
A. Active necrotizing lesions chronic disease, mesangiocapillary lesions are present with exten-
B. Active and sclerosing lesions sive subendothelial deposits (wire loops), duplication of the
C. Sclerosing lesions glomerular basement membrane (GBM), cellular interposition,
IV. Diffuse glomerulonephritis (Severe mesangial, endocapillary, or mesangiocapillary and varying increases of mesangial cells and matrix. On electron
proliferation, and/or extensive subendothelial deposits. Mesangial deposits are pre- microscopy, the deposits have a homogeneous or fine granular
sent invariably and subepithelial deposits often, and may be numerous.) structure with sometimes organized “fingerprint” patterns.
A. Without segmental lesions Frequently, tubuloreticular structures are present in the cytoplasm
B. With active necrotizing lesions of endothelial cells, inclusions also found in viral infections, such
C. With active and sclerosing lesions as human immunodeficiency virus, and related to -interferon.
D. With sclerosing lesions Class III is now restricted to patients with active or sclerosing focal
V. Diffuse membranous glomerulonephritis segmental necrotizing lesions accompanied by mild increase of
A. Pure membranous glomerulonephritis mesangial cells.
B. Associated with lesions of category II (A or B)
Membranous lupus nephritis (class V) is hardly distinguishable
from the idiopathic form of lupus nephritis. However, membranous
VI. Advanced sclerosing glomerulonephritis
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
FIGURE 11-12 subendothelial and mesangial deposits. The subepithelial deposits
The various morphologic manifestations of lupus nephritis are are either globally distributed along the glomerular basement mem-
classified in several categories based on criteria formulated in brane (GBM) or more segmentally localized. The subepithelial
1974, modified in 1982 and 1995, and designated as the World deposits also are a frequent occurrence in class IV lupus nephritis.
Health Organization (WHO) classification of lupus nephritis According to the most recent version of the WHO classification
[46,47]. The different forms of glomerulonephritis, as morphologi- [47], class V is now restricted to cases that are predominantly char-
cally defined by the WHO classification, also are characterized by acterized by subepithelial immune complexes. More advanced or
typical patterns of deposits of several classes of immunoglobulins end-stage cases of focal and diffuse proliferative lupus nephritis
and complement factors [48]. Class I lupus nephritis has been characterized by a pronounced sclerosis and hyalinosis are classified
defined by normal glomeruli by all techniques, or by normal as class VI lupus nephritis.
glomeruli on light microscopy, with minor deposits as seen on Interstitial fibrosis, accompanied by tubular atrophy and influx of
immunofluorescence (IF) or electron microscopy (EM). Class I mononuclear cells, is a frequent finding, especially in the chronic forms
lupus nephritis is believed to be a rare manifestation, and its exis- of classes III, IV, and V. Lesions resembling chronic tubulointerstitial
tence is challenged by many pathologists. nephritis without glomerular alterations also have been described in
The mildest form of lupus nephritis, class II, is characterized by a some patients with SLE. In these cases, on immunofluorescence, it is
mild or moderate increase of mesangial cells accompanied by mesan- not unusual to find granular immune complexes in the tubular base-
gial deposits of immunoglobulins and complement. These mesangial ment membranes. Reference 47 provides additional information on the
deposits are regarded as the most characteristic immunopathologic 1995 revised WHO classification. Examples of the different forms of
feature of lupus nephritis. The more severe forms of lupus nephritis SLE nephritis are presented in Figs. 11-14 to 11-20. (From Churg and
not only show an increase of mesangial deposits but also deposits coworkers [47]; with permission.)
FIGURE 11-13
NATIONAL INSTITUTES OF HEALTH HISTOLOGIC The value of the analysis of lupus glomerulonephritis according to
SCORING SYSTEM FOR ACTIVITY AND CHRONICITY the World Health Organization (WHO) classification for prognosis
IN LUPUS NEPHRITIS 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
Activity index Chronicity index lesions is assessed according to the scoring system here. A chronici-
ty index of 3 or higher and an activity index of 12 or higher are
Glomerular Endocapillary hypercellularity Glomerular sclerosis associated with a significantly greater risk for the development of
Leukocyte infiltration Fibrous crescents end-stage renal disease [14].
Fibrinoid necrosis, karyorrhexis*
Cellular crescents*
Hyalin deposits, wire loops
Tubulointerstitial Mononuclear cell infiltration Fibrosis
Tubular atrophy
Maximal score 24 12
Scoring per item from 0 to 3; for parameters with asterisks, the score is doubled.
Histology of Lupus Nephritis
A C
FIGURE 11-14
Lupus nephritis class II. A, A moderate increase of mesangial cells is seen on light micro-
scopy. B, Immunofluorescence. Mesangial deposits of immunoglobulin G. C, Electron
microscopy shows electron-dense deposits restricted to the mesangial area. L—capillary
lumen; U—urinary space. (Panel A, methenamine silver. Original magnification 400,
520, 10,000, respectively.)
B
A B C
FIGURE 11-15
Lupus nephritis class III. A, Segmental necrotizing lesion surrounded by deposits in a necrotizing lesion. According to the 1995 modified World
an increased number of epithelial cells. B, Immunofluorescence. Next Health Organization classification, this is a characteristic immuno-
to mesangial deposits of immuno-globulin G there also are deposits in pathologic lesion of class III lupus nephritis. (Panel A, methenamine
the periphery of some loops (arrows). C, Immunofluorescence. Fibrin silver. Original magnification 400, 400, 520, respectively.)
FIGURE 11-16
Lupus nephritis class IV on light micro-
scopy 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 mesangio-
capillary 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 (membra-
nous component) can be found on the
epithelial side of the GBM (arrow). D,
Immunofluorescence. The characteristic
pattern of the immune deposits
A B (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.)
C D
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). GBM—glomerular basement membrane;
U—urinary space. (Original magnification 12,000.)
GBM
U S
S L
A 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, Immunofluore-
scence. 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). L—capillary lumen; S—spikes; U—urinary space. (Panel A,
methenamine silver, original magnification 700, 400, 3100, respectively.)
B
FIGURE 11-19
Lupus nephritis class VI. Sclerosing glomerulonephritis with exten-
sive sclerosis of most of the capillary tuft. (Methenamine silver,
original magnification 700.)
FIGURE 11-20
Chronic tubulointerstitial nephritis.
A, Extensive interstitial fibrosis accompa-
nied 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.)
A B
FIGURE 11-21
Incidence of the different forms Incidence of the different forms of lupus nephritis classified according to the World Health
of lupus nephritis, % Organization (WHO) classification. The incidence of the different forms categorized accord-
ing to the WHO classification depends on patient selection and ethnic background. The
Class IV 57 Class III 15
percentages represent an average of the data reported in the literature. Most patients have
a diffuse proliferative form of lupus nephritis (WHO class IV).
Class II 10
Class I 1
Class VI 2
Class V 15
100
Class II
Class III
Class IV
Class V
80
60
Percentage
40
20
0
ent
3
uri
rom
wC
ctio
sio
im
tein
ten
/lo
un
ynd
sed
per
Pro
A+
al f
ic s
tive
ren
Hy
sDN
rot
Ac
red
ph
ti-d
pai
Ne
An
Im
FIGURE 11-22
Incidence of renal manifestations and serologic class V, nephritic sediment for WHO class IV), it is
abnormalities in the different forms of lupus nephri- clear that on the basis of clinical symptoms it is not
tis. The clinical manifestations of lupus nephritis are possible to classify the form of nephritis correctly.
not different from other forms of glomerulonephritis This inability underlines the necessity for obtaining a
and include a nephritic sediment (dysmorphic ery- renal biopsy specimen. In addition, listed are the
throcytes and erythrocyte casts), proteinuria or occurrence of both a positive result on performing a
nephrotic syndrome, impaired renal function, and Farr assay and a low complement 3 level for the dif-
hypertension. Although certain clinical manifesta- ferent forms of lupus nephritis. Anti-dsDNA—
tions are more prevalent in certain forms (nephrotic anti–double-stranded DNA. (Adapted from Appel
syndrome for World Health Organization (WHO) et al. [50]).
must be monitored for transition to a more severe form, which is

generally heralded by worsening of clinical renal symptoms.
TREATMENT OF THE DIFFERENT
For patients with classes III and IV lupus nephritis, corticosteroid
FORMS OF LUPUS NEPHRITIS
monotherapy is not sufficient (Fig. 11-24). Cytotoxic immunosup-
pressive therapy, either cyclophosphamide or azathioprine, should
be added to the treatment. The choice of one of these drugs over
World Health Organization the other is discussed in Figures 11-24, 11-25, and 11-26.
classification Treatment options According to a recent analysis [51], patients with a pure membra-
I Treatment guided by extrarenal lesions nous lupus nephritis without a proliferative component (class V,
II Corticosteroids: according to the 1995 revised WHO classification) respond satisfacto-
III, IV Cyclophosphamide pulses, oral prednisone rily to corticosteroid monotherapy. Patients who have a membranous
Methylprednisolone pulses, azathioprine, nephropathy with a proliferative component (formerly classified as
low doses oral prednisone WHO class VC or VD) have a much worse prognosis and should be
V Corticosteroids treated as are patients with a class IV lupus nephritis. When a patient
(and azathioprine or cyclophosphamide) with class V (A or B) lupus nephritis does not respond to cortico-
VI No further immunosuppression ? steroids, addition of azathioprine or cyclophosphamide should be
Supportive treatment considered (as in idiopathic membranous glomerulonephritis, in
which oral treatment seems to be superior over monthly intravenous
pulses [52–54]). When cyclophosphamide treatment is initiated the
therapeutic response should be evaluated after 6 months, and the
FIGURE 11-23 drug should be discontinued if no improvement has occurred [55].
Treatment options for the different forms of lupus nephritis are Treatment of WHO class VI nephritis should be balanced on
summarized. Only for World Health Organization (WHO) classes weighing the risks of intensification of immunosuppressive treat-
III, IV, and V are a limited number of prospective studies available. ment and the expected benefits. When renal function already is
For the other forms, a balanced compilation is made from the litera- strongly impaired and the renal biopsy specimen shows predomi-
ture and personal experience. Reference 14 supplies a more detailed nantly chronic irreversible lesions, further deterioration of renal
analysis of the therapeutic options. For class I lupus nephritis, no function may be unavoidable. Therefore, an increase in immuno-
specific renal therapy is necessary; treatment is dictated by the pres- suppressive therapy is questionable. This approach is strengthened
ence of extrarenal symptoms. by the fact that lupus disease activity mostly subsides during renal
In general, patients with class II lupus nephritis respond satisfacto- replacement therapy. Results of renal transplantation are good,
rily to monotherapy with oral corticosteroids. The patient, however, and the disease rarely recurs after transplantation [14].
FIGURE 11-24
Change in chronicity index in repeat biopsies after treatment
8
with prednisone (PRED) alone or prednisone and cytotoxic drugs
(CTD). The addition of cytotoxic drugs to the treatment regimen
6
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, dis-
4 playing the change in chronicity index between the first and sec-
ond kidney biopsies over time. As can be seen during prednisone
∆ Chronicity index
monotherapy, there is a clear increase of the chronicity index (A);

2 (Continued on next page)
PRED
-2
-4
0 33 66 99 132
A Time interval, m

8 Azathioprine whereas in patients treated with prednisone and cytotoxic drugs
Oral cyclophosphamide (B) the chronic lesions, on average, do not progress. Various stud-
Intravenous cyclophosphamide ies have shown that this chronicity index is the strongest predictor
Combined use of azathioprine and of development of end-stage renal disease [14]. (From Balow et al.
6 cyclophosphamide
4
∆ Chronicity index
-2
CTD
-4
0 33 66 99 132
B Time interval, m
Probability of end-stage renal disease
0 100
IVCY
AZCY
20 80
POCY
Cumulative survival, %
40 AZ 60
60 CPM
40
80
PRED
20 } AZA
100 0
0 20 40 60 80 100 120 140 160 180 200 220 0 24 48 72 96 120
A Months B Months
FIGURE 11-25
A, The probability of end-stage renal disease in patients with prolifer- effects of both drugs are not identical. Cyclophosphamide has
ative lupus nephritis treated with different drug regimens. This update a greater bone marrow toxicity, leads to amenorrhea in many
of the prospective trial by the National Institutes of Health (NIH) on patients, is teratogenic, and displays an unique urothelial toxicity
the treatment of these patients clearly demonstrates that prednisone (hemorrhagic cystitis and bladder carcinoma). Therefore, prospec-
monotherapy, in a significantly greater proportion of patients, leads tive studies comparing cyclophosphamide with azathioprine are
to the development of end-stage renal disease compared with patients warranted but not available. The results of the NIH trial are com-
on regimens containing cytotoxic drugs. The results between azathio- pared with those reported for azathioprine [57,60–62]. This analy-
prine and drug regimens containing cyclophosphamide are not signifi- sis, carried out by Cameron [57], does not reveal a significant dif-
cantly different. Note that in up to 7 years the results do not differ ference between cyclophosphamide and azathioprine. A recent
between the different treatment groups. From these studies it is clear meta-analysis [63] again showed that monotherapy with prednisone
that although the therapeutic efficacy is equal for the three treatment was inferior to treatment with cytotoxic drugs in combination with
regimens containing cyclophosphamide, less side effects occurred in steroids. However, as in the NIH trial and the analysis by Cameron,
patients treated with intravenous pulses of cyclophosphamide. no differences were found between cyclophosphamide and azathio-
B, Renal survival in patients with World Health Organization prine in preserving renal function. AZ—azathioprine; AZCY—
(WHO) class IV lupus nephritis treated with either cyclophos- combined therapy with azathioprine and cyclophosphamide;
phamide (CPM) or azathioprine (AZ). The NIH trial [56,59] did IVCY—intravenous pulses of cyclophosphamide; POCY—oral
not reveal a significant difference between the therapeutic efficacy cyclophosphamide. (Panel A from Steinberg and Steinberg [59];
of cyclophosphamide and azathioprine (A). However, the side with permission. Panel B from Cameron [57]; with permission.)
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 No normalization of elevated creatinine World Health Organization class IV Male gender
Nephrotic range proteinuria Treatment with prednisone only Activity index ≥ 12 Black race
Low C3 Chronicity index ≥ 3 Age ≤ 24 y
Hematocrit ≤ 26% Low socioeconomic status
Hypertension
Persistent disease activity
FIGURE 11-26
These risk factors were identified in different analyzes in follow-up, and so on. The most powerful predictors seem to be
different patient groups. Not all these parameters were con- an elevated serum creatinine level at entry into the trial, a
firmed in all studies, probably because of differences in defini- chronicity index of 3 or higher, and persistent or remitting renal
tions used, composition of the cohort studied, duration of disease activity [14,64].
100
100
Hemodialysis
80 80 CAPD
Survival, %
Patients, %
60 60
40 40
All patients
Hemodialysis
20 CAPD 20
0 0
0 12 24 36 48 60 0 1–10 >10
Months on dialysis Maximal Nonrenal SLEDAI

Survival of patients with systemic lupus erythematosus (SLE) on Severity of systemic lupus erythematosus (SLE) disease activity during
dialysis. Although initially dialysis treatment was not offered to hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).
patients with SLE because of the systemic nature of their illness, it Lupus disease activity generally decreases during dialysis treatment.
later became clear that patients with SLE tolerate dialysis treatment As assessed by the SLE Disease Activity Index (SLEDAI) [66], the
as well as do patients with non-SLE renal diseases. The overall maximal nonrenal SLEDAI decreased during dialysis in 49% of
patient survival is good (90% at 5 years), and no differences exist patients, remained stable in 42%, and showed progression in 9%.
in patient survival between those treated with continuous ambula- Despite the fact that immunosuppression was minimized, in 90%
tory peritoneal dialysis (CAPD) as compared with hemodialysis. of patients cytotoxic drug therapy was discontinued and in 55%
(Data from Nossent et al. [65].) 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 dis-
ease activity; 1 to 10, moderate extrarenal disease activity; over 10,
high extrarenal disease activity.
25
100 Before dialysis
During dialysis
20 After transplantation
80
Number of patients
Actuarial Survival, %
60 15
40 10
Patient/SLE
Patient/non-SLE
20 Graft/SLE 5
Graft/non-SLE
0 0
0 12 24 36 0 1–10 >10
Months after transplantation Maximal nonrenal SLEDAI score

Graft and patient survival after renal transplantation in patients Lupus disease activity after renal transplantation. Disease activity
with systemic lupus erythematosus (SLE). For this analysis only was assessed in 28 patients with systemic lupus erythematosus
patients with first transplantations using a cadaveric donor kidney (SLE) by calculating the maximal nonrenal SLE Disease Activity
were included. Both graft and patient survival were calculated for Index (SLEDAI) in the time periods before dialysis, during dialysis,
165 patients with SLE who received transplantation between 1984 and after renal transplantation. The maximal nonrenal SLEDAI
and 1992. These data are compared with the results in 21,726 scores were divided in three groups: 0, no extrarenal disease activi-
patients with non-SLE glomerular diseases who received transplan- ty; 1 to 10, moderate extrarenal disease activity; over 10, high
tation in the same time period. Both graft and patient survival were extrarenal disease activity. Note that before dialysis all patients had
not significantly different between the two groups. (From Berden extrarenal lupus disease activity but that after renal transplantation
[14]; with permission. Data from G. Persijn, Eurotransplant, no patient had high disease activity. These data illustrate that the
Leiden, the Netherlands.) 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

FIGURE 11-31
Frequency of isotypes of heavy and light chains produced by
Heavy chains Light chains non–immunoglobulin (Ig) M myelomas. Most paraproteins pro-
duced belong to the IgG class. Note that in approximately 20%
Only light chains None
17% 10%
of myelomas only light chains are produced, of which two thirds
belong to the isotype and one third to the isotype [69,70].
IgD/IgE These frequency distributions mirror those of Ig classes and light
1% chain isotypes in the serum.
IgG κ λ
60% 30%
59% IgA
23%
FIGURE 11-32
100 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].
90
Ig—immunoglobulin. (From Pruzanski [72]; with permission.)
80
70
Cumulative incidence, %
60
50
40
30
20
10
0
IgG IgA IgD κ λ
Paraproteinemia
deposit in the kidney and other vital

Types of renal involvement in dysproteinemias organs, depending on the immunoglobulin
class, light or heavy chain isotype, and
Uncontrolled proliferation of single B cell other only partly understood physiochemi-
cal properties. The terminology used in
these disorders is sometimes confusing and
Overproduction, secretion of monoclonal Ig or Ig fragment
inconsistent. We use the definitions pro-
posed by Gallo and Kumar [73]. All dis-
Monoclonal Ig deposition diseases eases characterized by deposits of mono-
Renal localization in different forms clonal immunoglobulin–related material
are named monoclonal immunoglobulin
Fibrils Crystals Casts Granular precipitates Organized structures deposition diseases (MIDD). These deposits
Tubules, fibrils can occur in several forms, as outlined in
the figure, and are identified by specific
AL (or AH) Fanconi's Myeloma cast LCDD Paraproteins
amyloidosis syndrome nephropathy LHCDD Cryoglobulins stains (such as congo red) and on immuno-
HCDD Type I fluorescence and electron microscopy. The
TypeII histologic and clinical manifestations are
Immunotactoid GN dependent on the type of deposition.
Fibrillary GN
Included in this overview are fibrillary and
immunotactoid glomerulonephritis, which
Nonamyloidotic in certain cases also show deposits contain-
ing monoclonal immunoglobulins. AH—
heavy chain amyloidosis; AL—light chain
FIGURE 11-33 amyloidosis; GN—glomerulonephritis;
Types of renal involvement in dysproteinemias. The uncontrolled proliferation of a HCDD—heavy chain deposition disease;
B-cell clone leads to overproduction of a monoclonal immunoglobulin (Ig), either an LCDD—light chain DD; LHCDD—light
intact molecule or fragments thereof (light or heavy chains). These molecules can and heavy chain DD.
events. Because some of these light chains are

Pathogenesis of renal lesions in dysproteinemias relatively resistant to proteolysis, they can
induce lysosomal damage. This damage can
Deposition either as light chain, give rise to functional impairment of the
amyloid, or cryglobulins Reabsorption of light chains proximal tubular cell, leading to a decreased
resorptive capacity (eg, for sodium and light
Toxic Decreased sodium and light chain
injury reabsorption and increased distal delivery chains) and thereby increasing the distal deliv-
Glomerulus
ery. When this lysosomal overload leads to
Tubular atrophy intracellular crystal formation, Fanconi’s syn-
PCT DT drome may ensue. Increased distal delivery of
light chains can then induce precipitation of
Cortex
light chains together with Tamm-Horsfall pro-
tein (THP) that is secreted in the loop of
Light chains
filtered CCT Henle. This precipitation is enhanced by an
PR increased tubular fluid sodium chloride con-
centration. Other factors that enhance cast
Cast Giant cell infiltration formation are listed in Figure 11-43. This
Outer injury interstitial infiltration intratubular cast formation leads to obstruc-
Plasma cell
medulla invasion tion, tubular damage, and an interstitial
TAL
LC + THP = cast inflammatory response with leakage of THP
in the interstitium, inducing macrophage
influx and giant cell formation. This entity is
Inner known as myeloma cast nephropathy. Finally,
medulla
interstitial plasma cell invasion may occur in
patients with myeloma, although this rarely
leads to clinical symptoms and most often is
FIGURE 11-34 only diagnosed by kidney biopsy specimen or
Pathogenesis of the different types of renal lesions in dysproteinemias. Paraproteins can is seen at autopsy. CCT—cortical collecting
deposit in the glomerular basement membrane (GBM) (and tubular basement membrane tubule; DT—distal tubule; LC—light chains;
[TBM]) either as light or heavy chains, unmodified immunoglobulins, amyloids, or cryoglobu- PCT—proximal convoluted tubule; PR—pars
lins. Because of their size of 22 kD, light chains are freely filtered through the GBM. These light recta; TAL—thin ascending limb. (Adapted
chains are then reabsorbed by proximal tubular cells. This process can induce a cascade of 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
red–stained sections viewed under polarized light reveal the specific apple-green birefringence,
the gold standard for the diagnosis. Amyloid deposits are sometimes stained with commercial-
ly available antisera against light chains. In addition, these deposits also are positive for amy-
loid 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 A, Amyloid deposits in mesangium and the capillary wall (arrows: spicules).

B, Amyloid deposits in the renal arteries
in a congo red–stained 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, methena-
mine silver. Original magnification 550,
350, 400, respectively.)
B C
FIGURE 11-36
U Light chain amyloidosis on electron micro-
scopy. A, Characteristic fibrillar pattern of
amyloid deposits. Long, randomly distrib-
uted, nonbranching fibrils with diameters
Pod 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
GBM 48,000, 20,000, respectively.)
A B
thickened, as seen in the PAS-stained sections.

In the remaining cases, no renal lesions can
be seen on light microscopy. On immunoflu-
orescence, linear staining of basement mem-
branes of glomeruli, tubuli, and vessels can
be observed for one of the light chains ( >
). In most cases, the TBMs are more heavi-
ly stained than are the glomerular basement
membranes (GBMs). Congo red staining is
negative for amyloid. On electron micro-
scopy, fine granular electron-dense material
can be found in most cases along the
endothelial side of the GBM, in the mesan-
gium, and along the interstitial side of the
TBM. A few cases of heavy chain and of light
A B and heavy chain deposition disease have been
described, in most cases with identical mor-
FIGURE 11-37 (see Color Plate) phologic characteristics as described in light
Light chain deposition disease. In about 60% of patients with this renal lesion, nodular chain deposition disease [77,78].
expansion of the mesangium is seen that resembles nodular diabetic nephropathy [75,76]. The A, Nodular glomerulosclerosis with nodu-
nodules stained purple with periodic acid–Schiff (PAS) stain have a homogeneous appearance, lar increase of mesangial matrix. B, Linear
and those stained with methenamine silver are pink-brownish in color. In a few cases, a more staining of the GBM, mesangium, Bowman’s
mesangiocapillary pattern of injury is present. The tubular basement membranes (TBMs) are capsule, and TBM for the light chain.

C and D, Electron-dense granular
deposits in the GBM (C) and around
Pod the TBM (D). L—capillary lumen; Pod—
podocyte. (Panel A, methenamine silver.
Original magnification 400, 400,
15,000, 6500, respectively.)
GBM
L
TBM
C D
A B C
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 pro-
tein (THP). Sometimes the tubular cells shows necrosis accompanied by disruptions of the
tubular basement membrane (TBM). Proximal tubular cells show hyaline droplets or vac-
uoles with needlelike, tubular, or complex crystalline material. Casts are surrounded by
macrophages and multinucleated giant cells. On electron microscopy, the casts have a gran-
ular, 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
D 160, 400, 600, 200, respectively.)
FIGURE 11-39
Fanconi’s 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 materi-
al in tubular cells is stained for light chains.
C, Low-power view of a proximal tubular
epithelial cell with vacuoles containing orga-
nized or crystalline material. D, High-power
view of the vacuoles containing tubular or
ladderlike crystalline structures. BB—brush
border. (Panel A, methenamine silver.
Original magnification 600, 400, 7000,
19,000, respectively.)
A B
BB
C D
C
FIGURE 11-40
A 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 B
Glomerular deposition of immunoglobulin G– in a patient closely packed tubules arranged in parallel. (Panel A,
with multiple myeloma. A, Glomerulus with many intracapil- toluidine blue. Original magnification 600, 130,000,
lary protein thrombi. B, The material was composed of respectively.)
A B C
FIGURE 11-42
Mixed cryoglobulinemia. Of the three types of cryoglobulins, types I and II contain mono-
clonal 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 malig-
nancies. Type II cryoglobulins consist of two components, a monoclonal immunoglobulin,
most frequently IgM, with rheumatoid factor activity directed to the polyclonal IgG compo-
nent. Various patterns of glomerular injury can be found, such as a diffuse endocapillary pro-
liferative glomerulonephritis with a prominent influx of monocytes, or a mesangiocapillary
glomerulonephritis. Less frequently, a diffuse mesangial proliferative, sclerosing glomeru-
lonephritis, or both can be seen. Eosinophilic aggregates along the glomerular basement mem-
brane (GBM) or in the lumina designated as thrombi frequently are present. Type II cryoglob-
ulinemia 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
D 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 Sjögren’s 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 tubu-
lar 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 glomeru-
lonephritis with immunoglobulin A–
deposits. The patient had no signs of a mon-
oclonal gammopathy or lymphoma. A, Mild
increase of mesangial matrix with segmental
irregularity of the capillary wall. B,
Immunofluorescence. The deposits are posi-
tive 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.)
A B (Continued on next page)

Immunotactoid and fibrillary glomerulonephritis are comprised of
lesions characterized by the deposition of immunoglobulins (and com-
plement) 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 glomeru-
lonephritis 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 lymphoprolifera-
tive disease. The deposited immunoglobulins frequently are of mono-
clonal composition. In contrast, fibrillary glomerulonephritis is char-
acterized by fibrils with diameters of about 18 to 20 nm. The deposit-
ed immunoglobulins usually are polyclonal and very rarely
monoclonal. An association with a lymphoproliferative disease is
C uncommon in contrast to immunotactoid glomerulonephritis.
A 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 magni-
fication 400, 300, 27,000, respectively.)
B
CLINICAL PRESENTATION, FREQUENCY, AND CAUSES RISK FACTORS FOR RENAL INVOLVEMENT
OF RENAL INVOLVEMENT IN DYSPROTEINEMIAS IN DYSPROTEINEMIAS
Acute deterioration of renal function (5–10%) Factors enhancing amyloid formation

Dehydration Unfolding of paraprotein
Hypercalcemia Light chain
Cast nephropathy Factors enhancing cast nephropathy
Crescentic glomerulonephritis High urinary excretion of light chains
Chronic renal insufficiency (45–75%) Binding of light chain to Tamm-Horsfall protein (THP)
Myeloma cast nephropathy Iso-electric point of light chain ≥5.1 ? (enhances binding to anionic THP (pI:3.2)
Light chain (AL) amyloidosis Tendency to self-aggregation of light chains
Interstitial plasma cell infiltration (rare) Light chain
Proteinuria-nephrotic syndrome (50–80%) High levels of acute-phase proteins
Light chain (AL) amyloidosis Resistance of light chain to urinary or macrophage-derived proteases
Light chain deposition disease Factors enhancing monoclonal immunoglobulin deposition
Heavy chain deposition disease Light chain
Cryoglobulinemic glomerular lesions Presence of hydrophobic aminoacids in CDR1 or CDR2 of VL-chain
Fanconi’s syndrome (1%) Deletion of CH1 domain Fc part immunoglobulin
Secondary lesions (20–30%) Factors enhancing acute renal failure
Pyelonephritis Hypercalcemia (19–44%)*
Nephrocalcinosis Dehydration (10–65%)
Hyperuricemic nephropathy Urinary tract infection (8–44%)
Nephrotoxic drugs (aminoglycosides; nonsteroidal anti-inflammatory drugs) (0–26%)
Intravenous radio contrast media (0–11%)
Loop diuretics
FIGURE 11-45
Renal involvement in dysproteinemias can lead to different clinical
*Percentage of patients in which this factor contributed to the development
manifestations: acute renal failure; progressive deterioration of renal of acute renal failure.
function; proteinuria, which very often is in the nephrotic range; or, From Winearls [69]; with permission.
seldom, Fanconi’s syndrome. Furthermore, a number of secondary
conditions may occur that can induce additional renal damage.
Certain features are associated with particular clinical symptoms. FIGURE 11-46
The type of clinical lesion that develops is predominantly determined Factors reported in the literature to be associated with development
by the so-called nephrotoxic characteristics of the excreted light of the different renal lesions in patients with myeloma are summarized.
chains, as demonstrated by infusion of light chains into mice. These The amyloidogenic potential is enhanced by certain amino acids that
infusions led to the same type of renal lesion as in humans [79,80]. promote unfolding of the light chain and by the isotype of the light
Some of these nephrotoxic factors are listed in Figure 11-43. 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 immuno-
globulin 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-6–mediated 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.
TREATMENT OF RENAL LESIONS IN DYSPROTEINEMIAS
Renal therapy Antitumor therapy

Preventive measures: Melphalan-prednisone
Rehydration, forced diuresis (>3 L/24 h) First-line therapy: 45% remission rate
Correction hypercalcemia
Alkalinization of urine (pH ≥7)
Cessation of nephrotoxic drugs
Treatment of infections
Colchicine ?
Plasmapheresis in acute renal failure Vincristine-adriamycine-dexamethazone (VAD)*
Recovery of renal function increases from 0–18% in the control group to Second-line therapy: relapses, 40% remission; refractory cases, 25% remission
43–84% with plasmapheresis
Dialysis High-dose chemotherapy and bone marrow transplantation
54% survival after 1 y, and 25% after 2 y Relatively good results in patients without renal involvement. No data for patients
Theoretically, PD could result in a better removal of light chains with renal involvement
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
*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 plasmapheresis that do those without cast formation and intersti-
reduction of the production of paraproteins. In patients with myelo- tial changes [81]. Of two controlled studies, only one showed a
ma it is very important to prevent situations that could precipitate beneficial effect of addition of plasmapheresis to chemotherapy
acute renal failure. In this respect, dehydration and hypercalcemia [82,83]. The major determinant for success seems to be a good
are very harmful. Measures should be taken to maintain a high fluid response to chemotherapy [83]. Furthermore, patients with exten-
intake. When radiocontrast agents are necessary, hydration before sive cast formation and interstitial changes seem to respond less
the study decreases the chance of intratubular cast formation well to chemotherapy than do those without cast formation and
between light chains and the contrast agent. Alkalization of the interstitial changes [81,83]. The patient with end-stage renal dis-
urine can reduce the interaction between light chains and Tamm- ease can be treated with dialysis, although survival is poor and
Horsfall protein (THP). Nephrotoxic drugs (such as nonsteroidal dependent on the success of chemotherapy.
anti-inflammatory drugs and gentamycin) should not be used The experience of renal transplantation in patients with dyspro-
because they further enhance tubular dysfunction. Experimental teinemias is, for obvious reasons, rather limited. The results are rather
studies suggest that colchicine may be helpful in reducing cast for- disappointing with a high mortality rate, especially in patients with
mation either by decreasing THP secretion or modifying the interac- multiple myeloma and amyloidosis. Patients surviving for more than
tion between THP and light chains. Presently, no data exist that 1 year show a high recurrence rate [84–87]. Discussion of antitumor
document the clinical efficacy of this treatment. therapy is beyond the scope of this review. Briefly, treatment with
Plasmapheresis has the potential to remove the toxic light chains melphalan and prednisone is considered to be the first choice, where-
from the circulation, although in certain patients the serum concen- as more aggressive treatment with vincristine-adriamycin-dexametha-
tration can be rather low. Plasmapheresis alone does not reduce the sone is given to patients who do not respond to or who relapse after
rate of production of the paraprotein; therefore, this treatment melphalan and prednisone therapy. Recently, more encouraging
should be combined with chemotherapy. Patients with extensive results have been obtained with ablative chemotherapy and stem-cell
cast formation and interstitial changes seem to respond less well to reinfusion [88]. PD—peritoneal dialysis.
Renal Involvement in Rheumatic Diseases

is positive for HLA-DR3 the risk for gold-induced MGN increases
Causes of renal involvement in 10- to 30-fold and that for D-penicillamine increases 3- to 10-fold.
rheumatoid arthritis Discontinuation of therapy leads to remission of the proteinuria-
MGN nephrotic syndrome in almost all cases, although it may be a year
14% MesPGN
23%
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
AA amyloidosis
amyloidosis is secondary to the deposition of the acute-phase reac-
18% tant serum amyloid A (SAA) protein. This SAA is partly digested
by macrophages and deposited in the tissues as AA amyloid. When
No lesions
a patient with active rheumatoid arthritis develops a nephrotic syn-
15% drome, AA amyloidosis is the most likely cause. No good treat-
ment options exist for AA amyloidosis, other than treating the
TIN underlying disease. Renal transplantation in these patients is associ-
9%
ated with a 3-year patient survival rate of 50% [92]. Especially in
the early period after transplantation, there were high cardiovascu-
Vasculitis, CGN, other
lar- and infection-related mortality rates. The rate of recurrence
21%
was approximately 20%.
The development of tubulointerstitial nephritis (TIN) in patients
FIGURE 11-48 with rheumatoid arthritis is related to the prolonged use of anal-
Causes of renal involvement in rheumatoid arthritis. In rheumatoid gesics, especially multicomponent analgesics and nonsteroidal anti-
arthritis, a variety of renal disorders may occur secondary to either inflammatory drugs. A number of other renal conditions may devel-
the underlying disease or to drugs used to treat it. The most fre- op in patients with rheumatoid arthritis. Vasculitis is associated
quent abnormality is a mesangial proliferative glomerulonephritis with long-standing and nodular rheumatoid arthritis with high
(MesPGN) with, in most cases, only mesangial immunoglobulin M levels of rheumatoid factor. This condition may be associated with
(IgM) and sometimes IgA and complement 3 (C3) deposits. IgG and a crescentic glomerulonephritis (CGN) that, on immunofluores-
C1q deposits are very rare. A correlation exists with the levels of cence, is negative for immunoglobulin and complement deposits,
rheumatoid factor; however, the underlying mechanism is unclear. as in Wegener’s granulomatosis. The best treatment consists of
Clinically, MPGN is characterized by hematuria and proteinuria. cyclophosphamide and prednisone. References 93 and 94 provide
Membranous glomerulopathy (MGN) in rheumatoid arthritis is more details on renal involvement in rheumatoid arthritis. Because
mostly associated with gold or D-penicillamine treatment. MGN the histologic abnormalities are not specific for rheumatoid arthritis,
is seen more frequently in patients after therapy with D-penicil- no histologic examples are given. They can be found elsewhere in
lamine (7–14%) than after gold therapy (3–9%). When a patient this book. (Data from Emery and Adu [94].)
FIGURE 11-49
RENAL MANIFESTATIONS IN SJÖGREN’S SYNDROME The clinical manifestations of the tubulointerstitial nephritis in
Sjögren’s syndrome can vary and depend on localization of the
functional impairment. Occasionally, symptoms of tubular dysfunc-
Manifestation % tion precede development of symptoms of Sjögren’s syndrome. It is
unclear what causes these tubular dysfunctions. When the degree
Interstitial nephritis with or without tubular dysfunction 30–60 of tubulointerstitial damage is not chronic, corticosteroids are benefi-
Tubular dysfunction (distal > proximal) associated with 20–25 cial. Glomerular involvement is rare in Sjögren’s syndrome. When
interstitial infiltrates and granuloma formation a glomerulonephritis is present, the patient should be evaluated for
Clinical symptoms: the presence of cryoglobulins and existence of systemic lupus ery-
Type 1 renal tubular acidosis thematosus. Reference 95 provides a more detailed description of
Fanconi’s syndrome this subject.
Nephrogenic diabetes insipidus
Hypokalemia
Glomerulonephritis 3–5
Mesangiocapillary glomerulonephritis
Membranous glomerulonephritis
Vasculitis <5
Mostly extrarenal (skin, muscle, nerve);
occasionally in the kidney
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, 60–70% Diffuse form of scleroderma Acute onset Prevention of reduction of renal perfusion
Based on clinical symptoms, 30–50% Rapid progression of skin lesions Marked to severe (malignant) hypertension (eg, dehydration, diuretics, cyclosporin A,
Scleroderma renal crisis, 10–15% HLA BW35, DR3, DR5 (10% of patients remain normotensive) nonsteroidal anti-inflammatory drugs)
Race (Blacks > whites) Features of malignant hypertension Angiotensin-converting enzyme inhibitors
Micro-angiopathic hemolytic anemia and (even in patients with normotension)
Use of corticosteroids or cyclosporine A?
thrombopenia Renal replacement therapy
Cold exposure ?
Mostly normal urinary sediment
(in cases with malignant hypertension
hematuria possible)
Progressive decline of renal function
FIGURE 11-50
The main features of renal involvement in scleroderma are summa- the mainstay of treatment for patients with scleroderma renal crisis,
rized. The major manifestation is the so-called renal crisis. Besides because it will significantly reduce progression to renal failure,
this often life-threatening manifestation, other patients may display increase the chance of recovery if renal failure has already developed,
milder forms of renal involvement, clinically characterized by mild and improve the 1-year patient survival rate. Renal replacement ther-
proteinuria or slight deterioration of kidney function. Renal involve- apy (hemodialysis or continuous ambulatory peritoneal dialysis)
ment is more common in patients with the diffuse form of scleroder- should be offered to patients whose renal function does not recover.
ma that is serologically characterized by antibodies against topoiso- The patient survival rate, however, is lower than in patients with
merase I or RNA polymerase III. Patients with progressive skin dis- other collagen-vascular diseases such as lupus nephritis. Limited
ease should be monitored carefully for hypertension and signs of experience with renal transplantation indicates that successful trans-
renal involvement. Early institution of angiotensin-converting enzyme plantation is possible, especially in patients with quiescent disease.
(ACE) inhibition in patients with micro-albuminuria can prevent fur- Recurrence in the transplanted kidney has been reported [84].
ther deterioration of kidney function [96,97]. ACE inhibition is also 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 narrow-
ing 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 (malig-
nant hypertension) or hemolytic-uremic syn-
drome. 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.
A B

C, Severe intimal fibrosis of a medium-sized artery of a more
chronic phase of scleroderma. (Panel A, methenamine silver, origi-
nal magnification 100. Panel B, alcian blue stain, original magni-
fication 100. Panel C, cellulose acetate butyrate stain, original
magnification 150.)
References
1. Tan EM, Cohen AS, Fries JF, et al.: The 1982 revised criteria for the 15. Mohan C, Adams S, Stanik V, Datta SK: Nucleosome, a major
classification of systemic lupus erythematosus. Arthritis Rheumatol immunogen for pathogenic autoantibody-inducing T cells of lupus.
1982, 25:1271–1277. J Exp Med 1993, 177:1367–1381.
2. Maddison PJ: Systemic lupus erythematosus variants. In Slide Atlas of 16. Kaliyaperumal A, Mohan C, Wu W, Datta SK: Nucleosomal peptide
Rheumatology. Edited by Dieppe PA, Bacon PA, Bamji AN, Watt I. epitopes for nephritis-inducing T helper cells of murine lupus. J Exp
London: Gower; 1984:9.1–9.14. Med 1996, 183:2459–2469.
3. Aarden LA, De Groot ER, Feltkamp TEW: Immunology of DNA. III. 17. Burlingame RW, Rubin RL, Balderas RS, Theofilopoulos AN: Genesis
Crithidia luciliae: a simple substrate for the detection of anti-dsDNA and evolution of anti-chromatin autoantibodies in murine lupus impli-
with the immunofluorescence technique. Ann NY Acad Sci 1975, cates T-dependent immunization with self antigen. J Clin Invest 1993,
254:505–509. 91:1687–1696.
4. Smeenk RJT, Berden JHM, Swaak AJG: dsDNA autoantibodies. In 18. Amoura Z, Chabre H, Koutouzov S, et al.: Nucleosome-restricted
Autoantibodies. Edited by Peter JB, Shoenfeld Y. Amsterdam: Elsevier; antibodies are detected before anti-dsDNA and/or antihistone anti-
1996:227–236.
bodies in serum of MRL-Mp lpr/lpr and +/+ mice, and are present in
5. Klippel JH, Croft JD: Systemic lupus erythematosus. In Slide Atlas of kidney eluates of lupus mice with proteinuria. Arthritis Rheumatol
Rheumatology. Edited by Dieppe PA, Bacon PA, Bamji AN, Watt I. 1994, 37:1684–1688.
London: Gower; 1984:8.1–8.14.
19. Burlingame RW, Boey ML, Starkebaum G, Rubin RL: The central role
6. ter Borg EJ, Horst G, Hummel EJ, et al.: Predictive value of rises in of chromatin in autoimmune responses to histones and DNA in sys-
anti–double-stranded DNA antibody levels for disease exacerbations temic lupus erythematosus. J Clin Invest 1994, 94:184–192.
in systemic lupus erythematosus: a long term prospective study.
Arthritis Rheumatol 1990, 33:634–643. 20. Chabre H, Amoura Z, Piette JC, et al.: Presence of nucleosome-
restricted antibodies in patients with systemic lupus erythematosus.
7. Verheyen R, Salden M, Van Venrooij WJ: Protein blotting. In Manual
Arthritis Rheumatol 1995, 38:1485–1491.
of Biological Markers of Disease. Edited by van Venrooij WJ, Maini
RN. Dordrecht: Kluwer; 1997:A4.1–A4.25. 21. Kramers C, Hylkema MN, van Bruggen MCJ, et al.: Anti-nucleosome
antibodies complexed to nucleosomal antigens show anti-DNA reac-
8. Van Venrooij WJ, De Rooij DJ, van de Putte LBA, Habets WJ: De
serologische herkenning van gedefinieerde kernantigenen bij collageen- tivity and bind to rat glomerular basement membrane in vivo. J Clin
ziekten: immunoblotting als nieuw diagnostisch middel. Ned Tijdschr Invest 1994, 94:568–577.
Geneeskd 1985, 129:1124–1129. 22. van Bruggen MCJ, Kramers C, Hylkema MN, et al.: Significance of anti-
9. Watanabe-Fukunaga R, Brannan CI, Copeland NG, et al.: Lympho- nuclear and anti-extra cellular matrix auto-antibodies for albuminuria in
proliferation disorder in mice explained by defects in Fas antigen that MRL/l mice. A longitudinal study on plasma and glomerular eluates.
mediates apoptosis. Nature 1992, 356:314–317. Clin Exp Immunol 1996, 105:132–139.
10. Singer GG, Carrera AC, Marshak-Rothstein A, et al.: Apoptosis, Fas 23. van Bruggen MCJ, Kramers C, Walgreen B, et al.: Nucleosomes and
and systemic autoimmunity: the MRL/lpr model. Curr Opinion histones are present in glomerular deposits in human lupus nephritis.
Immunol 1994, 6:913–920. Nephrol Dial Transplant 1997, 12:57–66.
11. Tax WJM, Kramers C, van Bruggen MCJ, Berden JHM: Apoptosis, 24. van den Born J, van den Heuvel LPWJ, Bakker MAH, et al.:
nucleosomes, and nephritis in systemic lupus erythematosus. Kidney Distribution of GBM heparan sulphate proteoglycan core protein and
Int 1995, 48:666–673. side chains in human glomerular diseases. Kidney Int 1993, 43:454–463.
1. Berden JHM: Systemic lupus erythematosus: disturbed apoptosis? 25. van Bruggen MCJ, Kramers C, Hylkema MN, et al.: Decrease of
Ned Tijdschr Geneeskd 1997, 141:1848–1854. heparan sulfate staining in the glomerular basement membrane in
13. Rumore PM, Steinman CR: Endogenous circulating DNA in systemic murine lupus nephritis. Am J Pathol 1995, 146:753–763.
lupus erythematosus. Occurrence as multimeric complexes bound to 26. van Bruggen MCJ, Walgreen B, Rijke GPM, et al.: Heparin and
histone. J Clin Invest 1990, 86:69–74. heparinoids prevent the binding of immune complexes containing
14. Berden JHM: Lupus nephritis. Nephrology Forum. Kidney Int 1997, nucleosomal antigens to the GBM and delay nephritis in MRL/l mice.
52:538–558. Kidney Int 1996, 50:1555–1564.
27. Strasser A, Whittingham S, Vaux DL, et al.: Enforced bcl-2 expression in 49. Austin III HA, Muenz LR, Joyce KM, et al.: Diffuse proliferative
B-lymphoid cells prolongs antibody responses and exhibits autoimmune lupus nephritis: identification of specific pathologic features affecting
diseases. Proc Natl Acad Sci USA 1991, 88:8661–8665. renal outcome. Kidney Int 1984, 25:689–695.
28. Mysler E, Bini P, Drappa J, et al.: The apoptosis-1/Fas protein in human 50. Appel GB, Silva FG, Pirani CL, et al.: Renal involvement in systemic
systemic lupus erythematosus. J Clin Invest 1994, 93:1029–1034. lupus erythematosus. Medicine 1975, 57:371–410.
29. Lorenz H, Gruenke M, Hieronymus T, et al.: In vitro apoptosis and 51. Sloan RP, Schwartz MM, Korbet SM, Borok RZ, and the Lupus
expression of apoptosis related molecules in lymphocytes from Nephritis Collaborative Study Group: Long-term outcome in systemic
patients with systemic lupus erythematosus and other autoimmune lupus erythematosus membranous glomerulonephritis. J Am Soc
diseases. Arthritis Rheumatol 1997, 40:306–317. Nephrol 1996, 7:299–305.
30. Cheng J, Zhou T, Liu C, et al.: Protection from Fas-mediated apoptosis 52. Bruns FJ, Adler S, Fraley DS, Segel DP: Sustained remission of mem-
by a soluble form of the Fas molecule. Science 1994, 263:1759–1762. branous glomerulonephritis after cyclophosphamide and prednisone.
Ann Intern Med 1991, 114:725–730.
31. Goel N, Ulrich DT, St.Clair EW, et al.: Lack of correlation between
serum soluble Fas/APO-1 levels and autoimmune disease. Arthritis 53. Reichert LJM, Huysmans FTM, Assmann KJM, et al.: Preserving
Rheumatol 1995, 38:1738–1743. renal function in patients with membranous nephropathy: daily oral
chlorambucil compared with intermittent monthly pulses of
32. Knipping E, Krammer PH, Onel KB, et al.: Levels of soluble Fas/APO- cyclophosphamide. Ann Intern Med 1994, 121:328–333.
1/CD95 in systemic lupus erythematosus and juvenile rheumatoid
arthritis. Arthritis Rheumatol 1995, 38:1735–1737. 54. Falk RJ, Hogan SL, Muller KE, Jenette C, and the Glomerular Disease
Collaborative Network: Treatment of progressive membranous
33. Emlen W, Niebur J, Kadera R: Accelerated in vitro apoptosis of lym- glomerulopathy. A randomized trial comparing cyclophosphamide
phocytes from patients with systemic lupus erythematosus. J Immunol and corticosteroids with corticosteroids alone. Ann Intern Med 1992,
1994, 152:3685–3692. 116:438–445.
34. Kovacs B, Vassilopoulos D, Vogelgesang SA, Tsokos GC: Defective CD3- 55. Appel GB, Valeri A: The course and treatment of lupus nephritis. Ann
mediated cell death in activated T cells from patients with systemic lupus Rev Med 1994, 45:525–537.
erythematosus: role of decreased intracellular TNF-. Clin Immunol
56. Austin III HA, Klippel JH, Balow JE, et al.: Therapy of lupus nephri-
Immunopathol 1996, 81:293–302.
tis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med
35. Casciola-Rosen LA, Anhalt G, Rosen A: DNA-dependent protein kinase 1986, 314:614–619.
is one of a subset of autoantigens specifically cleaved early during apop-
57. Cameron JS: What is the role of long-term cytotoxic agents in the
tosis. J Exp Med 1995, 182:1625–1634.
treatment of lupus nephritis? J Nephrol 1993, 6:172–176.
36. Casiano CA, Martin SJ, Green DR, Tan EM: Selective cleavage of nuclear
58. Balow JE, Austin III HA, Muenz LR, et al.: Effect of treatment of the
autoantigens during CD95(Fas/APO-1)-mediated T cell apoptosis. J Exp
evolution of renal abnormalities in lupus nephritis. N Engl J Med
Med 1996, 183:765–770. 1984, 311:491–495.
37. Rosen A, Casciola-Rosen LA: Macromolecular substrates for the ICE- 59. Steinberg AD, Steinberg SC: Longterm preservation of renal function
like proteases during apoptosis. J Cell Biochem 1997, 64:50–54. in patients with lupus nephritis receiving treatment that includes
38. Casiano C, Tan EM: Recent developments in the understanding of anti- cyclophosphamide versus those treated with prednisone only. Arthritis
nuclear autoantibodies. Int Arch Allergy Immunol 1996, 111:308–313. Rheumatol 1991, 34:945–950.
39. Utz P, Hottelet M, Schur PH, Anderson P: Proteins phosphorylated 60. Esdaile JM, Levinton C, Federgreen W, et al.: The clinical and renal
during stress-induced apoptosis are common targets for autoantibody biopsy predictors of long term outcome in lupus nephritis. Q J Med
production in patients with systemic lupus erythematosus. J Exp Med 1989, 72:779–833.
1997, 185:843–854. 61. Ponticelli C, Zucchelli P, Moroni G, et al.: Long-term prognosis of
40. Cooke MS, Mistry N, Wood C, et al.: Immunogenicity of DNA dam- diffuse lupus nephritis. Clin Nephrol 1987, 28:263–271.
aged by reactive oxygen species. Implications for anti-DNA antibodies 62. Cameron JS, Turner BR, Ogg CS, et al.: Systemic lupus with nephritis:
in lupus. Free Rad Bio Med 1997, 22:151–159. a long term study. Q J Med 1979, 48:1–24.
41. Casciola-Rosen LA, Anhalt G, Rosen A: Autoantigens targeted in sys- 63. Bansal VK, Beto JA: Treatment of lupus nephritis: a meta-analysis of
temic lupus erythematosus are clustered in two populations of surface clinical trials. Am J Kidney Dis 1997, 29:193–199.
structures on apoptotic keratinocytes. J Exp Med 1994, 179:1317–1330. 64. Nossent HC, Henzen-Logmans SC, Vroom TM, et al.: Contribution
42. Jordan P, Kuebler D: Autoimmune diseases: nuclear autoantigens can of renal biopsy data in predicting outcome in lupus nephritis. Arthritis
be found at the cell surface. Mol Biol Rep 1996, 22:63–66. Rheumatol 1990, 33:970–977.
43. Hermann M, Voll RE, Zoller RM, et al.: Impaired phagocytosis of 65. Nossent JC, Swaak AJG, Berden JHM: Systemic lupus erythematosus:
apoptotic cell material by monocyte-derived macrophages from analysis of disease activity in 55 patients with end stage renal failure
patients with systemic lupus erythematosus. Arthritis Rheum 1998, treated with hemodialysis or continuous ambulatory peritoneal dialysis.
41:1241–1250. Am J Med 1990, 89:169–174.
44. Mamula MJ: Lupus autoimmunity: from peptides to particles. 66. Bombardier C, Gladman DD, Urowitz MB, et al.: Derivation of the
Immunol Rev 1995, 144:301–314. SLEDAI. A disease activity index for lupus patients. Committee on
45. Datta SK, Kaliyaperumal A: Nucleosome-driven autoimmune response Prognosis Studies in SLE. Arthritis Rheumatol 1992, 35:630–640.
in lupus. Pathogenic T helper cell epitopes and co-stimulatory signals. 67. Nossent JC: End stage renal disease in patients with systemic lupus
In B Lymphocytes and Autoimmunity. Edited by Chiorazzi N, Lahita erythematosus. In Lupus Nephritis. Edited by Lewis EJ. Oxford:
RG, Pavelka K, Ferrarini M. New York: New York Academy of Oxford University Press; 1998: in press.
Sciences; 1997:155–170. 68. Nossent JC, Swaak AJG, Berden JHM: Systemic lupus erythematosus
46. Churg J, Sobin LH: Lupus nephritis. In Renal Diseases. Classification after renal transplantation: patient and graft survival and disease
and Atlas of Glomerular Diseases. Edited by Churg J. Tokyo: Igaku- activity. Ann Intern Med 1991, 114:183–188.
Shoin; 1982:127–149. 69. Winearls CG: Acute myeloma kidney. Nephrology Forum. Kidney Int
47. Churg J, Bernstein J, Glassock RJ: Lupus nephritis. In Renal Diseases. 1995, 48:1347–1361.
Classification and Atlas of Glomerular Diseases, edn 2. Edited by Churg 70. Kyle RA: Multiple myeloma. Review of 869 cases. Mayo Clin Proc
J, Bernstein J, Glassock RJ. New York: Igaku-Shoin; 1995:151–180. 1975, 50:29–40.
48. D’Agati VD: Systemic lupus erythematosus. In Renal Biopsy 71. Alexanian R, Barlogie B, Dixon D: Renal failure in multiple myeloma.
Interpretation. Edited by Silva FG, D’Agati VD, Nadasdy T. New Pathogenesis and prognostic implications. Arch Int Med 1990,
York: Churchill Livingstone; 1996:181–220. 150:1693–1695.
72. Pruzanski W: Clinical manifestations of multiple myeloma: relation 85. Harrison KL, Alpers CE, Davis CL: De novo amyloidosis in a renal
to class and type of the M component. Can Med Assoc J 1976, allograft: a case report and review of the literature. Am J Kidney Dis
114:896–897. 1993, 22:468–476.
73. Gallo G, Kumar V: Hematopoietic disorders. In Renal Biopsy 86. Sammett D, Dagher F, Abbi R, et al.: Renal transplantation in multiple
Interpretation. Edited by Silva FG, D’Agati VD, Nadasdy T. New myeloma. Transplantation 1996, 62:1577–1580.
York: Churchill Livingstone; 1996:259–282. 87. Gerlag PGG, Koene RAP, Berden JHM: Renal transplantation in light
74. Enlitz M, Weiss DT, Solomon A: Immunoglobulin heavy-chain-associ- chain nephropathy: case report and review of the literature. Clin
ated amyloidosis. Proc Natl Acad Sci USA 1990, 87:6542–6546. Nephrol 1986, 25:101–104.
75. Preudhomme JL, Aucouturier P, Touchard G, et al.: Monoclonal 88. Varet B, Choukroun G, Grunfeld JP: Multiple myeloma. Part II: treat-
immunoglobulin deposition disease (Randall type). Relationship with ment. Nephron 1995, 70:18–20.
structural abnormalities of immunoglobulin chains. Kidney Int 1994, 89. Iskander SS, Falk RJ, Jenette JC: Clinical and pathologic features of
46:965–972. fibrillary glomerulonephritis. Kidney Int 1992, 42:1401–1407.
76. Sanders PW, Herrera GA: Monoclonal immunoglobulin light chain- 90. Fogo A, Qureshi N, Horn RG: Morphologic and clinical features of
related renal diseases. Semin Nephrol 1993, 13:324–341. fibrillary versus immunotactoid glomerulonephritis. Am J Kidney Dis
77. Buxbaum JN, Chuba JV, Hellman GC, et al.: Monoclonal immuno- 1993, 22:367–377.
globulin deposition disease: light chain and light and heavy chain 91. Alpers CE: Fibrillary glomerulonephritis and immunotactoid glomeru-
deposition diseases and their relation to light chain amyloidosis: clinical lopathy. Curr Opinion Nephrol Hyperts 1994, 3:349–355.
features, immunopathology, and molecular analyses. Ann Intern Med
92. Pasternack A, Ahonen J, Kuhlback B: Renal transplantation in 45
1990, 112:455–464.
patients with amyloidosis. Transplantation 1986, 42:598–601.
78. Autocouterier P, Khamlichi AA, Touchard G, et al.: Brief report: heavy- 93. Helin H, Korpela M, Mustonen J, Pasternack A: Rheumatoid arthritis
chain deposition disease. Nucl Acids Res 1993, 329:1389–1393. and ankylosing spondylitis. In The Kidney in Collagen-Vascular Diseases.
79. Solomon A, Weiss DT, Kattine AA: Nephrotoxic potential of Bence Edited by Grishman E, Churg J, Needle MA, Vankataseshan VS. New
Jones proteins. N Engl J Med 1991, 324:1845–1851. York: Raven Press; 1993:149–166.
80. Sanders PW, Booker BB: Pathobiology of cast nephropathy from 94. Emery P, Adu D: The patient with rheumatoid arthritis, mixed con-
human Bence Jones proteins. J Clin Invest 1992, 89:630–639. nective tissue disease or polymyositis. In Oxford Textbook of Clinical
81. Johnson WJ, Kyle RA, Pineda AA, et al.: Treatment of renal failure Nephrology, edn 2. Edited by Davison AM, Cameron JS, Grunfeld JP,
associated with multiple myeloma. Plasmapheresis, hemodialysis and et al. Oxford: Oxford University Press; 1998:975–993.
chemotherapy. Arch Intern Med 1990, 150:863–869. 95. Winer RL: Sjögren’s syndrome. In The Kidney in Collagen-Vascular
82. Zucchelli P, Pasquali S, Cagnoli L, Ferrari G: Controlled plasma Diseases. Edited by Grishman E, Churg J, Needle MA, Venkataseshan
exchange trial in acute renal failure due to multiple myeloma. Kidney VS. New York: Raven Press; 1993:179–187.
Int 1988, 33:1175–1180. 96. Donohue JF: Scleroderma and the kidney. Kidney Int 1992, 41:462–477.
83. Misiani R, Tiraboschi G, Mingardi G, Mecca G: Management of 97. Steen VD: Scleroderma renal crisis. Rheumatol Dis Clin North Am
myeloma kidney: an anti–light chain approach. Am J Kidney Dis 1996, 22:861–878.
1987, 10:28–33. 98. D’Agati VD, Cannon PJ: Scleroderma (systemic sclerosis). In The Kidney
84. Ramos EL, Tisher CC: Recurrent disease in the kidney transplant. in Collagen-Vascular Diseases. Edited by Grishman E, Churg J, Needle
Am J Kidney Dis 1994, 24:142–154. MA, Venkataseshan VS. New York: Raven Press; 1993:121–147.
Principles of Dialysis:
Diffusion, Convection,
and Dialysis Machines
Robert W. Hamilton
C
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, magne-
sium, 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-dihy-
droxycholecalciferol (calcitriol).
Dialysis procedures remove nitrogenous end-products of catabo-
lism and begin the correction of the salt, water, and acid-base derange-
ments 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, CHAPTER
anorexia, fatigability, diminished sensorium) and signs (pericardial
friction rub, refractory pulmonary edema, metabolic acidosis, foot or
1
wrist drop, asterixis) of uremia, dialysis treatments are urgently indicated.
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 Salt, water, and acid-base balance
Water balance Fluid retention and hyponatremia
Sodium balance Edema, congestive heart failure, hypertension
Potassium balance Hyperkalemia
Bicarbonate balance Metabolic acidosis, osteodystrophy
Magnesium balance Hypermagnesemia
Phosphate balance Hyperphosphatemia, osteodystrophy
Excretion of nitrogenous end products Excretion of nitrogenous end products
Urea ?Anorexia, nausea, pruritus, pericarditis, polyneuropa-
Creatinine thy, encephalopathy, thrombocytopathy
Uric acid
Amines
Guanidine derivatives
Endocrine-metabolic Endocrine-metabolic
Conversion of vitamin D to active metabolite Osteomalacia, osteodystrophy
Production of erythropoietin Anemia
Renin Hypertension
FIGURE 1-2
Statue of Thomas Graham in George
Square, Glasgow, Scotland. The physico-
FIGURE 1-1 chemical basis for dialysis was first
Functions of the kidney and pathophysiology of renal failure. 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
Blood Membrane Dialysate 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 concentra-
tion gradient. This is the principal process for removing the end-products of nitrogen
Na+ Na+ 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.
K+ K+
Ca2+ Ca2+
HCO3– HCO3–
Creatinine Creatinine
Urea Urea
Principles of Dialysis: Difusion, Convection, and Dialysis Machines 1.3
Acidified Bicarbonate Air

concentrate concentrate embolus
detector
Water
Pump Heater Pump Membrane unit
Patient
Conductivity
Mix 1 Mix 2 monitor
Volume
balance
Deaerator system
Blood
pump
Spent Spent Blood
dialysate leak
dialysate pump detector
Ultrafiltrate Heparin
Heat pump pump
Drain exchanger
FIGURE 1-4
Simplified schematic of typical hemodialysis system. In hemodialysis, pumps that mix a concentrated salt solution with water purified by
blood from the patient is circulated through a synthetic extracorporeal reverse osmosis and/or deionization to produce the dialysate, a means
membrane and returned to the patient. The opposite side of that of removing excess fluid from the blood (mismatching dialysate
membrane is washed with an electrolyte solution (dialysate) contain- inflow and outflow to the dialysate compartment), and a series of
ing the normal constituents of plasma water. The apparatus contains pressure, conductivity, and air embolus monitors to protect the
a blood pump to circulate the blood through the system, proportioning patient. Dialysate is warmed to body temperature by a heater.
FIGURE 1-5
Dialysate 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 manufac-
Blood Blood
turer. 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.
Dialysate 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
Blood the center of these fibers, and dialysate circulates around the outside
of the fibers but inside a plastic casing. Water for dialysis must meet
Dialysate
critical chemical and bacteriologic standards. These are listed in
Figures 1-6 and 1-7.
FIGURE 1-6
ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL Association for the Advancement of Medical Instrumentation
INSTRUMENTATION CHEMICAL STANDARD FOR (AAMI) chemical standards for water for hemodialysis. Before
WATER FOR HEMODIALYSIS hemodialysis can be performed, water analysis is performed.
Water for hemodialysis generally requires reverse osmosis treat-
ment and a deionizer for “polishing” the water. Organic materials,
Substance Concentration (mg/L) chlorine, and chloramine are removed by charcoal filtration.
(From Vlchek [2]; with permission.)
Aluminum 0.01
Arsenic 0.005
Barium 0.1
Cadmium 0.001
Calcium 2.0
Chloramine 0.1
Chlorine 0.5
Chromium 0.014
Copper 0.1
Fluoride 0.2
Lead 0.005
Magnesium 4.0
Mercury 0.0002
Nitrate 2.0
Potassium 8.0
Selenium 0.009
Silver 0.005
Sodium 70
Sulfate 100
Zinc 0.1
FIGURE 1-7
ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL Association for the Advancement of Medical Instrumentation
INSTRUMENTATION BACTERIOLOGIC STANDARDS (AAMI) bacteriologic standards for dialysis water and prepared
FOR DIALYSIS WATER AND PREPARED DIALYSATE 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
Colony-forming units/mL chloramine) have been removed in water treatment, the water is
prone to develop such problems if stagnation is allowed. (From
Dialysis water <200 Bland and Favero [3]; with permission.)
Prepared dialysate <2000
A = area of the boundary through which molecules move; dc = concentration

dn dc
= –DA gradient; and dx = distance through which molecules move. Hemodialysis depends
dt dx
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
FIGURE 1-8 travels, and the area through which diffusion takes place. For this reason those
Factors that govern diffusion, where dn/dt dialyzers that have a large surface area, thin membranes, and are designed to maximize
= the rate of movement of molecules per the effect of concentration gradient (countercurrent design) are most efficient at
unit time; D = Fick’s diffusion coefficient; removing solutes.
Principles of Dialysis: Difusion, Convection, and Dialysis Machines 1.5
kΤ 3 4πN
FIGURE 1-9
D=
6πη 3Μυ Fick’s diffusion constant, where D = Fick’s diffusion coefficient, k = Boltzman’s constant;
T = absolute temperature; = viscosity; N = Avogadro’s 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.
FIGURE 1-10
250 Effect of blood flow on clearance of various solutes, Fresenius F-5 membrane. The amount
Urea
Creatinine of solute cleared by a dialyzer depends on the amount delivered to the membrane. The
200 Phosphate usual blood flow is 300–400 mL/min, which is adequate to deliver the dialysis prescrip-
Clearance, mL/min
Vitamin B12 tion. On institution of dialysis to a very uremic patient the blood flow is decreased to 160
150 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
100 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).
50
0
0 100 200 300 400
Blood flow, mL/min
200 FIGURE 1-11

Hydrostatic ultrafiltration also takes place during hemodialysis.
Because the spent dialysate effluent pump (see Fig. 1-4) creates neg-
100 ative pressure on the dialysate compartment of the membrane unit
and the blood pump creates positive pressure in the blood compart-
ment, there is a net hydrostatic pressure gradient between the com-
partments. This causes a flow of water and dissolved substances
0
from blood to the dialysate compartment. The process of solute
Pressure, mmHg
transfer associated with this flow of water is called “convective

transport.” In hemodialysis, the amount of low–molecular weight
–100 solute (eg, urea) removed by convection is negligible. In the continu-
ous renal replacement therapies, this is a major mechanism for
solute transport.
–200
–300
–400
Blood Dialysate Net transmembrane
compartment compartment pressure
FIGURE 1-12
35 Dialysis membranes differ in their ability to remove fluid. Differences in ultrafiltration
30 coefficient (UFR) are shown for two different membranes, F-5 and F-50. The F-50 is
considered a high-flux membrane.
UFR, mL/h/mmHg
25
20
15
10
5
0
F–5 F–50
References
1. Graham T: The Bakerian lecture—on osmotic force. Philos Trans R 3. Bland LA, Favero MS: Microbiologic aspects of hemodialysis systems. In
Soc Lond 1854, 144:177–228. AAMI Standards and Recommended Practices, vol. 3. Arlington, VA:
2. Vlchek DL: Monitoring a hemodialysis water treatment system. In AAMI Association for the Advancement of Medical Instrumentation; 1993:257–265.
Standards and Recommended Practices, vol. 3. Arlington, VA: Association 4. Daniels F, Alberty RA: Physical Chemistry. New York : John Wiley &
for the Advancement of Medical Instrumentation; 1993:267–277. Sons; 1955.
Dialysate Composition
in Hemodialysis and
Peritoneal Dialysis
Biff F. Palmer
T
he goal of dialysis for patients with chronic renal failure is to
restore the composition of the body’s 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 nonphysio-
logic 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 over-
load 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 dur-

CHAPTER
ing dialysis. It soon became apparent that changes in the serum sodium
2
concentration—and 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

fluid shift from the extracellular space to the intracellular erbate hemodynamic instability during the dialysis procedure
[21]. In this regard, the intradialysis drop in blood pressure
space, thus exacerbating the volume-depleting effects of dialy- noted in patients dialyzed against a low-calcium bath, while
sis. With the advent of high-clearance dialyzers and more effi- statistically significant, is minor in degree [22,23]. Nevertheless,
for patients who are prone to intradialysis hypotension avoid-
cient dialysis techniques, this decline in plasma osmolality ing low calcium dialysate concentration may be of benefit. On
the other hand, the use of a lower calcium concentration in the
becomes more apparent, as solute is removed more rapidly. dialysate allows the use of increased doses of calcium-containing
phosphate binders and lessens dependence on binders containing
Use of dialysate of low sodium concentration would tend fur-
aluminum. In addition, use of 1,25-dihydroxyvitamin D can be
ther to enhance the intracellular shift of fluid, as plasma tends liberalized to reduce circulating levels of parathyroid hormone
and, thus, the risk of inducing hypercalcemia. With dialysate
to become calcium concentrations below 1.5 mmol/L, however, patients
need close monitoring to ensure that negative calcium balance
even more hyposmolar consequent to the movement of sodi-
does not develop and that parathyroid hormone levels remain
um from in an acceptable range [24].
plasma to dialysate. The use of a higher sodium concentration Dialysate Composition for Peritoneal Dialysis
To meet the ultrafiltration requirements of patients on peritoneal
dialysate (>140 mEq/L) has been among the most efficacious
dialysis, the peritoneal dialysate is deliberately rendered hyper-
and best tolerated therapies for episodic hypotension [1–3]. osmolar relative to plasma, to create an osmotic gradient that
favors net movement of water into the peritoneal cavity. In
The high sodium concentration prevents a marked decline in commercially available peritoneal dialysates, glucose serves as
the osmotic agent that enhances ultrafiltration. Available con-
the plasma osmolality during dialysis, thus protecting the extra- centrations range from 1.5% to 4.25% dextrose. Over time, the
cellular volume by minimizing osmotic fluid loss into the cells. osmolality of the dialysate declines as a result of water moving
In the early 1960s acetate became the standard dialysate into the peritoneal cavity and of absorption of dialysate glucose.
buffer for correcting uremic acidosis and offsetting the diffusive The absorption of glucose contributes substantially to the calorie
losses of bicarbonate during hemodialysis. Over the next several intake of patients on continuous peritoneal dialysis. Over time,
years reports began to accumulate that linked routine use of this carbohydrate load is thought to contribute to progressive
acetate with cardiovascular instability and hypotension during obesity, hypertriglyceridemia, and decreased nutrition as a
dialysis. As a result, dialysate containing bicarbonate began to result of loss of appetite and decreased protein intake. In addition,
re-emerge as the principal dialysate buffer, especially as advances the high glucose concentrations and high osmolality of currently
in biotechnology made bicarbonate dialysate less expensive and available solutions may have inhibitory effects on the function
less cumbersome to use. For the most part, the bicarbonate con- of leukocytes, peritoneal macrophages, and mesothelial cells
centration used consistently in most dialysis centers is 35 [25]. In an attempt to develop a more physiologic solution, various
mmol/L. Emphasis is now being placed on individually adjusting new osmotic agents are now under investigation. Some of these
the dialysate bicarbonate concentration so as to maintain the may prove useful as alternatives to the standard glucose solutions.
predialysis tCO2 concentration above 23 mmol/L [12–16]. Those that contain amino acids have received the most attention.
Increasing evidence suggests that correction of chronic acidosis The sodium concentration in the ultrafiltrate during peri-
is of clinical benefit in terms of bone metabolism and nutrition. toneal dialysis is usually less than that of extracellular fluid, so
Dialysis assumes a major role in the maintenance of a normal there is a tendency toward water loss and development of hyper-
serum potassium concentration in patients with end-stage renal natremia. Commercially available peritoneal dialysates have a
disease. Excess potassium is removed by using a dialysate with a sodium concentration of 132 mEq/L to compensate for this ten-
lower potassium concentration, so that a gradient is achieved dency toward dehydration. The effect is more pronounced with
that favors movement of potassium. In general, one can expect increasing frequency of exchanges and with increasing dialysate
only up to 70 to 90 mEq of potassium to be removed during a glucose concentrations. Use of the more hypertonic solutions
typical dialysis session. As a result, one should not overestimate and frequent cycling can result in significant dehydration and
the effectiveness of dialysis in the treatment of severe hyper- hypernatremia. As a result of stimulated thirst, water intake and
kalemia. The total amount removed varies considerably and is weight may increase, resulting in a vicious cycle.
affected by changes in acid-base status, in tonicity, in glucose and Potassium is cleared by peritoneal dialysis at a rate similar to
insulin concentration, and in catecholamine activity [17–20]. that of urea. With chronic ambulatory peritoneal dialysis and
The concentration of calcium in the dialysate has implications 10 L of drainage per day, approximately 35 to 46 mEq of potas-
for metabolic bone disease and hemodynamic stability. Like the sium is removed per day. Daily potassium intake is usually
other constituents of the dialysate, the calcium concentration greater than this, yet significant hyperkalemia is uncommon in
should be tailored to the individual patient [21]. Some data suggest these patients. Presumably potassium balance is maintained by
that lowering the dialysate calcium concentration would exac- increased colonic secretion of potassium and by some residual
Dialysate Composition in Hemodialysis and Peritoneal Dialysis 2.3
renal excretion. Given these considerations, potassium is not absorption. The pH of commercially available peritoneal dialysis
routinely added to the dialysate. solutions is purposely made acidic by adding hydrochloric acid
The buffer present in most commercially available peritoneal to prevent dextrose from caramelizing during the sterilization
dialysate solutions is lactate. In patients with normal hepatic procedure. Once instilled, the pH of the solution rises to values
function, lactate is rapidly converted to bicarbonate, so that greater than 7.0. There is some evidence that the acidic pH of
each mM of lactate absorbed generates one mM of bicarbonate. the dialysate, in addition to the high osmolality, may impair the
Even with the most aggressive peritoneal dialysis there is no host’s peritoneal defenses [25,26].
appreciable accumulation of circulating lactate. The rapid To avoid negative calcium balance—and possibly to suppress
metabolism of lactate to bicarbonate maintains the high circulating parathyroid hormone—commercially available peri-
dialysate-plasma lactate gradient necessary for continued toneal dialysis solutions evolved to have a calcium concentration
150
Baseline Low-sodium dialysate High-sodium dialysate Step
Linear
Interstitial Exponential
space
BUN H2O BUN H2O
Cell Cell
Intravascular Decreased Stable osmolality

Na concentration, mEq/L
space osmolality
BUN H2O 145

BUN Na H2O
• Less vascular refilling
•↓Peripheral vasoconstriction
•Exacerbated autonomic
insufficiency
-inhibits afferent sensing
-↓ CNS efferent outflow
•Venous pooling secondary
to ↑ PGE2
140
Hypotension
1 2 3 4
Time, h
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 of administered calcium, contributing to the development of
most patients treated with a conventional chronic ambulatory hypercalcemia. As a result, there has been increased interest in
peritoneal dialysis regimen. As the use of calcium-containing using a strategy similar to that employed in hemodialysis,
phosphate binders has increased, hypercalcemia has become a namely, lowering the calcium content of the dialysate. This
common problem when utilizing the 3.5 mEq/L calcium strategy can allow increased use of calcium-containing phosphate
dialysate. This complication has been particularly common in binders and more liberal use of 1,25-dihydroxyvitamin D to
patients treated with peritoneal dialysis, since they have a much effect decreases in the circulating level of parathyroid hormone.
greater incidence of adynamic bone disease than do hemodialysis In this way, development of hypercalcemia can be minimized.
patients [27]. In fact, the continual positive calcium balance
associated with the 3.5-mEq/L solution has been suggested to
Dialysate Na in Hemodialysis
be a contributing factor in the development of this lesion. The
low bone turnover state typical of this disorder impairs accrual
FIGURE 2-1
INDICATIONS AND CONTRAINDICATIONS FOR USE Use of a low-sodium dialysate is more often associated with intra-
OF SODIUM MODELING (HIGH/LOW PROGRAMS) dialysis 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
Indications refilling of the intravascular space. This intracellular movement of
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
Dialysate Buffer in Hemodialysis

Acid concentrate
water, combined with removal of water by ultrafiltration, leads to contraction of the
intravascular space and contributes to the development of hypotension. High-sodium
NaCl dialysate helps to minimize the development of hypo-osmolality. As a result, fluid can be
CaCl mobilized from the intracellular and interstitial compartments to refill the intravascular
KCL
MgCl space during volume removal. Other potential mechanisms whereby low-sodium dialysate
Acetic acid contributes to hypotension are indicated. Na—sodium; BUN—blood urea nitrogen;
Dextrose PGE2—prostaglandin E2.
Final dialysate FIGURE 2-2
NaHCO3 Na 137 mEq/L There has been interest in varying the concentration of sodium (Na) in the dialysate during
concentrate Cl 105 mEq/L the dialysis procedure so as to minimize the potential complications of a high-sodium solution
NaHCO3 Ca 3.0 mEq/L
Acetate 4.0 mEq/L and yet retain the beneficial hemodynamic effects. A high sodium concentration dialysate is
K 2.0 mEq/L used initially and progressively the concentration is reduced toward isotonic or even hypo-
HCO3 33 mEq/L
Mg 0.75 mEq/L
Pure H2O Dextrose 200 mg/dl
H 2O
tonic levels by the end of the procedure. The concentration of sodi-

um can be reduced in a linear, exponential, or step pattern. This
MECHANISMS BY WHICH ACETATE BUFFER
method of sodium control allows for a diffusive sodium influx early
CONTRIBUTES TO HEMODYNAMIC INSTABILITY
in the session to prevent a rapid decline in plasma osmolality sec-
ondary to efflux of urea and other small-molecular weight solutes.
During the remainder of the procedure, when the reduction in
Directly decreases peripheral vascular resistance in approximately 10% of patients osmolality accompanying urea removal is less abrupt, the dialysate
Stimulates release of the vasodilator compound interleukin 1 is sodium level is set lower, thus minimizing the development of
Induces metabolic acidosis via bicarbonate loss through the dialyzer
Produces arterial hypoxemia and increased oxygen consumption
?Decreased myocardial contractility
hypertonicity and any resultant excessive thirst, fluid gain, and hypertension in the interdialysis period. In some but not all studies, sodi-
um modeling has been shown to be effective in treating intradialysis hypotension
and cramps [5-11].

Start hemodialysis FIGURE 2-3
5.0 Indications and contraindications for use of sodium modeling
(high/low programs). Use of a sodium modeling program is not indi-
cated in all patients. In fact most patients do well with the dialysate
4.5 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.
Plasma potassium, mM
4.0
3.5
3.0
End hemodialysis
2.5
0 1 2 3 4 5
Time, h
FACTORS RELATED TO DIALYSIS THAT AFFECT Dialysis Dialysis

membrane membrane
DISTRIBUTION OF POTASSIUM BETWEEN CELLS
AND THE EXTRACELLULAR FLUID
K+ K+ K+ K+ Less K
removal
Factors that enhance cell potassium uptake
Insulin A B
Glucose-containing dialysate
2-adrenergic receptor agonists Correction of metabolic acidosis
Alkalemia during hemodialysis
Factors that reduce cell potassium uptake or increase potassium efflux Pre-dialysis treatment with β-stimulants
2-adrenergic receptor blockers
Acidemia (mineral acidosis) concentrate reacts with an equimolar amount of bicarbonate to
Hypertonicity generate carbonic acid and carbon dioxide. The generation of car-
-adrenergic receptor agonists bon dioxide causes the pH of the final solution to fall to approxi-
mately 7.0–7.4. The acidic pH and the lower concentrations in the
final mixture allow the calcium and magnesium to remain in solu-
tion. The final concentration of bicarbonate in the dialysate is
FIGURE 2-4 approximately 33–38 mmol/L.
The current utilization of a bicarbonate dialysate requires a special-
ly designed system that mixes a bicarbonate and an acid concen-
trate 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
FIGURE 2-5
Mechanisms by which acetate buffer contributes to hemodynamic

Step 1: Control serum Step 2: Normalize Step 3: Control instability. Although bicarbonate is the standard buffer in use
phosphate serum calcium secondary today, hemodynamically stable patients can be dialyzed safely using
hyperparathyroidism as acetate-containing dialysis solution. Since muscle is the primary
Low-phosphate diet If calcium is still low
(800–1000 mg/d) after control of Treat with 1,25(OH)2 site of metabolism of acetate, patients with reduced muscle mass
Phophate binders phosphate, treat with vitamin D tend to be acetate intolerant. Such patients include malnourished
1,25-(OH)2 vitamin D and elderly patients and women.
Use calcium-containing
phosphate binders
1.0–1.5 g dietary calcium
Dialysate Potassium in
Hemodialysis
Individualize
dialysate calcium
Low-calcium dialysate Low-calcium dialysate

High-calcium dialysate
Helps prevent hypercalcemia Promotes positive

secondary to high-dose calcium balance
calcium containing phosphate Suppresses parathyroid
binders and vitamin D hormone levels
Better hemodynamic stability
Monitor for negative
Risk of hypercalcemia
calcium balance ? Risk of adynamic bone disease
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
Decreased (rarely used) Less interdialytic weight gain Intradialytic hypotension and cramping more common
Calcium:
Increased Suppression of PTH, promotes hemodynamic stability in HD Hypercalcemia with vitamin D and high-dose calcium-containing
phosphate binders, ? contribution to adynamic bone disease in PD
Decreased Permits greater use of vitamin D and calcium containing Potential for negative calcium balance, stimulation of PTH,
phosphate binders slight decrease in hemodynamic stability
Potassium:
Increased Less arrhythmias in setting of digoxin or coronary heart disease Limited by hyperkalemia
? improved hemodynamic stability
Decreased Permits greater dietary intake of potassium with less hyperkalemia Increased arrhythmias, may exacerbate autonomic insufficiency
? improvement in myocardial contractility
Bicarbonate:
Increased Corrects chronic acidosis thereby benefits nutrition and bone metabolism Post-dialysis metabolic alkalosis
Decreased Less metabolic alkalosis Potential for chronic acidosis
Magnesium:
Increased ? Less arrhythmias, ? hemodynamic benefit Potential for hypermagnesemia
Decreased Permits greater use of magnesium containing phosphate binders which in tum Symptomatic hypomagnesemia
permits reduced dose of calcium binders and results in less hypercalcemia
Plasma potassium concentration can be expected to fall rapidly in the early stages of dialy-
sis, 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.
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
COMPOSITION OF A
disequilibrium is created. The rate of potassium removal is largely a function of its predialysis
COMMERCIALLY AVAILABLE
concentration. The higher the initial plasma concentration, the greater is the plasma-dialysate
PERITONEAL 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
Solute Dianeal PD-2 attempt to re-establish the intracellular-extracellular potassium gradient.
Sodium, mEq/L 132 FIGURE 2-7
Potassium, mEq/L 0
Chloride , mEq/L 96
Calcium , mEq/L 3.5
Magnesium, mEq/L 0.5
D, L-Lactate, mEq/L 40
Glucose, g/dL 1.5, 2.5, 4.25
Osmolality 346, 396, 485
pH 5.2
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 mech-
anisms are of particular importance in patients with end-stage FIGURE 2-8

renal disease since the major route of potassium excretion During a typical dialysis session approximately 80 to 100 mEq/L
is eliminated from the body by residual renal clearance and of potassium is removed from the body. A, Potassium (K) flux from
enhanced gastrointestinal excretion. 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 con-
trolled by a number of factors that can be modified during the dial-
ysis 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
H
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 2-
microglobulin 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 well-
defined. 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
Dialyzers
FIGURE 3-2
50
HIGH-PERFORMANCE EXTRA- The four high-
CORPOREAL THERAPIES FOR performance extra-
END-STAGE RENAL DISEASE corporeal therapies
40
for end-stage renal
disease are listed [2].
30 High-efficiency hemodialysis
Centers, %
High-flux hemodialysis
Hemofiltration, intermittent
20 Hemodiafiltration, intermittent
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.)
FIGURE 3-3
DEFINITIONS OF FLUX, PERMEABILITY, AND EFFICIENCY Definitions of flux, permeability, and efficiency. The urea value KoA,
as conventionally defined in hemodialysis, is an estimate of the clear-
ance of urea (a surrogate marker of low molecular weight uremic
Flux toxins) under conditions of infinite blood and dialysate flow rates.
Measure of ultrafiltration capacity The following equation is used to calculate this value:
Low and high flux are based on the ultrafiltration coefficient (Kuf)
QbQd 1-Kd/Qb
KoA= ln
Low flux: Kuf <10 mL/h/mm Hg
Qb-Qd 1-Kd/Qd
where Ko = mass transfer coefficient
High flux: Kuf >20 mL/h/mm Hg
A = surface area
Permeability
Qb = blood flow rate
Measure of the clearance of the middle molecular weight molecule (eg, 2-microglobulin)
Qd = dialysate flow rate
General correlation between flux and permeability
ln = natural log
Low permeability: 2-microglobulin clearance <10 mL/min
Kd = mean of blood and dialysate side urea clearance
High permeability: 2-microglobulin clearance >20 mL/min As conventionally defined in hemodialysis, flux is the rate of water
Efficiency transfer across the hemodialysis membrane. Dissolved solutes are
Measure of urea clearance removed by convection (solvent drag effect).
Low and high efficiency are based on the urea KoA value Permeability is a measure of the clearance rate of molecules of
Low efficiency: KoA <500 mL/min middle molecular weight, sometimes defined using 2-microglobulin
High efficiency: KoA >600 mL/min (molecular weight, 11,800 D) as the surrogate [3,4]. Dialyzers that
permit 2-microglobulin clearance of over 20 mL/min under usual
Ko—mass transfer coefficient; A—surface area. clinical flow and ultrafiltration conditions have been defined as high-
permeability 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 3.3
FIGURE 3-4
1000
Theoretic KoA profile of high- and low-flux dialyzers and high-
High flux and low-efficiency dialyzers. Note that here the definition of KoA
100 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]. Ko—mass transfer coefficient; A—surface area. (From Cheung
10
KOA, mL/min
and Leypoldt [3]; with permission.)

Low flux
High efficiency
0.1 Low efficiency
0.01
10 100 1000 10,000 100,000
Solute molecular weight, D
FIGURE 3-5
CLASSIFICATION OF HIGH- Classification of high-performance dialysis. Some authors have defined high-efficiency
PERFORMANCE DIALYSIS 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].
High-efficiency low-flux hemodialysis
High-efficiency high-flux hemodialysis
Low-efficiency high-flux hemodialysis
400
CHARACTERISTICS OF HIGH-EFFICIENCY DIALYSIS
350 KOA=1000
Urea clearance rate, mL/min
300
Urea clearance rate is usually >210 mL/min
250
KOA=500 Urea KoA of the dialyzer is usually >600 mL/min
200 Ultrafiltration coefficient of the dialyzer (Kuf) may be high or low
Clearance of middle molecular weight molecules may be high or low
150
Dialysis can be performed using either cellulosic or synthetic membrane dialyzers
100
50 Ko—mass transfer coefficient; A—surface area.
0
0 50 150 250 350 450 500 FIGURE 3-7
Blood flow rate, mL/min 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
FIGURE 3-6 synthetic materials. Depending on the membrane material and surface
Comparison of urea clearance rates between low- and high-efficiency area, the removal of water (as measured by the ultrafiltration coeffi-
hemodialyzers (urea KoA = 500 and 1000 mL/min, respectively). cient or Kuf) and molecules of middle molecular weight (as measured
The urea clearance rate increases with the blood flow rate and by 2-microglobulin clearance) may be high or low [3,4,6,7].
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-efficien-
cy dialyzer cannot be exploited and the clearance rate is similar to
that of the low-flux dialyzer [3,6]. Ko—mass transfer coefficient;
A—surface area. (From Collins [6]; with permission.)
FIGURE 3-8
DIFFERENCES BETWEEN HIGH- AND Differences between high- and low-efficiency hemodialysis.
LOW-EFFICIENCY HEMODIALYSIS Conventional hemodialysis refers to low-efficiency low-flux
hemodialysis that was the popular modality before the 1980s [3,6].
High efficiency, mL/min Low efficiency, mL/min

Dialyzer KoA ≥600 <500
Blood flow ≥350 <350
Dialysate flow ≥500 <500
Bicarbonate dialysate Necessary Optimal
Ko—mass transfer coefficient; A—surface area.
TECHNICAL REQUIREMENTS CONCENTRATION OF DIALYSATE FACTORS INFLUENCING BLOOD

FOR HIGH-EFFICIENCY DIALYSIS IN HIGH-EFFICIENCY DIALYSIS FLOW IN HIGH-EFFICIENCY
HEMODIALYSIS
High-efficiency dialyzer Dialysate Concentration

Large surface area (A) Type of access
Sodium 139–145 mEq/L
High mass transfer coefficient (Ko) Native arteriovenous fistulae, polytetrafluoroethyl-
Potassium 0–4 mEq/L
Both (high KoA) ene grafts, twin catheter systems:
Acetate 2.5–4.5 mEq/L
High blood flow (≥350 mL/min) high blood flow rate, >350 mL/min
Bicarbonate 35–40 mEq/L
High dialysate flow (≥500 mL/min) Permanent catheters, temporary intravenous
Magnesium 1 mEq/L catheters: low blood flow rate, <350 mL/min
Bicarbonate dialysate
Calcium 2.5–3.5 mEq/L Needle design: size, thickness, and length
Glucose 0–200 mg/dL Blood tubing
Pump design
FIGURE 3-9
Technical requirements for high-efficiency FIGURE 3-10
dialysis. The KoA is the theoretic value of
Concentration of dialysate in high-efficiency FIGURE 3-11
the urea clearance rate under conditions of
dialysis. Although the concentration of Factors influencing blood flow in high-effi-
infinite blood and dialysate flow. High blood
other ions is variable, high bicarbonate ciency hemodialysis. Arteriovenous fistulae
and dialysate flow rates are necessary to
concentration, relative to that of acetate, often have blood flow rates of over 1000
achieve optimal performance of high-effi-
is essential for high-efficiency dialysis in mL/min, as measured by current noninvasive
ciency dialyzers. Bicarbonate-containing
order to minimize the transfer of acetate devices. Polytetrafluoroethylene grafts and
dialysate is necessary to prevent symptoms
into the patient. the newly introduced twin catheter systems
associated with acetate intolerance (ie, nausea,
vomiting, headache, and hypotension), also are capable of providing the blood
worsening of metabolic acidosis, and car- flow rates necessary for high-efficiency
diac arrhythmia [6,8,9]. Ko—mass transfer hemodialysis. In contrast, most other tem-
coefficient; A—surface area. porary 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 con-
tribute to this problem [8,9].
CAUSES OF HIGH-EFFICIENCY BENEFITS OF HIGH- LIMITATIONS OF HIGH-

DIALYSIS FAILURE EFFICIENCY DIALYSIS EFFICIENCY DIALYSIS
Access-related Higher clearance of small solutes, such as urea, Hemodynamic instability

Low blood flow rate compared with conventional dialysis without Low margin of safety if short treatment
High recirculation rate increase in treatment time time is prescribed
Time-related Better control of chemistry Potential vascular access damage
Patient not adherent to prescribed time Potentially reduced morbidity Dialysis disequilibrium syndrome
Staff not adherent to prescribed time Potentially higher patient survival rates
Failure to adjust time for conditions such as alarm,
dialysate bypass, and hypotension
FIGURE 3-14
FIGURE 3-13 Limitations of high-efficiency dialysis.
Benefits of high-efficiency dialysis. With Removal of a large volume of fluid over a
FIGURE 3-12 improved control of biochemical parameters short time period (2–2.5 h) increases the like-
Causes of high-efficiency dialysis failure. (such as potassium, hydrogen ions, phosphate, lihood of hypotension, especially in patients
The maintenance of a high blood flow rate urea, and other nitrogenous compounds) with poor cardiac function or autonomic
(>350 mL/min) is essential for high-efficiency the potential exists for reduced morbidity neuropathy. The loss of a fixed amount of
hemodialysis. Fistula recirculation, regardless and mortality without increasing dialysis treatment time has a proportionally greater
of the blood flow rate, compromises treatment time [5,7]. impact during a short treatment time than
achievement of the urea Kt/V goal. during a long treatment time. Thus, the
Interruptions during the prescribed short margin of safety is narrower if a short
treatment time further compromise the treatment time is used in conjunction with
overall delivery of the prescribed Kt/V [6,7]. high-efficiency dialysis compared with
K—urea clearance; t—time of therapy; conventional hemodialysis with a longer
V—volume of distribution. treatment time. Although unproved, high
blood flow rates may predispose patients to
vascular access damage. Rapid solute shifts
potentially precipitate the dialysis disequilib-
rium 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 Characteristics of high-flux dialysis. Because of the high ultrafiltra-
tion coefficients of high-flux membranes, high-flux dialysis requires
an automated ultrafiltration control system to avoid accidental
Dialyzer membranes are characterized by a high ultrafiltration coefficient profound intravascular volume depletion. Because high-flux mem-
(Kuf > 20 mL/h/mm Hg) branes tend to have larger pores, clearance of middle molecular
High clearance of middle molecular weight molecules occurs (eg, 2-microglobulin) weight molecules is usually high. Urea clearance rates for high-flux
Urea clearance can be high or low, depending on the urea KoA of the dialyzer dialyzers are still dependent on urea KoA values, which can be
Dialyzers are made of either synthetic or cellulosic membranes either high (ie, high-flux high-efficiency) or low (ie, high-flux low-
High-flux dialysis requires an automated ultrafiltration control system efficiency) [3,4,10]. Ko—mass transfer coefficient; A—surface area.
TECHNICAL REQUIREMENTS POTENTIAL BENEFITS OF LIMITATIONS OF

FOR HIGH-FLUX DIALYSIS HIGH-FLUX DIALYSIS HIGH-FLUX DIALYSIS
High-flux dialyzer Delayed onset and risk of dialysis-related amyloidosis Enhanced drug clearance, requiring supplemental
Automated ultrafiltration control system because of enhanced 2-microglobulin clearance dose after dialysis
[11,12] High cost of dialyzers
Increased patient survival resulting from higher
clearance of middle molecular weight molecules
[12,13,15,16]
FIGURE 3-16
Reduced morbidity and hospital admissions [14,16]
Technical requirements for high-flux dialysis. FIGURE 3-18
Improved lipid profile [16,17]
Because of the potential for reverse filtration Limitations of high-flux dialysis. The
Higher clearance of aluminum [18]
(movement of fluid from dialysate to the enhanced clearance of drugs depends on
Improved nutritional status [19,20]
blood compartment) to occur, use of a the physicochemical characteristics of
Reduced risk of infection [16,21]
pyrogen-free dialysate is preferred but not the specific drug and dialysis membrane.
Preserved residual renal function [22] Because of their relative high costs, high-
mandatory. Bicarbonate concentrate used
to prepare dialysate is particularly prone to flux dialyzers are usually reused.
bacterial overgrowth when stored for more
than 2 days [5,8].
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.
FIGURE 3-19
EXAMPLES OF COMMONLY USED DIALYZERS Examples of commonly used dialyzers.
“Efficiency” refers to the capacity to remove
urea; “flux” refers to the capacity to remove
Dialyzer type Material KoA (in vitro), mL/min water, and indirectly, the capacity to remove
Surface area, m2
molecules of middle molecular weight.
Low-flux low-efficiency Cellulosic membranes can be either low flux
CA90 Cellulose acetate 0.9 410 or high flux. Similarly, synthetic membranes
CF12 Cuprammonium 0.7 418 can be either low flux or high flux. High-
Low-flux high-efficiency efficiency membranes usually have large
CA150 Cellulose acetate 1.5 660 surface areas.
T150 Cuprammonium 1.5 730
High-flux low-efficiency
F50 Polysulfone 0.9 520
PAN 150P Polyacrylonitrile 1.0 420
High-flux high-efficiency
CT190 Cellulose triacetate 1.9 920
F80 Polysulfone 1.8 945
Ko—mass transfer coefficient; A—surface area.

Adapted from Leypoldt and coworkers [4] and Van Stone [22].
Solutes
Cb Cb Cb Postdilution
Ultrafiltrate
Solute flux
Fluid flux
Cd Solute flux
Predilution
Blood Membrane Ultrafiltrate Blood Membrane Ultrafiltrate
Blood

Solute transport in hemodialysis. The primary Solute clearance in hemofiltration. Fluid replacement in hemofiltration.
mechanism of solute transport in hemodialysis Hemofiltration achieves solute clearance Because hemofiltration achieves substan-
is diffusion, although convective transport by convection (or the solvent drag effect) tial solute clearance by removing large
is also contributory. Solutes small enough through the membrane. In contrast to volumes of plasma water (which contains
to pass through the dialysis membrane diffuse diffusive hemodialysis, fluid flux is a pre- the dissolved solutes), the removed fluid
down a concentration gradient from a higher requisite for the removal of solutes during must be replaced. The replacement fluid
plasma concentration (Cb) to a lower dialysate hemofiltration, whereas the concentration can be infused into the extracorporeal
concentration (Cd). The arrow represents gradient is not. For small solutes (eg, urea) circuit before the blood enters the filter
the direction of solute transport. that traverse the membrane unimpeded, (predilution, or replacement before expen-
concentrations in the blood compartment diture) or after the blood leaves the filter
(Cb) and ultrafiltrate compartment (Cuf) (postdilution). More replacement fluid is
are equivalent. For some molecules of mid- required when it is given before filtration
dle molecular weight whose movement rather than after to provide equivalent
across the membrane is partially restricted, solute clearance because the plasma in
Cuf is lower than is Cb (ie, the sieving coef- the filter (and therefore the ultrafiltrate)
ficient, defined as Cuf/Cb, is less than 1.0). is diluted in the predilution mode.
FIGURE 3-23
Addition of diffusive transport in hemodiafiltration. In hemodiafiltration, diffusive transport
Postdilution 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
Ultrafiltrate who have hypercatabolism with large urea generation.
Dialysate
Predilution
Blood
Membranes
Bacteria 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
Macrophage dialysate is heavily contaminated with bacteria (>2000 CFU/mL) and may result in pyrogenic
ET
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
FIGURE 3-25
H 2O
Dialysis membranes with small and large pores. Although a general correlation exists
H 2O
between the (water) flux and the (middle molecular weight molecule) permeability of dialysis
H 2O membranes, they are not synonymous. A, Membrane with numerous small pores that allow
H 2O high water flux but no 2-microglobulin transport. B, Membrane with a smaller surface
H 2O 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.
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 struc-
ture, ie, finger, sponge, and skin. The skin is a thin semipermeable layer B
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).
Dialysate flow rate

FIGURE 3-27
300
Effect of the dialysate flow rate (Qd) on the urea clearance rate by
280 a high-efficiency dialyzer with a urea KoA value of 800 mL/min.
260 At low blood flow rates (<200 mL/min), no difference exists in
Urea clearance rate, mL/min
urea clearance rates between the two different Qd conditions,

240
because equilibrium in urea concentrations between blood and
220 dialysate is readily achieved. When the blood flow rate is high
200 (>300 mL/min), the higher Qd maintains a higher concentration
gradient for diffusion of urea, and therefore, the urea clearance
180 rate is higher. Recent studies have shown that the KoA value of dia-
160 lyzers also increases with higher dialysate flow rates [4], presumably
because of more uniform distribution of dialysate flow. Therefore, the
140 Qd=800 actual urea clearance rate may increase further (red line). Ko—mass
120 Qd=500 transfer coefficient; A—surface area.
100
200 250 300 350 400 450 500
Blood flow rate, mL/min
Backfiltration
FIGURE 3-28
Pressure inside the blood compartment (dark colored arrow) and
Blood flow Dialysate flow the dialysate compartment (light colored arrow) with a fixed net
zero ultrafiltration rate. The pressure gradually decreases in the
Blood /Dialysate Blood /Dialysate blood compartment as blood travels from the inlet toward the outlet.
150 inlet outlet outlet inlet
Pbi Beyond a certain point along the dialyzer length (x, where the two
pressure lines intersect), the pressure in the dialysate compartment
140 exceeds that in the blood compartment, forcing fluid to move from
Pressure, mm Hg
Pdi
the dialysate to the blood compartment. This movement of fluid
in the direction opposite to that of the designed ultrafiltration is
130
Ultrafiltrate x called backfiltration. Backfiltration may carry with it contaminants
Back filtrate (eg, endotoxins) from the dialysate. Increasing the net ultrafiltra-
120 tion rate shifts the pressure intersection point to the right and
Pdo
diminishes backfiltration.
110
Pbo
100
References
1. Tokars JI, Alter MJ, Miller E, et al.: National surveillance of dialysis 13. Chandran PKG, Liggett R, Kirkpatrick B: Patient survival on
associated disease in the United States: 1994. ASAIO J 1997, PAN/AN 69 membrane hemodialysis: a ten year analysis. J Am Soc
43:108–119. Nephrol 1993, 4:1199–1204.
2. United States Renal Data System, 97: Treatment modalities for ESRD 14. Hornberger JC, Chernew M, Petersen J, Garber AM: A multivariate
patients. Am J Kidney Dis 1997, 30:S54–S66. analysis of mortality and hospital admissions with high-flux dialysis.
3. Cheung AK, Leypoldt JK: The hemodialysis membranes: a historical J Am Soc Nephrol 1992, 3:1227–1236.
perspective, current state and future prospect. Sem Nephrol 1997, 15. Hakim RM, Held PJ, Stannard DC, et al.: Effect of the dialysis membrane
17:196–213. on mortality of chronic hemodialysis patients. Kidney Int 1996,
4. Leypoldt JK, Cheung AK, Agodoa LY, et al.: Hemodialyzer mass 50:566–570.
transfer–area coefficients for urea increase at high dialysate flow rates. 16. Churchill DN: Clinical impact of biocompatible dialysis membranes
Kidney Int 1997, 51:2013–2017. on patient morbidity and mortality: an appraisal of evidence. Nephrol
5. Collins AJ, Keshaviah P: High-efficiency, high flux therapies in Dial Trans 1995, 10(suppl):52–56.
clinical dialysis. In Clinical Dialysis, edn 3. Edited by Nissenson AR. 17. Seres DS, Srain GW, Hashim SA, et al.: Improvement of plasma
1995:848–863. lipoprotein profiles during high flux dialysis. J Am Soc Nephrol 1993,
6. Collins AJ: High-flux, high-efficiency procedures. In Principles and 3:1409–1415.
Practice of Hemodialysis. Edited by Henrich W. Norwalk, CT: 18. Mailloux LU: Dialysis modality and patient outcome. UpToDate Med
Appleton & Large; 1996:76–88. 1995.
7. von Albertini B, Bosch JP: Short hemodialysis. Am J Nephrol 1991, 19. Parker TF III, Wingard RL, Husni L, et al.: Effect of the membrane
11:169–173. biocompatibility on nutritional parameters in chronic hemodialysis
8. Keshaviah P, Luehmann D, Ilstrup K, Collins A: Technical requirements patients. Kidney Int 1996, 49:551–556.
for rapid high-efficiency therapies. Artificial Organs 1986, 10:189–194. 20. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney
9. Shinaberger JH, Miller JH, Gardner PW: Short treatment. In Int 1996, 50:343–357.
Replacement of Renal Function by Dialysis, edn 3. Edited by Maher 21. Hakim RM, Wingard RL, Parker RA, et al.: Effects of biocompatibility
JF. Norwell, MA: Kluwer Academic Publishers; 1989:360–381. on hospitalizations and infectious morbidity in chronic hemodialysis
10. Barth RH: High flux hemodialysis: overcoming the tyranny of time. patients. J Am Soc Nephrol 1994, 5:450.
Contrib Nephrol 1993, 102:73–97. 22. Van Stone JC: Hemodialysis apparatus. In Handbook of Dialysis, edn 2.
11. Van Ypersele, De Strihou C, Jadoul M, et al.: The working party on Edited by Daugirdas JT, Ing TS. Boston/New York: Little, Brown &
dialysis amyloidosis: effect of dialysis membrane and patient’s age on Co.; 1994:31–52.
signs of dialysis-related amyloidosis. Kidney Int 1991, 39:1012–1019.
12. Koda Y, Nishi S, Miyazaki S, et al.: Switch from conventional to high-
flux membrane reduces the risk of carpal tunnel syndrome and mor-
tality of hemodialysis patients. Kidney Int 1997, 52:1096–1101.
Principles of
Peritoneal Dialysis
Ramesh Khanna
Karl D. Nolph
P
eritoneal dialysis is a technique whereby infusion of dialysis solu-
tion into the peritoneal cavity is followed by a variable dwell
time and subsequent drainage. Continuous ambulatory peri-
toneal 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 real-
ity, 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 non-
fenestrated 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 popu-
lated large pores (radius of approximately 0.25 nm, perhaps mainly
venular) transport macromolecules passively. Diffusion and convection CHAPTER
move small molecules through the interstitium with its gel and sol
phases, which are restrictive owing to the phenomenon of exclusion
4
[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 lym-
phatic vessels located primarily in the subdiaphragmatic region drain
fluid and solutes from the peritoneal cavity through bulk transport.
The extent of lymph drainage from the peritoneal cavity is a sub- fraction of glucose absorbed from the dialysate at specific times can
ject of controversy owing to the lack of a direct method to mea- be determined by the ratio of dialysate glucose concentrations
sure lymph flow. at specific times to the initial level in the dialysis solution. Tests
Dialysis solution contains electrolytes in physiologic con- are standardized for the following: duration of the preceding
centrations to facilitate correction of acid-base and electrolyte exchange before the test; inflow volume; positions during
abnormalities. High concentrations of glucose in the dialysis inflow, drain, and dwell; durations of inflow and drain; sam-
solution generate ultrafiltration in proportion to the overall pling methods and processing; and laboratory assays [7].
osmotic gradient, the reflection coefficients of small solutes Creatinine and urea clearance rates are the most commonly used
relative to the peritoneum, and the peritoneal membrane indices of dialysis adequacy in clinical settings. Contributions
hydraulic permeability. Removal of solutes such as urea, creati- of residual renal clearances are significant in determining the
nine, phosphate, and other metabolic end products from the body adequacy of dialysis. The mass-transfer area coefficient (MTAC)
depends on the development of concentration gradients between represents the clearance rate by diffusion in the absence of ultrafil-
blood and intraperitoneal fluid, and the transport is driven by the tration and when the rate of solute accumulation in the dialysis
process of diffusion. The amount of solute removal is a function solution is zero. Peritoneal clearance is influenced by both blood
of the degree of its concentration gradient, the molecular size, and dialysate flow rates and by the MTAC [8]. Therefore, the
membrane permeability and surface area, duration of dialysis, and maximum clearance rate can never be higher than any of these
charge. Ultrafiltration adds a convective component proportion- parameters. At infinite blood and dialysate flow rates, the clearance
ately more important as the molecular size of the solute increases. rate is equal to the MTAC and is mass-transfer–limited. Large mol-
The peritoneal equilibration test is a clinical tool used to charac- ecular weight solutes are mass-transfer–limited; therefore, their
terize the peritoneal membrane transport properties [6]. Solute clearance rates do not increase significantly with high dialysate flow
transport rates are assessed by the rates of their equilibration rates [9]. In CAPD, blood flow and MTAC rates are higher than is
between the peritoneal capillary blood and dialysate (see Fig. 4-8). the maximum achievable urea clearance rate. However, the urea
The ratio of solute concentrations in dialysate and plasma at specif- clearance rate approximately matches the dialysate flow rate, sug-
ic times during the dwell signifies the extent of solute transport. The gesting that the dialysate flow rate limits CAPD clearances.
Peritoneal Dialysis Regimens

FIGURE 4-1
Continuous peritoneal dialysis regimens.
Day Night Day Night
A, Continuous ambulatory peritoneal dialy-
sis (CAPD); B, continuous cyclic peritoneal
Left
2.0 dialysis (CCPD) is shown. Multiple sequen-
tial exchanges are performed during the day
1.0 and night so that dialysis occurs 24 hours a
day, 7 days a week.
0.0
A
Day Night Day Night
Right
2.0
1.0
0.0
B Exchanges, n
Principles of Peritoneal Dialysis 4.3
FIGURE 4-2
Day Night Day Night Intermittent peritoneal dialysis regimens.
Left Peritoneal dialysis is performed every day
2.0
but only during certain hours. A, In daytime
ambulatory peritoneal dialysis (DAPD),
1.0 multiple manual exchanges are performed
during the waking hours. B, Nightly peri-
0.0 toneal dialysis (NPD) is also performed
while patients are asleep using an automated
A
cycler machine. One or two additional day-
time manual exchanges are added to
enhance solute clearances.
Left Day Night Day Night
2.0
1.0
0.0
B
Solute Removal
24
Blood urea nitrogen, mg/dL
100
20
80
Creatinine, mg/dL
16
60
40 12
20 8
0 Dialysate
Blood 4 Dialysate
–20 Blood
0 80 160 240 320 400 480 560 0
0 40 80 120 160 200 240 280 320 360
A Time, min B Time, min
FIGURE 4-3
Solute removal. Solute concentration gradients are at maximum at rate by either increasing the intraperitoneal dialysate volume per
the beginning of dialysis and diminish gradually as dialysis progress- exchange or increasing the frequency of exchange. By convection
es. As the gradients diminish, the solute removal rates decrease. or enhanced diffusion, solutes are able to accompany the bulk flow
Solute removal can be enhanced by increasing the dialysate flow of water. (From Nolph and coworkers [10]; with permission.)
1.0 1.0
0.9 0.9
Dialysate to plasma ratio

0.8
0.8
0.7 0.7
0.6 0.6
0.5 0.5
0.4 Urea 0.4 Urea
0.3 Creatinine 0.3 Creatinine
Uric acid Uric acid
0.2 Phosphorus 0.2 Phosphorus
0.1 Inulin 0.1 Inulin
Calcium Calcium
0 100 200 300 400 500 0 100 200 300 400 500
A Dwell time, min B Dwell time, min
FIGURE 4-4
Solute removal. The rates of change of solute concentrations are is near 1.0. Smaller size solutes (ie, urea and creatinine) diffuse
similar for 1.5% dextrose dialysis solutions (panel A) and 4.25% across the membrane faster, equilibrate sooner, and are influenced
dextrose dialysis solutions (panel B). Hypertonic exchanges enhance more by exchange frequency as compared with larger size solutes
solute removal owing to larger drain volumes. Net solute diffusion (ie, uric acid, phosphates, inulin, and proteins). (From Nolph and
ceases at equilibration when the dialysate to plasma solute ratio (D/P) coworkers [10]; with permission.)
Total dialysate volume (V)
Creatinine clearance
per exchange (Ccr)
Creatnine dialysate to
D/P=1
plasma ratio (D/P)
High transport
1.0 2600 Ccr=V
2
Low transport
2300
0.5 1
2000
NIPD DAPD CAPD Ccr=V × D/P
1700 NTPD CCPD CCPD
0 (NE) (DE) 0
1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
1 2 3 4 5 6 7
A Dwell time, h B Dwell time, h C Dwell time, h
FIGURE 4-5
Solute removal. In a highly permeable membrane, smaller molecules Consequently, intraperitoneal volume peaks later. Ultrafiltration in
(ie, urea and creatinine) are transported at a faster rate from the a low transporter peaks late during dwell time. Therefore, a low
blood to dialysate than are larger molecules, enhancing solute removal. transporter continues to generate ultrafiltration even after 8 to 10
Similarly, glucose (a small solute used in the peritoneal dialysis solution hours of dwell. The solute creatinine dialysate to plasma ratio
to generate osmotic force for ultrafiltration across the peritoneal mem- (D/P) increases linearly during the dwell time. Patients with average
brane) is also transported faster, but in the opposite direction. This solute transfer rates have ultrafiltration and mass transfer patterns
high transporter dissipates the osmotic force more rapidly than does between those of high and low transporters. NIPD—nightly inter-
the low transporter. Both osmotic and glucose equilibriums are mittent peritoneal dialysis; NTPD—nighttime tidal peritoneal dialy-
attained eventually in both groups, but sooner in the high trans- sis; DAPD—daytime ambulatory peritoneal dialysis; CAPD—con-
porter group. Intraperitoneal volume peaks and begins to diminish tinuous ambulatory peritoneal dialysis; CCPD (NE)—continuous
earlier in the high transporter group. When the membrane is less cyclic peritoneal dialysis (night exchange); CCPD (DE)—continu-
permeable, solute removal is lower, ultrafiltration volume is larger ous cyclic peritoneal dialysis (day exchange). (From Twardowski
at 2 hours or more, and glucose equilibriums are attained later. [11]; with permission.)
FIGURE 4-6
150 Solute sieving. A, Dialysate sodium concentration is initially reduced and tends to return
Serum and dialysate to baseline later during a long dwell exchange of 6 to 8 hours. B, Dialysate sodium con-
Sodium, mLq/L
140
130 centration decreases, particularly when using 4.25% dextrose dialysis solution, because of
120 1.5% dextrose
dialysis solutions the sieving phenomenon. Removal of water during ultrafiltration unaccompanied by sodium,
110 in proportion to its extracellular concentration, is called sodium sieving [7,12]. The peri-
100 toneum offers greater resistance to the movement of solutes than does water. This probably
90
Inflow
relates to approximately half the ultrafiltrate being generated by solute-free water movement
0 100 200 300 400 500
through aquaporins channels. Therefore, ultrafiltrate is hypotonic compared with plasma.
A Dwell time, min 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
150 thirst, and hypertension may develop. This hindrance can be overcome by lowering the
Serum and
Sodium, mLq/L
140 dialysate dialysate sodium concentration to 132 mEq/L. In patients who use cyclers with short dwell
130
4.25% dextrose exchanges and who generate large ultrafiltration volumes, lower sodium concentrations
120
110
dialysis solutions may need to be used (such as 118 mEq/L for 2.5% glucose solutions or 109 mEq/L for
100 4.25% solutions). In continuous ambulatory peritoneal dialysis with long dwell exchanges
90 of 6 to 8 hours, significant sieving usually does not occur, whereas in automated peritoneal
Inflow dialysis with short dwell exchanges, sieving may occur. Sieving predisposes patients to
0 100 200 300 400 500 thirst and less than optimum blood pressure control, especially in those who have low-nor-
B Dwell time, min mal serum sodium levels, those with low peritoneal membrane transporter rates, or both.
(From Nolph and coworkers [10]; with permission.)
FIGURE 4-7
Transcapillary ultrafiltration Fluid removal by ultrafiltration. During peritoneal dialysis, hyperosmolar glucose solution
Lymphatic absorption
600 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
500 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
400 pressure. Net ultrafiltration would equal the resulting increment in intraperitoneal fluid
volume if it were not for peritoneal reabsorption, mostly through the peritoneal lymphatics.
mL/h
Peritoneal reabsorption is continuous and reduces the intraperitoneal volume throughout

300 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
Peak ultrafiltration
volume glucose absorption and dilution of the solution glucose by the ultrafiltration. Later in the
200 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
100
negative. Consequently, the intraperitoneal volume begins to diminish. Thus, peak ultrafiltra-
tion and intraperitoneal volumes are observed before osmotic equilibrium during an exchange.
0 1 2 3
A Dwell time, h
Peak intraperitoneal volume Dialysate

2800
Intraperitoneal
2600
2400
0 1 2 3 4
B Dwell time, h

360 Dialysate
Serum C, Osmotic equilibrium most likely precedes glucose equilibrium
Osmolality, mOsm/L
because of both solute sieving and the higher peritoneal reflection

340 coefficient of glucose compared with other dialysate solutes, allow-
Osmotic ing net transcapillary ultrafiltration to continue at a low rate even
320 equilibrium after osmotic equilibrium. D, Ultrafiltration can be maximized by
measures that delay osmotic equilibrium, which can be accom-
plished by using hypertonic glucose solutions, larger volumes, or
300
both, during an exchange. More frequent exchanges shorten dwell
0 1 2 3 4 times and increase the dialysate flow rate and thus avert attaining
C Dwell time, h osmotic equilibrium. Additionally, potential exists for enhancing
ultrafiltration by measures that reduce the peritoneal reabsorption
rate. (From Mactier and coworkers [13]; with permission.)
2000 Dialysate
Glucose, mOsm/L
Serum
Hypothetical
1000 glucose
equilibrium
0 1 2 3 4
D Dwell time, h
FIGURE 4-8
STANDARDIZED 4-HOUR PERITONEAL EQUILIBRATION TEST Standardized 4-hour peritoneal equilibra-
tion test. Dt/D0 glucose—final 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.
FIGURE 4-9
Correction of creatinine levels
Equation to correct the creatinine levels in dialysate and serum.
Corrected creatinine (mg/dL) The creatinine levels in dialysate and serum need to be corrected
= Observed creatinine (mg/dL) – (glucose [mg/dL] x 0.000531415) 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 Missouri–Columbia, 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
Intraperitoneal residual volume Equation to calculate the intraperitoneal residual volume. Residual volume is the volume
Vin(S3 – S2) of dialysate remaining in the peritoneal cavity after drainage over 20 minutes. The residual
R=
(S1 – S3) 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 com-
plete. 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 useful-
ness; however, it is of great value in a research setting in which accurate determination of
intraperitoneal volume is required.
FIGURE 4-11
1.1 1.1
Urea Creatinine Classification of peritoneal transport func-
tion. Based on the peritoneal equilibrium
0.9 0.9 test results, peritoneal transport function
Dialysis to plasma ratio
Dialysis to plasma ratio
may be classified into average, high (H),

0.7 and low (L) transport types. The average
0.7
transport group is further subdivided into
high-average (HA) and low-average (LA)
0.5 0.5 types. For the population studied by
Twardowski and coworkers [6], the trans-
0.3 port classification is based on means; stan-
0.3
dard deviations (SDs); and minimum and
maximum dialysate to plasma ratio (D/P)
0.1 0.1 values over 4 hours for urea, creatinine,
glucose, protein, potassium, sodium, and
0 1/ 1 2 3 4 0 1/
2 1 2 3 4 corrected creatinine (panels A–G).
2
A Hours B Hours (Continued on next page)
1.1 35
Glucose Protein
Final to initial dialysate glucose ratio
30
Dialysate to plasma ratio × 1000
0.9
25
0.7
20
0.5
15
0.3 10
5
0.1
0
0 1/ 1 2 3 4
0 1/
2 1 2 3 4 2
C Hours D Hours

Potassium Sodium
1.1 1.00 The volume of drainage correlates positively
with dialysate glucose and negatively with
0.9
D/P creatinine values at 4-hour dwell times
(panel H). (From Twardowski and cowork-

0.90
ers [6]; with permission.)
0.7
0.5
0.80
0.3
Max H
+SD HA
0.1 –SD LA
Min L
0 0.70
1/ 0 1/ 1 2 3 4
0 2 1 2 3 4 2
E Hours F Hours
ADK vol05 ch p04 fig11F
1.1 3500
Corrected creatinine Max
+SD
3000 x
0.9 –SD
Min
2500
0.7
2000
mL
0.5 1500
1000
0.3
H 500
HA
0.1 LA
L 0
0 Drain Residual Volume
0 1/
2 1 2 3 4 volume pre-eq post-eq
G Hours H
FIGURE 4-12
CLINICAL APPLICATIONS OF THE In clinical practice it is customary to perform the baseline standard-
PERITONEAL EQUILIBRATION TEST ized 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
Peritoneal membrane transport classification creatinine and glucose levels at 0, 2, and 4 hours of dwell time
1. Choose peritoneal dialysis regimen. and serum levels of creatinine and glucose at any time during
2. Monitor peritoneal membrane function.
the test. The extensive unabridged test, as originally proposed
by Twardowski and coworkers [6], has become a very important
3. Diagnose acute membrane injury.
research tool.
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.
FIGURE 4-13
Baseline peritoneal equilibrium test 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
High High average Low average Low
transporter transporter transporter transporter 68% have average transport rates, 16% have high transport rates,
D/P creatinine D/P creatinine D/P creatinine D/P creatinine and another 16% have low transport rates [6]. Similar distributions
of transport types have been documented worldwide [14–16].
D/P—dialysate to plasma ratio.
16% 68% 16%
FIGURE 4-14
Baseline peritoneal equilibrium test Using transport type to select a peritoneal dialysis regimen. Because
clearance rates continue to increase with time, patients with low
High High average Low average Low transport rates are treated with long dwell exchanges, ie, continu-
ous cyclic peritoneal dialysis (CCPD). Owing to the low rate of
NIPD NIPD High-dose CAPD increase in the dialysate to plasma ratio (D/P), the clearance rate
High-dose CCPD
DAPD CAPD High-dose CCPD only when significant per unit of time is augmented relatively little by rapid exchange
residual renal techniques such as nightly intermittent peritoneal dialysis (NIPD).
function is present 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 tech-
niques using short dwell exchanges, ie, NIPD or daytime ambulato-
ry peritoneal dialysis (DAPD). Patients with average transport rates
can be effectively treated with either short or long dwell exchange
techniques. CAPD—continuous ambulatory peritoneal dialysis.
FIGURE 4-15
1.0
0.97 Diagnosis of early ultrafiltration failure. The dialysate to plasma ratio (D/P) curve of sodi-
um, 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
0.92 sieving, the ultrafiltrate is low in sodium. Consequently, the dialysate sodium is lowered,
0.9 resulting in a lower D/P ratio of sodium. Later, during the dwell when ultrafiltration ceas-
0.88
es, 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 indi-
0.85
cation of ultrafiltration failure and is typically seen in the early phase of sclerosing encap-
0.8 0.80
sulating peritonitis. (From Dobbie and coworkers [17]; with permission.)
High
High average
Low average
Low
0.7
0.0 1.0 2.0 3.0 4.0
FIGURE 4-16
(DxV)
C= Creatinine and urea clearances rates. These rates are estimated by dividing the amount of
P
where C = clearance in mL/min: solute removed per unit of time by the plasma solute concentration. Alternatively, clearance
DxV = dialysate solute removed per minute; also can be estimated by multiplying the solute equilibration rate per unit of time by the
D = dialysate solute concentration; volume of dialysate into which equilibration occurred over the same unit of time. By con-
V = volume of dialysate in mL/min; and vention, the creatinine clearance rate is normalized to body surface area.
P = plasma solute concentration
The urea clearance is normalized to total body water (volume of urea distribution in the
or body) and is expressed as Kt/V. The Kt/Vvalue is a number without a unit ([mL/min min]/
C=(D/P) x V
mL). During intermittent dialysis, with a dialysate flow rate of 30 mL/min, the typical urea
where C = clearance in mL/exchange at time t; clearance is about 18 to 20 mL/min [18]. Increasing the dialysate flow rates to 3.5 to 12
D/P = solute equilibrium rate at time t; and
V = volume of dialysate at time t L/h by rapid exchanges increases the urea clearance rate to a maximum of 30 to 40 mL/min.
A Beyond this maximum rate, the clearance rate begins to decrease owing to the loss of mem-
brane-fluid contact time with infusion and drainage; inadequate mixing may also occur
Kt/V [19–22]. Clearance could be enhanced by increasing the membrane-solution contact [23].
where K = urea clearance in mL/min; Continuous dialysate flow techniques using either two catheters or double-lumen catheters
t = minutes of therapy; and also have enhanced the urea clearance rate to a maximum of 40 mL/min. At these high flow
V = volume of urea distribution or total
body water rates, poor mixing, channeling, abdominal pain, and poor drainage limit successful applica-
B tion. 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 [24–29]. 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 2.5-
and 3.0-L volumes has been reported in adult patients undergoing CAPD; however, hernial
complications are increased [32,33].
FIGURE 4-17
Mass-transfer area coefficient
The mass-transfer area coefficient (MTAC). The MTAC represents the clearance rate by
The diffusive mass transfer is estimated by
diffusion in the absence of ultrafiltration and when the solute accumulation in the dialysis
solution is zero [34–39]. MTAC is equal to the product of peritoneal membrane perme-
A ability (P) and effective peritoneal membrane surface area (S). Thus, when both capillary
M=I (C – C )
R P D
blood and dialysate flows are infinite, the clearance rate is directly proportional to the
where M = diffusive mass transfer: effective peritoneal surface area and inversely proportional to the overall membrane resis-
A = effective membrane surface area;
tance. However, infinite blood and dialysate flows cannot be achieved, and the maximum
I = coefficient of proportionality;
R = sum of all resistances; clearance rate is unattainable. The closest measurable value, the MTAC, was introduced.
Cp = solute concentration in the potential The MTAC represents an instantaneous clearance without being influenced by ultrafiltra-
capillary blood; and tion and solute accumulation in the dialysate. The MTAC is measured over a test exchange
CD = solute concentration in the dialysate during which at least two blood and dialysate samples are obtained at different dwell
A
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.
Dividing both sides of the equation by solute
concentration in peripheral blood (CB) will
yield instantaneous clearance or the MTAC;
M A CP CD
CB
=K=I (
–
R CB CB (
B
If the peritoneal capillary blood flow is infinite,

Cp will equal Cb and
A C
Ki=I
R ( (
1– D
CB
If the dialysate flow is also infinite,

then Co will equal 0, and
A
Ki=Kmax=I
R
C
References
1. Clough G, Michel CC: Quantitative comparisons of hydraulic perme- 22. Tenckhoff H, Ward G, Boen ST: The influence of dialysate volume
ability and endothelial intercellular cleft dimensions in single form and flow rate on peritoneal clearance. Proc Eur Dial Transplant Assoc
capillaries. J Physiol 1988, 405:563–576. 1965, 2:113–117.
2. Pannekeet MM, Mulder JB, Weening JJ, et al.: Demonstration of 23. Trivedi HS, Twardowski ZJ: Long-term successful nocturnal intermittent
aquaporin-CHIP in peritoneal tissue of uremic and CAPD patients. peritoneal dialysis: a ten-year case study. In Advances in Peritoneal
Peritoneal Dial Int 1996, 16(suppl 1):S54. Dialysis. Edited by Khanna R. Toronto, Canada: Peritoneal Dialysis
3. Flessner MF, Dedrick RL, Schultz JS: Exchange of macromolecules Publications; 1994:81–84.
between peritoneal cavity and plasma. Am J Physiol 1985, 248:H15. 24. Di Paolo N: Semicontinuous peritoneal dialysis. Dial Transplant
4. Flessner MF, Fenstermacher JD, Blasberg RG, Dedrick RL: Peritoneal 1978, 7:839–842.
absorption of macromolecules studied by quantitative autoradiography. 25. Finkelstein FO, Kliger AS: Enhanced efficiency of peritoneal dialysis
Am J Physiol 1985, 248:H26. using rapid, small-volume exchanges. ASAIO J 1979, 2:103–106.
5. Wade OL, Combes B, Childs AW, et al.: The effect of exercise on the 26. Twardowski ZJ, Nolph KD, Khanna R, et al.: Tidal peritoneal dialysis.
splanchnic blood flood and splanchnic blood volume in normal man. In Ambulatory Peritoneal Dialysis: Proceedings of the IVth Congress
Clin Sci 1956, 15:457. of the International Society for Peritoneal Dialysis, Venice, Italy, June
6. Twardowski ZJ, Nolph KD, Khanna R, et al.: Peritoneal equilibration 1987. Edited by Avram MM, Giordano C. New York: Plenum;
test. Peritoneal Dial Bull 1987, 7:138–147. 1990:145–149.
7. Ahearn DJ, Nolph KD: Controlled sodium removal with peritoneal 27. Twardowski ZJ, Prowant BF, Nolph KD, et al.: Chronic nightly tidal
dialysis. Trans Am Soc Artif Intern Organs 1972, 28:423. peritoneal dialysis (NTPD). ASAIO Trans 1990, 36:M584–M588.
8. Popovich RP, Moncrief JW: Kinetic modeling of peritoneal transport: 28. Twardowski ZJ: Tidal peritoneal dialysis: acute and chronic studies.
In Today’s Art of Peritoneal Dialysis. Edited by Trevino-Bacerra A, Eur Dial Transplant Nurses Assoc Eur Renal Care Assoc September
Boen FST. Basel, Switzerland: Karger; 1979:59–72. [Contributions to 1990, 15:4–9.
Nephrology, 1.] 29. Twardowski ZJ: Tidal peritoneal dialysis. In Dialysis Therapy. Edited
9. Twardowski ZJ: Physiology of peritoneal dialysis. In Clinical Dialysis. by Nissenson AR, Fine RN. Philadelphia: Hanley & Belfus;
Edited by Nissenson AR, Fine RN, Gentile DE, edn 3. Norwalk, CT: 1993:153–156.
Appleton & Lange; 1995:322. 30. Twardowski ZJ, Nolph KD, Prowant BF, et al.: Efficiency of high vol-
10. Nolph KD, Twardowski ZJ, Popovich RP, et al.: Equilibration of peri- ume low frequency continuous ambulatory peritoneal dialysis
toneal dialysis solutions during long dwell exchanges. J Lab Clin Med (CAPD). ASAIO Trans 1983, 29:53–57.
1979, 93:246–256. 31. Krediet RT, Boeschoten EW, Zuyderhoudt FMJ, et al.: Differences in
11. Twardowski ZJ: Nightly peritoneal dialysis (why? who? how? and the peritoneal transport of water, solutes and proteins between dialy-
when?). Trans Am Soc Artif Intern Organs 1990, 36:8–16. sis with two- and with three-litre exchanges [thesis]. In Peritoneal
Permeability in Continuous Ambulatory Peritoneal Dialysis Patients.
12. Nolph KD, Hano JE, Teschan PE: Peritoneal sodium transport during Edited by Krediet RT. Amsterdam, Holland: University of Amsterdam;
hypertonic peritoneal dialysis: physiologic mechanisms and clinical 1986:129–146.
implications. Ann Intern Med 1969; 70:931.
32. Twardowski Z, Janicka L: Three exchanges with a 2.5 liter volume
13. Mactier RA, Khanna R, Twardowski ZJ, et al.: Contribution of lym- for continuous ambulatory peritoneal dialysis. Kidney Int 1981,
phatic absorption to loss of ultrafiltration and solute clearances in 20:281–284.
continuous ambulatory peritoneal dialysis. J Clin Invest 1987,
80:1311–1316. 33. Twardowski ZJ, Prowant BF, Nolph KD, et al.: High volume, low fre-
quency continuous ambulatory peritoneal dialysis. Kidney Int 1983,
14. Zabetakis PM, Krapf R, DeVita MV, et al.: Determining peritoneal 23:64–70.
dialysis prescriptions by employing a patient-specific protocol.
Peritoneal Dial Int 1993, 13:189–193. 34. Randerson DH: Continuous ambulatory peritoneal dialysis-a critical
appraisal [thesis]. Sydney, Australia: University of New South Wales;
15. Wolf CJ, Polsky J, Ntoso KA, et al.: Adequacy of dialysis in CAPD and 1980.
cycler PD; the PET is enough. Peritoneal Dial Bull 1992, 8:208–211.
35. Pyle WK: Mass transfer in peritoneal dialysis [thesis]. Austin: University
16. Struijk DG, Krediet RT, Koomen GCM, et al.: A prospective study of of Texas; 1981.
peritoneal transport in CAPD. Kidney Int 1994, 1739–1744.
36. Farrell PC, Randerson DH: Mass transfer kinetics in continuous ambu-
17. Dobbie JW, Krediet RT, Twardowski ZJ, et al.: A 39-year-old man latory peritoneal dialysis. In Proceedings of the First International
with loss of ultrafiltration. Peritoneal Dial Int 1994, 14:384–394. Symposium on Continuous Ambulatory Peritoneal Dialysis. Edited by
18. Nolph KD, Popovich RP, Ghods AJ, et al.: Determinants of low Legrain M. Amsterdam, Holland: Excerpta Medica; 1980:34–41.
clearances of small solutes during peritoneal dialysis. Kidney Int 37. Pyle WK, Moncrief JW, Popovich RP: Peritoneal transport evaluation
1978, 13:117–123. in CAPD. In CAPD Update. Edited by Moncrief JW, Popovich RP.
19. Boen ST: Kinetics of Peritoneal Dialysis. Baltimore, MD: Medicine; New York: Masson; 1981:35–52.
1961:243–287. 38. Pyle WK, Popovich RP, Moncrief JW: Mass transfer in peritoneal dial-
20. Penzotti SC, Mattocks AM: Effects of dwell time, volume of dialysis ysis. In Advances in Peritoneal Dialysis. Edited by Gahl GM, Kessel
fluid, and added accelerators on peritoneal dialysis of urea. J Pharm M, Nolph KD. Amsterdam, Holland: Excerpta Medica; 1981:41–46.
Sci 1971, 60:1520–1522. 39. Garred LF, Canaud B, Farrell PC: A simple kinetic model for assessing
21. Pirpasopoulos M, Lindsay RM, Rahman M, et al.: A cost-effectiveness peritoneal mass transfer in continuous ambulatory peritoneal dialysis.
study of dwell time in peritoneal dialysis. Lancet 1972, 2:1135–1136. ASAIO J 1983, 6:131–137.
Dialysis Access
and Recirculation
Toros Kapoian
Jeffrey L. Kaufman
John Nosher
Richard A. Sherman
S
ince its inception, hemodialysis has been bedeviled by problems
of vascular access. Access, from the time of creation and through-
out a patient’s 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 hos-
pitalization 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 patient’s 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
Arteriovenous Dialysis Access: Evaluation and Placement

FIGURE 5-1
EVALUATION FOR HEMODIALYSIS VASCULAR ACCESS 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
History Physical examination and physical examination. A history of arterial and venous line place-
ments should be sought. The upper extremities are examined for
Surgical cutdown Asymmetry of pulse
edema and asymmetry of pulse and blood pressure. Access should be
Multiple peripheral catheters Asymmetry of blood pressure
placed at the wrist only after it is verified that the radial artery is not
Peripherally inserted central catheter Abnormal capillary refill the dominant arterial conduit to the hand. The classic study is the
line placement Abnormal Allen test Allen test, in which an observer compresses both the radial and ulnar
Transvenous pacemaker Presence of surgical or other scars arteries, has the patient exercise the hand by opening and closing to
Axillary dissection cause blanching, then releases one vessel to be certain that the fingers
Intravenous drug use become perfused. An alternative, and perhaps more precise, test is to
Obesity verify by Doppler imaging that flow to all digits is maintained despite
Peripheral vascular disease occlusion of the radial artery. If indicated, vascular imaging studies
Atherosclerotic disease
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 criti-
cally 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 end-
vein to side-artery, A and B, or side-to-side, C, between the two ves-
sels. The exposure is conveniently obtained using a transverse inci-
sion 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 tech-
nique 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 5.3
incidence of steal is likely the result of the lower flow rate associat-
ed 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 stag-
nation, they are of no harm to the patient’s 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 demon-
strates marked muscle atrophy secondary to advanced diabetic neu-
ropathy, which particularly involves the thenar eminence and the
FIGURE 5-3 interosseus muscle groups. Complaints of weakness and loss of
The Brescia-Cimino (radial-cephalic) fistula. The radial-cephalic fis- grip strength in the arm are common and may represent symptoms
tula offers many advantages. It is simple to create and preserves of steal. In this case, however, the symptoms are due to the intrin-
more proximal vessels for future access construction. The lower sic 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 ante-
cubital 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 antecu-
bital 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.
C
during manufacture. The process of healing

after implantation involves ingrowth of
fibroblasts into the pore structure, giving a
final graft-tissue amalgam that is “incorpo-
rated” when encountered by the surgeon for
revision. There is virtually no neovascular-
ization 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 resis-
tance 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 artery-
to-vein grafts, and a variety of other con-
FIGURE 5-5 structions. The sites of choice are limited by
Polytetrafluoroethylene (PTFE) vein graft. The most common synthetic material used for the requirements of hemodialysis: delivery
dialysis access construction is the PTFE conduit. This material replaced bovine heterografts; of a high rate of blood flow and accessibility
alternative materials such as the umbilical vein graft have not yet made much headway. to the dialysis staff for cannulation with an
Because of the infection risk, Dacron bypass grafts have never functioned well for dialysis. adequate length of graft to keep the needles
PTFE is an inert material that is formed into a pliable conduit. Its ultramicroscopic struc- sufficiently separated and allow rotation of
ture is a series of nodes connected by tiny filaments, leaving pores whose size can be varied 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 increas-
ing 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 tempo-
rary use while an arteriovenous vascular access was being con-
structed, 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 infec-
tion, central vein stenosis, and thrombosis.
Complications of Arteriovenous Dialysis Access Placement
A B
FIGURE 5-7
Arteriovenous fistula anastomotic stenosis. Arteriovenous fistulas most common site for a stenotic lesion in native vein fistulas.
exhibit better long-term patency compared with polytetrafluoroeth- B, Angioplasty successfully eliminated the anastomotic stenosis.
ylene (PTFE) grafts. A, This arteriogram, performed by injecting Limitations on balloon size are often encountered when treating
the brachial artery, demonstrates an end-to-side arteriovenous fistu- lesions in arteriovenous fistulas because a portion of the balloon
la involving the brachial artery and the cephalic vein. The arrow must often extend into the donor artery, which typically is of
indicates an area of narrowing adjacent to the anastomosis, the 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 photo-
graph 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 hemor-
rhage. 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 expo-
sure, and allowing secondary wound healing.
A B
FIGURE 5-9
Extravasation injury to the access site. A, A relatively fresh seg- potentially huge volume of fluid can enter the soft tissue before
ment of polytetrafluoroethylene graft was removed during a revi- the pump stops in response to the alarm for elevated venous pres-
sion procedure. There is virtually no fibrosis or calcification (asso- sure. In many cases, the graft is unusable for weeks after such an
ciated with repeated puncture). The luminal surface displays the episode. Continued use of the access in this setting may result in
results of multiple sites of puncture and healing. Among the most loss of the access site. B, In this example, the infiltration was com-
dramatic and troublesome complications of dialysis is access infil- posed of approximately 400 mL of priming crystalloid and blood,
tration. In most cases the infiltration is minor and usually results located both deep and superficial to the investing fascia of the
from either inadequate hemostasis at the end of dialysis or needle arm. The access remained patent and was eventually restored to
perforation through the access site. Extravasation injury to the function; however, a series of percutaneous drainage procedures
access is more likely when a needle errantly transfixes a graft or and open drainage were necessary. Compartment syndrome, with
vein or when it accidentally becomes dislodged into the subcuta- loss of distal motor function or sensation in the arm, is another
neous tissue. The venous return needle presents the biggest prob- concern in this setting, and drainage must be performed to treat
lem. In the face of typical pump speeds of 400 to 500 mL/min a this surgical emergency.
FIGURE 5-10
Outflow vein stenosis. Stenotic lesions are most often found
at a polytetrafluoroethylene (PTFE) graft’s 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 dilata-
tion 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 hyper-
plasia that can develop in a dialysis access site. B, Resected
graft-venous anastomosis from a one-year-old PTFE graft. The
A 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.
B
A B
C D
be necessary to permit removal of this material under direct visual-
ization. Failure to remove this meniscus invariably leads to rethrom-
bosis. B, This type of clot is demonstrated in an arteriogram per-
formed through the brachial artery following thrombolytic therapy.
The arterial end of this polytetrafluoroethylene (PTFE) graft demon-
strates 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
Poiseuille’s 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.
E Eighty percent of thrombosed accesses have an associated stenotic
lesion. C, An eccentric focal stenosis is demonstrated at the anasto-
FIGURE 5-11 mosis of a PTFE forearm graft and its outflow vein (arrow), which
Graft thrombosis due to outflow vein stenosis requiring use of an did not respond to percutaneous transluminal angioplasty. The lesion
atherectomy catheter. Thrombectomy of a dialysis access site involves was subsequently resected using a Simpson atherectomy catheter,
removal of three types of clot. A, The body of a thrombosed access which consists of a concealed cutting chamber that is deflected into
contains a red or purplish thrombus that is often gelatinous. It is eas- contact with the stenotic lesion of the vessel wall by inflating the
ily removed with a balloon-tipped thrombectomy/embolectomy associated balloon. With the lesion projecting into the cutting cham-
catheter. This photograph also demonstrates the small meniscus of ber, a high-speed cylindrical cutting blade resects tissue into a collect-
firm, laminar, platelet-rich clot that usually obstructs arterial inflow. ing chamber. This chamber is rotated sequentially until the circum-
On occasion, it is also found at the venous end. This type of clot can ference of the lesion has been treated. D, The Simpson atherectomy
be tenacious and may not be removed with thrombolytic therapy or catheter is placed across the stenotic lesion. E, The postprocedure
the balloon catheter. A cutdown at the arterial end of the graft may venogram shows that the lesion was successfully resected.
FIGURE 5-12
Pulse spray catheter. To increase the efficiency of drug thrombolysis,
pulse spray catheters are often used. The technique involves embed-
ding 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.
A B
C D
FIGURE 5-14
Outflow vein stenosis with stenting. A, Arteriography in this develop vigorous fibrosis at the venous site of a stent. D, This
patient with a Brescia-Cimino fistula demonstrates stenosis of the photograph demonstrates what had occurred only 1 month after
outflow vein approximately 15 cm central to the fistula (arrow). stent placement. Stents can be a problem when dealing with sub-
B, Percutaneous transluminal angioplasty was performed in this sequent vascular access dysfunction. During thrombectomy, the
patient; however, because of immediate elastic recoil, the lesion tiny wires of a stent can puncture balloon catheters. When stent-
looks no different after angioplasty. C, Following stent placement ed segments restenose, it is impossible to perform open patch
(arrow), there is no residual stenosis, and good flow through the angioplasty over such segments, and it becomes necessary to
stent is apparent. Stents have proven controversial in access sites. jump to a different venous outflow site. It is not clear whether
Although they may improve patency in central vein stenoses (vide stents in or adjacent to dialysis grafts are cost effective in main-
infra), in the periphery they may be a hindrance. Some patients taining graft patency.
A B
FIGURE 5-15
Intragraft stenosis. A, This arteriogram demonstrates a forearm atherectomy or surgical revision. Since this region of the access is
loop polytetrafluoroethylene (PTFE) graft with an intragraft stenosis subject to needle cannulation, the placement of a stent would be
(arrow). Stenotic lesions in this site are less common than those inadvisable. Intragraft stenoses may be located between the sites of
involving either the venous anastomosis or the outflow vein. the arterial and venous needle placements during dialysis. If so, the
B, These lesions can be treated successfully with percutaneous trans- most common screening studies, namely venous pressure measure-
luminal angioplasty (arrow). In cases where angioplasty is unsuccess- ments and recirculation, do not have abnormal findings and the
ful, intragraft stenoses can also be treated using percutaneous lesion may remain undetected until access thrombosis develops.
A B
FIGURE 5-16
Aneurysmal degeneration. Severe aneurysmal degeneration poses a significant surgical prob-
lem 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 enlarge-
ment 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 demon-
strating 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 sur-
rounding 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 patient’s severe phobia of
central vein catheters, this access was revised in two separate procedures to maintain dialy-
sis continuity. The lateral area of the loop was initially replaced, and when this was healed
C and functioning well the medial segment was replaced.
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 seg-
ment proximal to an access site (so that the native artery cannot dilate to meet the increas-
ing 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 gan-
grene. Several treatment strategies are available to the surgeon. The access can be “band-
ed,” 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.
screening methods may help detect grafts at high risk for thrombo-
sis at a point where graft revision (surgical or radiologic) may
increase its longevity.
Measurement of graft blood flow (using Doppler imaging, ultra-
sound 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 nee-
dle. 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
FIGURE 5-18 flow (adjusting for the difference in height between the graft and
Vascular access screening methods. Dialysis grafts have a high inci- the transducer). To increase accuracy, this pressure can be normal-
dence of thrombosis, the risk of which increases when graft flow ized by dividing it by the mean arterial pressure. More commonly,
rates (A) fall below 600 to 700 mL/min, particularly with stenotic this intragraft pressure is determined indirectly by using the dialysis
lesions in or near the graft. Most often, stenoses occur just distal to machine’s pressure transducer and a pump speed of 200 mL/min.
the graft-vein anastomosis (B) but they can occur proximal to the In this case the measured pressure often exceeds 100 mm Hg in a
graft-artery anastomosis (C) or within the graft itself (D). Various normal graft, owing to the resistance in the venous needle.
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 thrombo-
sis, 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 posi-
tioning 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.
FIGURE 5-20
Central vein steno-
sis. A, Venogram of
the central outflow
veins performed in
a patient with a left
upper extremity
polytetrafluoroeth-
ylene graft and arm
edema, B.
(Continued on
next page)
A B

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).
A B
FIGURE 5-21
Stent deployment. When angioplasty fails, metal stents are intro-
duced to treat outflow vein occlusion. These stents are either balloon
expandable or self-expanding. The stages of deployment of the self-
expanding 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.
C

D, To improve central vein patency follow-
ing angioplasty, metal stents have been
placed in the innominate vein and the superi-
or vena cava. E, A postprocedure venogram
demonstrates no residual stenosis.
D E
FIGURE 5-22
Central vein catheter complications. A, This
radiograph demonstrates the tip of this dialy-
sis catheter abutting the wall of the left
innominate vein at its junction with the supe-
rior vena cava. To maintain adequate dialysis
flow rates and minimize fibrin sheath forma-
tion, 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 con-
trast 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
A 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.
B C

D, The clot is typical of one that is remarkably tenacious. Before
replacement of this catheter, a variety of manipulations were per-
formed, 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.
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, includ-
ing 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
H
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 patient’s well-being. In
chronic renal failure, hemodialysis results in a dramatic reversal of uremic
symptoms and helps improve the patient’s 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 [1–4]. 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 func-
tion of its distributional volume. The fractional clearance is opera-
tionally defined as the product of dialyzer clearance (K) and the treat-
ment 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 CHAPTER
dialysis (KoA >600 mL/min, where KoA is the constant indicating the
efficiency of dialyzers in removing urea). Eventually, increases in blood
6
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.
Ultrafiltration during dialysis is performed to remove volume that has been used as a marker of biocompatibility is evidence of
that has accumulated during the interdialytic period so that complement activation. Cellulosic membranes generally tend to be
patients can be returned to their dry weight. Dry weight is bioincompatible, whereas noncellulosic or synthetic membranes
determined somewhat crudely, being based on clinical findings. have more biocompatible characteristics. Whether any clinical
The patient’s dry weight is the weight just preceding the devel- difference exists in acute or chronic outcomes between biocom-
opment of hypotension. The patient should be normotensive patible and bioincompatible membranes is still a matter of debate.
and show no evidence of pulmonary or peripheral edema. A Trials designed to address this issue have been mostly uncon-
patient’s dry weight frequently changes over time and therefore trolled, limited in sample size, and often retrospective in nature.
must be assessed regularly to avoid hypotension or progressive Nevertheless, some evidence exists to suggest that bioincompati-
volume overload. ble membranes may have a greater association with 2 microglob-
During ultrafiltration the driving force for fluid removal is the ulin-induced amyloidosis, susceptibility to infection, enhanced
establishment of a pressure gradient across the dialysis membrane. protein catabolism, and increased patient mortality [5–9].
The water permeability of a dialysis membrane is a function of Another aspect of the dialysis prescription is the composition
membrane thickness and pore size and is indicated by its ultrafil- of the dialysate. The concentrations of sodium, potassium,
tration coefficient (KUf). During ultrafiltration additional solute calcium, and bicarbonate in the dialysate can be individualized
removal occurs by solvent drag or convection. Because of such that ionic composition of the body is restored toward
increased pore size, high-flux membranes (KUf >20 mL/h/mm Hg) normal during the dialytic procedure. This topic is discussed in
are associated with much higher clearances of average to high mol- detail in chapter 2.
ecular weight solutes such as 2 microglobulin. Because blood Although hemodialysis is effective in removing uremic toxins
flow rates over 50 to 100 mL/min result in little or no further and provides adequate control of fluid and electrolyte abnor-
increase in the clearance of these molecules, clearance is primarily malities, the procedure does not provide for the endocrine or
membrane-limited. In contrast, clearance values for urea are not metabolic functions of the normal kidney. Therefore, the dialy-
significantly greater with a high-flux membrane compared with a sis prescription often includes medications such as erythropoi-
high-efficiency membrane because the blood flow rate, and not the etin and 1,25(OH)2 vitamin D. The dose of erythropoietin
membrane, is the principal determinant of small solute clearance. should be adjusted to maintain the hematocrit between 33%
The biocompatibility of the dialysis membrane is another and 36% (hemoglobin of 11 g/dL and 12 g/dL, respectively)
consideration in the dialysis prescription. A biocompatible dialysis [10]. Vitamin D therapy is often used in patients undergoing
membrane is one in which minimal reaction occurs between the dialysis to help limit the severity of secondary hyperparathy-
humoral and cellular components of blood as they come into roidism. Dosages usually range from 1 to 2 µg given intra-
contact with the surface of the dialyzer [6]. One such reaction venously with each treatment.
Treatment
FIGURE 6-1
Diffusion Diffusional and convective flux in hemodialysis. Dialysis is a
Blood Dialysate process whereby the composition of blood is altered by exposing it to
dialysate through a semipermeable membrane. Solutes are transported
Urea, 100 mg/dL Urea, 0 mg/dL 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 potassi-
Potassium, 5.0 mEq/L Potassium, 2.0 mEq/L um 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.
Bicarbonate, 20 mEq/L Bicarbonate, 35 mEq/L
A Dialysis membrane
The Dialysis Prescription and Urea Modeling 6.3
Ultrafiltration
Blood Dialysate TREATMENT OF HEMODYNAMIC INSTABILITY
90 mm Hg –150 mm Hg
Exclude nondialysis-related causes (eg, cardiac ischemia, pericardial effusion, infection)
Set the dry weight accurately
H 2O
Optimize the dialysate composition
Use a sodium concentration of ≥140 mEq/L
H 2O
Use sodium modeling
Use a bicarbonate buffer
H 2O 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
B Dialysis membrane Use cool temperature dialysate
Maximize cardiac performance
Have patients avoid food on day of dialysis
FIGURE 6-1 (Continued) Have patients avoid antihypertensive medicines on day of dialysis
B, During hemodialysis water moves from blood to dialysate Pharmacologic prevention
driven by a hydrostatic pressure gradient between the blood and Erythropoietin therapy to keep hematocrit >30%
dialysate compartments, a process referred to as ultrafiltration. Experimental (eg,caffeine, midodrine, ephedrine, phenylephrine, carnitine)
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 sol-
vent drag. The contribution of convective transport to total solute FIGURE 6-2
transport is only significant for average-to-high molecular weight
The common treatments for hemodynamic instability of patients
solutes because they tend to have a smaller diffusive flux.
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 rea-
son 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 Acceptable methods to measure hemodialysis adequacy as recom-
HEMODIALYSIS ADEQUACY* mended 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 con-
• Formal urea kinetic modeling (Kt/V) using computational software
sidered the minimum targets.
• 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.
Considerations in Choice of Membranes

FIGURE 6-4
400
Relationships between membrane efficiency and clearance and
blood flow rates in hemodialysis. When prescribing the blood flow
KoA 900 High-efficiency
rate for a hemodialysis procedure the following must be considered:
Urea clearance, mL/min
300 dialyzer
KoA 650 the relationship between the type of dialysis membrane used, blood
flow rate, and clearance rate of a given solute. For a small solute
KoA 300 Conventional such as urea (molecular weight, 60) initially a linear relationship
200 dialyzer
e-lim ited exists between clearance and blood flow rates. Small solutes are
Membran
therefore said to be flow-limited because their clearance is highly
d
flow-dependent. At higher blood flow rates, increases in clearance

ite
100
lim
rates progressively decrease as the characteristics of the dialysis

w-
Flo
membrane become the limiting factor. The efficiency of a dialyzer

0 in removing urea can be described by a constant referred to as
0 100 200 300 400 KoA, which is determined by factors such as surface area, pore
Blood flow rate, mL/min 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
2000 Water permeability of a membrane and control of volumetric
ultrafiltration in hemodialysis. The water permeability of a dialysis
1800 membrane can vary considerably and is a function of membrane
thickness and pore size. The water permeability is indicated by its
1600 ultrafiltration coefficient (KUf). The KUf is defined as the number
KUf=60 mL/h/mm Hg
KUf=4 mL/h/mm Hg of milliliters of fluid per hour that will be transferred across the
1400 membrane per mm Hg pressure gradient across the membrane.
A high-flux membrane is characterized by an ultrafiltration coeffi-
Ultrafiltration, mL/h
1200 cient of over 20 mL/h /mm Hg. With such a high water permeabili-
ty value a small error in setting the transmembrane pressure can
1000 KUf=3 mL/h/mm Hg result in excessively large amounts of fluid to be removed. As a
result, use of these membranes should be restricted to dialysis
800 machines that have volumetric ultrafiltration controls so that the
amount of ultrafiltration can be precisely controlled.
600
400
200
0
0 100 200 300 400 500 600
Transmembrane pressure, mm Hg
FIGURE 6-6
High-efficiency dialyzer High-efficiency and high-flux membranes in hemodialysis. These
High-flux dialyzer membranes have similar clearance values for low molecular weight
Normal kidney solutes such as urea (molecular weight, 60). In this respect both
types of membranes have similar KoA values (over 600 mL/min),
150 where KoA is the constant indicating the efficiency of the dialyzer
in removing urea. As a result of increased pore size, use of high-
flux 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
Clearance, mL/min
some high-flux membranes, 400 to 600 mg/wk of 2-microglobulin

100 can be removed. The clinical significance of enhanced clearance of
2-microglobulin and other middle molecules using a high-flux dia-
lyzer is currently being studied in a national multicenter hemodial-
ysis trial.
50
0
0 10 100 1000 10,000 100,000
60)
11, ulin
35 2
(m Urea
β - w=1 B1
(m icrog 5)
w=
(m amin
)
w= lob
800
Vit
2 m
Solute molecular weight, Daltons
FIGURE 6-7
80
Effects of membrane biocompatibility in hemodialysis. Another
consideration in the choice of a dialysis membrane is whether it is
Patients recovering renal function, %
biocompatible. In chronic renal failure some evidence exists to suggest

60 Polymethyl methacrylate 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 [5–9].
In the study results shown here, the effect of biocompatibility on
40
Cuprophane
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
20 activate complement and neutrophils) or a synthetic membrane
made of polymethyl methacrylate (a biocompatible membrane
associated with more limited complement and neutrophil activation).
0 The two groups of patients were similar in age, degree of renal failure,
0 5 10 15 20 25 30 and severity of the underlying disease as defined by the Acute
Number of hemodialysis treatments 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.)
FIGURE 6-8
300
Dialysate flow rate in hemodialysis. The clearance of urea also
280 is influenced by the dialysate flow rate. Increased flow rates help
QD=800 maximize the urea concentration gradient along the entire length of
260 Dialyzer the dialysis membrane. Increasing the dialysate flow rate from 500
KoA=800
240
to 800 mL/min can be expected to increase the urea clearance rate
QD=500 on the order of 10% to 15%. This effect is most pronounced at
Clearance, mL/min
220 high blood flow rates and with use of high KoA dialyzers. KoA—
constant indicating the efficiency of the dialyzer in removing urea;
200 QD=800 QD—dialysate flow rate.
Dialyzer
180 KoA=400
QD=500
160
140
120
100
200 250 300 350 400 450 500
Blood flow rate, mL/min
Prescription for Dose Delivery

FIGURE 6-9
Delivering an adequate dose of dialysis in hemodialysis. Providing
1. Dialyzer urea clearance rate
KoA of membrane
an adequate amount of dialysis is an important part of the dialysis
Blood flow prescription. During the dialytic procedure a sharp decrease in the
Dialysate flow concentration of urea occurs followed by a gradual increase during
Convective urea flux the interdialytic period. The decrease in urea during dialysis is
2. Treatment time
determined by three main parameters: dialyzer urea clearance rate
Urea concentration
3. Volume of distribution
(K), dialysis treatment time (t), and the volume of urea distribution
(V). The dialyzer urea clearance rate (K) is influenced by the charac-
teristics of the dialysis membrane (KoA), blood flow rate, dialysate
1. Urea generation rate flow rate, and convective urea flux that occurs with ultrafiltration.
Protein catabolic rate
2. Volume of distribution
The gradual increase in urea during the interdialytic period depends
3. Residual renal function 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.
Dialysis Interdialytic
time time
Time on Time off Time on (next dialysis)

FIGURE 6-10
FACTORS RESULTING IN A REDUCTION OF THE Each of the factors listed may play a major role in the reduction of
PRESCRIBED DOSE OF HEMODIALYSIS DELIVERED 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
Compromised urea clearance dialysis time has to do with premature discontinuation of dialysis
Access recirculation for the convenience of the patient or staff. Delays in starting dialysis
Inadequate blood flow from the vascular access
treatment are frequent and may result in a significant loss of dialysis
prescription. Finally, particular attention should be paid to the correct
Dialyzer clotting during dialysis (reduction of effective surface area)
sampling of the blood urea nitrogen level and the site from which
Blood pump or dialysate flow calibration error
the sample is drawn.
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
BUN—blood urea nitrogen.
FIGURE 6-11
Increasing
ultrafiltation Monitoring the delivered dose in hemodialysis. Use of the urea reduc-
tion ratio (URR) is the simplest way to monitor the delivered dose of
0.0 0
0.0 8
hemodialysis. However, a shortcoming of this method compared with

0.0 6
4
0.1
1.80 0.02 formal urea kinetic modeling is that the URR does not account for the
contribution of ultrafiltration to the final delivered dose of dialysis.
0.00 During ultrafiltration, convective transfer of urea from blood to
dialysate occurs without a decrease in urea concentration. As a result,
1.60 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
Kt/v by formal urea kinetic modeling
low as 1.1 in the absence of ultrafiltration or as high as 1.35 when

1.40 ultrafiltration of 10% of body weight occurs.
1.20
1.00
0.80
0.60
0.40 0.50 0.60 0.70 0.80
Urea reduction ratio, %
45 MAJOR COMPONENTS OF DIALYSIS PRESCRIPTION

500 U/kg
40 150 U/kg Choose a biocompatible membrane

Prescribe a Kt/V ≥1.3 or a URR ≥70%
Rigorously ensure that the delivered dose equals the amount prescribed
35
When the delivered dose is less than that prescribed do the following:
Exclude factors listed in Figure 6-10
Hematocrit, %
Increase blood flow rate ≥400 mL/min

30
Increase dialysate flow rate to ≥800 mL/min
50 U/kg
Use a high-efficiency dialyzer
Increase treatment time
25
15 U/kg 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%
20
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
15 hypotension
0 2 4 6 8 10 12 14 16
Weeks of rHuEpo therapy
URR–urea reduction ratio.
FIGURE 6-12
Correction of anemia in chronic renal failure. Anemia is a pre- FIGURE 6-13
dictable complication of chronic renal failure that is due partly All these components are important as contributors to a successful
to reduction in erythropoietin production. Use of recombinant ery- dialysis prescription. The Dialysis Outcomes Quality Initiative
thropoietin to correct the anemia in patients with chronic renal (DOQI) recommendations should be followed to achieve an adequate
failure has become standard therapy. The rate of increase in hemat- dialysis prescription, and the time on dialysis should be monitored
ocrit is dose-dependent. The indicated doses were given intra- carefully. When the delivered dialysis dose is less that prescribed,
venously three times per week. Current guidelines for the initiation the reversible factors listed in Figure 6-10 should be addressed first.
of intravenous therapy suggest a starting dosage of 120 to 180 Subsequently, an increase in blood flow to 400 mL/min should be
U/kg/wk (typically 9000 U/wk) administered in three divided doses. attempted. Increases in dialyzer surface area and treatment time
Administration of erythropoietin subcutaneously has been shown also may be attempted. In addition, attention should be paid to the
to be more efficient than is intravenous administration. That is, on correct dialysis composition and to the ultrafiltration rate to make
average, any given increment in hematocrit can be achieved with certain that patients achieve a weight as close as possible to their
less erythropoietin when it is given subcutaneously as compared dry weight. Hematocrit should be sustained at 33% to 36%. Finally,
with intravenously. In adults, the subcutaneous dosage of erythro- vitamin D supplementation to prevent secondary hyperparathyroidism
poietin is 80 to 120 U/kg/wk (typically 6000 U/wk) in two to three and use of normal saline or other volume expanders are encouraged
divided doses. rHuEpo—recombinant human erythropoietin. Data to treat hypotension during dialysis. KoA—constant indicating the
from Eschbach and coworkers [12]; with permission. efficiency of the dialyzer in removing urea.
References
1. Owen WF, Lew NL, Liu Y, Lowrie EG: The urea reduction ratio and 7. Vanholder R, Ringoir S, Dhondt A, et al.: Phagocytosis in uremic and
serum albumin concentration as predictors of mortality in patients hemodialysis patients: a prospective and cross sectional study. Kidney
undergoing hemodialysis. N Engl J Med 1993, 329:1001–1006. Int 1991, 39:320–327.
2. Hakim RM, Breyer J, Ismail N, Schulman G: Effects of dose of dialysis 8. Gutierrez A, Alvestrand A, Bergstrom J: Membrane selection and
on morbidity and mortality. Am J Kidney Dis 1994, 23:661–669. muscle protein catabolism. Kidney Int 1992, 42:S86–S90.
3. Held PJ, Port FK, Wolfe RA, et al.: The dose of hemodialysis and 9. Hornberger JC, Chernew M, Petersen J, Garber AM: A multivariate
patient mortality. Kidney Int 1996, 50:550–556. analysis of mortality and hospital admissions with high-flux dialysis.
J Am Soc Nephrol 1992, 3:1227–1237.
4. Parker TF III, Husni L, Huang W, et al.: Survival of hemodialysis
10. Hemodialysis Adequacy Work Group: Dialysis Outcomes Quality
patients in the United States is improved with a greater quantity of Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 3:S199–S201.
dialysis. Am J Kidney Dis 1994, 23:670–680.
11. Hakim RM, Wingard RL, Parker RA: Effect of the dialysis membrane
5. Hemodialysis Adequacy Work Group: Dialysis Outcomes Quality in the treatment of patients with acute renal failure. N Engl J Med
Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 2:S22–S31. 1994, 331:1338–1342.
6. Hakim, RM: Clinical implications of hemodialysis membrane biocom- 12. Eschbach JW, Egrie JC, Downing MR, et al.: Correction of the anemia
patibility. Kidney Int 1993, 44:484–494. of end-stage renal disease with recombinant human erythropoietin.
N Engl J Med 1987, 316:73–78.
Complications of Dialysis:
Selected Topics
Robert W. Hamilton
C
omplications observed in end-stage renal disease may be due to
the side effects of treatment or to the alterations of pathophys-
iology that go with kidney failure.
CHAPTER
7
Complications of Hemodialysis
COMPLICATIONS OF HEMODIALYSIS
Complication Differential diagnosis

Fever Bacteremia, water-borne pyrogens, overheated dialysate
Hypotension Excessive ultrafiltration, cardiac arrhythmia, air embolus, pericardial
tamponade; hemorrhage (gastrointestinal, intracranial,
retroperitoneal); anaphylactoid reaction
Hemolysis Inadequate removal of chloramine from dialysate, failure of dialysis
concentrate delivery system
Dementia Incomplete removal of aluminum from dialysate water, prescription
of aluminum antacids
Seizure Excessive urea clearance (first treatment), failure of dialysis
concentrate delivery system
Bleeding Excessive heparin or other anticoagulant
Muscle cramps Excessive ultrafiltration
Dialyzer hypersensitivity. This patient was switched from a cellulose
acetate dialysis membrane to a cuprammonium cellulose one. Within
FIGURE 7-1 8 minutes of starting hemodialysis he developed apprehension,
diaphoresis, pruritus, palpitations, and wheezing. This eruption
Complications associated with hemodialysis.
was seen over the arm used for arteriovenous access for dialysis.
(From Caruana and coworkers [1]; with permission.)

Thrombosis of the left innominate vein. Thrombosis can be a com- Dilation of a stricture of the left innominate vein using balloon
plication of reliance on subclavian catheters for vascular access for angioplasty in the patient shown in Figure 7-3.
hemodialysis. This was discovered during investigation of edema of
the left arm.
Complications of Dialysis: Selected Topics 7.3

Ischemia of the index finger. Occasionally the arteriovenous fistula results in radial-to-
brachiocephalic 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.

Peritonitis. In continuous ambulatory peritoneal dialysis (CAPD)
peritonitis can easily be recognized by the fact that drained peritoneal FIGURE 7-9 (see Color Plate)
fluid becomes opacified. The inability to read the writing on the
Tunnel abscess in patient undergoing continuous ambulatory peritoneal
opposite side of the drained bag (or a newspaper through the bag)
dialysis. Pericatheter infections are a common source of peritonitis.
correlates with a peritoneal leukocyte count of more than 100 cells
Sometimes, the findings are more subtle than in this case. Prompt
per microliter.
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 peri-
toneum. At laparotomy the mesentery was encased in a “marble-
like” fibrotic mass. The patient required long-term home parenteral
hyperalimentation for recovery. (From Pusateri and coworkers [3];
with permission.)
Complications of Renal Failure
Pericardial effusion
Ventricular septum
Right ventricle
Left ventricle
FIGURE 7-11
Pericardial tamponade. Narrow pulse pressure and a pain. Pericardial tamponade may present as dialysis-induced
pericardial friction rub suggest pericarditis (a frequent hypotension. (Courtesy of T. Pappas, MD, Medical College
complication of uremia) especially in patients with chest of Ohio.)

Perforating folliculitis. The skin of uremic patients can be intensely Acquired cystic disease of the kidney. Abdominal computed tomog-
pruritic. Earlier, it was attributed to deposition of calcium and raphy demonstrates cystic disease in this patient, who had focal
phosphorus in the skin. Today, we know that is the result of segmental glomerulosclerosis complicated by protein C deficiency
repeated trauma to the skin associated with scratching. 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.
FIGURE 7-14
15 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].
10
Risk of death
0
>4.5 4.0–4.4 3.5–3.9 3.0–3.4 2.5–2.9 <2.5
Serum albumin, g/dL
Radiologic Manifestations of Renal Osteodystrophy

Radiograph of a shoulder involved by osteoporosis. The shoulder Diffuse bone demineralization as demonstrated in skull radiograph.
joint demonstrates diffuse osteoporosis. There is distal resorption This radiograph demonstrates the generalized granular appear-
of the clavicle. A small amount of calcification can be seen on the ance that is characteristic of the diffuse demineralization seen in
clavicular side of the coracoclavicular ligament. These findings are renal osteodystrophy.
suggestive of osteitis fibrosa cystica.
10 min 30 30
FIGURE 7-17 50 1 hr 2 hr
Radiograph of the hands of a patient who has renal osteodystrophy.
The hands demonstrate diffuse bilateral osteoporosis. The resorption FIGURE 7-18
of the distal phalanges is best seen in the first and second digits of Parathyroid scan. The patient was injected with 24.6 mCi of 99m
the right hand. The radial side of the middle phalanges of the second Tc Cardiolite. Hyperfunction of four parathyroid glands is seen.
and third digits bilaterally demonstrates subperiosteal bone resorption. This technique is often useful to determine the location and number
Soft tissue calcification is present on the radial side of the proximal of parathyroid glands before performing subtotal parathyroidectomy.
interphalangeal joint of the second digit of the left hand. At operation, diffuse hyperplasia of four parathyroid glands was
found. (From Ishibashi and coworkers [5].)
References
1. Caruana RJ, Hamilton RW, Pearson FC: Dialyzer hypersensitivity syn- 4. Owens WF, Lew NL, Liu L, et al.: The urea reduction ratio and serum
drome: possible role of allergy to ethylene oxide. Am J Nephrol 1985, albumin concentration as predictors of mortality in patients undergoing
5:271–274. hemodialysis. N Engl J Med 1993, 329:1001–1006.
2. van Ypersele de Strihou C, Jadoul M, Malghem J, et al.: Effect of dialysis 5. Ishibashi M, Nishida H, Hiromatsu Y, et al.: Localization of ectopic
membrane and patient’s age on signs of dialysis-related amyloidosis. parathyroid glands using technetium-99m sestamibi imaging: comparison
The working party on dialysis amyloidosis. Kidney Int 1991, with magnetic resonance and computed tomographic imaging. Eur J
39:1012–1019. Nuclear Med 1997, 24:197–201.
3. 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, 8:56–60.
Histocompatibility Testing
and Organ Sharing
Lauralynn K. Lebeck
Marvin R. Garovoy
H
istocompatibility and its current application in kidney trans-
plantation are discussed. Both theoretic and clinical aspects of
human leukocyte antigen testing are described, including anti-
gen typing, antibody detection, and lymphocyte crossmatching. Living
related, living unrelated, and cadaveric donor-recipient matching algo-
rithms are discussed with regard to mandatory organ sharing and
graft outcomes.
CHAPTER
8
8.2 Transplantation as Treatment of End-Stage Renal Disease
Chromosome 6
(short arm) Class II Class III Class I HLA complex
Glyoxylase DP DQ DR B C A
DZ DO Cyp21 TNF
A
Class II Class III Class I
0 1000 2000 3000 4000

DQA2
DQA1
LMP 2
LMP 7
DQB2
DQB1
TAP 1
TAP 2
DRB
DPA1
DPA2
DMA
DPB1
DPB2
DMB
DNA
DRA
H
G
A
C
X
B
F
J
500 3000
CYP 21-A
CYP 21-B
HSP 70
TNF α
TNF β
C4A
C4B
C2
BF
B 1500
FIGURE 8-1
The major histocompatibility complex (MHC) is a group of closely region encode the a or heavy chain of the class I antigens, HLA-A,
linked genes that was first appreciated because it was found to B, and C. The class I region is composed of other genes, most of
contain the structural genes for transplantation antigens. A, The which are pseudogenes and are not expressed. The MHC class II
MHC, located on the short arm of chromosome 6, is now recog- region is more complex, with structural genes for both the a and
nized to include many other genes important in the regulation of b chains of the class II molecules. The class II region includes four
immune responses. B, Regions of the MHC classes I, II, and III. DP genes, one DN gene, one DO gene, five DQ genes, and a vary-
The MHC can be divided into three regions, of which the class I ing number of DR genes (two to 10), depending on the halotype.
and II regions contain the loci for the human histocompatibility Many other immune response genes are coded within the class III
antigen or human leukocyte antigen (HLA). Genes in the class I region. TNF—tumor necrosis factor.
FIGURE 8-2
Specific locus
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
HLA C w 8
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
The major histocompatibility Provisional before the serologic antigen, indicating it is a workshop designation
complex in humans specificity and the specific assignment is provisional.
Specific antigen
Locus Allele designation
HLA DRB1 * 04 03
Corresponding antigen Specific allele

Histocompatibility Testing and Organ Sharing 8.3
FIGURE 8-3
PRETRANSPLANTATION In an immunogenetics and transplantation laboratory, three major types of renal pretrans-
TESTING FOR RENAL PATIENTS plantation testing are performed routinely. The human leukocyte antigen (HLA) assignments
are assigned by serologic methods (ie, complement-dependent cytotoxicity); however, molec-
ular-based methodologies are becoming widely accepted. Most laboratories now have the
HLA phenotype capability of reporting at least low-resolution molecular class II types.
Patient cells tested with known antisera The sera of patients awaiting cadaveric donor kidney transplantation are tested for the
HLA antibody screen
degree of alloimmunization by determining the percentage of panel reactive antibodies
(PRAs). Current federal regulations require that the serum screening test use lymphocytes
Known cells tested with patient sera
as targets; however, because these same regulations no longer mandate monthly screening,
HLA crossmatch
assays using soluble antigens may be used as adjuncts to the classic lymphocytotoxic assays.
Donor cells tested with patient sera
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.
FIGURE 8-4
MHC I AND II CHARACTERISTICS 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
Class I Class II (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
Composed of HLA-A, -B, and -C Composed of HLA-DR, -DQ, and -DP light chain (b2-microglobulin). The a chain is attached to the cell
Ubiquitous distribution Restricted distribution membrane, whereas b2-microglobulin is associated with the a
Autosomal codominant Autosomal codominant chain but is not covalently bonded. The HLA class I molecules are
Target for immune effector mechanism Major role in immune response found on almost all cells; however, only vestigial amounts remain
Serologic and molecular detection induction on mature erythrocytes. Class II antigens (HLA-DR, DQ, and DP)
Heterodimer noncovalently linked Serologic, molecular, and cellular have a molecular weight of approximately 63,000 D and consist of
Heavy chain (a): detection two dissimilar glycoprotein chains, designated a and b, both of
Contains variable regions Heterodimer noncovalently linked which are attached to the membrane. Each chain consists of two
Confers human leukocyte antigen a Chain: extramembranous amino acid domains, and the outer domains of
specificity Nonvariable in HLA-DR each molecule contain the variable regions corresponding to class II
Light chain (b2-microglobulin): Contains variable regions in HLA-DQ alleles. Although class I antigens are expressed on all nucleated cells
Invariant and -DP of the body, the expression of class II antigens is more restricted. Class
b Chain: II antigens are found on B lymphocytes, activated T lymphocytes,
Contains variable regions monocyte-macrophages, dendritic cells, and early hematopoietic
Confers most of HLA-DR specificity cells, and of importance in transplantation, endothelial cells.
8.4 Transplantation as Treatment of End-Stage Renal Disease
FIGURE 8-5
MHC T-cell
protein receptor Biology of the major histocompatibility complex (MHC). A, The
biologic function of MHC antigens is to present antigenic peptides
α chain to T lymphocytes. In fact, it is an absolute requirement of T-lym-
phocyte 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
Processed β chain domains of the MHC molecules are formed by the folding of por-
antigen tions 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.
A
α1 α2
β2m α3
B C
FIGURE 8-6
Peptide
Peptide 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
Heavy β2m subunit α subunit β subunit is more flexible and relatively open at one
subunit
end, more like a “hotdog bun,” permitting
larger peptides from 13 to 25 amino acid
residues in length to bind.
A B
Histocompatibility Testing and Organ Sharing 8.5
FIGURE 8-7
HLA SPECIFICITIES Allelic polymorphism. Allelic polymorphism
is a hallmark of the human leukocyte antigen
(HLA) system. The extreme polymorphism of
A B B C DR DQ DP the HLA system is seen in the large numbers
of different alleles that exist for the multiple
A1 B5 B51(5) Cw1 DR1 DQ1 DPw1 major histocompatibility complex (MHC)
A2 B7 B5102 Cw2 DR103 DQ2 DPw2 loci. At any given locus, one of several
A203 B703 B5103 Cw3 DR2 DQ3 DPw3 alternative forms or alleles of a gene can
A210 B8 B52(5) Cw4 DR3 DQ4 DPw4 exist. Because so many alleles are possible
A3 B12 B53 Cw5 DR4 DQ5(1) DPw5 for each HLA locus, the system is extremely
A9 B13 B54(22) Cw6 DR5 DQ6(1) DPw6 polymorphic. The currently accepted World
A10 B14 B55(22) Cw7 DR6 DQ7(3) Health Organization serologically defined
A11 B15 B56(22) Cw8 DR7 DQ8(3) alleles are shown here. Established HLA
A19 B16 B57(17) Cw9(w3) DR8 DQ9(3) antigens are designated by a number following
A23(9) B17 B58(17) Cw10(w3) DR9 the letter that denotes the HLA locus (eg,
A24(9) B18 B59 DR10 HLA-A1 and HLA-B8). For example, by
A2403 B21 B60(40) DR11(5) serologic techniques, 28 distinct antigens
A25(10) B22 B61(40) DR12(5) are recognized at the HLA-A locus, and
A26(10) B27 B62(15) DR13(6) 59 defined antigens at the HLA-B locus.
A28 B2708 B63(15) DR14(6) Sequencing studies of the HLA-DRB1 gene
A29(19) B35 B64(14) DR1403
have identified over 100 distinct alle

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Diseases of Water

Physiology of the Renal Diluting

Water intake and distribution

volume of blood filtered by the kidney is

Generation of medullary hypertonicity

;;;;;;;;;;;; Impermeable antidiuretic substances. GFR—glomerular

Absence of other antidiuretic substances

FIGURE 1-4 (continued)

Pathway A Urea Inner

900 its volume in the proximal tubule; however,

AQUAPORINS AND THEIR CHARACTERISTICS

AQP-1 AQP-2 AQP-3 AQP-4

Control of Water Balance and

Increased plasma osmolality Decreased plasma osmolality

Increased water Decreased water Decreased water Decreased water

Water retention Water excretion

Decreased plasma osmolality Increased plasma osmolality

Disorder involving urine Disorder involving urine

Approach to the Hyponatremic Patient

Assessment of volume status

Hypovolemia Euvolemia (no edema) Hypervolemia

DRUGS ASSOCIATED WITH HYPONATREMIA CAUSES OF THE SYNDROME OF INAPPROPRIATE

Antidiuretic hormone analogues

FIGURE 1-17 FIGURE 1-18

HYPONATREMIC PATIENTS AT RISK FOR SYMPTOMS OF CENTRAL PONTINE MYELINOLYSIS

A. GENERAL GUIDELINES FOR THE TREATMENT OF B. TREATMENT OF CHRONIC SYMPTOMATIC

MANAGEMENT OPTIONS FOR CHRONIC ASYMPTOMATIC HYPONATREMIA

Treatment Mechanism of Action Dose Advantages Limitations

Approach to the Hypernatremic Patient

Assessment of volume status

Hypovolemia Euvolemia (no edema) Hypervolemia

UNa>20 UNa<20 UNa variable UNa>20

WATER DEPRIVATION TEST CLINICAL FEATURES OF

Urine Osmolality with Plasma Arginine Increase in Urine

ACQUIRED NEPHROGENIC DIABETES INSIPIDUS: PATIENT GROUPS AT

SIGNS AND SYMPTOMS OF Hypovolemic Euvolemic Hypervolemic

Correction of volume deficit Correction of water deficit Removal of sodium

Normal Extracellular Fluid Volume Homeostasis

Dietary sodium intake, g

Urinary sodium excretion, g/d Urinary sodium excretion, g/d

in extracellular fluid (ECF) volume result

↑ ANP ↑ Arterial pressure ↑ Kinins

↓ Renal tubular sodium reabsoption

FIGURE 2-14 (continued)

Mechanisms of Sodium and Chloride

Lumen Interstitum ↑GFR

Causes, Signs, and Symptoms of Extracellular

CAUSES OF VOLUME EXPANSION CAUSES OF VOLUME DEPLETION

CLINICAL SIGNS OF VOLUME CLINICAL SIGNS OF VOLUME LABORATORY SIGNS OF VOLUME

Edema Orthostatic decrease in blood pressure and increase Hypernatremia

Mechanisms of Extracellular Fluid Volume

Mean arterial pressure, mmHg

ANP Effects of high-output heart failure induced in dogs by arteriovenous

Mechanisms of Extracellular Fluid

Control subjects, n=16 Cirrhotic patients, n=60

increased plasma renin activity (PRA) and plasma arginine vaso-

cirrhosis. A primary decrease in systemic

Mechanisms of Extracellular Fluid Volume

10 ma protein concentration decreases below 5 g/dL do changes become significant. (Data

PRA, ng/L × sec

reduction in GFR in the nephrotic group, a finding that is common

60 60 in human nephrosis. Fractional reabsorption rates along the proxi-

Extracellular Fluid Volume

(24-h urine Mg) ([Preinfusion urine Mg:Cr] [24-h urine Cr])