Atlas of Diseases of The Kidney Vol V

1
Principles of Dialysis:
Diffusion, Convection,
and Dialysis Machines
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 m
2
body surface
area (15 mL/min/1.73 m
2
in diabetics.) Others institute treatment
when the patient loses the stamina to sustain normal daily work and
activity. Most agree that, in the face of symptoms (nausea, vomiting,
anorexia, fatigability, diminished sensorium) and signs (pericardial
friction rub, refractory pulmonary edema, metabolic acidosis, foot or
wrist drop, asterixis) of uremia, dialysis treatments are urgently indicated.
Rober t W. H a m il t on
CHA P T ER
2
1.2 Dialysis as Treatment of End-Stage Renal Disease
FUNCTIONS OF THE KIDNEY AND PATHOPHYSIOLOGY OF RENAL FAILURE
Function
Salt, water, and acid-basebalance
Water balance
Sodiumbalance
Potassiumbalance
Bicarbonatebalance
Magnesiumbalance
Phosphatebalance
Excretion of nitrogenousend products
Urea
Creatinine
Uric acid
Amines
Guanidinederivatives
Endocrine-metabolic
Conversion of vitamin D to activemetabolite
Production of erythropoietin
Renin
Dysfunction
Salt, water, and acid-basebalance
Fluid retention and hyponatremia
Edema, congestiveheart failure, hypertension
Hyperkalemia
Metabolic acidosis, osteodystrophy
Hypermagnesemia
Hyperphosphatemia, osteodystrophy
Excretion of nitrogenousend products
?Anorexia, nausea, pruritus, pericarditis, polyneuropa-
thy, encephalopathy, thrombocytopathy
Endocrine-metabolic
Osteomalacia, osteodystrophy
Anemia
Hypertension
FIGURE 1-1
Functions of the kidney and pathophysiology of renal failure.
FIGURE 1-2
Statue of Thomas Graham in George
Square, Glasgow, Scotland. The physico-
chemical basis for dialysis was first
described by the Scottish chemist Thomas
Graham. In his 1854 paper On Osmotic
Force he described the movements of
various solutes of differing concentrations
through a membrane he had fashioned
from an ox bladder. (FromGraham [1].)
Urea Urea
Creatinine Creatinine
HCO
3
HCO
3
Ca
2+
Ca
2+
K
+
K
+
Na
+
Na
+
Blood Membrane Dialysate
FIGURE 1-3
Membrane fluxes in dialysis. Dialysis is the process of separating elements in a solution by
diffusion across a semipermeable membrane (diffusive solute transport) down a concentra-
tion gradient. This is the principal process for removing the end-products of nitrogen
metabolism (urea, creatinine, uric acid), and for repletion of the bicarbonate deficit of the
metabolic acidosis associated with renal failure in humans. The preponderance of diffusion
as the result of gradient is shown by the displacement of the arrow.
3
1.3 Principles of Dialysis: Difusion, Convection, and Dialysis Machines
Acidified
concentrate
Bicarbonate
concentrate
Conductivity
monitor
Membraneunit
Heparin
pump
Blood
pump
Patient
Pump
Water
Drain
Heat
exchanger
Spent
dialysate
Heater Pump
Mix 1
Deaerator
Mix 2
Spent
dialysate
pump
Blood
leak
detector
Air
embolus
detector
Volume
balance
system
Ultrafiltrate
pump
FIGURE 1-4
Simplified schematic of typical hemodialysis system. In hemodialysis,
blood from the patient is circulated through a synthetic extracorporeal
membrane and returned to the patient. The opposite side of that
membrane is washed with an electrolyte solution (dialysate) contain-
ing the normal constituents of plasma water. The apparatus contains
a blood pump to circulate the blood through the system, proportioning
pumps that mix a concentrated salt solution with water purified by
reverse osmosis and/or deionization to produce the dialysate, a means
of removing excess fluid from the blood (mismatching dialysate
inflow and outflow to the dialysate compartment), and a series of
pressure, conductivity, and air embolus monitors to protect the
patient. Dialysate is warmed to body temperature by a heater.
Blood Blood
Dialysate
Dialysate
Blood
Dialysate
FIGURE 1-5
The hemodialysis membrane. Most membranes are derived from
cellulose. (The earliest clinically useful hemodialyzers were made
from cellophane sausage casing.) Other names of these materials
include cupraphane, hemophan, cellulose acetate. They are usually
sterilized by ethylene oxide or gamma irradiation by the manufac-
turer. They are relatively porous to fluid and solute but do not
allow large molecules (albumin, vitamin B
12
) to pass freely. There
is some suggestion that cupraphane membranes sterilized by ethylene
oxide have a high incidence of biosensitization, meaning that the
patient may have a form of allergic reaction to the membrane.
Polysulfone, polyacrylonitrile, and polymethylmethacrylate membranes
are more biocompatible and more porous (high flux membranes).
They are most often formed into hollow fibers. Blood travels down
the center of these fibers, and dialysate circulates around the outside
of the fibers but inside a plastic casing. Water for dialysis must meet
critical chemical and bacteriologic standards. These are listed in
Figures 1-6 and 1-7.
4
ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL
INSTRUMENTATION CHEMICAL STANDARD FOR
WATER FOR HEMODIALYSIS
Substance
Aluminum
Arsenic
Barium
Cadmium
Calcium
Chloramine
Chlorine
Chromium
Copper
Fluoride
Lead
Magnesium
Mercury
Nitrate
Potassium
Selenium
Silver
Sodium
Sulfate
Zinc
Concentration (mg/L)
0.01
0.005
0.1
0.001
2.0
0.1
0.5
0.014
0.1
0.2
0.005
4.0
0.0002
2.0
8.0
0.009
0.005
70
100
0.1
FIGURE 1-6
Association for the Advancement of Medical Instrumentation
(AAMI) chemical standards for water for hemodialysis. Before
hemodialysis can be performed, water analysis is performed.
Water for hemodialysis generally requires reverse osmosis treat-
ment and a deionizer for polishing the water. Organic materials,
chlorine, and chloramine are removed by charcoal filtration.
(FromVlchek [2]; with permission.)
ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL
INSTRUMENTATION BACTERIOLOGIC STANDARDS
FOR DIALYSIS WATER AND PREPARED DIALYSATE
Dialysiswater
Prepared dialysate
Colony-forming units/mL
<200
<2000
FIGURE 1-7
Association for the Advancement of Medical Instrumentation
(AAMI) bacteriologic standards for dialysis water and prepared
dialysate. Excess bacteria in water can lead to pyrogen reactions.
Treated water supply systems are designed so that there are no
dead-end connections. Because the antiseptic agents (chlorine and
chloramine) have been removed in water treatment, the water is
prone to develop such problems if stagnation is allowed. (From
Bland and Favero [3]; with permission.)
dn
dt
dc
dx
=DA
FIGURE 1-8
Factors that govern di ffusi on, where dn/dt
= the rate of movement of mol ecul es per
uni t ti me; D = Fi cks di ffusi on coeffi ci ent;
A = area of the boundary through whi ch mol ecul es move; dc = concentrati on
gradi ent; and dx = di stance through whi ch mol ecul es move. Hemodi al ysi s depends
on the process of di ffusi on for removal of sol utes. The amount of materi al removed
depends on the magni tude of the concentrati on gradi ent, the di stance the mol ecul e
travel s, and the area through whi ch di ffusi on takes pl ace. For thi s reason those
dialyzers that have a large surface area, thin membranes, and are designed to maximize
the effect of concentrati on gradi ent (countercurrent desi gn) are most effi ci ent at
removi ng sol utes.
5
1.5 Principles of Dialysis: Difusion, Convection, and Dialysis Machines
k
6
4N
3
D=
3
Blood flow, m L/ m in
C
l
e
a
r
a
n
c
e
,

m
L
/
m
i
n
400 0 100 200 300
250
200
150
Urea
Creatinine
Phosphate
Vitamin B
12
100
50
0
FIGURE 1-9
Ficks diffusion constant, where D = Ficks diffusion coefficient, k = Boltzmans constant;
T = absolute temperature; = viscosity; N = Avogadros number; M = molecular weight;
and = partial molal volume. The diffusion constant is proportional to the temperature of
the solution and inversely proportional to the viscosity and the size of the molecule removed.
FIGURE 1-10
Effect of blood flow on clearance of various solutes, Fresenius F-5 membrane. The amount
of solute cleared by a dialyzer depends on the amount delivered to the membrane. The
usual blood flow is 300400 mL/min, which is adequate to deliver the dialysis prescrip-
tion. On institution of dialysis to a very uremic patient the blood flow is decreased to 160
to 180 mL/min to avoid disequilibrium syndrome. As time goes on, blood flow can be
increased to standard flows as the patient adjusts to dialysis. Most patients require
hemodialysis at least thrice weekly. From this graph it is also evident that small molecules
such as urea (molecular weight 60 D) are cleared more easily than large molecules such as
vitamin B
12
(molecular weight 1355 D).
P
r
e
s
s
u
r
e
,

m
m
H
g
400
300
200
100
0
100
200
Blood
compartment
Dialysate
compartment
Net transmembrane
pressure
FIGURE 1-11
Hydrostatic ultrafiltration also takes place during hemodialysis.
Because the spent dialysate effluent pump (see Fig. 1-4) creates neg-
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
from blood to the dialysate compartment. The process of solute
transfer associated with this flow of water is called convective
transport. In hemodialysis, the amount of lowmolecular weight
solute (eg, urea) removed by convection is negligible. In the continu-
ous renal replacement therapies, this is a major mechanism for
solute transport.
6
F5 F50
35
30
25
20
15
10
5
0
U
F
R
,

m
L
/
h
/
m
m
H
g
FIGURE 1-12
Dialysis membranes differ in their ability to remove fluid. Differences in ultrafiltration
coefficient (UFR) are shown for two different membranes, F-5 and F-50. The F-50 is
considered a high-flux membrane.
References
1. Graham T: The Bakerian lectureon osmotic force. Philos Trans R
Soc Lond 1854, 144:177228.
2. Vlchek DL: Monitoring a hemodialysis water treatment system. In AAMI
Standards and Recommended Practices, vol. 3. Arlington, VA: Association
for the Advancement of Medical Instrumentation; 1993:267277.
3. Bland LA, Favero MS: Microbiologic aspects of hemodialysis systems. In
AAMI Standards and Recommended Practices, vol. 3. Arlington, VA:
Association for the Advancement of Medical Instrumentation; 1993:257265.
4. Daniels F, Alberty RA: Physical Chemistry. New York : John Wiley &
Sons; 1955.
7
2
Dialysate Composition
in Hemodialysis and
Peritoneal Dialysis
T
he goal of dialysis for patients with chronic renal failure is to
restore the composition of the bodys fluid environment toward
normal. This is accomplished principally by formulating a
dialysate whose constituent concentrations are set to approximate
normal values in the body. Over time, by diffusional transfer along
favorable concentration gradients, the concentrations of solutes that
were initially increased or decreased tend to be corrected. When an
abnormal electrolyte concentration poses immediate danger, the
dialysate concentration of that electrolyte can be set at a 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-
ing dialysis. It soon became apparent that changes in the serum sodium
concentrationand more specifically changes in serum osmolality
were contributing to the development of this hemodynamic instability.
A decline in plasma osmolality during regular hemodialysis favors a
Biff F. Pa l m er
CHA P T ER
8
fluid shift from the extracellular space to the intracellular
space, thus exacerbating the volume-depleting effects of dialy-
sis. With the advent of high-clearance dialyzers and more effi-
cient dialysis techniques, this decline in plasma osmolality
becomes more apparent, as solute is removed more rapidly.
Use of dialysate of low sodium concentration would tend fur-
ther to enhance the intracellular shift of fluid, as plasma tends
to become
even more hyposmolar consequent to the movement of sodi-
um from
plasma to dialysate. The use of a higher sodium concentration
dialysate (>140 mEq/L) has been among the most efficacious
and best tolerated therapies for episodic hypotension [13].
The high sodium concentration prevents a marked decline in
the plasma osmolality during dialysis, thus protecting the extra-
cellular volume by minimizing osmotic fluid loss into the cells.
In the early 1960s acetate became the standard dialysate
buffer for correcting uremic acidosis and offsetting the diffusive
losses of bicarbonate during hemodialysis. Over the next several
years reports began to accumulate that linked routine use of
acetate with cardiovascular instability and hypotension during
dialysis. As a result, dialysate containing bicarbonate began to
re-emerge as the principal dialysate buffer, especially as advances
in biotechnology made bicarbonate dialysate less expensive and
less cumbersome to use. For the most part, the bicarbonate con-
centration used consistently in most dialysis centers is 35
mmol/L. Emphasis is now being placed on individually adjusting
the dialysate bicarbonate concentration so as to maintain the
predialysis tCO2 concentration above 23 mmol/L [1216].
Increasing evidence suggests that correction of chronic acidosis
is of clinical benefit in terms of bone metabolism and nutrition.
Dialysis assumes a major role in the maintenance of a normal
serum potassium concentration in patients with end-stage renal
disease. Excess potassium is removed by using a dialysate with a
lower potassium concentration, so that a gradient is achieved
that favors movement of potassium. In general, one can expect
only up to 70 to 90 mEq of potassium to be removed during a
typical dialysis session. As a result, one should not overestimate
the effectiveness of dialysis in the treatment of severe hyper-
kalemia. The total amount removed varies considerably and is
affected by changes in acid-base status, in tonicity, in glucose and
insulin concentration, and in catecholamine activity [1720].
The concentration of calcium in the dialysate has implications
for metabolic bone disease and hemodynamic stability. Like the
other constituents of the dialysate, the calcium concentration
should be tailored to the individual patient [21]. Some data suggest
that lowering the dialysate calcium concentration would exac-
erbate hemodynamic instability during the dialysis procedure
[21]. In this regard, the intradialysis drop in blood pressure
noted in patients dialyzed against a low-calcium bath, while
statistically significant, is minor in degree [22,23]. Nevertheless,
for patients who are prone to intradialysis hypotension avoid-
ing low calcium dialysate concentration may be of benefit. On
the other hand, the use of a lower calcium concentration in the
dialysate allows the use of increased doses of calcium-containing
phosphate binders and lessens dependence on binders containing
aluminum. In addition, use of 1,25-dihydroxyvitamin D can be
liberalized to reduce circulating levels of parathyroid hormone
and, thus, the risk of inducing hypercalcemia. With dialysate
calcium concentrations below 1.5 mmol/L, however, patients
need close monitoring to ensure that negative calcium balance
does not develop and that parathyroid hormone levels remain
in an acceptable range [24].
Dialysate Composition for Peritoneal Dialysis
To meet the ultrafiltration requirements of patients on peritoneal
dialysis, the peritoneal dialysate is deliberately rendered hyper-
osmolar relative to plasma, to create an osmotic gradient that
favors net movement of water into the peritoneal cavity. In
commercially available peritoneal dialysates, glucose serves as
the osmotic agent that enhances ultrafiltration. Available con-
centrations range from 1.5% to 4.25% dextrose. Over time, the
osmolality of the dialysate declines as a result of water moving
into the peritoneal cavity and of absorption of dialysate glucose.
The absorption of glucose contributes substantially to the calorie
intake of patients on continuous peritoneal dialysis. Over time,
this carbohydrate load is thought to contribute to progressive
obesity, hypertriglyceridemia, and decreased nutrition as a
result of loss of appetite and decreased protein intake. In addition,
the high glucose concentrations and high osmolality of currently
available solutions may have inhibitory effects on the function
of leukocytes, peritoneal macrophages, and mesothelial cells
[25]. In an attempt to develop a more physiologic solution, various
new osmotic agents are now under investigation. Some of these
may prove useful as alternatives to the standard glucose solutions.
Those that contain amino acids have received the most attention.
The sodium concentration in the ultrafiltrate during peri-
toneal dialysis is usually less than that of extracellular fluid, so
there is a tendency toward water loss and development of hyper-
natremia. Commercially available peritoneal dialysates have a
sodium concentration of 132 mEq/L to compensate for this ten-
dency toward dehydration. The effect is more pronounced with
increasing frequency of exchanges and with increasing dialysate
glucose concentrations. Use of the more hypertonic solutions
and frequent cycling can result in significant dehydration and
hypernatremia. As a result of stimulated thirst, water intake and
weight may increase, resulting in a vicious cycle.
Potassium is cleared by peritoneal dialysis at a rate similar to
that of urea. With chronic ambulatory peritoneal dialysis and
10 L of drainage per day, approximately 35 to 46 mEq of potas-
sium is removed per day. Daily potassium intake is usually
greater than this, yet significant hyperkalemia is uncommon in
these patients. Presumably potassium balance is maintained by
increased colonic secretion of potassium and by some residual
9
2.3 Dialysate Composition in Hemodialysis and Peritoneal Dialysis
renal excretion. Given these considerations, potassium is not
routinely added to the dialysate.
The buffer present in most commercially available peritoneal
dialysate solutions is lactate. In patients with normal hepatic
function, lactate is rapidly converted to bicarbonate, so that
each mM of lactate absorbed generates one mM of bicarbonate.
Even with the most aggressive peritoneal dialysis there is no
appreciable accumulation of circulating lactate. The rapid
metabolism of lactate to bicarbonate maintains the high
dialysate-plasma lactate gradient necessary for continued
absorption. The pH of commercially available peritoneal dialysis
solutions is purposely made acidic by adding hydrochloric acid
to prevent dextrose from caramelizing during the sterilization
procedure. Once instilled, the pH of the solution rises to values
greater than 7.0. There is some evidence that the acidic pH of
the dialysate, in addition to the high osmolality, may impair the
hosts peritoneal defenses [25,26].
To avoid negative calcium balanceand possibly to suppress
circulating parathyroid hormonecommercially available peri-
toneal dialysis solutions evolved to have a calcium concentration
Lessvascular refilling
Peripheral vasoconstriction
Exacerbated autonomic
insufficiency
-inhibitsafferent sensing
- CNSefferent outflow
Venouspoolingsecondary
to PGE
2
Hypotension
Baseline
Interstitial
space
Intravascular
space
Stableosmolality
Low-sodiumdialysate High-sodiumdialysate
Cell Cell
Decreased
osmolality
BUN
BUN
BUN
BUN Na
H
2
O
H
2
O
H
2
O
H
2
O
150
140
N
a

c
o
n
c
e
n
t
r
a
t
i
o
n
,

m
E
q
/
L
1 3 2 4
Time, h
Step
Linear
Exponential
145
of 3.5 mEq/L (1.75 mmol/L). This concentration is equal to or
slightly greater than the ionized concentration in the serum of
most patients. As a result, there is net calcium absorption in
most patients treated with a conventional chronic ambulatory
peritoneal dialysis regimen. As the use of calcium-containing
phosphate binders has increased, hypercalcemia has become a
common problem when utilizing the 3.5 mEq/L calcium
dialysate. This complication has been particularly common in
patients treated with peritoneal dialysis, since they have a much
greater incidence of adynamic bone disease than do hemodialysis
patients [27]. In fact, the continual positive calcium balance
associated with the 3.5-mEq/L solution has been suggested to
be a contributing factor in the development of this lesion. The
low bone turnover state typical of this disorder impairs accrual
of administered calcium, contributing to the development of
hypercalcemia. As a result, there has been increased interest in
using a strategy similar to that employed in hemodialysis,
namely, lowering the calcium content of the dialysate. This
strategy can allow increased use of calcium-containing phosphate
binders and more liberal use of 1,25-dihydroxyvitamin D to
effect decreases in the circulating level of parathyroid hormone.
In this way, development of hypercalcemia can be minimized.
Dialysate Na in Hemodialysis
10
INDICATIONS AND CONTRAINDICATIONS FOR USE
OF SODIUM MODELING (HIGH/LOW PROGRAMS)
Indications
Intradialysishypotension
Cramping
Initiation of hemodialysisin settingof severeazotemia
Hemodynamic instability(eg, intensivecaresetting)
Contraindications
Intradialysisdevelopment of hypertension
Largeinterdialysisweight gain induced byhigh-sodiumdialysate
Hypernatremia
FIGURE 2-1
Use of a low-sodium dialysate is more often associated with intra-
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
refilling of the intravascular space. This intracellular movement of
Na
Cl
Ca
Acetate
K
HCO
3
Mg
Dextrose
137 mEq/L
105 mEq/L
3.0 mEq/L
4.0 mEq/L
2.0 mEq/L
33 mEq/L
0.75 mEq/L
200 mg/dl
NaCl
CaCl
KCL
MgCl
Acetic acid
Dextrose
NaHCO
3
NaHCO
3
concentrate
Acid concentrate
Final dialysate
H
2
O
PureH
2
O
water, combined with removal of water by ultrafiltration, leads to contraction of the
intravascular space and contributes to the development of hypotension. High-sodium
dialysate helps to minimize the development of hypo-osmolality. As a result, fluid can be
mobilized from the intracellular and interstitial compartments to refill the intravascular
space during volume removal. Other potential mechanisms whereby low-sodium dialysate
contributes to hypotension are indicated. Nasodium; BUNblood urea nitrogen;
PGE
2
prostaglandin E
2
.
FIGURE 2-2
There has been interest in varying the concentration of sodium (Na) in the dialysate during
the dialysis procedure so as to minimize the potential complications of a high-sodium solution
and yet retain the beneficial hemodynamic effects. A high sodium concentration dialysate is
used initially and progressively the concentration is reduced toward isotonic or even hypo-
MECHANISMS BY WHICH ACETATE BUFFER
CONTRIBUTES TO HEMODYNAMIC INSTABILITY
Directlydecreasesperipheral vascular resistancein approximately10%of patients
Stimulatesreleaseof thevasodilator compound interleukin 1
Inducesmetabolic acidosisviabicarbonatelossthrough thedialyzer
Producesarterial hypoxemiaand increased oxygen consumption
?Decreased myocardial contractility
tonic levels by the end of the procedure. The concentration of sodi-
um can be reduced in a linear, exponential, or step pattern. This
method of sodium control allows for a diffusive sodium influx early
in the session to prevent a rapid decline in plasma osmolality sec-
ondary to efflux of urea and other small-molecular weight solutes.
During the remainder of the procedure, when the reduction in
osmolality accompanying urea removal is less abrupt, the dialysate
is sodium level is set lower, thus minimizing the development of
Dialysate Buffer in Hemodialysis
11
3.5
5.0
4.5
2.5
P
l
a
s
m
a

p
o
t
a
s
s
i
u
m
,

m
M
1 0 3 2 5 4
Time, h
Start hemodialysis
End hemodialysis
3.0
4.0
and cramps [5-11].
FIGURE 2-3
Indications and contraindications for use of sodium modeling
(high/low programs). Use of a sodium modeling program is not indi-
cated in all patients. In fact most patients do well with the dialysate
sodium set at 140 mEq/L. As a result the physician needs to be
aware of the benefits as well as the dangers of sodium remodeling.
FACTORS RELATED TO DIALYSIS THAT AFFECT
DISTRIBUTION OF POTASSIUM BETWEEN CELLS
AND THE EXTRACELLULAR FLUID
Factorsthat enhancecell potassiumuptake
Insulin
2
-adrenergic receptor agonists
Alkalemia
Factorsthat reducecell potassiumuptakeor increasepotassiumefflux
2
-adrenergic receptor blockers
Acidemia(mineral acidosis)
Hypertonicity
-adrenergic receptor agonists
LessK
removal
Glucose-containingdialysate
Correction of metabolic acidosis
duringhemodialysis
Pre-dialysistreatment with -stimulants
Dialysis
membrane
Dialysis
membrane
K
+
K
+
K
+
K
+
A B
FIGURE 2-4
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
concentrate reacts with an equimolar amount of bicarbonate to
generate carbonic acid and carbon dioxide. The generation of car-
bon dioxide causes the pH of the final solution to fall to approxi-
mately 7.07.4. 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
approximately 3338 mmol/L.
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
12
Helps prevent hypercalcemia
secondary to high-dose
calciumcontainingphosphate
binders and vitamin D
Monitor for negative
calciumbalance
Low-calciumdialysate Low-calciumdialysate
Promotes positive
calciumbalance
Suppresses parathyroid
hormonelevels
Better hemodynamic stability
Risk of hypercalcemia
?Risk of adynamic bonedisease
Step 3: Control
secondary
hyperparathyroidism
Individualize
dialysatecalcium
Step 2: Normalize
serumcalcium
Step 1: Control serum
phosphate
Treat with 1,25(OH)
2
vitamin D
If calciumisstill low
after control of
phosphate, treat with
1,25-(OH)
2
vitamin D
Usecalcium-containing
phosphatebinders
1.01.5gdietarycalcium
Low-phosphatediet
(8001000mg/d)
Phophatebinders
High-calciumdialysate
Mechanisms by which acetate buffer contributes to hemodynamic
instability. Although bicarbonate is the standard buffer in use
today, hemodynamically stable patients can be dialyzed safely using
as acetate-containing dialysis solution. Since muscle is the primary
site of metabolism of acetate, patients with reduced muscle mass
tend to be acetate intolerant. Such patients include malnourished
and elderly patients and women.
Dialysate Potassium in
Hemodialysis
FIGURE 2-5
13
ADVANTAGES AND DISADVANTAGES OF INDIVIDUALIZING VARIOUS COMPONENTS OF HEMODIALYSATE
Dialysate component
and adjustment
Sodium:
Increased
Decreased (rarelyused)
Calcium:
Increased
Decreased
Potassium:
Increased
Decreased
Bicarbonate:
Increased
Decreased
Magnesium:
Increased
Decreased
Advantages
Morehemodynamic stability, lesscramping
Lessinterdialytic weight gain
Suppression of PTH, promoteshemodynamic stabilityin HD
Permitsgreater useof vitamin D and calciumcontaining
phosphatebinders
Lessarrhythmiasin settingof digoxin or coronaryheart disease
?improved hemodynamic stability
Permitsgreater dietaryintakeof potassiumwith lesshyperkalemia
?improvement in myocardial contractility
Correctschronic acidosistherebybenefitsnutrition and bonemetabolism
Lessmetabolic alkalosis
?Lessarrhythmias, ?hemodynamic benefit
Permitsgreater useof magnesiumcontainingphosphatebinderswhich in tum
permitsreduced doseof calciumbindersand resultsin lesshypercalcemia
Disadvantages
Dipsogenic effect, increased interdialytic weight gain,
?chronic hypertension
Intradialytic hypotension and crampingmorecommon
Hypercalcemiawith vitamin D and high-dosecalcium-containing
phosphatebinders, ?contribution to adynamic bonediseasein PD
Potential for negativecalciumbalance, stimulation of PTH,
slight decreasein hemodynamic stability
Limited byhyperkalemia
Increased arrhythmias, mayexacerbateautonomic insufficiency
Post-dialysismetabolic alkalosis
Potential for chronic acidosis
Potential for hypermagnesemia
Symptomatic hypomagnesemia
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
COMPOSITION OF A
COMMERCIALLY AVAILABLE
PERITONEAL DIALYSATE
Solute
Sodium, m Eq / L
Potassium, m Eq / L
Chloride, m Eq / L
Calcium, m Eq / L
Magnesium, m Eq / L
D, L-Lactate, m Eq / L
Glucose, g/ d L
Osmolality
pH
Dianeal PD-2
132
0
96
3.5
0.5
40
1.5, 2.5, 4.25
346, 396, 485
5.2
Presumably, the movement of potassium out of cells and into the extracellular space is
slower than the removal of potassium from the extracellular space into the dialysate, so a
disequilibrium is created. The rate of potassium removal is largely a function of its predialysis
concentration. The higher the initial plasma concentration, the greater is the plasma-dialysate
gradient and, thus, the more potassium is removed. After the completion of a standard
dialysis treatment there is an increase in the plasma concentration of potassium secondary
to continued exit of potassium from the intracellular space to the extracellular space in an
attempt to re-establish the intracellular-extracellular potassium gradient.
FIGURE 2-7
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.
FIGURE 2-6
14
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
renal disease since the major route of potassium excretion
is eliminated from the body by residual renal clearance and
enhanced gastrointestinal excretion.
FIGURE 2-8
During a typical dialysis session approximately 80 to 100 mEq/L
of potassium is removed from the body. A, Potassium (K) flux from
the extracellular space across the dialysis membrane exceeds the
flux of potassium out of the intracellular space. B, The movement
of potassium between the intra- and extracellular spaces is 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].
15
3
High-Efficiency and
High-Flux Hemodialysis
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 hi gh-effi ci ency and hi gh-fl ux di al ysi s have been confusi ng.
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.
Siva sa nk a r a n A m ba l a va na n
Ga r y Ra bet oy
A l f r ed K. Cheung
CHA P T ER
16
Dialyzers
1986 1988 1990 1992 1994
0
50
40
30
20
10
1996
C
e
n
t
e
r
s
,

%

Year
HIGH-PERFORMANCE EXTRA-
CORPOREAL THERAPIES FOR
END-STAGE RENAL DISEASE
High-efficiencyhemodialysis
High-flux hemodialysis
Hemofiltration, intermittent
Hemodiafiltration, intermittent
FIGURE 3-1
Centers using high-flux dialyzers have increased threefold from
1986 to 1996 because of their ability to remove middle molecules.
(FromTokars and coworkers [1]; with permission.)
FIGURE 3-2
The four high-
performance extra-
corporeal therapies
for end-stage renal
disease are listed [2].
DEFINITIONS OF FLUX, PERMEABILITY, AND EFFICIENCY
Flux
Measureof ultrafiltration capacity
Low and high flux arebased on theultrafiltration coefficient (K
uf
)
Low flux: K
uf
<10mL/h/mmHg
High flux: K
uf
>20mL/h/mmHg
Permeability
Measureof theclearanceof themiddlemolecular weight molecule(eg,
2
-microglobulin)
General correlation between flux and permeability
Low permeability:
2
-microglobulin clearance<10mL/min
High permeability:
2
-microglobulin clearance>20mL/min
Efficiency
Measureof ureaclearance
Low and high efficiencyarebased on theureaK
o
A value
Low efficiency: K
o
A <500mL/min
High efficiency: K
o
A >600mL/min
K
o
masstransfer coefficient; Asurfacearea.
FIGURE 3-3
Definitions of flux, permeability, and efficiency. The urea value K
o
A,
as conventionally defined in hemodialysis, is an estimate of the clear-
ance of urea (a surrogate marker of low molecular weight uremic
toxins) under conditions of infinite blood and dialysate flow rates.
The following equation is used to calculate this value:
Q
b
Q
d
1-K
d
/Q
b
K
o
A=
Q
b
-Q
d
ln
1-K
d
/Q
d
where K
o
= mass transfer coefficient
A = surface area
Q
b
= blood flow rate
Q
d
= dialysate flow rate
ln = natural log
K
d
= mean of blood and dialysate side urea clearance
As conventionally defined in hemodialysis, flux is the rate of water
transfer across the hemodialysis membrane. Dissolved solutes are
removed by convection (solvent drag effect).
Permeability is a measure of the clearance rate of molecules of
middle molecular weight, sometimes defined using
2
-microglobulin
(molecular weight, 11,800 D) as the surrogate [3,4]. Dialyzers that
permit
2
-microglobulin clearance of over 20 mL/min under usual
clinical flow and ultrafiltration conditions have been defined as 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 membranehas been used
commonly to denote high-permeability membrane.
17
3.3 High-Efficiency and High-Flux Hemodialysis
10 100 1000 10,000
0.01
1000
100
10
1
0.1
100,000
Low flux
High efficiency
Low efficiency
High flux
K
O
A
,

m
L
/
m
i
n
Solutemolecular weight, D
FIGURE 3-4
Theoretic K
o
A profile of high- and low-flux dialyzers and high-
and low-efficiency dialyzers. Note that here the definition of K
o
A
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]. K
o
mass transfer coefficient; Asurface area. (FromCheung
and Leypoldt [3]; with permission.)
CLASSIFICATION OF HIGH-
PERFORMANCE DIALYSIS
High-efficiencylow-flux hemodialysis
High-efficiencyhigh-flux hemodialysis
Low-efficiencyhigh-flux hemodialysis
FIGURE 3-5
Classification of high-performance dialysis. Some authors have defined high-efficiency
hemodialysis as treatment in which the urea clearance rate exceeds 210 mL/min. High-flux
dialysis, arbitrarily defined as a
2
-microglobulin clearance of over 20 mL/min, is achieved
using high-flux membranes [3,4].
0
0
50
100
150
200
250
300
350
400
500 450 350 250 150 50
U
r
e
a

c
l
e
a
r
a
n
c
e

r
a
t
e
,

m
L
/
m
i
n
K
O
A=1000
K
O
A=500
Blood flow rate, m L/ m in
FIGURE 3-6
Comparison of urea clearance rates between low- and high-efficiency
hemodialyzers (urea K
o
A = 500 and 1000 mL/min, respectively).
The urea clearance rate increases with the blood flow rate and
gradually reaches a plateau for both types of dialyzers. The plateau
value of K
o
A 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]. K
o
mass transfer coefficient;
Asurface area. (FromCollins [6]; with permission.)
CHARACTERISTICS OF HIGH-EFFICIENCY DIALYSIS
Ureaclearancerateisusually>210mL/min
UreaK
o
A of thedialyzer isusually>600mL/min
Ultrafiltration coefficient of thedialyzer (K
uf
) maybehigh or low
Clearanceof middlemolecular weight moleculesmaybehigh or low
Dialysiscan beperformed usingeither cellulosic or synthetic membranedialyzers
K
o
FIGURE 3-7
Characteristics of high-efficiency dialysis. High-efficiency dialysis is
arbitrarily defined by a high clearance rate of urea (>210 mL/min).
High-efficiency membranes can be made from either cellulosic or
synthetic materials. Depending on the membrane material and surface
area, the removal of water (as measured by the ultrafiltration coeffi-
cient or K
uf
) and molecules of middle molecular weight (as measured
by
2
-microglobulin clearance) may be high or low [3,4,6,7].
18
DIFFERENCES BETWEEN HIGH- AND
LOW-EFFICIENCY HEMODIALYSIS
Dialyzer K
o
A
Blood flow
Dialysateflow
Bicarbonatedialysate
High efficiency, mL/min
600
350
500
Necessary
Low efficiency, mL/min
<500
<350
<500
Optimal
K
o
FIGURE 3-8
Differences between high- and low-efficiency hemodialysis.
Conventional hemodialysis refers to low-efficiency low-flux
hemodialysis that was the popular modality before the 1980s [3,6].
TECHNICAL REQUIREMENTS
FOR HIGH-EFFICIENCY DIALYSIS
High-efficiencydialyzer
Largesurfacearea(A)
High masstransfer coefficient (K
o
)
Both (high K
o
A)
High blood flow (350mL/min)
High dialysateflow (500mL/min)
Bicarbonatedialysate
FIGURE 3-9
Technical requirements for high-efficiency
dialysis. The K
o
A is the theoretic value of
the urea clearance rate under conditions of
infinite blood and dialysate flow. High blood
and dialysate flow rates are necessary to
achieve optimal performance of high-effi-
ciency dialyzers. Bicarbonate-containing
dialysate is necessary to prevent symptoms
associated with acetate intolerance (ie, nausea,
vomiting, headache, and hypotension),
worsening of metabolic acidosis, and car-
diac arrhythmia [6,8,9]. K
o
mass transfer
coefficient; Asurface area.
CONCENTRATION OF DIALYSATE
IN HIGH-EFFICIENCY DIALYSIS
Dialysate
Sodium
Potassium
Acetate
Bicarbonate
Magnesium
Calcium
Glucose
Concentration
139145mEq/L
04mEq/L
2.54.5mEq/L
3540mEq/L
1mEq/L
2.53.5mEq/L
0200mg/dL
FACTORS INFLUENCING BLOOD
FLOW IN HIGH-EFFICIENCY
HEMODIALYSIS
Typeof access
Nativearteriovenousfistulae, polytetrafluoroethyl-
enegrafts, twin catheter systems:
high blood flow rate, >350mL/min
Permanent catheters, temporaryintravenous
catheters: low blood flow rate, <350mL/min
Needledesign: size, thickness, and length
Blood tubing
Pump design
FIGURE 3-10
Concentration of dialysate in high-efficiency
dialysis. Although the concentration of
other ions is variable, high bicarbonate
concentration, relative to that of acetate,
is essential for high-efficiency dialysis in
order to minimize the transfer of acetate
into the patient.
FIGURE 3-11
Factors influencing blood flow in high-effi-
ciency hemodialysis. Arteriovenous fistulae
often have blood flow rates of over 1000
mL/min, as measured by current noninvasive
devices. Polytetrafluoroethylene grafts and
the newly introduced twin catheter systems
also are capable of providing the blood
flow rates necessary for high-efficiency
hemodialysis. In contrast, most other tem-
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].
19
CAUSES OF HIGH-EFFICIENCY
DIALYSIS FAILURE
Access-related
Low blood flow rate
High recirculation rate
Time-related
Patient not adherent to prescribed time
Staff not adherent to prescribed time
Failureto adjust timefor conditionssuch asalarm,
dialysatebypass, and hypotension
BENEFITS OF HIGH-
EFFICIENCY DIALYSIS
Higher clearanceof small solutes, such asurea,
compared with conventional dialysiswithout
increasein treatment time
Better control of chemistry
Potentiallyreduced morbidity
Potentiallyhigher patient survival rates
LIMITATIONS OF HIGH-
EFFICIENCY DIALYSIS
Hemodynamic instability
Low margin of safetyif short treatment
timeisprescribed
Potential vascular accessdamage
Dialysisdisequilibriumsyndrome
FIGURE 3-12
Causes of high-efficiency dialysis failure.
The maintenance of a high blood flow rate
(>350 mL/min) is essential for high-efficiency
hemodialysis. Fistula recirculation, regardless
of the blood flow rate, compromises
achievement of the urea Kt/V goal.
Interruptions during the prescribed short
treatment time further compromise the
overall delivery of the prescribed Kt/V [6,7].
Kurea clearance; ttime of therapy;
Vvolume of distribution.
FIGURE 3-13
Benefits of high-efficiency dialysis. With
improved control of biochemical parameters
(such as potassium, hydrogen ions, phosphate,
urea, and other nitrogenous compounds)
the potential exists for reduced morbidity
and mortality without increasing dialysis
treatment time [5,7].
FIGURE 3-14
Limitations of high-efficiency dialysis.
Removal of a large volume of fluid over a
short time period (22.5 h) increases the like-
lihood of hypotension, especially in patients
with poor cardiac function or autonomic
neuropathy. The loss of a fixed amount of
treatment time has a proportionally greater
impact during a short treatment time than
during a long treatment time. Thus, the
margin of safety is narrower if a short
treatment time is used in conjunction with
high-efficiency dialysis compared with
conventional hemodialysis with a longer
treatment time. Although unproved, high
blood flow rates may predispose patients to
vascular access damage. Rapid solute shifts
potentially precipitate the dialysis disequilib-
rium syndrome in those patients with a very
high blood urea nitrogen concentration,
especially during the first treatment [3,7,9].
CHARACTERISTICS OF HIGH-FLUX DIALYSIS
Dialyzer membranesarecharacterized byahigh ultrafiltration coefficient
(K
uf
>20mL/h/mmHg)
High clearanceof middlemolecular weight moleculesoccurs(eg,
2
-microglobulin)
Ureaclearancecan behigh or low, dependingon theureaK
o
A of thedialyzer
Dialyzersaremadeof either synthetic or cellulosic membranes
High-flux dialysisrequiresan automated ultrafiltration control system
FIGURE 3-15
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
profound intravascular volume depletion. Because high-flux mem-
branes tend to have larger pores, clearance of middle molecular
weight molecules is usually high. Urea clearance rates for high-flux
dialyzers are still dependent on urea K
o
A values, which can be
either high (ie, high-flux high-efficiency) or low (ie, high-flux low-
efficiency) [3,4,10]. K
o
mass transfer coefficient; Asurface area.
20
POTENTIAL BENEFITS OF
HIGH-FLUX DIALYSIS
Delayed onset and risk of dialysis-related amyloidosis
becauseof enhanced
2
-microglobulin clearance
[11,12]
Increased patient survival resultingfromhigher
clearanceof middlemolecular weight molecules
[12,13,15,16]
Reduced morbidityand hospital admissions[14,16]
Improved lipid profile[16,17]
Higher clearanceof aluminum[18]
Improved nutritional status[19,20]
Reduced risk of infection [16,21]
Preserved residual renal function [22]
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.
LIMITATIONS OF
HIGH-FLUX DIALYSIS
Enhanced drugclearance, requiringsupplemental
doseafter dialysis
High cost of dialyzers
FIGURE 3-18
Limitations of high-flux dialysis. The
enhanced clearance of drugs depends on
the physicochemical characteristics of
the specific drug and dialysis membrane.
Because of their relative high costs, high-
flux dialyzers are usually reused.
EXAMPLES OF COMMONLY USED DIALYZERS
Dialyzer type
Low-flux low-efficiency
CA90
CF12
Low-flux high-efficiency
CA150
T150
High-flux low-efficiency
F50
PAN 150P
High-flux high-efficiency
CT190
F80
Material
Celluloseacetate
Cuprammonium
Celluloseacetate
Cuprammonium
Polysulfone
Polyacrylonitrile
Cellulosetriacetate
Polysulfone
Surface area, m
2
0.9
0.7
1.5
1.5
0.9
1.0
1.9
1.8
K
o
A (in vitro), mL/min
410
418
660
730
520
420
920
945
K
o
A d a pt ed f rom Leypoldt and coworkers[4] and Van Stone[22].
FIGURE 3-19
Examples of commonly used dialyzers.
Efficiency refers to the capacity to remove
urea; flux refers to the capacity to remove
water, and indirectly, the capacity to remove
molecules of middle molecular weight.
Cellulosic membranes can be either low flux
or high flux. Similarly, synthetic membranes
can be either low flux or high flux. High-
efficiency membranes usually have large
surface areas.
TECHNICAL REQUIREMENTS
FOR HIGH-FLUX DIALYSIS
High-flux dialyzer
Automated ultrafiltration control system
FIGURE 3-16
Technical requirements for high-flux dialysis.
Because of the potential for reverse filtration
(movement of fluid from dialysate to the
blood compartment) to occur, use of a
pyrogen-free dialysate is preferred but not
mandatory. Bicarbonate concentrate used
to prepare dialysate is particularly prone to
bacterial overgrowth when stored for more
than 2 days [5,8].
21
Soluteflux
Fluid flux
C
b
C
b
Membrane Ultrafiltrate Blood
Blood
Predilution
Ultrafiltrate
Postdilution
Soluteflux
C
b
C
d
Membrane Ultrafiltrate Blood
Blood
Predilution
Ultrafiltrate
Postdilution
Dialysate
Solutes
FIGURE 3-20
Solute transport in hemodialysis. The primary
mechanism of solute transport in hemodialysis
is diffusion, although convective transport
is also contributory. Solutes small enough
to pass through the dialysis membrane diffuse
down a concentration gradient from a higher
plasma concentration (C
b
) to a lower dialysate
concentration (C
d
). The arrow represents
the direction of solute transport.
FIGURE 3-21
Solute clearance in hemofiltration.
Hemofiltration achieves solute clearance
by convection (or the solvent drag effect)
through the membrane. In contrast to
diffusive hemodialysis, fluid flux is a pre-
requisite for the removal of solutes during
hemofiltration, whereas the concentration
gradient is not. For small solutes (eg, urea)
that traverse the membrane unimpeded,
concentrations in the blood compartment
(C
b
) and ultrafiltrate compartment (C
uf
)
are equivalent. For some molecules of mid-
dle molecular weight whose movement
across the membrane is partially restricted,
C
uf
is lower than is C
b
(ie, the sieving coef-
ficient, defined as C
uf
/C
b
, is less than 1.0).
FIGURE 3-22
Fluid replacement in hemofiltration.
Because hemofiltration achieves substan-
tial solute clearance by removing large
volumes of plasma water (which contains
the dissolved solutes), the removed fluid
must be replaced. The replacement fluid
can be infused into the extracorporeal
circuit before the blood enters the filter
(predilution, or replacement before expen-
diture) or after the blood leaves the filter
(postdilution). More replacement fluid is
required when it is given before filtration
rather than after to provide equivalent
solute clearance because the plasma in
the filter (and therefore the ultrafiltrate)
is diluted in the predilution mode.
FIGURE 3-23
Addition of diffusive transport in hemodiafiltration. In hemodiafiltration, diffusive transport
is added to hemofiltration to augment the clearance of solutes (usually small solutes such
as urea and potassium). Solute clearance is accomplished by circulating dialysate in the
dialysate-ultrafiltrate compartment. Hemodiafiltration is particularly useful in patients
who have hypercatabolism with large urea generation.
22
Membranes
ET
ET fragments
Macrophage
Bacteria
Dialysate Membrane Blood
H
2
O
H
2
O
H
2
O
H
2
O
H
2
O
H
2
O
H
2
O
H
2
O
H
2
O
A
B
FIGURE 3-24
Backfiltration, or reverse filtration, of endotoxins (ET) from dialysate to blood. Reverse
filtration of ET is particularly prone to occur when high-flux membranes are used and the
dialysate is heavily contaminated with bacteria (>2000 CFU/mL) and may result in pyrogenic
reactions. The dialysis membranes are impermeable to intact ET; however, their fragments
(some of which still are pyrogenic) may be small enough to traverse the membrane. Although
the membrane is impermeable to bacteria and blood cells, a mechanical break in the membrane
could result in bacteremia.
FIGURE 3-25
Dialysis membranes with small and large pores. Although a general correlation exists
between the (water) flux and the (middle molecular weight molecule) permeability of dialysis
membranes, they are not synonymous. A, Membrane with numerous small pores that allow
high water flux but no
2
-microglobulin transport. B, Membrane with a smaller surface
area and fewer pores, with the pore size sufficiently large to allow
2
-microglobulin transport.
The ultrafiltration coefficient and hence the water flux of the two membranes are equivalent.
B
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
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).
23
Dialysate flow rate
200 500 450 400 350 300 250
100
300
280
260
240
220
200
180
160
140
120
U
r
e
a

c
l
e
a
r
a
n
c
e

r
a
t
e
,

m
L
/
m
i
n
Blood flow rate,m L/ m in
Q
d
=800
Q
d
=500
x
100
110
120
130
140
150
P
bo
P
bi
P
do
P
di
Blood flow Dialysateflow
Blood
inlet
Dialysate
outlet
Blood
outlet
Dialysate
inlet
/ /
P
r
e
s
s
u
r
e
,

m
m

H
g
Ultrafiltrate
Back filtrate
FIGURE 3-27
Effect of the dialysate flow rate (Q
d
) on the urea clearance rate by
a high-efficiency dialyzer with a urea K
o
A value of 800 mL/min.
At low blood flow rates (<200 mL/min), no difference exists in
urea clearance rates between the two different Q
d
conditions,
because equilibrium in urea concentrations between blood and
dialysate is readily achieved. When the blood flow rate is high
(>300 mL/min), the higher Q
d
maintains a higher concentration
gradient for diffusion of urea, and therefore, the urea clearance
rate is higher. Recent studies have shown that the K
o
A value of dia-
lyzers also increases with higher dialysate flow rates [4], presumably
because of more uniform distribution of dialysate flow. Therefore, the
actual urea clearance rate may increase further (red line). K
o
mass
transfer coefficient; Asurface area.
FIGURE 3-28
Pressure inside the blood compartment (dark colored arrow) and
the dialysate compartment (light colored arrow) with a fixed net
zero ultrafiltration rate. The pressure gradually decreases in the
blood compartment as blood travels from the inlet toward the outlet.
Beyond a certain point along the dialyzer length (x, where the two
pressure lines intersect), the pressure in the dialysate compartment
exceeds that in the blood compartment, forcing fluid to move from
the dialysate to the blood compartment. This movement of fluid
in the direction opposite to that of the designed ultrafiltration is
called backfiltration. Backfiltration may carry with it contaminants
(eg, endotoxins) from the dialysate. Increasing the net ultrafiltra-
tion rate shifts the pressure intersection point to the right and
diminishes backfiltration.
Backfiltration
24
References
1. Tokars JI, Alter MJ, Miller E, et al.: National surveillance of dialysis
associated disease in the United States: 1994. ASAI O J 1997,
43:108119.
2. United States Renal Data System, 97: Treatment modalities for ESRD
patients. Am J Kidney Dis 1997, 30:S54S66.
3. Cheung AK, Leypoldt JK: The hemodialysis membranes: a historical
perspective, current state and future prospect. Sem Nephrol 1997,
17:196213.
4. Leypoldt JK, Cheung AK, Agodoa LY, et al.: Hemodialyzer mass
transferarea coefficients for urea increase at high dialysate flow rates.
Kidney I nt 1997, 51:20132017.
5. Collins AJ, Keshaviah P: High-efficiency, high flux therapies in
clinical dialysis. In Clinical Dialysis, edn 3. Edited by Nissenson AR.
1995:848863.
6. Collins AJ: High-flux, high-efficiency procedures. In Principles and
Practice of Hemodialysis. Edited by Henrich W. Norwalk, CT:
Appleton & Large; 1996:7688.
7. von Albertini B, Bosch JP: Short hemodialysis. Am J Nephrol 1991,
11:169173.
8. Keshaviah P, Luehmann D, Ilstrup K, Collins A: Technical requirements
for rapid high-efficiency therapies. Artificial Organs1986, 10:189194.
9. Shinaberger JH, Miller JH, Gardner PW: Short treatment. In
Replacement of Renal Function by Dialysis, edn 3. Edited by Maher
JF. Norwell, MA: Kluwer Academic Publishers; 1989:360381.
10. Barth RH: High flux hemodialysis: overcoming the tyranny of time.
Contrib Nephrol 1993, 102:7397.
11. Van Ypersele, De Strihou C, Jadoul M, et al.: The working party on
dialysis amyloidosis: effect of dialysis membrane and patients age on
signs of dialysis-related amyloidosis. Kidney I nt 1991, 39:10121019.
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 I nt 1997, 52:10961101.
13. Chandran PKG, Liggett R, Kirkpatrick B: Patient survival on
PAN/AN 69 membrane hemodialysis: a ten year analysis. J Am Soc
Nephrol 1993, 4:11991204.
14. Hornberger JC, Chernew M, Petersen J, Garber AM: A multivariate
analysis of mortality and hospital admissions with high-flux dialysis.
J Am Soc Nephrol 1992, 3:12271236.
15. Hakim RM, Held PJ, Stannard DC, et al.: Effect of the dialysis membrane
on mortality of chronic hemodialysis patients. Kidney I nt 1996,
50:566570.
16. Churchill DN: Clinical impact of biocompatible dialysis membranes
on patient morbidity and mortality: an appraisal of evidence. Nephrol
Dial Trans 1995, 10(suppl):5256.
17. Seres DS, Srain GW, Hashim SA, et al.: Improvement of plasma
lipoprotein profiles during high flux dialysis. J Am Soc Nephrol 1993,
3:14091415.
18. Mailloux LU: Dialysis modality and patient outcome. UpToDate Med
1995.
19. Parker TF III, Wingard RL, Husni L, et al.: Effect of the membrane
biocompatibility on nutritional parameters in chronic hemodialysis
patients. Kidney I nt 1996, 49:551556.
20. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney
I nt 1996, 50:343357.
21. Hakim RM, Wingard RL, Parker RA, et al.: Effects of biocompatibility
on hospitalizations and infectious morbidity in chronic hemodialysis
patients. J Am Soc Nephrol 1994, 5:450.
22. Van Stone JC: Hemodialysis apparatus. In Handbook of Dialysis, edn 2.
Edited by Daugirdas JT, Ing TS. Boston/New York: Little, Brown &
Co.; 1994:3152.
25
4
Principles of
Peritoneal Dialysis
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
move small molecules through the interstitium with its gel and sol
phases, which are restrictive owing to the phenomenon of exclusion
[3,4]. The splanchnic blood flow in the normal adult ranges from 1.0
to 2.4 L/min, arising from celiac and mesenteric arteries [5]. The lym-
phatic vessels located primarily in the subdiaphragmatic region drain
fluid and solutes from the peritoneal cavity through bulk transport.
Ra m esh Kha nna
Ka r l D . N ol ph
CHA P T ER
26
The extent of lymph drainage from the peritoneal cavity is a sub-
ject of controversy owing to the lack of a direct method to mea-
sure lymph flow.
Dialysis solution contains electrolytes in physiologic con-
centrations to facilitate correction of acid-base and electrolyte
abnormalities. High concentrations of glucose in the dialysis
solution generate ultrafiltration in proportion to the overall
osmotic gradient, the reflection coefficients of small solutes
relative to the peritoneum, and the peritoneal membrane
hydraulic permeability. Removal of solutes such as urea, creati-
nine, phosphate, and other metabolic end products from the body
depends on the development of concentration gradients between
blood and intraperitoneal fluid, and the transport is driven by the
process of diffusion. The amount of solute removal is a function
of the degree of its concentration gradient, the molecular size,
membrane permeability and surface area, duration of dialysis, and
charge. Ultrafiltration adds a convective component proportion-
ately more important as the molecular size of the solute increases.
The peritoneal equilibration test is a clinical tool used to charac-
terize the peritoneal membrane transport properties [6]. Solute
transport rates are assessed by the rates of their equilibration
between the peritoneal capillary blood and dialysate (see Fig. 4-8).
The ratio of solute concentrations in dialysate and plasma at specif-
ic times during the dwell signifies the extent of solute transport. The
fraction of glucose absorbed from the dialysate at specific times can
be determined by the ratio of dialysate glucose concentrations
at specific times to the initial level in the dialysis solution. Tests
are standardized for the following: duration of the preceding
exchange before the test; inflow volume; positions during
inflow, drain, and dwell; durations of inflow and drain; sam-
pling methods and processing; and laboratory assays [7].
Creatinine and urea clearance rates are the most commonly used
indices of dialysis adequacy in clinical settings. Contributions
of residual renal clearances are significant in determining the
adequacy of dialysis. The mass-transfer area coefficient (MTAC)
represents the clearance rate by diffusion in the absence of ultrafil-
tration and when the rate of solute accumulation in the dialysis
solution is zero. Peritoneal clearance is influenced by both blood
and dialysate flow rates and by the MTAC [8]. Therefore, the
maximum clearance rate can never be higher than any of these
parameters. At infinite blood and dialysate flow rates, the clearance
rate is equal to the MTAC and is mass-transferlimited. Large mol-
ecular weight solutes are mass-transferlimited; therefore, their
clearance rates do not increase significantly with high dialysate flow
rates [9]. In CAPD, blood flow and MTAC rates are higher than is
the maximum achievable urea clearance rate. However, the urea
clearance rate approximately matches the dialysate flow rate, sug-
gesting that the dialysate flow rate limits CAPD clearances.
Peritoneal Dialysis Regimens
2.0
1.0
0.0
Day Night Day Night
Left
A
2.0
1.0
0.0
Exchanges, n
Right
B
Day Night Day Night
FIGURE 4-1
Continuous peritoneal dialysis regimens.
A, Continuous ambulatory peritoneal dialy-
sis (CAPD); B, continuous cyclic peritoneal
dialysis (CCPD) is shown. Multiple sequen-
tial exchanges are performed during the day
and night so that dialysis occurs 24 hours a
day, 7 days a week.
27
4.3 Principles of Peritoneal Dialysis
FIGURE 4-2
Intermittent peritoneal dialysis regimens.
Peritoneal dialysis is performed every day
but only during certain hours. A, In daytime
ambulatory peritoneal dialysis (DAPD),
multiple manual exchanges are performed
during the waking hours. B, Nightly peri-
toneal dialysis (NPD) is also performed
while patients are asleep using an automated
cycler machine. One or two additional day-
time manual exchanges are added to
enhance solute clearances.
Night
2.0
1.0
0.0
Day Day Night
Left
A
2.0
1.0
0.0
Left
B
Night Day Day Night
100
80
60
40
20
0
20
0 80 160 240 320 400 480 560
A
Dialysate
Blood
Time, m in
B
l
o
o
d

u
r
e
a

n
i
t
r
o
g
e
n
,

m
g
/
d
L
24
20
16
12
8
4
0
0 40 80 120 160 200 280 240 320 360
C
r
e
a
t
i
n
i
n
e
,

m
g
/
d
L
Time,m in B
Dialysate
Blood
FIGURE 4-3
Solute removal. Solute concentration gradients are at maximum at
the beginning of dialysis and diminish gradually as dialysis progress-
es. As the gradients diminish, the solute removal rates decrease.
Solute removal can be enhanced by increasing the dialysate flow
rate by either increasing the intraperitoneal dialysate volume per
exchange or increasing the frequency of exchange. By convection
or enhanced diffusion, solutes are able to accompany the bulk flow
of water. (FromNolph and coworkers [10]; with permission.)
Solute Removal
28
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 100 200 300 400 500
Urea
Creatinine
Uric acid
Phosphorus
Inulin
Calcium
D
i
a
l
y
s
a
t
e

t
o

p
l
a
s
m
a

r
a
t
i
o
Dwell time, m in A
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 100 200 300 400 500
Urea
Creatinine
Uric acid
Phosphorus
Inulin
Calcium
D
i
a
l
y
s
a
t
e

t
o

p
l
a
s
m
a

r
a
t
i
o
Dwell time, m in B
FIGURE 4-4
Solute removal. The rates of change of solute concentrations are
similar for 1.5% dextrose dialysis solutions (panel A) and 4.25%
dextrose dialysis solutions (panel B). Hypertonic exchanges enhance
solute removal owing to larger drain volumes. Net solute diffusion
ceases at equilibration when the dialysate to plasma solute ratio (D/P)
is near 1.0. Smaller size solutes (ie, urea and creatinine) diffuse
across the membrane faster, equilibrate sooner, and are influenced
more by exchange frequency as compared with larger size solutes
(ie, uric acid, phosphates, inulin, and proteins). (FromNolph and
coworkers [10]; with permission.)
High transport
Low transport
C
r
e
a
t
n
i
n
e

d
i
a
l
y
s
a
t
e

t
o

p
l
a
s
m
a

r
a
t
i
o

(
D
/
P
)
A
Dwell time, h
1.0
0.5
0
2 4 3 1 5 7 6
2600
2300
2000
1700
T
o
t
a
l

d
i
a
l
y
s
a
t
e

v
o
l
u
m
e

(
V
)

B
NIPD
NTPD CCPD
(NE)
CCPD
(DE)
DAPD CAPD
0
Dwell time, h
2 4 3 1 5 7 6
2
1
C
r
e
a
t
i
n
i
n
e

c
l
e
a
r
a
n
c
e

p
e
r

e
x
c
h
a
n
g
e

(
C
c
r
)
C
0
D/P=1
Ccr=V
Ccr=V D/P
Dwell time, h
2 4 3 1 5 7 6
FIGURE 4-5
Solute removal. In a highly permeable membrane, smaller molecules
(ie, urea and creatinine) are transported at a faster rate from the
blood to dialysate than are larger molecules, enhancing solute removal.
Similarly, glucose (a small solute used in the peritoneal dialysis solution
to generate osmotic force for ultrafiltration across the peritoneal mem-
brane) is also transported faster, but in the opposite direction. This
high transporter dissipates the osmotic force more rapidly than does
the low transporter. Both osmotic and glucose equilibriums are
attained eventually in both groups, but sooner in the high trans-
porter group. Intraperitoneal volume peaks and begins to diminish
earlier in the high transporter group. When the membrane is less
permeable, solute removal is lower, ultrafiltration volume is larger
at 2 hours or more, and glucose equilibriums are attained later.
Consequently, intraperitoneal volume peaks later. Ultrafiltration in
a low transporter peaks late during dwell time. Therefore, a low
transporter continues to generate ultrafiltration even after 8 to 10
hours of dwell. The solute creatinine dialysate to plasma ratio
(D/P) increases linearly during the dwell time. Patients with average
solute transfer rates have ultrafiltration and mass transfer patterns
between those of high and low transporters. NIPDnightly inter-
mittent peritoneal dialysis; NTPDnighttime tidal peritoneal dialy-
sis; DAPDdaytime ambulatory peritoneal dialysis; CAPDcon-
tinuous ambulatory peritoneal dialysis; CCPD (NE)continuous
cyclic peritoneal dialysis (night exchange); CCPD (DE)continu-
ous cyclic peritoneal dialysis (day exchange). (FromTwardowski
[11]; with permission.)
29
Serumand dialysate
1.5%dextrose
dialysissolutions
150
140
130
120
110
100
90
0 100 200 300 400 500
S
o
d
i
u
m
,

m
L
q
/
L
Dwell time,m in A
Inflow
Serumand
dialysate
4.25%dextrose
dialysissolutions
150
140
130
120
110
100
90
0 100 200 300 400 500
S
o
d
i
u
m
,

m
L
q
/
L
Dwell time,m in B
Inflow
FIGURE 4-6
Solute sieving. A, Dialysate sodium concentration is initially reduced and tends to return
to baseline later during a long dwell exchange of 6 to 8 hours. B, Dialysate sodium con-
centration decreases, particularly when using 4.25% dextrose dialysis solution, because of
the sieving phenomenon. Removal of water during ultrafiltration unaccompanied by sodium,
in proportion to its extracellular concentration, is called sodium sieving[7,12]. The peri-
toneum offers greater resistance to the movement of solutes than does water. This probably
relates to approximately half the ultrafiltrate being generated by solute-free water movement
through aquaporins channels. Therefore, ultrafiltrate is hypotonic compared with plasma.
Dialysate chloride is also reduced below simple Gibbs-Donnan equilibrium, particularly
during hypertonic exchanges. Patients with a low peritoneal membrane transport type tend
to reduce dialysate sodium concentration more than do other patients. Therefore, during a
short dwell exchange of 2 to 4 hours, net electrolyte removal per liter of ultrafiltrate is
well below the extracelluar fluid concentration. As a result, severe hypernatremia, excessive
thirst, and hypertension may develop. This hindrance can be overcome by lowering the
dialysate sodium concentration to 132 mEq/L. In patients who use cyclers with short dwell
exchanges and who generate large ultrafiltration volumes, lower sodium concentrations
may need to be used (such as 118 mEq/L for 2.5% glucose solutions or 109 mEq/L for
4.25% solutions). In continuous ambulatory peritoneal dialysis with long dwell exchanges
of 6 to 8 hours, significant sieving usually does not occur, whereas in automated peritoneal
dialysis with short dwell exchanges, sieving may occur. Sieving predisposes patients to
thirst and less than optimum blood pressure control, especially in those who have low-nor-
mal serum sodium levels, those with low peritoneal membrane transporter rates, or both.
(FromNolph and coworkers [10]; with permission.)
2800
2600
2400
I
n
t
r
a
p
e
r
i
t
o
n
e
a
l

Peak intraperitoneal volume
0 1 2 3 4
Dwell time, h B
Dialysate
Peak ultrafiltration
volume
Transcapillaryultrafiltration
Lymphatic absorption
600
500
400
300
200
100
m
L
/
h
0 1 2 3
Dwell time, h A
FIGURE 4-7
Fluid removal by ultrafiltration. During peritoneal dialysis, hyperosmolar glucose solution
generates ultrafiltration by the process of osmosis. Water movement across the peritoneal
membrane is proportional to the transmembrane pressure, membrane area, and membrane
hydraulic permeability. The transmembrane pressure is the sum of hydrostatic and osmotic
pressure differences between the blood in the peritoneal capillary and dialysis solution in
the peritoneal cavity. Net transcapillary ultrafiltration defines net fluid movement from the
peritoneal microcirculation into the peritoneal cavity primarily in response to osmotic
pressure. Net ultrafiltration would equal the resulting increment in intraperitoneal fluid
volume if it were not for peritoneal reabsorption, mostly through the peritoneal lymphatics.
Peritoneal reabsorption is continuous and reduces the intraperitoneal volume throughout
the dwell. A, The net transcapillary ultrafiltration rate decreases exponentially during the
dwell time, owing to dissipation of the glucose osmotic gradient secondary to peritoneal
glucose absorption and dilution of the solution glucose by the ultrafiltration. Later in the
exchange net, ultrafiltration ceases when the transcapillary ultrafiltration is reduced to a
rate equal to the peritoneal reabsorption. B, When the transcapillary ultrafiltration rate
decreases below that of the peritoneal reabsorption rate, the net ultrafiltration rate becomes
negative. Consequently, the intraperitoneal volume begins to diminish. Thus, peak ultrafiltra-
tion and intraperitoneal volumes are observed before osmotic equilibrium during an exchange.
(Continued on next page)
30
STANDARDIZED 4-HOUR PERITONEAL EQUILIBRATION TEST
1. Performan overnight 8- to 12-h preexchange.
2. Drain theovernight exchange(drain timenot to exceed 25min) with patient in theupright position.
3. Infuse2L of dialysissolution over 10min with patient in thesupineposition. Roll thepatient fromsideto sideafter
every400-mL infusion.
4. After thecompletion of infusion (0time) and at 120min, drain 200mL of dialysate. Takea10-mL sample, and
reinfusetheremaining190mL into theperitoneal cavity.
5. Position thepatient upright, and allow patient ambulation if able.
6. Obtain aserumsampleat 120min.
7. At theend of study(240min), drain thedialysatewith thepatient in theupright position
(drain timenot to exceed 20min).
8. Measurethedrained volume, and takea10-mL samplefromthedrained volumeafter agood mixing.
9. Analyzetheblood and dialysatesamplesfor creatinineand glucoseconcentrations.
10. Correct theserumand dialysatecreatinineconcentrationsfor high glucoselevel (correction factor 0.000531415).
11. Calculatethedialysateto plasmaratiosfor creatinine, and so on, and calculatetheDt/D0glucose.
FIGURE 4-8
Standardized 4-hour peritoneal equilibra-
tion test. Dt/D0 glucosefinal to initial
dialysate glucose ratio.
Corrected creatinine(mg/dL)
=Observed creatinine(mg/dL) (glucose[mg/dL] x 0.000531415)
Correction of creatinine levels
FIGURE 4-9
Equation to correct the creatinine levels in dialysate and serum.
The creatinine levels in dialysate and serum need to be corrected
for high glucose levels, which contribute to formation of noncreatinine
chromogens during the creatinine assay. The correction factor may
vary from one laboratory to another. In our laboratory at the University
of MissouriColumbia, the correction factor is 0.000531415.
Accordingly, the corrected creatinine is calculated as in the equation.
The correction in the serum is minimal due to low blood sugar levels;
however, it is significant in dialysate, especially during the early
phase of dwell (0- and 2-hour dialysate samples).
O
s
m
o
l
a
l
i
t
y
,

m
O
s
m
/
L
0 1 2 3 4
Dwell time, h C
360
340
320
300
Osmotic
equilibrium
Dialysate
Serum
Hypothetical
glucose
equilibrium
G
l
u
c
o
s
e
,

m
O
s
m
/
L
0 1 2 3 4
Dwell time, h
D
Dialysate
Serum
2000
1000
FIGURE 4-7 (Co n t i n u e d )
C, Osmotic equilibrium most likely precedes glucose equilibrium
because of both solute sieving and the higher peritoneal reflection
coefficient of glucose compared with other dialysate solutes, allow-
ing net transcapillary ultrafiltration to continue at a low rate even
after osmotic equilibrium. D, Ultrafiltration can be maximized by
measures that delay osmotic equilibrium, which can be accom-
plished by using hypertonic glucose solutions, larger volumes, or
both, during an exchange. More frequent exchanges shorten dwell
times and increase the dialysate flow rate and thus avert attaining
osmotic equilibrium. Additionally, potential exists for enhancing
ultrafiltration by measures that reduce the peritoneal reabsorption
rate. (FromMactier and coworkers [13]; with permission.)
31
Vin(S3 S2)
(S1 S3)
Intraperitoneal residual volume
R=
FIGURE 4-10
Equation to calculate the intraperitoneal residual volume. Residual volume is the volume
of dialysate remaining in the peritoneal cavity after drainage over 20 minutes. The residual
volume can be determined by knowing the dilution factor for solutes such as potassium, urea,
and creatinine during the next instillation. The calculation of residual volumes is based on
the assumption that the mixing of fluid in the peritoneal cavity is instantaneous and 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.
Urea
1.1
0.9
0.7
0.5
0.3
0.1
D
i
a
l
y
s
i
s

t
o

p
l
a
s
m
a

r
a
t
i
o
0
Hours
A
1 2 3 4 1
/
2
1.1
0.9
0.7
0.5
0.3
0.1
Hours
D
i
a
l
y
s
i
s

t
o

p
l
a
s
m
a

r
a
t
i
o
B
0 1 2 3 4 1
/
2
Creatinine
Hours C
0 1 2 3 4 1
/
2
1.1
0.9
0.7
0.5
0.3
0.1
Glucose
F
i
n
a
l

t
o

i
n
i
t
i
a
l

d
i
a
l
y
s
a
t
e

g
l
u
c
o
s
e

r
a
t
i
o
FIGURE 4-11
Classification of peritoneal transport func-
tion. Based on the peritoneal equilibrium
test results, peritoneal transport function
may be classified into average, high (H),
and low (L) transport types. The average
transport group is further subdivided into
high-average (HA) and low-average (LA)
types. For the population studied by
Twardowski and coworkers [6], the trans-
port classification is based on means; stan-
dard deviations (SDs); and minimum and
maximum dialysate to plasma ratio (D/P)
values over 4 hours for urea, creatinine,
glucose, protein, potassium, sodium, and
corrected creatinine (panels AG).
Hours
D
0 1 2 3 4
1
/
2
35
30
25
20
15
10
5
0
D
i
a
l
y
s
a
t
e

t
o

p
l
a
s
m
a

r
a
t
i
o

1
0
0
0
Protein
32
Hours G
0 1 2 3 4
1
/
2
D
i
a
l
y
s
a
t
e

t
o

p
l
a
s
m
a

r
a
t
i
o

Corrected creatinine
1.1
0.9
0.7
0.5
0.3
0.1
0
H
HA
LA
L
H
3500
3000
2500
2000
1500
1000
500
0
m
L
Drain
volume
Residual
pre-eq
Volume
post-eq
Max
+SD
x
SD
Min
The volume of drainage correlates positively
with dialysate glucose and negatively with
D/P creatinine values at 4-hour dwell times
(panel H). (FromTwardowski and cowork-
ers [6]; with permission.)
CLINICAL APPLICATIONS OF THE
PERITONEAL EQUILIBRATION TEST
Peritoneal membranetransport classification
1. Chooseperitoneal dialysisregimen.
2. Monitor peritoneal membranefunction.
3. Diagnoseacutemembraneinjury.
4. Diagnosecausesof inadequateultrafiltration.
5. Diagnosecausesof inadequatesoluteclearance.
6. Estimatedialysateto plasmaratio of asoluteat timet.
7. Diagnoseearlyultrafiltration failure.
8. Predict dialysisdose.
9. Assessinfluenceof systemic diseaseon peritoneal membranefunction.
FIGURE 4-12
In clinical practice it is customary to perform the baseline standard-
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
creatinine and glucose levels at 0, 2, and 4 hours of dwell time
and serum levels of creatinine and glucose at any time during
the test. The extensive unabridged test, as originally proposed
by Twardowski and coworkers [6], has become a very important
research tool.
Hours E
0 1 2 3 4
1
/
2
D
i
a
l
y
s
a
t
e

t
o

p
l
a
s
m
a

r
a
t
i
o

Potassium
1.1
0.9
0.7
0.5
0.3
0.1
0
Max
+SD
SD
Min
Hours F
0 1 2 3 4
1
/
2
D
i
a
l
y
s
a
t
e

t
o

p
l
a
s
m
a

r
a
t
i
o

Sodium
1.00
0.90
0.80
0.70
H
HA
LA
L
ADK vol05 ch p04 fig11F
33
Baselineperitoneal equilibriumtest
High
transporter
D/P creatinine
High average
transporter
D/P creatinine
Low average
transporter
D/P creatinine
Low
transporter
D/P creatinine
16% 68% 16%
Baselineperitoneal equilibriumtest
High High average Low average Low
High-doseCCPD
only when significant
residual renal
function is present
NIPD
CAPD
NIPD
DAPD
High-doseCAPD
High-doseCCPD
FIGURE 4-13
Population distribution of peritoneal membrane transport types.
Baseline peritoneal equilibrium test results of patients on long-term
peritoneal dialysis in the United States suggest that approximately
68% have average transport rates, 16% have high transport rates,
and another 16% have low transport rates [6]. Similar distributions
of transport types have been documented worldwide [1416].
D/Pdialysate to plasma ratio.
FIGURE 4-14
Using transport type to select a peritoneal dialysis regimen. Because
clearance rates continue to increase with time, patients with low
transport rates are treated with long dwell exchanges, ie, continu-
ous cyclic peritoneal dialysis (CCPD). Owing to the low rate of
increase in the dialysate to plasma ratio (D/P), the clearance rate
per unit of time is augmented relatively little by rapid exchange
techniques such as nightly intermittent peritoneal dialysis (NIPD).
On the contrary, the clearance per exchange rate over long dwell
exchanges would be less in patients with high transport rates.
During the short dwell time, patients with high transport rates
capture maximum ultrafiltration and small solutes are completely
equilibrated. Therefore, these patients are best treated with 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. CAPDcontinuous ambulatory peritoneal dialysis.
0.97
0.92
0.88
0.85
0.80
1.0
0.9
0.8
0.7
D
i
a
l
y
s
a
t
e

t
o

p
l
a
s
m
a

r
a
t
i
o
0.0 1.0 2.0 3.0 4.0
High
High average
Low average
Low
FIGURE 4-15
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
sieving, the ultrafiltrate is low in sodium. Consequently, the dialysate sodium is lowered,
resulting in a lower D/P ratio of sodium. Later, during the dwell when ultrafiltration ceas-
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-
cation of ultrafiltration failure and is typically seen in the early phase of sclerosing encap-
sulating peritonitis. (FromDobbie and coworkers [17]; with permission.)
34
C
D
=soluteconcentration in thedialysate
M=I (C
P
C
D
)
A
R
whereM =diffusivemass transfer:
A =effectivemembranesurfacearea;
I =coefficient of proportionality;
R =sumof all resistances;
C
p
=soluteconcentration in thepotential
capillary blood; and
Thediffusivemass transfer is estimated by
A
B
Dividingboth sides of theequation by solute
concentration in peripheral blood (CB) will
yield instantaneous clearanceor theMTAC;
M
C
B
A
R
C
P
C
B
C
D
C
B
=K=I
( (
If theperitoneal capillary blood flow is infinite,

Cp will equal Cb and
If thedialysateflow is also infinite,
then Co will equal 0, and
Ki=I
Ki=Kmax=I
1
A
R
C
D
C
B
( (
A
R
C
Mass-transfer area coefficient
FIGURE 4-17
The mass-transfer area coefficient (MTAC). The MTAC represents the clearance rate by
diffusion in the absence of ultrafiltration and when the solute accumulation in the dialysis
solution is zero [3439]. MTAC is equal to the product of peritoneal membrane perme-
ability (P) and effective peritoneal membrane surface area (S). Thus, when both capillary
blood and dialysate flows are infinite, the clearance rate is directly proportional to the
effective peritoneal surface area and inversely proportional to the overall membrane resis-
tance. However, infinite blood and dialysate flows cannot be achieved, and the maximum
clearance rate is unattainable. The closest measurable value, the MTAC, was introduced.
The MTAC represents an instantaneous clearance without being influenced by ultrafiltra-
tion and solute accumulation in the dialysate. The MTAC is measured over a test exchange
during which at least two blood and dialysate samples are obtained at different dwell
times. The precision of the measurement is enhanced with more data points. The MTAC
is seldom used clinically; however, it is a very useful research tool.
C=(D/P) x V
whereC =clearancein mL/exchangeat timet;
D/P =soluteequilibriumrateat timet; and
V =volumeof dialysateat timet
Kt/V
whereK =ureaclearancein mL/min;
t =minutes of therapy; and
V =volumeof ureadistribution or total
body water
or
C=
(DxV)
P
whereC =clearancein mL/min:
DxV =dialysatesoluteremoved per minute;
D =dialysatesoluteconcentration;
V =volumeof dialysatein mL/min; and
P =plasma soluteconcentration
A
B
FIGURE 4-16
Creatinine and urea clearances rates. These rates are estimated by dividing the amount of
solute removed per unit of time by the plasma solute concentration. Alternatively, clearance
also can be estimated by multiplying the solute equilibration rate per unit of time by the
volume of dialysate into which equilibration occurred over the same unit of time. By con-
vention, the creatinine clearance rate is normalized to body surface area.
The urea clearance is normalized to total body water (volume of urea distribution in the
body) and is expressed as Kt/V. The Kt/Vvalue is a number without a unit ([mL/min min]/
mL). During intermittent dialysis, with a dialysate flow rate of 30 mL/min, the typical urea
clearance is about 18 to 20 mL/min [18]. Increasing the dialysate flow rates to 3.5 to 12
L/h by rapid exchanges increases the urea clearance rate to a maximum of 30 to 40 mL/min.
Beyond this maximum rate, the clearance rate begins to decrease owing to the loss of mem-
brane-fluid contact time with infusion and drainage; inadequate mixing may also occur
[1922]. Clearance could be enhanced by increasing the membrane-solution contact [23].
Continuous dialysate flow techniques using either two catheters or double-lumen catheters
also have enhanced the urea clearance rate to a maximum of 40 mL/min. At these high flow
rates, poor mixing, channeling, abdominal pain, and poor drainage limit successful applica-
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 [2429]. During
continuous ambulatory peritoneal dialysis (CAPD) in adults, the optimum volume that
ensures complete membrane-solution contact is about 2 L [30,32]. Successful use of 2.5-
and 3.0-L volumes has been reported in adult patients undergoing CAPD; however, hernial
complications are increased [32,33].
35
References
1. Clough G, Michel CC: Quantitative comparisons of hydraulic perme-
ability and endothelial intercellular cleft dimensions in single form
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2. Pannekeet MM, Mulder JB, Weening JJ, et al.: Demonstration of
aquaporin-CHIP in peritoneal tissue of uremic and CAPD patients.
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3. Flessner MF, Dedrick RL, Schultz JS: Exchange of macromolecules
between peritoneal cavity and plasma. Am J Physiol 1985, 248:H15.
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absorption of macromolecules studied by quantitative autoradiography.
Am J Physiol 1985, 248:H26.
5. Wade OL, Combes B, Childs AW, et al.: The effect of exercise on the
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6. Twardowski ZJ, Nolph KD, Khanna R, et al.: Peritoneal equilibration
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7. Ahearn DJ, Nolph KD: Controlled sodium removal with peritoneal
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8. Popovich RP, Moncrief JW: Kinetic modeling of peritoneal transport:
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9. Twardowski ZJ: Physiology of peritoneal dialysis. In Clinical Dialysis.
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Appleton & Lange; 1995:322.
10. Nolph KD, Twardowski ZJ, Popovich RP, et al.: Equilibration of peri-
toneal dialysis solutions during long dwell exchanges. J Lab Clin Med
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11. Twardowski ZJ: Nightly peritoneal dialysis (why? who? how? and
when?). Trans Am Soc Artif I ntern Organs 1990, 36:816.
12. Nolph KD, Hano JE, Teschan PE: Peritoneal sodium transport during
hypertonic peritoneal dialysis: physiologic mechanisms and clinical
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13. Mactier RA, Khanna R, Twardowski ZJ, et al.: Contribution of lym-
phatic absorption to loss of ultrafiltration and solute clearances in
continuous ambulatory peritoneal dialysis. J Clin I nvest 1987,
80:13111316.
14. Zabetakis PM, Krapf R, DeVita MV, et al.: Determining peritoneal
dialysis prescriptions by employing a patient-specific protocol.
Peritoneal Dial I nt 1993, 13:189193.
15. Wolf CJ, Polsky J, Ntoso KA, et al.: Adequacy of dialysis in CAPD and
cycler PD; the PET is enough. Peritoneal Dial Bull 1992, 8:208211.
16. Struijk DG, Krediet RT, Koomen GCM, et al.: A prospective study of
peritoneal transport in CAPD. Kidney I nt 1994, 17391744.
17. Dobbie JW, Krediet RT, Twardowski ZJ, et al.: A 39-year-old man
with loss of ultrafiltration. Peritoneal Dial I nt 1994, 14:384394.
18. Nolph KD, Popovich RP, Ghods AJ, et al.: Determinants of low
clearances of small solutes during peritoneal dialysis. Kidney I nt
1978, 13:117123.
19. Boen ST: Kinetics of Peritoneal Dialysis. Baltimore, MD: Medicine;
1961:243287.
20. Penzotti SC, Mattocks AM: Effects of dwell time, volume of dialysis
fluid, and added accelerators on peritoneal dialysis of urea. J Pharm
Sci 1971, 60:15201522.
21. Pirpasopoulos M, Lindsay RM, Rahman M, et al.: A cost-effectiveness
study of dwell time in peritoneal dialysis. Lancet 1972, 2:11351136.
22. Tenckhoff H, Ward G, Boen ST: The influence of dialysate volume
and flow rate on peritoneal clearance. Proc Eur Dial Transplant Assoc
1965, 2:113117.
23. Trivedi HS, Twardowski ZJ: Long-term successful nocturnal intermittent
peritoneal dialysis: a ten-year case study. In Advances in Peritoneal
Dialysis. Edited by Khanna R. Toronto, Canada: Peritoneal Dialysis
Publications; 1994:8184.
24. Di Paolo N: Semicontinuous peritoneal dialysis. Dial Transplant
1978, 7:839842.
25. Finkelstein FO, Kliger AS: Enhanced efficiency of peritoneal dialysis
using rapid, small-volume exchanges. ASAI O J 1979, 2:103106.
26. Twardowski ZJ, Nolph KD, Khanna R, et al.: Tidal peritoneal dialysis.
In Ambulatory Peritoneal Dialysis: Proceedings of the I Vth Congress
of the I nternational Society for Peritoneal Dialysis, Venice, Italy, June
1987. Edited by Avram MM, Giordano C. New York: Plenum;
1990:145149.
27. Twardowski ZJ, Prowant BF, Nolph KD, et al.: Chronic nightly tidal
peritoneal dialysis (NTPD). ASAI O Trans 1990, 36:M584M588.
28. Twardowski ZJ: Tidal peritoneal dialysis: acute and chronic studies.
Eur Dial Transplant Nurses Assoc Eur Renal Care Assoc September
1990, 15:49.
29. Twardowski ZJ: Tidal peritoneal dialysis. In Dialysis Therapy. Edited
by Nissenson AR, Fine RN. Philadelphia: Hanley & Belfus;
1993:153156.
30. Twardowski ZJ, Nolph KD, Prowant BF, et al.: Efficiency of high vol-
ume low frequency continuous ambulatory peritoneal dialysis
(CAPD). ASAI O Trans 1983, 29:5357.
31. Krediet RT, Boeschoten EW, Zuyderhoudt FMJ, et al.: Differences in
the peritoneal transport of water, solutes and proteins between dialy-
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Permeability in Continuous Ambulatory Peritoneal Dialysis Patients.
Edited by Krediet RT. Amsterdam, Holland: University of Amsterdam;
1986:129146.
32. Twardowski Z, Janicka L: Three exchanges with a 2.5 liter volume
for continuous ambulatory peritoneal dialysis. Kidney I nt 1981,
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33. Twardowski ZJ, Prowant BF, Nolph KD, et al.: High volume, low fre-
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34. Randerson DH: Continuous ambulatory peritoneal dialysis-a critical
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36. Farrell PC, Randerson DH: Mass transfer kinetics in continuous ambu-
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New York: Masson; 1981:3552.
38. Pyle WK, Popovich RP, Moncrief JW: Mass transfer in peritoneal dial-
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ASAI O J 1983, 6:131137.
36
5
Dialysis Access
and Recirculation
S
ince its inception, hemodialysis has been bedeviled by problems
of vascular access. Access, from the time of creation and through-
out a patients dialysis life, consumes significant time, effort, and
expense and creates much anxiety and risk for patient and family.
Vascular access complications remain the single leading cause of 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 patients dialysis
life. Despite the advances made in hemodialysis technology, the same
vascular access problems that plagued dialysis pioneers continue
today to confound patient care teams.
Tor os Ka poia n
Jeff r ey L. Ka u fm a n
John N osher
Ri cha r d A . Sher m a n
CHA P T ER
37
FIGURE 5-1
Evaluation for hemodialysis access. The creation of optimal vascular
access requires an integrated approach among patient, nephrologist,
and surgeon. The preoperative evaluation includes a thorough history
and physical examination. A history of arterial and venous line place-
ments should be sought. The upper extremities are examined for
edema and asymmetry of pulse and blood pressure. Access should be
placed at the wrist only after it is verified that the radial artery is not
the dominant arterial conduit to the hand. The classic study is the
Allen test, in which an observer compresses both the radial and ulnar
arteries, has the patient exercise the hand by opening and closing to
cause blanching, then releases one vessel to be certain that the fingers
become perfused. An alternative, and perhaps more precise, test is to
verify by Doppler imaging that flow to all digits is maintained despite
occlusion of the radial artery. If indicated, vascular imaging studies
should be used to delineate the vascular anatomy and rule out arterial
or venous disease. Clinically silent stenosis involving the central veins
is becoming increasingly common with the improved survival of criti-
cally ill patients for whom central vein catheters are commonplace.
EVALUATION FOR HEMODIALYSIS VASCULAR ACCESS
History
Surgical cutdown
Multipleperipheral catheters
Peripherallyinserted central catheter
lineplacement
Transvenouspacemaker
Axillarydissection
Intravenousdruguse
Obesity
Peripheral vascular disease
Atherosclerotic disease
Physical examination
Asymmetryof pulse
Asymmetryof blood pressure
Abnormal capillaryrefill
Abnormal Allen test
Presenceof surgical or other scars
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.
Arteriovenous Dialysis Access: Evaluation and Placement
38
5.3 Dialysis Access and Recirculation
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 patients dialysis life. They do,
however, become obvious targets for the dialysis technical staff,
who have a tendency to puncture them repeatedly rather than to
utilize new needle insertion sites. The patients arm also demon-
strates marked muscle atrophy secondary to advanced diabetic neu-
ropathy, which particularly involves the thenar eminence and the
interosseus muscle groups. Complaints of weakness and loss of
grip strength in the arm are common and may represent symptoms
of steal. In this case, however, the symptoms are due to the intrin-
sic loss of muscle mass, rather than to steal.
A
C
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.
FIGURE 5-3
The Brescia-Cimino (radial-cephalic) fistula. The radial-cephalic fis-
tula offers many advantages. It is simple to create and preserves
more proximal vessels for future access construction. The lower
39
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-
structions. The sites of choice are limited by
the requirements of hemodialysis: delivery
of a high rate of blood flow and accessibility
to the dialysis staff for cannulation with an
adequate length of graft to keep the needles
sufficiently separated and allow rotation of
cannulation sites.
FIGURE 5-5
Polytetrafluoroethylene (PTFE) vein graft. The most common synthetic material used for
dialysis access construction is the PTFE conduit. This material replaced bovine heterografts;
alternative materials such as the umbilical vein graft have not yet made much headway.
Because of the infection risk, Dacron bypass grafts have never functioned well for dialysis.
PTFE is an inert material that is formed into a pliable conduit. Its ultramicroscopic struc-
ture is a series of nodes connected by tiny filaments, leaving pores whose size can be varied
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.
40
A B
FIGURE 5-7
Arteriovenous fistula anastomotic stenosis. Arteriovenous fistulas
exhibit better long-term patency compared with polytetrafluoroeth-
ylene (PTFE) grafts. A, This arteriogram, performed by injecting
the brachial artery, demonstrates an end-to-side arteriovenous fistu-
la involving the brachial artery and the cephalic vein. The arrow
indicates an area of narrowing adjacent to the anastomosis, the
most common site for a stenotic lesion in native vein fistulas.
B, Angioplasty successfully eliminated the anastomotic stenosis.
Limitations on balloon size are often encountered when treating
lesions in arteriovenous fistulas because a portion of the balloon
must often extend into the donor artery, which typically is of
smaller diameter than the outflow vein.
FIGURE 5-8
Exposed polytetrafluoroethylene (PTFE) graft. Proper placement of
a PTFE graft is crucial for its long-term survival. The graft cannot
be too short, as it will deteriorate quickly from puncture limited to
only a few sites; if it is too long, however, it will have a greater
impedance to flow and a tendency toward thrombosis. The graft
should be neither too deep to the skin nor too shallow. When the
graft is too shallow, puncture by the dialysis staff is easier, but the
skin may be eroded with scarring from repeated use. This 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.
Complications of Arteriovenous Dialysis Access Placement
41
FIGURE 5-9
Extravasation injury to the access site. A, A relatively fresh seg-
ment of polytetrafluoroethylene graft was removed during a revi-
sion procedure. There is virtually no fibrosis or calcification (asso-
ciated with repeated puncture). The luminal surface displays the
results of multiple sites of puncture and healing. Among the most
dramatic and troublesome complications of dialysis is access infil-
tration. In most cases the infiltration is minor and usually results
from either inadequate hemostasis at the end of dialysis or needle
perforation through the access site. Extravasation injury to the
access is more likely when a needle errantly transfixes a graft or
vein or when it accidentally becomes dislodged into the subcuta-
neous tissue. The venous return needle presents the biggest prob-
lem. In the face of typical pump speeds of 400 to 500 mL/min a
potentially huge volume of fluid can enter the soft tissue before
the pump stops in response to the alarm for elevated venous pres-
sure. In many cases, the graft is unusable for weeks after such an
episode. Continued use of the access in this setting may result in
loss of the access site. B, In this example, the infiltration was com-
posed of approximately 400 mL of priming crystalloid and blood,
located both deep and superficial to the investing fascia of the
arm. The access remained patent and was eventually restored to
function; however, a series of percutaneous drainage procedures
and open drainage were necessary. Compartment syndrome, with
loss of distal motor function or sensation in the arm, is another
concern in this setting, and drainage must be performed to treat
this surgical emergency.
A B
A
B
FIGURE 5-10
Outfl ow vei n stenosi s. Stenoti c l esi ons are most often found
at a pol ytetrafl uoroethyl ene (PTFE) grafts venous anastomoti c
si te or wi thi n i ts outfl ow vei n. A, Radi ograph depi cti ng an
angi opl asty bal l oon i nfl ated across an outfl ow vei n wi th a
stenoti c l esi on. The wai st i n the bal l oon (arrow) i ndi cates the
l ocati on of the stenosi s. Wi th i ncreasi ng i nfl ati on pressure the
wai st di sappears, an i ndi cati on of successful angi opl asty. Fai l ure
to el i mi nate the wai st i n the bal l oon i ndi cates i ncompl ete di l ata-
ti on of the l esi on. Occasi onal l y, outfl ow vei n stenoses are very
resi stant to di l atati on and requi re hi gh i nfl ati on pressures. Thi s
i s not surpri si ng gi ven the amount of scarri ng and i nti mal hyper-
pl asi a that can devel op i n a di al ysi s access si te. B, Resected
graft-venous anastomosi s from a one-year-ol d PTFE graft. The
vei n wal l seen here i s enormousl y thi ckened. Angi opl asty of
l esi ons such as these i s often unsuccessful , as thi s ri gi d materi al
i s l i kel y to rebound to i ts stenoti c state wi th any mani pul ati on.
42
A B
C D
E
FIGURE 5-11
Graft thrombosis due to outflow vein stenosis requiring use of an
atherectomy catheter. Thrombectomy of a dialysis access site involves
removal of three types of clot. A, The body of a thrombosed access
contains a red or purplish thrombus that is often gelatinous. It is eas-
ily removed with a balloon-tipped thrombectomy/embolectomy
catheter. This photograph also demonstrates the small meniscus of
firm, laminar, platelet-rich clot that usually obstructs arterial inflow.
On occasion, it is also found at the venous end. This type of clot can
be tenacious and may not be removed with thrombolytic therapy or
the balloon catheter. A cutdown at the arterial end of the graft may
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
Poiseuilles law, if blood pressure remains constant, a 6-mm graft
with 1 mm of circumferential laminar clot accommodates only 20%
of the flow originally present, since flow is inversely related to the
fourth power of the radius.
Eighty percent of thrombosed accesses have an associated stenotic
lesion. C, An eccentric focal stenosis is demonstrated at the anasto-
mosis of a PTFE forearm graft and its outflow vein (arrow), which
did not respond to percutaneous transluminal angioplasty. The lesion
was subsequently resected using a Simpson atherectomy catheter,
which consists of a concealed cutting chamber that is deflected into
contact with the stenotic lesion of the vessel wall by inflating the
associated balloon. With the lesion projecting into the cutting cham-
ber, a high-speed cylindrical cutting blade resects tissue into a collect-
ing chamber. This chamber is rotated sequentially until the circum-
ference of the lesion has been treated. D, The Simpson atherectomy
catheter is placed across the stenotic lesion. E, The postprocedure
venogram shows that the lesion was successfully resected.
43
FIGURE 5-13
Thrombectomy brush. Several types of mechanical thrombectomy
devices have been developed as alternatives to pharmaceutical
fibrinolysis. All mechanically macerate or disrupt clot into small
fragments that embolize into the central veins and, eventually, the
pulmonary vascular bed. This photograph demonstrates a brush
attached to a motor drive that imparts high-speed rotary motion
to disrupt the thrombus. The danger of most mechanical devices
is the risk of vascular injury.
FIGURE 5-12
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.
A B
D C
FIGURE 5-14
Outflow vein stenosis with stenting. A, Arteriography in this
patient with a Brescia-Cimino fistula demonstrates stenosis of the
outflow vein approximately 15 cm central to the fistula (arrow).
B, Percutaneous transluminal angioplasty was performed in this
patient; however, because of immediate elastic recoil, the lesion
looks no different after angioplasty. C, Following stent placement
(arrow), there is no residual stenosis, and good flow through the
stent is apparent. Stents have proven controversial in access sites.
Although they may improve patency in central vein stenoses (vide
infra), in the periphery they may be a hindrance. Some patients
develop vigorous fibrosis at the venous site of a stent. D, This
photograph demonstrates what had occurred only 1 month after
stent placement. Stents can be a problem when dealing with sub-
sequent vascular access dysfunction. During thrombectomy, the
tiny wires of a stent can puncture balloon catheters. When stent-
ed segments restenose, it is impossible to perform open patch
angioplasty over such segments, and it becomes necessary to
jump to a different venous outflow site. It is not clear whether
stents in or adjacent to dialysis grafts are cost effective in main-
taining graft patency.
44
FIGURE 5-15
Intragraft stenosis. A, This arteriogram demonstrates a forearm
loop polytetrafluoroethylene (PTFE) graft with an intragraft stenosis
(arrow). Stenotic lesions in this site are less common than those
involving either the venous anastomosis or the outflow vein.
B, These lesions can be treated successfully with percutaneous trans-
luminal angioplasty (arrow). In cases where angioplasty is unsuccess-
ful, intragraft stenoses can also be treated using percutaneous
atherectomy or surgical revision. Since this region of the access is
subject to needle cannulation, the placement of a stent would be
inadvisable. Intragraft stenoses may be located between the sites of
the arterial and venous needle placements during dialysis. If so, the
most common screening studies, namely venous pressure measure-
ments and recirculation, do not have abnormal findings and the
lesion may remain undetected until access thrombosis develops.
A B
C
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 patients 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
and functioning well the medial segment was replaced.
45
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.
FIGURE 5-18
Vascular access screening methods. Dialysis grafts have a high inci-
dence of thrombosis, the risk of which increases when graft flow
rates (A) fall below 600 to 700 mL/min, particularly with stenotic
lesions in or near the graft. Most often, stenoses occur just distal to
the graft-vein anastomosis (B) but they can occur proximal to the
graft-artery anastomosis (C) or within the graft itself (D). Various
screening methods may help detect grafts at high risk for 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
flow (adjusting for the difference in height between the graft and
the transducer). To increase accuracy, this pressure can be normal-
ized by dividing it by the mean arterial pressure. More commonly,
this intragraft pressure is determined indirectly by using the dialysis
machines pressure transducer and a pump speed of 200 mL/min.
In this case the measured pressure often exceeds 100 mm Hg in a
normal graft, owing to the resistance in the venous needle.
46
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.
B
A
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)
B
Central Venous Dialysis Access
47
C
FIGURE 5-20 ( Co n t i n u e d )
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
C
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.
48
D E
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.
A
B C
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. Band 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
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.
49
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.
D
FIGURE 5-23
Translumbar catheter placement. Patients receiving chronic hemodialysis may exhaust
potential sites for permanent vascular access. Additionally, after long-term use of central
vein catheters, these sites also develop irreversible occlusion. In most cases, these patients
are trained for peritoneal dialysis; however, some patients cannot tolerate this modality.
This patient failed all attempts at arteriovenous and central vein access placement, 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.
50
6
The Dialysis Prescription
and Urea Modeling
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 patients well-being. In
chronic renal failure, hemodialysis results in a dramatic reversal of uremic
symptoms and helps improve the patients functional status and increase
patient survival. To achieve these goals the dialysis prescription must
ensure that an adequate amount of dialysis is delivered to the patient.
Numerous studies have shown a correlation between the delivered dose
of hemodialysis and patient morbidity and mortality [14]. Therefore, the
delivered dose should be measured and monitored routinely to ensure
that the patient receives an adequate amount of dialysis. One method
of assessing the amount of dialysis delivered is to calculate the Kt/V. The
Kt/V is a unitless value that is indicative of the dose of hemodialysis.
The Kt/V is best described as the fractional clearance of urea as a 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
dialysis (KoA >600 mL/min, where KoA is the constant indicating the
efficiency of dialyzers in removing urea). Eventually, increases in blood
and dialysate flow rates, even when combined with a high-efficiency
membrane, result in no further increase in the urea clearance rate. At
this point the most important determinant affecting the dose of dialysis
is the amount of time the patient is dialyzed.
Biff F. Pa l m er
CHA P T ER
51
Ultrafiltration during dialysis is performed to remove volume
that has accumulated during the interdialytic period so that
patients can be returned to their dry weight. Dry weight is
determined somewhat crudely, being based on clinical findings.
The patients dry weight is the weight just preceding the devel-
opment of hypotension. The patient should be normotensive
and show no evidence of pulmonary or peripheral edema. A
patients dry weight frequently changes over time and therefore
must be assessed regularly to avoid hypotension or progressive
volume overload.
During ultrafiltration the driving force for fluid removal is the
establishment of a pressure gradient across the dialysis membrane.
The water permeability of a dialysis membrane is a function of
membrane thickness and pore size and is indicated by its ultrafil-
tration coefficient (KUf). During ultrafiltration additional solute
removal occurs by solvent drag or convection. Because of
increased pore size, high-flux membranes (KUf >20 mL/h/mm Hg)
are associated with much higher clearances of average to high mol-
ecular weight solutes such as
2
microglobulin. Because blood
flow rates over 50 to 100 mL/min result in little or no further
increase in the clearance of these molecules, clearance is primarily
membrane-limited. In contrast, clearance values for urea are not
significantly greater with a high-flux membrane compared with a
high-efficiency membrane because the blood flow rate, and not the
membrane, is the principal determinant of small solute clearance.
The biocompatibility of the dialysis membrane is another
consideration in the dialysis prescription. A biocompatible dialysis
membrane is one in which minimal reaction occurs between the
humoral and cellular components of blood as they come into
contact with the surface of the dialyzer [6]. One such reaction
that has been used as a marker of biocompatibility is evidence of
complement activation. Cellulosic membranes generally tend to be
bioincompatible, whereas noncellulosic or synthetic membranes
have more biocompatible characteristics. Whether any clinical
difference exists in acute or chronic outcomes between biocom-
patible and bioincompatible membranes is still a matter of debate.
Trials designed to address this issue have been mostly uncon-
trolled, limited in sample size, and often retrospective in nature.
Nevertheless, some evidence exists to suggest that bioincompati-
ble membranes may have a greater association with
2
microglob-
ulin-induced amyloidosis, susceptibility to infection, enhanced
protein catabolism, and increased patient mortality [59].
Another aspect of the dialysis prescription is the composition
of the dialysate. The concentrations of sodium, potassium,
calcium, and bicarbonate in the dialysate can be individualized
such that ionic composition of the body is restored toward
normal during the dialytic procedure. This topic is discussed in
detail in chapter 2.
Although hemodialysis is effective in removing uremic toxins
and provides adequate control of fluid and electrolyte abnor-
malities, the procedure does not provide for the endocrine or
metabolic functions of the normal kidney. Therefore, the dialy-
sis prescription often includes medications such as erythropoi-
etin and 1,25(OH)
2
vitamin D. The dose of erythropoietin
should be adjusted to maintain the hematocrit between 33%
and 36% (hemoglobin of 11 g/dL and 12 g/dL, respectively)
[10]. Vitamin D therapy is often used in patients undergoing
dialysis to help limit the severity of secondary hyperparathy-
roidism. Dosages usually range from 1 to 2 g given intra-
venously with each treatment.
Treatment
Diffusion
Dialysis membrane A
Blood
Urea, 100 mg/dL
Potassium, 5.0 mEq/L
Bicarbonate, 20 mEq/L
Dialysate
Urea, 0 mg/dL
Potassium, 2.0 mEq/L
Bicarbonate, 35 mEq/L
FIGURE 6-1
Diffusional and convective flux in hemodialysis. Dialysis is a
process whereby the composition of blood is altered by exposing it to
dialysate through a semipermeable membrane. Solutes are transported
across this membrane by either diffusional or convective flux. A, In
diffusive solute transport, solutes cross the dialysis membrane in a
direction dictated by the concentration gradient established across
the membrane of the hemodialyzer. For example, urea and potassi-
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.
52
6.3 The Dialysis Prescription and Urea Modeling
Ultrafiltration
Dialysis membrane B
Blood Dialysate
H
2
O
H
2
O
H
2
O
150 mmHg 90 mmHg
B, During hemodialysis water moves from blood to dialysate
driven by a hydrostatic pressure gradient between the blood and
dialysate compartments, a process referred to as ultrafiltration.
The rate of ultrafiltration is determined by the magnitude of this
pressure gradient. Movement of water tends to drag solute across
the membrane, a process referred to as convective transport or sol-
vent drag. The contribution of convective transport to total solute
transport is only significant for average-to-high molecular weight
solutes because they tend to have a smaller diffusive flux.
TREATMENT OF HEMODYNAMIC INSTABILITY
Excludenondialysis-related causes(eg, cardiac ischemia, pericardial effusion, infection)
Set thedryweight accurately
Optimizethedialysatecomposition
Useasodiumconcentration of 140mEq/L
Usesodiummodeling
Useabicarbonatebuffer
Avoid low magnesiumdialysate
Avoid low calciumdialysate
Optimizethemethod of ultrafiltration
Usevolume-controlled ultrafiltration
Useultrafiltration modeling
Usesequential ultrafiltration and isovolemic dialysis
Usecool temperaturedialysate
Maximizecardiac performance
Havepatientsavoid food on dayof dialysis
Havepatientsavoid antihypertensivemedicineson dayof dialysis
Pharmacologic prevention
Erythropoietin therapyto keep hematocrit >30%
Experimental (eg,caffeine, midodrine, ephedrine, phenylephrine, carnitine)
FIGURE 6-2
The common treatments for hemodynamic instability of patients
undergoing dialysis. It is important to begin by excluding reversible
causes associated with hypotension because failure to recognize
these abnormalities can be lethal. Perhaps the most common 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.
ACCEPTABLE METHODS TO MEASURE
HEMODIALYSIS ADEQUACY
*
Formal ureakinetic modeling(Kt/V) usingcomputational software
Kt/V =-LN (R0.008t)
+(4-3.5 R)
Uf/w
t
Ureareduction ratio
*
Recommended bytheNational KidneyFoundation DialysisOutcomesQuality
InitiativeClinical PracticeGuidelines, which suggest aprescribed minimumKt/V of
1.3and aminimumureareduction ratio of 70%.
t
LN isthenatural logarithm; R ispostdialysisblood ureanitrogen (BUN)/predialysis
BUN; t istimein hours, Uf isultrafiltration volumein liters; w ispostdialysisweight
in kilograms.
FIGURE 6-3
Acceptable methods to measure hemodialysis adequacy as recom-
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-
sidered the minimum targets.
53
U
r
e
a

c
l
e
a
r
a
n
c
e
,

m
L
/
m
i
n
100
0
300
400
200
100 0 400 300 200
Membrane-limited
KoA 900
KoA 650
High-efficiency
dialyzer
Conventional
dialyzer
F
l
o
w
-
l
i
m
i
t
e
d
KoA 300
Transmembranepressure, m m Hg
100 0 200 300 400
KUf=60mL/h/mmHg
KUf=4mL/h/mmHg
KUf=3mL/h/mmHg
500 600
2000
1800
1600
1400
1200
1000
800
600
400
200
0
U
l
t
r
a
f
i
l
t
r
a
t
i
o
n
,

m
L
/
h
Considerations in Choice of Membranes
FIGURE 6-4
Relationships between membrane efficiency and clearance and
blood flow rates in hemodialysis. When prescribing the blood flow
rate for a hemodialysis procedure the following must be considered:
the relationship between the type of dialysis membrane used, blood
flow rate, and clearance rate of a given solute. For a small solute
such as urea (molecular weight, 60) initially a linear relationship
exists between clearance and blood flow rates. Small solutes are
therefore said to be flow-limited because their clearance is highly
flow-dependent. At higher blood flow rates, increases in clearance
rates progressively decrease as the characteristics of the dialysis
membrane become the limiting factor. The efficiency of a dialyzer
in removing urea can be described by a constant referred to as
KoA, which is determined by factors such as surface area, pore
size, and membrane thickness. Use of a high-efficiency membrane
(KoA >600 mL/min) can result in further increases in urea clearance
rates at high blood flow rates. In contrast, at low blood flow rates no
significant difference exists in urea clearance between a conventional
and a high-efficiency membrane because blood flow, and not the
membrane, is the primary determinant of clearance.
FIGURE 6-5
Water permeability of a membrane and control of volumetric
ultrafiltration in hemodialysis. The water permeability of a dialysis
membrane can vary considerably and is a function of membrane
thickness and pore size. The water permeability is indicated by its
ultrafiltration coefficient (KUf). The KUf is defined as the number
of milliliters of fluid per hour that will be transferred across the
membrane per mm Hg pressure gradient across the membrane.
A high-flux membrane is characterized by an ultrafiltration coeffi-
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
result in excessively large amounts of fluid to be removed. As a
result, use of these membranes should be restricted to dialysis
machines that have volumetric ultrafiltration controls so that the
amount of ultrafiltration can be precisely controlled.
54
C
l
e
a
r
a
n
c
e
,

m
L
/
m
i
n
150
100
High-efficiencydialyzer
High-flux dialyzer
Normal kidney
50
0
100,000 10,000 1000 100 10 0
U
r
e
a
(
m
w
=
6
0
)
Solutemolecular weight, Da lt on s
V
i
t
a
m
i
n

B
1
2
(
m
w
=
1
3
5
5
)
2
-
m
i
c
r
o
g
l
o
b
u
l
i
n
(
m
w
=
1
1
,
8
0
0
)
FIGURE 6-6
High-efficiency and high-flux membranes in hemodialysis. These
membranes have similar clearance values for low molecular weight
solutes such as urea (molecular weight, 60). In this respect both
types of membranes have similar KoA values (over 600 mL/min),
where KoA is the constant indicating the efficiency of the dialyzer
in removing urea. As a result of increased pore size, use of 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
some high-flux membranes, 400 to 600 mg/wk of
2
-microglobulin
can be removed. The clinical significance of enhanced clearance of
2
-microglobulin and other middle molecules using a high-flux dia-
lyzer is currently being studied in a national multicenter hemodial-
ysis trial.
Number of hemodialysis treatments
Polymethyl methacrylate
Cuprophane
P
a
t
i
e
n
t
s

r
e
c
o
v
e
r
i
n
g

r
e
n
a
l

f
u
n
c
t
i
o
n
,

%
80
60
40
20
0
0 5 10 15 20 25 30
FIGURE 6-7
Effects of membrane biocompatibility in hemodialysis. Another
consideration in the choice of a dialysis membrane is whether it is
biocompatible. In chronic renal failure some evidence exists to suggest
that long-term use of biocompatible membranes may be associated
with favorable effects on nutrition, infectious risk, and possibly
mortality when compared with bioincompatible membranes [59].
In the study results shown here, the effect of biocompatibility on
renal outcome in a group of patients with acute renal failure who
required hemodialysis was examined. Patients received dialysis with
a cuprophane membrane (a bioincompatible membrane known to
activate complement and neutrophils) or a synthetic membrane
made of polymethyl methacrylate (a biocompatible membrane
associated with more limited complement and neutrophil activation).
The two groups of patients were similar in age, degree of renal failure,
and severity of the underlying disease as defined by the Acute
Physiology and Chronic Health Evaluation (APACHE) II score. As
compared with the bioincompatible membrane, those patients treated
with the synthetic biocompatible membrane had a significantly shorter
duration of renal failure in terms of number of treatments and
duration of dialysis. In the setting of acute renal failure, particularly
in patients after transplantation, a biocompatible membrane may
be the preferred dialyzer. (FromHakim and coworkers [11];
with permission.)
55
C
l
e
a
r
a
n
c
e
,

m
L
/
m
i
n
300
280
260
240
220
200
180
160
140
120
100
200 500 450 400 350 300 250
Dialyzer
KoA=800
Dialyzer
KoA=400
Q
D
=800
Q
D
=500
Q
D
=800
Q
D
=500
Timeoff
1. Dialyzer ureaclearancerate
KoA of membrane
Blood flow
Dialysateflow
Convectiveureaflux
2. Treatment time
3. Volumeof distribution
1. Ureageneration rate
Protein catabolic rate
2. Volumeof distribution
3. Residual renal function
Interdialytic
time
Dialysis
time
Timeon Timeon (next dialysis)
U
r
e
a

c
o
n
c
e
n
t
r
a
t
i
o
n
FIGURE 6-8
Dialysate flow rate in hemodialysis. The clearance of urea also
is influenced by the dialysate flow rate. Increased flow rates help
maximize the urea concentration gradient along the entire length of
the dialysis membrane. Increasing the dialysate flow rate from 500
to 800 mL/min can be expected to increase the urea clearance rate
on the order of 10% to 15%. This effect is most pronounced at
high blood flow rates and with use of high KoA dialyzers. KoA
constant indicating the efficiency of the dialyzer in removing urea;
Q
D
dialysate flow rate.
Prescription for Dose Delivery
FIGURE 6-9
Delivering an adequate dose of dialysis in hemodialysis. Providing
an adequate amount of dialysis is an important part of the dialysis
prescription. During the dialytic procedure a sharp decrease in the
concentration of urea occurs followed by a gradual increase during
the interdialytic period. The decrease in urea during dialysis is
determined by three main parameters: dialyzer urea clearance rate
(K), dialysis treatment time (t), and the volume of urea distribution
(V). The dialyzer urea clearance rate (K) is influenced by the charac-
teristics of the dialysis membrane (KoA), blood flow rate, dialysate
flow rate, and convective urea flux that occurs with ultrafiltration.
The gradual increase in urea during the interdialytic period depends
on the rate of urea generation that, in an otherwise stable patient,
reflects the dietary protein intake, distribution volume of urea, and
presence or absence of residual renal function.
56
FACTORS RESULTING IN A REDUCTION OF THE
PRESCRIBED DOSE OF HEMODIALYSIS DELIVERED
Compromised ureaclearance
Accessrecirculation
Inadequateblood flow fromthevascular access
Dialyzer clottingduringdialysis(reduction of effectivesurfacearea)
Blood pump or dialysateflow calibration error
Reduction in treatment time
Prematurediscontinuation of dialysisfor staff or unit convenience
Prematurediscontinuation of dialysisper patient request
Delayin startingtreatment owingto patient or staff tardiness
Timeon dialysiscalculated incorrectly
Laboratoryor blood samplingerrors
Dilution of predialysisBUN blood samplewith saline
Drawingof predialysisBUN blood sampleafter start of theprocedure
DrawingpostdialysisBUN >5minutesafter theprocedure
Ureareduction ratio, %
K
t
/
v

b
y

f
o
r
m
a
l

u
r
e
a

k
i
n
e
t
i
c

m
o
d
e
l
i
n
g
1.80
0.60
0.80
1.00
1.20
1.40
1.60
0.40 0.80 0.50 0.60 0.70
0.02
0
.
1
0
0
.
0
8
0
.
0
6
0
.
0
4
0.00
Increasing
ultrafiltation
FIGURE 6-10
Each of the factors listed may play a major role in the reduction of
delivered dialysis dose. Particular attention should be paid to the
vascular access and to a reduction in the effective surface area of
the dialyzer. Perhaps the most important cause for reduction in
dialysis time has to do with premature discontinuation of dialysis
for the convenience of the patient or staff. Delays in starting dialysis
treatment are frequent and may result in a significant loss of dialysis
prescription. Finally, particular attention should be paid to the correct
sampling of the blood urea nitrogen level and the site from which
the sample is drawn.
FIGURE 6-11
Monitoring the delivered dose in hemodialysis. Use of the urea reduc-
tion ratio (URR) is the simplest way to monitor the delivered dose of
hemodialysis. However, a shortcoming of this method compared with
formal urea kinetic modeling is that the URR does not account for the
contribution of ultrafiltration to the final delivered dose of dialysis.
During ultrafiltration, convective transfer of urea from blood to
dialysate occurs without a decrease in urea concentration. As a result,
with increasing ultrafiltration volumes the Kt/V, as determined by
formal urea kinetic modeling, progressively increases at any given
URR. For example, a URR of 65% may correspond to a Kt/V as
low as 1.1 in the absence of ultrafiltration or as high as 1.35 when
ultrafiltration of 10% of body weight occurs.
BUNblood ureanitrogen.
57
Weeks of rHuEpo therapy
0 2 4 6 8 10
500U/kg
150U/kg
50U/kg
15U/kg
12 14 16
H
e
m
a
t
o
c
r
i
t
,

%
45
40
35
30
25
20
15
MAJOR COMPONENTS OF DIALYSIS PRESCRIPTION
Chooseabiocompatiblemembrane
PrescribeaKt/V 1.3or aURR 70%
Rigorouslyensurethat thedelivered doseequalstheamount prescribed
When thedelivered doseislessthan that prescribed do thefollowing:
Excludefactorslisted in Figure6-10
Increaseblood flow rate400mL/min
Increasedialysateflow rateto 800mL/min
Useahigh-efficiencydialyzer
Increasetreatment time
Choosedialysatecomposition: sodium, potassium, bicarbonate, and calcium
Adjust ultrafiltration rateto achievepatients dryweight (assessdryweight regularly)
Adjust recombinant erythropoietin to maintain hematocrit between 33%and 36%
When indicated, use1,25(OH)
2
vitamin D for treatment of secondary
hyperparathyroidism
Usenormal saline, hypertonic saline, or mannitol for treatment of intradialytic
hypotension
URRureareduction ratio.
FIGURE 6-12
Correction of anemia in chronic renal failure. Anemia is a pre-
dictable complication of chronic renal failure that is due partly
to reduction in erythropoietin production. Use of recombinant ery-
thropoietin to correct the anemia in patients with chronic renal
failure has become standard therapy. The rate of increase in hemat-
ocrit is dose-dependent. The indicated doses were given intra-
venously three times per week. Current guidelines for the initiation
of intravenous therapy suggest a starting dosage of 120 to 180
U/kg/wk (typically 9000 U/wk) administered in three divided doses.
Administration of erythropoietin subcutaneously has been shown
to be more efficient than is intravenous administration. That is, on
average, any given increment in hematocrit can be achieved with
less erythropoietin when it is given subcutaneously as compared
with intravenously. In adults, the subcutaneous dosage of erythro-
poietin is 80 to 120 U/kg/wk (typically 6000 U/wk) in two to three
divided doses. rHuEporecombinant human erythropoietin. Data
fromEschbach and coworkers [12]; with permission.
FIGURE 6-13
All these components are important as contributors to a successful
dialysis prescription. The Dialysis Outcomes Quality Initiative
(DOQI) recommendations should be followed to achieve an adequate
dialysis prescription, and the time on dialysis should be monitored
carefully. When the delivered dialysis dose is less that prescribed,
the reversible factors listed in Figure 6-10 should be addressed first.
Subsequently, an increase in blood flow to 400 mL/min should be
attempted. Increases in dialyzer surface area and treatment time
also may be attempted. In addition, attention should be paid to the
correct dialysis composition and to the ultrafiltration rate to make
certain that patients achieve a weight as close as possible to their
dry weight. Hematocrit should be sustained at 33% to 36%. Finally,
vitamin D supplementation to prevent secondary hyperparathyroidism
and use of normal saline or other volume expanders are encouraged
to treat hypotension during dialysis. KoAconstant indicating the
efficiency of the dialyzer in removing urea.
References
1. Owen WF, Lew NL, Liu Y, Lowrie EG: The urea reduction ratio and
serum albumin concentration as predictors of mortality in patients
undergoing hemodialysis. N Engl J Med 1993, 329:10011006.
2. Hakim RM, Breyer J, Ismail N, Schulman G: Effects of dose of dialysis
on morbidity and mortality. Am J Kidney Dis 1994, 23:661669.
3. Held PJ, Port FK, Wolfe RA, et al.: The dose of hemodialysis and
patient mortality. Kidney I nt 1996, 50:550556.
4. Parker TF III, Husni L, Huang W, et al.: Survival of hemodialysis
patients in the United States is improved with a greater quantity of
dialysis. Am J Kidney Dis 1994, 23:670680.
5. Hemodialysis Adequacy Work Group: Dialysis Outcomes Quality
Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 2:S22S31.
6. Hakim, RM: Clinical implications of hemodialysis membrane biocom-
patibility. Kidney I nt 1993, 44:484494.
7. Vanholder R, Ringoir S, Dhondt A, et al.: Phagocytosis in uremic and
hemodialysis patients: a prospective and cross sectional study. Kidney
I nt 1991, 39:320327.
8. Gutierrez A, Alvestrand A, Bergstrom J: Membrane selection and
muscle protein catabolism. Kidney I nt 1992, 42:S86S90.
9. Hornberger JC, Chernew M, Petersen J, Garber AM: A multivariate
analysis of mortality and hospital admissions with high-flux dialysis.
J Am Soc Nephrol 1992, 3:12271237.
10. Hemodialysis Adequacy Work Group: Dialysis Outcomes Quality
Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 3:S199S201.
11. Hakim RM, Wingard RL, Parker RA: Effect of the dialysis membrane
in the treatment of patients with acute renal failure. N Engl J Med
1994, 331:13381342.
12. Eschbach JW, Egrie JC, Downing MR, et al.: Correction of the anemia
of end-stage renal disease with recombinant human erythropoietin.
N Engl J Med 1987, 316:7378.
58
7
Complications of Dialysis:
Selected Topics
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.
Rober t W. H a m il t on
CHA P T ER
59
Complications of Hemodialysis
COMPLICATIONS OF HEMODIALYSIS
Complication
Fever
Hypotension
Hemolysis
Dementia
Seizure
Bleeding
Musclecramps
Differential diagnosis
Bacteremia, water-bornepyrogens, overheated dialysate
Excessiveultrafiltration, cardiac arrhythmia, air embolus, pericardial
tamponade; hemorrhage(gastrointestinal, intracranial,
retroperitoneal); anaphylactoid reaction
Inadequateremoval of chloraminefromdialysate, failureof dialysis
concentratedeliverysystem
Incompleteremoval of aluminumfromdialysatewater, prescription
of aluminumantacids
Excessiveureaclearance(first treatment), failureof dialysis
concentratedeliverysystem
Excessiveheparin or other anticoagulant
Excessiveultrafiltration
FIGURE 7-1
Complications associated with hemodialysis.
FIGURE 7-2 (s e e Color Plate)
Dialyzer hypersensitivity. This patient was switched from a cellulose
acetate dialysis membrane to a cuprammonium cellulose one. Within
8 minutes of starting hemodialysis he developed apprehension,
diaphoresis, pruritus, palpitations, and wheezing. This eruption
was seen over the arm used for arteriovenous access for dialysis.
(FromCaruana and coworkers [1]; with permission.)
FIGURE 7-3
Thrombosis of the left innominate vein. Thrombosis can be a com-
plication of reliance on subclavian catheters for vascular access for
hemodialysis. This was discovered during investigation of edema of
the left arm.
FIGURE 7-4
Dilation of a stricture of the left innominate vein using balloon
angioplasty in the patient shown in Figure 7-3.
60
7.3 Complications of Dialysis: Selected Topics
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 -
2
microglobulin using low-permeability, cellulose dialysis membranes.
(Fromvan Ypersele de Strihou and coworkers [2]; with permission.)
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.
Complications of Peritoneal Dialysis
61
Tunnel abscess in patient undergoing continuous ambulatory peritoneal
dialysis. Pericatheter infections are a common source of peritonitis.
Sometimes, the findings are more subtle than in this case. Prompt
treatment with antibiotics is indicated. If the infection fails to
respond, removal of the catheter is indicated.
FIGURE 7-10
Sclerosing encapsulating peritonitis. This patient had several bouts
of peritonitis during the course of her treatment on peritoneal dialysis.
She developed partial small bowel obstruction. Abdominal computed
tomography revealed a homogeneous mass filling the anterior peri-
toneum. At laparotomy the mesentery was encased in a marble-
like fibrotic mass. The patient required long-term home parenteral
hyperalimentation for recovery. (FromPusateri and coworkers [3];
with permission.)
Peritonitis. In continuous ambulatory peritoneal dialysis (CAPD)
peritonitis can easily be recognized by the fact that drained peritoneal
fluid becomes opacified. The inability to read the writing on the
opposite side of the drained bag (or a newspaper through the bag)
correlates with a peritoneal leukocyte count of more than 100 cells
per microliter.
62
FIGURE 7-11
Peri cardi al tamponade. Narrow pul se pressure and a
peri cardi al fri cti on rub suggest peri cardi ti s (a frequent
compl i cati on of uremi a) especi al l y i n pati ents wi th chest
Complications of Renal Failure
Perforating folliculitis. The skin of uremic patients can be intensely
pruritic. Earlier, it was attributed to deposition of calcium and
phosphorus in the skin. Today, we know that is the result of
repeated trauma to the skin associated with scratching.
FIGURE 7-13
Acquired cystic disease of the kidney. Abdominal computed tomog-
raphy demonstrates cystic disease in this patient, who had focal
segmental glomerulosclerosis complicated by protein C deficiency
and renal vein thrombosis. Eleven years after the initial diagnosis,
he developed renal failure requiring hemodialysis. Two years after
starting dialysis, he developed hematuria, and these cysts were
found. The appearance and clinical course are consistent with
acquired cystic disease of the kidney. These cysts carry some risk of
malignant transformation.
pai n. Peri cardi al tamponade may present as di al ysi s-i nduced
hypotensi on. (Courtesy of T. Pappas, MD, Medi cal Col l ege
of Ohi o.)
Perica rd ia l ef f u sion
Ven t ricu la r sept u m
Righ t v en t ricle
Lef t v en t ricle
63
FIGURE 7-16
Diffuse bone demineralization as demonstrated in skull radiograph.
This radiograph demonstrates the generalized granular appear-
ance that is characteristic of the diffuse demineralization seen in
renal osteodystrophy.
Radiologic Manifestations of Renal Osteodystrophy
FIGURE 7-15
Radiograph of a shoulder involved by osteoporosis. The shoulder
joint demonstrates diffuse osteoporosis. There is distal resorption
of the clavicle. A small amount of calcification can be seen on the
clavicular side of the coracoclavicular ligament. These findings are
suggestive of osteitis fibrosa cystica.
R
i
s
k

o
f

d
e
a
t
h
Serumalbumin, g/ d L
>4.5
15
10
5
0
4.04.4 3.53.93.03.42.52.9 <2.5
FIGURE 7-14
Malnutrition. Malnutrition is an important risk factor for dialysis patients, as reflected in this
graph depicting the relation of death to serum albumin values. Albumin may have antioxidant
properties. Low concentrations of serum albumin may favor oxidation of lipids, which
renders them more atherogenic. (Data fromOwens and coworkers [4].
64
FIGURE 7-17
Radiograph of the hands of a patient who has renal osteodystrophy.
The hands demonstrate diffuse bilateral osteoporosis. The resorption
of the distal phalanges is best seen in the first and second digits of
the right hand. The radial side of the middle phalanges of the second
and third digits bilaterally demonstrates subperiosteal bone resorption.
Soft tissue calcification is present on the radial side of the proximal
interphalangeal joint of the second digit of the left hand.
10 min 30 30
50 1 hr 2 hr
FIGURE 7-18
Parathyroid scan. The patient was injected with 24.6 mCi of
99m
Tc Cardiolite. Hyperfunction of four parathyroid glands is seen.
This technique is often useful to determine the location and number
of parathyroid glands before performing subtotal parathyroidectomy.
At operation, diffuse hyperplasia of four parathyroid glands was
found. (FromIshibashi and coworkers [5].)
References
1. Caruana RJ, Hamilton RW, Pearson FC: Dialyzer hypersensitivity syn-
drome: possible role of allergy to ethylene oxide. Am J Nephrol 1985,
5:271274.
2. van Ypersele de Strihou C, Jadoul M, Malghem J, et al.: Effect of dialysis
membrane and patients age on signs of dialysis-related amyloidosis.
The working party on dialysis amyloidosis. Kidney I nt 1991,
39:10121019.
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, 8:5660.
4. Owens WF, Lew NL, Liu L, et al.: The urea reduction ratio and serum
albumin concentration as predictors of mortality in patients undergoing
hemodialysis. N Engl J Med 1993, 329:10011006.
5. Ishibashi M, Nishida H, Hiromatsu Y, et al.: Localization of ectopic
parathyroid glands using technetium-99m sestamibi imaging: comparison
with magnetic resonance and computed tomographic imaging. Eur J
Nuclear Med 1997, 24:197201.
65
8
Histocompatibility Testing
and Organ Sharing
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.
La ur a l ynn K. Lebeck
M a r vin R. Ga r ovoy
CHA P T ER
66
8.2 Transplantation as Treatment of End-Stage Renal Disease
A
Chromosome6
(short arm)
Class II Class III Class I HLA complex
Glyoxylase DP
DZ DO Cyp21TNF
DQ DR B C A
FIGURE 8-1
The major histocompatibility complex (MHC) is a group of closely
linked genes that was first appreciated because it was found to
contain the structural genes for transplantation antigens. A, The
MHC, located on the short arm of chromosome 6, is now recog-
nized to include many other genes important in the regulation of
immune responses. B, Regions of the MHC classes I, II, and III.
The MHC can be divided into three regions, of which the class I
and II regions contain the loci for the human histocompatibility
antigen or human leukocyte antigen (HLA). Genes in the class I
B
Class II
0
1500
500 3000
1000
D
P
A
1
D
P
A
2
D
P
B
1
D
P
B
2
D
N
A
D
M
B
D
M
A
L
M
P

2
T
A
P

1
L
M
P

7
T
A
P

2
D
Q
B
2
D
Q
B
1
D
Q
A
1
D
Q
A
2
D
R
B
D
R
A
BCXEJAHGF
C
Y
P

2
1
-
B
C
4
B
C
Y
P

2
1
-
A
C
4
A
B
F
C
2H
S
P

7
0
T
N
F

T
N
F

2000 3000 4000

Class III Class I
Specific locus
w 8
Themajor histocompatibility
complex in humans
Provisional
specificity
Specific antigen
Alleledesignation
Specific allele Correspondingantigen
Locus
HLA
HLA DRB1 * 04 03
C
FIGURE 8-2
Nomenclature of human leukocyte antigen (HLA) specificities. HLA
nomenclature may be confusing to the newcomer, but the format is
logical. The prefix HLA precedes all antigens or alleles to define
the major histocompatibility complex (MHC) of the species. The
designation, A, B, C, DR, and so on, is next and defines the locus.
The locus is followed by a number that denotes the serologically
defined antigen or a number with an asterisk that denotes the
molecularly defined allele. In some cases the letter w is placed
before the serologic antigen, indicating it is a workshop designation
and the specific assignment is provisional.
region encode the or heavy chain of the class I antigens, HLA-A,
B, and C. The class I region is composed of other genes, most of
which are pseudogenes and are not expressed. The MHC class II
region is more complex, with structural genes for both the and
chains of the class II molecules. The class II region includes four
DP genes, one DN gene, one DO gene, five DQ genes, and a vary-
ing number of DR genes (two to 10), depending on the halotype.
Many other immune response genes are coded within the class III
region. TNFtumor necrosis factor.
67
8.3 Histocompatibility Testing and Organ Sharing
PRETRANSPLANTATION
TESTING FOR RENAL PATIENTS
HLA phenotype
Patient cellstested with known antisera
HLA antibodyscreen
Known cellstested with patient sera
HLA crossmatch
Donor cellstested with patient sera
FIGURE 8-3
In an immunogenetics and transplantation laboratory, three major types of renal pretrans-
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
capability of reporting at least low-resolution molecular class II types.
The sera of patients awaiting cadaveric donor kidney transplantation are tested for the
degree of alloimmunization by determining the percentage of panel reactive antibodies
(PRAs). Current federal regulations require that the serum screening test use lymphocytes
as targets; however, because these same regulations no longer mandate monthly screening,
assays using soluble antigens may be used as adjuncts to the classic lymphocytotoxic assays.
The purpose of cross-match testing is to detect the presence of antibodies in the patients
serum that are directed against the HLA antigens of the potential donor. When present,
the antibodies indicate that the immune system of the recipient has been sensitized to the
donor antigens. The various test methods differ in sensitivity, including the multiple variations
of the lymphocytotoxicity text, flow cytometry, and enzyme-linked immunosorbent assay
(ELISA). The degree of acceptable risk is one factor to be considered in selecting a method
of appropriate sensitivity. For example, when the only risk considered unacceptable is that
of hyperacute rejection, a technique having lower sensitivity is adequate. A second approach
may be to consider the degree to which an individual patient or type of patient is at risk
for graft rejection. The patient having a repeat graft is at higher risk for graft rejection
than is the patient receiving a primary graft. Because patients differ in their degree of risk,
it is appropriate to use different techniques to offset that risk.
MHC I AND II CHARACTERISTICS
Class I
Composed of HLA-A, -B, and -C
Ubiquitousdistribution
Autosomal codominant
Target for immuneeffector mechanism
Serologic and molecular detection
Heterodimer noncovalentlylinked
Heavychain ():
Containsvariableregions
Confershuman leukocyteantigen
specificity
Light chain (
2
-microglobulin):
Invariant
Class II
Composed of HLA-DR, -DQ, and -DP
Restricted distribution
Autosomal codominant
Major rolein immuneresponse
induction
Serologic, molecular, and cellular
detection
Heterodimer noncovalentlylinked
Chain:
Nonvariablein HLA-DR
Containsvariableregionsin HLA-DQ
and -DP
Chain:
Containsvariableregions
Confersmost of HLA-DRspecificity
FIGURE 8-4
Human leukocyte antigens (HLAs) are heterodimeric cell-surface
glycoproteins. HLAs are divided into two classes, according to
their biochemical structure and respective functions. Class I antigens
(A, B, and C) have a molecular weight of approximately 56,000 D
and consist of two chains: a glycoprotein heavy chain () and a
light chain (
2
-microglobulin). The chain is attached to the cell
membrane, whereas
2
-microglobulin is associated with the
chain but is not covalently bonded. The HLA class I molecules are
found on almost all cells; however, only vestigial amounts remain
on mature erythrocytes. Class II antigens (HLA-DR, DQ, and DP)
have a molecular weight of approximately 63,000 D and consist of
two dissimilar glycoprotein chains, designated and , both of
which are attached to the membrane. Each chain consists of two
extramembranous amino acid domains, and the outer domains of
each molecule contain the variable regions corresponding to class II
alleles. Although class I antigens are expressed on all nucleated cells
of the body, the expression of class II antigens is more restricted. Class
II antigens are found on B lymphocytes, activated T lymphocytes,
monocyte-macrophages, dendritic cells, and early hematopoietic
cells, and of importance in transplantation, endothelial cells.
68
A
MHC
protein
T-cell
receptor
chain
chain Processed
antigen
FIGURE 8-5
Biology of the major histocompatibility complex (MHC). A, The
biologic function of MHC antigens is to present antigenic peptides
to T lymphocytes. In fact, it is an absolute requirement of T-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
domains of the MHC molecules are formed by the folding of por-
tions of their component chains in -pleated sheets and helices.
C, The sheet portions form a floor, and the helices form the sides
of a peptide-binding groove.
2m
3
B C
A
Peptide
2m
subunit Heavy
subunit
B
Peptide
subunit subunit
FIGURE 8-6
The structure of class I and II molecules.
Comparison of the crystalline structures of
classes I and II molecules has revealed overall
structural similarity, with a few significant
differences. A, Class I molecules have a
groove with deep anchor pockets at each
end (a pita pocket ). These pockets restrict
the binding of peptides to those of eight to
nine amino acid residues in length. B, The
peptide-binding groove of class II molecules
is more flexible and relatively open at one
end, more like a hotdog bun, permitting
larger peptides from 13 to 25 amino acid
residues in length to bind.
69
FIGURE 8-7
Allelic polymorphism. Allelic polymorphism
is a hallmark of the human leukocyte antigen
(HLA) system. The extreme polymorphism of
the HLA system is seen in the large numbers
of different alleles that exist for the multiple
major histocompatibility complex (MHC)
loci. At any given locus, one of several
alternative forms or alleles of a gene can
exist. Because so many alleles are possible
for each HLA locus, the system is extremely
polymorphic. The currently accepted World
Health Organization serologically defined
alleles are shown here. Established HLA
antigens are designated by a number following
the letter that denotes the HLA locus (eg,
HLA-A1 and HLA-B8). For example, by
serologic techniques, 28 distinct antigens
are recognized at the HLA-A locus, and
59 defined antigens at the HLA-B locus.
Sequencing studies of the HLA-DRB1 gene
have identified over 100 distinct alleles, and
preliminary analysis indicates that this level
of polymorphism will be as high for other
loci such as HLA-B. MHC polymorphism
ensures effective antigen presentation of
most pathogens; however, clinically, MHC
polymorphism complicates attempts to find
histocompatible donors for solid organ
transplantation.
HLA SPECIFICITIES
A
A1
A2
A203
A210
A3
A9
A10
A11
A19
A23(9)
A24(9)
A2403
A25(10)
A26(10)
A28
A29(19)
A30(19)
A31(19)
A32(19)
A33(19)
A34(10)
A36
A43
A66(10)
A68(28)
A69(28)
A74(19)
A80
B
B5
B7
B703
B8
B12
B13
B14
B15
B16
B17
B18
B21
B22
B27
B2708
B35
B37
B38(16)
B39(16)
B3901
B3902
B40
B4005
B41
B42
B44(12)
B45(12)
B46
B47
B48
B49(21)
B50(21)
B
B51(5)
B5102
B5103
B52(5)
B53
B54(22)
B55(22)
B56(22)
B57(17)
B58(17)
B59
B60(40)
B61(40)
B62(15)
B63(15)
B64(14)
B65(14)
B67
B70
B71(70)
B72(70)
B73
B75(15)
B76(15)
B77(15)
B7801
B81
Bw4
Bw6
C
Cw1
Cw2
Cw3
Cw4
Cw5
Cw6
Cw7
Cw8
Cw9(w3)
Cw10(w3)
DR
DR1
DR103
DR2
DR3
DR4
DR5
DR6
DR7
DR8
DR9
DR10
DR11(5)
DR12(5)
DR13(6)
DR14(6)
DR1403
DR1404
DR15(2)
DR16(2)
DR17(3)
DR18(3)
DR51
DR52
DR53
DQ
DQ1
DQ2
DQ3
DQ4
DQ5(1)
DQ6(1)
DQ7(3)
DQ8(3)
DQ9(3)
DP
DPw1
DPw2
DPw3
DPw4
DPw5
DPw6
Antigenslisted in parenthesesarethebroad antigens, antigensfollowed bybroad antigensin parentheses
aretheantigen splits.
70
Father Mother
a b c d
A1 A3 A2 A9
Cw7 Cw7 Cw7 Cw4
B8 B7 B12 B35
DR3 DR2 DR5 DR3
Children
a c a d
A1 A2 A1 A9
Cw7 Cw7 Cw7 Cw4
B8 B12 B8 B35
DR3 DR5 DR3 DR3
b c b d
A3 A2 A3 A9
Cw7 Cw7 Cw7 Cw4
B7 B12 B7 B35
DR2 DR5 DR2 DR3
Wash 3
Add AHG 2 min
Stage 1
Stage 2
Stage 3
Add rabbit serum
(complement)
30 min
RT
60 min
RT
Visualizemembraneinjury
(Eosin-y, AO/EB, etc.)
Incubatecells
and serum
FIGURE 8-8
Genetic principles of the major histocompatibility complex (MHC).
The MHC demonstrates a number of genetic principles. Each person
has two chromosomes and thus two MHC haplotypes, each inherited
from one parent. Because the human leukocyte antigen (HLA) genes
are autosomal and codominant, the phenotype represents the
combined expression of both haplotypes. Each child receives one
chromosome and hence one haplotype from each parent. Because
each parent has two different number 6 chromosomes, four different
combinations of haplotypes are possible in the offspring. This
inheritance pattern is an important factor in finding compatible
related donors for transplantation. Thus, an individual has a 25%
chance of having an HLA-identical or a completely dissimilar sibling
and a 50% chance of having a sibling matched for one haplotype.
The genes of the HLA region occasionally ( 1%) demonstrate
chromosomal crossover. These recombinations are then transmitted
as new haplotypes to the offspring.
FIGURE 8-9
Complement-dependent technique. The standard technique used to
detect human leukocyte antigen (HLA)-A, -B, -C, -DR, and -DQ anti-
gens has been the microlymphocytotoxicity test. This assay is a com-
plement-dependent cytotoxicity (CDC) in which lymphocytes are used
as targets because the HLA antigens are expressed to varying degrees
on lymphocytes and a relatively pure suspension of cells can be
obtained from anticoagulated peripheral blood. Lymphocytes obtained
from lymph nodes or the spleen also may be used. HLA antisera of
known specificity are placed in wells on a Terasaki microdroplet
tray. A concentrated suspension of lymphocytes is added to each
well. If the target lymphocytes possess the antigen corresponding to
the antibody present in the antiserum, the antibody will affix to the
cells. Rabbit complement is then added to the wells and, when suffi-
cient antibody is bound to the lymphocyte membranes, complement is
activated. Complement activation injures the cell membranes (lympho-
cytotoxicity) and increases their permeability. Cell injury is detected by
dye exclusion: cells with intact membranes (negative reactions)
exclude vital dyes; cells with permeable membranes (positive reac-
tions) take up the dye. Sensitivity of the CDC assay is increased by
wash techniques or the use of AHG reagents prior to the addition of
complement. Because HLA-DR and -DQ antigens are expressed on
B cells and not on resting T cells, typing for these antigens usually
requires that the initial lymphocyte preparation be manipulated before
testing to yield an enriched B-cell preparation. AHGantiglobulin-
augmented lymphocytotoxicity; RTroom temperature.
SCORING OF COMPLEMENT-DEPENDENT
CYTOTOXICITY REACTIONS
Assigned value
1
2
4
6
8
0
Dead cells, %
010
1120
2150
5180
80100
Unreadable
Interpretation
Negative
Borderlinenegative
Weak positive
Positive
Strongpositive
No cells, contamination, bubble
FIGURE 8-10
Scoring of complement-dependent cytotoxicity. In an effort to
standardize interpretation of complement-dependent cytotoxicity
(CDC) reactions, a uniform set of scoring criteria have been estab-
lished. When most of the cells are alive, visually refractile on
microscopic examination, a score of 1 is assigned. Conversely,
when most of the cells are dead, a score of 8 is assigned. This
method of interpretation for CDC reactions is universally used in
cross-match testing, antibody screening, and antigen phenotyping
for serologically defined HLA-A, -B, -C, -DR, and -DQ. (Adapted
fromGebel and Lebeck [1]; with permission.)
71
1
2
3
4
5
6
7
8
9
10
11
FIGURE 8-11
The United Network for Organ Sharing (UNOS) regions. UNOS is
a not-for-profit corporation within the United States organized
exclusively for charitable, educational, and scientific purposes
related to organ procurement and transplantation. Its formation
established a national Organ Procurement and Transplantation
Network with the mandate to improve the effectiveness of the
nations renal and extrarenal organ procurement, distribution, and
transplantation systems by increasing the availability of and access
to donor organs for patients with end-stage organ failure. Additionally,
the UNOS maintains quality assurance activities and systematically
gathers and analyzes data and regularly publishes the results of the
national experience in organ procurement and preservation, tissue
typing, and clinical organ transplantation. Functionally, the United
States is divided into UNOS regions as detailed on this map.
Additional geographic divisions (ie, local designation) defined by
the individual organ procurement organizations and the transplan-
tation centers they service comprise the working system for cadav-
eric renal allocation.
UNITED NETWORK FOR ORGAN SHARING: NUMBER OF PATIENT REGISTRATIONS
ON THE NATIONAL TRANSPLANT WAITING LIST AS OF OCTOBER 31, 1997
Kidney number
by blood type (%)
TypeO: 19,654(52.04)
TypeA: 10,612(28.10)
TypeB: 6579(17.42)
TypeAB: 923(2.44)
Total: 37,768
Kidney number
by race (%)
White: 18,353(48.59)
Black: 13,290(35.19)
Hispanic: 3441(9.11)
Asian: 2200(5.83)
Other: 484(1.28)
Total: 37,768
Kidney number
by gender (%)
Female: 16,269(43.08)
Male: 21,499(56.92)
Total: 37,768
Kidney number by
transplantation center region (%)
Region 1: 1738(4.60)
Region 2: 6060(16.05)
Region 3: 3844(10.18)
Region 4: 2191(5.80)
Region 5: 7361(19.49)
Region 6: 855(2.26)
Region 7: 3826(10.13)
Region 8: 1559(4.13)
Region 9: 3936(10.42)
Region 10:3121(8.26)
Region 11: 3277(8.68)
Total: 37,768
Kidney number
by age (%)
05: 76(0.20)
610: 119(0.32)
1117: 429(1.14)
1849: 21,102(55.87)
5064: 12,942(34.27)
65+: 3100(8.21)
Tota: 37,768
FIGURE 8-12
The United Network for Organ Sharing (UNOS) patient waiting
list. The UNOS patient waiting list is a computerized list of
patients waiting to be matched with specific donor organs in the
hope of receiving a transplantation. Patients on the waiting list
are registered on the UNOS computer by UNOS member trans-
plantation centers, programs, or organ procurement organiza-
tions. The UNOS Match System is an algorithm used to prioritize
pati ents wai ti ng for organs. The system el i mi nates potenti al
reci pi ents whose si ze or ABO type i s i ncompati bl e wi th that
of a donor and then ranks those remai ni ng potenti al reci pi ents
accordi ng to a UNOS board-approved system. As i ndi cated
here, nearl y 40,000 pati ents are awai ti ng ki dney transpl antati on
i n the Uni ted States. (Adapted fromthe Uni ted Network for
Organ Shari ng [2]).
72
FIGURE 8-13
Point system for kidney allocation. Kidneys
that cannot be allocated to a human leuko-
cyte antigen (HLA)matched patient are
distributed locally to candidates who are
ranked according to waiting time, with
additional points for degrees of HLA mis-
match and antibody sensitization. Pediatric
patients, medically urgent cases, and previous
donors (living related donors, and so on)
also are given a point advantage.
POINT SYSTEM FOR KIDNEY ALLOCATION
Timeof waiting
Thetimeof waitingbeginswhen apatient islisted and meetstheminimumestablished criteriaon theUnited
Network for Organ SharingPatient WaitingList. Onepoint will beassigned to thepatient waitingfor thelongest
period, with fractionsof pointsbeingassigned proportionatelyto all other patientsaccordingto their relative
timeof waiting.
Qualityof HLA mismatch
10pointsif thereareno A, B, or DR mismatches.
7pointsif thereareno Bor DR mismatches.
5pointsif thereisoneBor DRmismatch.
2pointsif thereisatotal of two mismatchesat theBand DR loci.
Panel reactiveantibody
Patientswill beassigned 4pointsif theyhaveapanel reactiveantibodylevel of 80%or more.
Medical urgency
No pointswill beassigned to patientsbased on medical urgencyfor regional or national allocation of kidneys.
Locally, thepatientsphysician hastheauthorityto usemedical judgment in assignment of pointsfor medical
urgency. When thereismorethan onelocal renal transplantation center, acooperativemedical decision is
required beforeassignment of pointsfor medical urgency.
Pediatric kidneytransplantation candidates
4pointsif thepatient isunder 11yearsof age.
3pointsif thepatient isover 11and under 18yearsof age.
CROSSMATCH METHODS
Lymphocytotoxicity:
Autocrossmatch v s allocrossmatch
T or Bcell
Short/long/wash/AHG methods
IgG v s IgM
Flow cytometry
Enzyme-linked immunosorbent assay
FIGURE 8-14
Crossmatch methods. Early reports correlating a positive crossmatch between recipient
serum and donor lymphocytes with hyperacute rejection of transplanted kidneys led to
establishing tests of recipient sera as the standard of practice in transplantation. However,
controversy remains regarding 1) the level of sensitivity needed for crossmatch testing;
2) the relevance of B-cell crossmatches, a surrogate for class II incompatibilities; 3) the
relevance of immunoglobulin class and subclass of donor-reactive antibodies; 4) the significance
of historical antibodies, ie, antibodies present previously but not at the time of transplantation;
5) the techniques and type of analyses to be performed for serum screening; and 6) the
appropriate frequency and timing of serum screening. Despite a number of variables, when
the data from reported studies are considered collectively, several observations can be
made. Human leukocyte antigendonor-specific antibodies present in the recipient at the
time of transplantation are a serious risk factor that significantly diminishes graft function
and graft survival. Antibodies specific for human leukocyte antigen class II antigens (HLA-DR
and -DQ) are as detrimental as are those specific for class I antigens (HLA-A, -B, and -C). The
degree of risk resulting from HLA-specific antibodies varies among immunoglobulin classes,
with immunoglobulin G antibodies representing the most serious risk. AHGantiglobulin-
augmented lymphocytotoxicity.
73
A
S
S
C
250
200
150
100
50
0
0 50 100 150 200 250
FSC
R1
Human IgG-Fc-FITC C
C
o
u
n
t
s
200
160
120
80
40
0
0 50 100 150 200 250
T cell
M1
D
100
90
80
70
60
50
40
30
0 6 12 0 6 12
Months after transplantation
Neg(n =508)
Pos(n =106)
Neg(n =75)
Pos(n =43)
First Regraft
B
C
D
3

P
E
250
200
150
100
50
0
0 50 100 150 200 250
FSC
R2
FIGURE 8-15
Techniques of crossmatch testing. Early crossmatch testing provided a means to prevent
most but not all hyperacute rejections. These early tests were performed with a technique
of rather low sensitivity. Subsequently, more sensitive techniques were employed in an
attempt to not only prevent all hyperacute rejections but also improve graft survival
rates. Techniques that have been used include variations of the lymphocytotoxicity test
that incorporate wash steps, change in incubation times or temperatures, or both, or add
an antiglobulin reagent. Flow cytometry and an array of other methods such as antibody-
ALTERNATIVE APPROACHES TO HLA MATCHING
CREG*
1C
2C
5C
7C
8C
12C
4C
6C
Associated human leukocyte
antigen gene products
A1,3,9,10,11,28,29,30,31,32,33
A2,9,28, B17
B5,15,17,18,35,53,70,49
B7,13,22,2740,41,47,48
B8,14,16,18
B12,13,21,40,41
A24,25,32,34, Bw4
Bw6, Cw1,3,7
Approximate
epitope frequency, %
80
66
59
64
37
44
85
87
C refersto major public epitopeor cross-reactivegroups(CREG).
FIGURE 8-16
Alternative approaches to human leukocyte antigen (HLA) matching.
Because completely mismatched kidney transplantations function
well over long periods, an alternative approach might begin with the
hypothesis that six-antigen mismatched transplantations were not
completely mismatched. Interest in reevaluating the potential roles
of cross-reactive groups (CREGs) in transplantation is one such
approach. In the early days of serologic HLA testing, a high panel
reactive antibody sera was considered to be composed of many anti-
HLA antibodies. It was later noted, however, that sera of highly sensi-
tized patients awaiting solid organ transplantation were generally com-
posed of a small number of antibodies directed at public antigens, also
called CREGs, rather than multiple antibodies, each reacting with a
specific conventional HLA antigen. Furthermore, the frequency of the
CREGs was much higher, eg, 35% to 88%, than that of even the most
common HLA-A and -B antigens. By inference, therefore, matching for
donor and recipient antigens included in the same CREG, ie, CREG
matching, could result in a higher number of matched transplantations
and a lower level of sensitization in patients having repeat grafts. In
addition, because of the inclusion of several private HLA-A and -B
antigens within a single CREG, a number of relatively rare antigens
can be matched more easily, offering the possibility of improved graft
survival for a greater number of both white and nonwhite patients.
(Adapted fromThelan and Rodey [4]; with permission.)
dependent cellular cytotoxicity also have
been tried. Two of the most sensitive tech-
niques are the antiglobulin-augmented lym-
phocytotoxicity (AHG) and flow cytomet-
ric crossmatching. A, The use of flow
cytometry to define the lymphocyte popu-
lation by light scatter parameters, followed
by a specific marker for T lymphocytes,
ie, CD3 (B) allows this technique to be
highly specific for human leukocyte antigen
(HLA) class Ipositive cells. The donor
lymphocytes have been preincubated with
recipient serum, washed, and subsequently
stained with AHG-Fluorescsin isothio-
cyanate (FITC), a fluorochrome-labeled
antihuman globulin. C, Results of flow
cytometric cross-matching are evaluated as
shifts in the fluorescence from negative sera
and are interpreted as positive or negative
based on independently defined cutoffs
above the negative. D, Multiple studies in
renal transplantation have shown correla-
tions between positive AHG or flow cyto-
metric cross-matches and decreased graft
survival at 1 year or more. The largest
differences are seen when patients are
grouped as primary grafts versus repeat
grafts. In some instances the effect of using
a more sensitive cross-match technique
only can be seen in patients having repeat
grafts or those with a higher immunologic
risk. CD3 PEmonoclonal antibody to
CD3 fluorescent labelled with phycoery-
thrin; FCconstant fragment of IgG mole-
cule; FITCfluorescent labelled with fluo-
rescein isothiocynate; FSCforward scat-
ter; R1region 1; R2region 2; SSCside
scatter. (Panel D adapted fromCook [3];
with permission.)
74
A
100
80
60
40
30
20
10
0 1 2 3 4 5 6 7 8 9 10
Years after transplantation
G
r
a
f
t

s
u
r
v
i
v
a
l

(
l
o
g
)
,

%
White
1st cadaver
UNOS(19911996)
ABDR
MM
0
1
2
3
4
5
6
n
3023
1305
3736
6312
6414
3641
1209
T 1 2
14
12
12
12
11
11
10
B
100
80
60
40
30
20
10
Black
1st cadaver
UNOS(19911996)
0 1 2 3 4 5 6 7 8 9 10
G
r
a
f
t

s
u
r
v
i
v
a
l

(
l
o
g
)
,

%
ABDR
MM
0
1
2
3
4
5
6
n
301
255
970
2459
3251
2078
739
T 1 2
7
7
6
6
6
6
6
FIGURE 8-17
The role of human leukocyte antigen (HLA) matching in the United
States in whites (A) and blacks (B). Recent large registry analyses
of the role for HLA matching in renal transplantation consistently
have shown a stepwise decrease in long-term graft survival rates
with increasing antigen mismatches. Based on these results the United
Network of Organ Sharing (UNOS) incorporated the level of HLA
match into its algorithm used nationally for kidney allocation. The
UNOS initially determined that transplantations for which all six
HLA-A, -B, and -DR antigens matched in the donor and recipient
should be performed. Each cadaveric donor type was compared by a
computer search with the HLA types of all patients awaiting kidney
transplantation. When a patient with six antigen matches was
identified in an ABO-compatible recipient, the kidney was offered
for that patient, and if accepted by the transplantation center, was
shipped for transplantation. (Normally, kidneys from a patient
with blood type O are allocated only to patients with type O blood,
except in the case of patients with six antigen matches.) The UNOS
policy regarding mandatory sharing of HLA-matched kidneys has
been liberalized twice. The first time was in 1990 to include pheno-
typically matched pairs with fewer than six antigens. The policy
was changed for a second time in 1995 to include zero-mismatched
pairs in which the donor could have fewer antigens than the recipient,
provided none were mismatched. (Adapted fromCecka [5]; with
permission.)
HLA-DR13
HLA-DR14
*1301*1312 *1314*1330
*1401, *1402, *1405*1429
HLA-DR6
DR1403
DR1404
Serology
(antibody defined)
Molecular
(Low Intermediate High resolution)
versus
FIGURE 8-18
Serologic testing and antigen assignment. Most of the published
transplantation outcome data is based on serologic testing and
assignment of antigens. These data include algorithm matching
based on broad human leukocyte antigen (HLA) specificities
such as HLA-DR6 that includes HLA-DR13 and HLA-DR14 and
their many alleles. The question has now become one of what level
of HLA testing is useful clinically for matching purposes in renal
transplantation. Although this issue has not been resolved, recent
data published from the European Registry upholds the positive
effect that correct HLA matching has had on renal graft outcome.
75
A
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
100
90
80
70
60
50
40
0 3 6 9 12
Time, m o
DNA: DR0mm
(n =64)
DNA: DR>0mm
(n =22)
B
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
100
90
80
70
60
50
0
0 3 6 9 12
Time, m o
DNA: A+B0mm
(n =183)
DNA: A+B>0mm
(n =32)
FIGURE 8-19
Classes II and I mismatches in supposed 0 mm shared renal transplantations. The effect on
graft survival of shared human leukocyte antigen (HLA) 0mm organs when defined by sero-
logic typing and then confirmed by molecular typing. A strong effect of HLA matching is
seen at even 1 year on the graft survival. A, Eighty-six first cadaveric kidney transplantations
that were reported by serologic typing as HLA-A, -B, -DR identical-compatible were tested
by molecular methods. Sixty-four transplantations were confirmed to be HLA-DR compati-
ble; however, mismatches were found in the remaining 22 transplantations. Transplantations
in which HLA compatibility was confirmed had a functional success rate of 90% at 1 year
compared with 68% for transplantations in which the DNA typing revealed HLA-DR mis-
matches (P < 0.02). B, An analysis of the influence of HLA-class I DNA typing on kidney
graft survival is shown. A total of 183 cadaveric transplantations were confirmed to be
HLA-A and B compatible after DNA typing, whereas mismatches were found in the remain-
ing 32 cases. Transplantations in which compatibility was confirmed had a functional success
rate of 86.9% at 1 year compared with a 71.9% rate for those in which DNA typing
revealed HLA-A or -B mismatches (P = 0.033.) (Panel A adapted fromOpelz and coworkers
[6]; panel B adapted fromMytilineous and coworkers [7]; with permission.)
A
100
80
90
70
50
0
60
40
30
20
10
0 1 2 3 4 5 6 7 8
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
88
89
90
91
n
1809
1895
2086
2385
t 1 2
12.5
14.3
14.9
14.6
Livingdonor
92
93
94
95
n
2527
2828
2914
3117
t 1 2
17.0
16.3
17.5
8.8
B
50
0
60
40
30
20
10
Parent Offspring Sibling Other
relative
Spouse/other
unrelated
%
1988
1996
FIGURE 8-20
Living donor kidney transplantation graft survival rates (A) and
donor sources (B). The high graft survival rates reported for
recipients of living donor kidneys improved from 89% in 1988
to 93% in 1991 (P < 0.001), even though a substantial increase
has occurred in both the number of living donors and centers
performing these transplantations. Some of the increase in living
donations has been due to a growing acceptance of so-called
unconventional donors, ie, spouses and other genetically
unrelated donors, as well as distant relatives and half-siblings.
In 19881989, unrelated donors accounted for 4% of living
donor transplantations and distant relatives for 2%. These
numbers have tripled and are now at 12% and 6%, respectively.
(Panel A fromCecka [8]; panel B adapted fromthe United
Network for Organ Sharing [9]; with permission.)
76
References
1. Gebel HM, Lebeck LK: Crossmatch procedures used in organ
transplantation. Clin Lab Med 1991, 11:609.
2. United Network for Organ Sharing: UNOS Bulletin 1997, 2.
3. Cook DJ, et al.: An approach to reducing early kidney transplant
failure by flow cytometry crossmatching. Clin Transpl 1987, 1:25.
4. Thelan D, Rodey G: American Society of Histocompatibility and
I mmunogenetics Laboratory Manual, edn 3. Lenexa, KS: ASHI.
5. Cecka JM: The role of HLA in renal transplantation. Human
I mmunology 1997, 56:616.
6. Opelz et al.: Transplantation 1998, 55:782785.
7. Mytilenous et al.: Tissue Antigens 1997, 50:355358.
8. Cecka JM: UNOS Scientific Renal Transplant Registry. In Clinical
Transplant Registry. Edited by Cecka JM, Terasaki P. Los Angeles:
UCLA; 1996:114.
9. United Network for Organ Sharing: UNOS Bulletin 1997, 2.
77
9
Transplant Rejection
and Its Treatment
R
ejection is the major cause of graft failure, and if the injury to
the tubules and glomeruli is severe, the kidney may not recover.
It is therefore important to diagnose acute rejection as soon as
possible to institute prompt antirejection therapy. Generally, the success
with which rejection can be reversed by immunosuppressive agents
determines the chance of long-term success of the transplant [1,2].
La ur ence Cha n
CHA P T ER
78
Mechanisms of Renal Allograft Rejection
Graft
destruction
Allograft
APC
CD8
T cells
CD8
T cells
CD4
T cells
CD4
T cells
Clonal
expansion
Bcells
NK cells
Cytokines
IL-2
IFN-
etc.
IL-1
HLA-
classI
HLA-
classI
HLA-
classI
HLA-
classII
HLA-
classII
HLA-
classII
CD3
CD3
CD3
CD58
CD58
CD3
CD2
CD2
CD2
CD4
CD4
CD2
CD8
CD8
TCR
TCR
TCR
TCR
IL-2R
IL-2R
Immune response cascade
A
FIGURE 9-1
Aspects of the rejection response. A, The immune response
cascade. Rejection is a complex and redundant response to grafted
tissue. The major targets of this response are the major histo-
compatibility complex (MHC) antigens, which are designated as
human leukocyte antigens (HLAs) in humans. The HLA region on
the short arm of chromosome 6 encompasses more than 3 million
nucleotide base pairs. It encodes two structurally distinct classes
of cell-surface molecules, termed class I (HLA-A, -B, and -C) and
class II (-DR, -DQ, -DP).
B, Overview of rejection events. T cells recognize foreign antigens
only when the antigen or an immunogenic peptide is associated
with a self-HLA molecule on the surface of an accessory cell called
the antigen-presenting cell (APC). Helper T cells (CD4) are activated
to proliferate, differentiate, and secrete a variety of cytokines. These
cytokines increase expression of HLA class II antigens on engrafted
tissues, stimulate B lymphocytes to produce antibodies against the
allograft, and help cytotoxic T cells, macrophages, and natural killer
cells develop cytotoxicity against the graft.
C, Possible mechanisms for allorecognition by host T cells. In the
direct pathway, T cells recognize intact allo-MHC on the surface of
donor cells. The T-cell response that results in early acute cellular
rejection is caused mainly by direct allorecognition. In the indirect
pathway, T cells recognize processed alloantigens in the context of
self-APCs. Indirect presentation may be important in maintaining
and amplifying the rejection response, especially in chronic rejection.
IFN-interferon gamma; IL-1interleukin-1; IL-2Rinter-
leukin-2 receptor; NKnatural killer. (Panel A adapted from[3];
with permission; panel C adapted from[4]; with permission.)
Allogeneic
cell
Shed
allogeneic
MHC
Taken up and
processed by host
antigen-presentingcell
CD8+
cytotoxic cell
CD8+
cytoxic cell Th cell Th cell
Responder antigen-presentingcell
Peptidederived from
allogeneic MHC presented
on host MHC
Allogeneic (stimulator)
antigen presentingcell
ClassI stimulator
ClassII haplotype
ClassIII responder
haplotype
2
microglobulin
IL-2 IL-2
(ClassIderived peptide
presented byresponder
classII molecule)
Indirect allorecognition Direct allorecognition
II
I
I
II
C
B. OVERVIEW OF REJECTION EVENTS
Antigen-presentingcellstrigger CD4and CD8T cells
Both alocal and systemic immuneresponsedevelop
Cytokinesrecruit and activatenonspecific cellsand accumulatein graft, which facilitates
thefollowingevents:
Development of specific T cells, natural killer cells, or macrophage-mediated cytotoxicity
Allograft destruction
79
9.3 Transplant Rejection and its Treatment
Classification of Rejection
A. VARIETIES OF REJECTION
Types of rejection
Hyperacute
Accelerated
Acute
Chronic
B. IMMUNE MECHANISMS OF
RENAL ALLOGRAFT REJECTION
Type
Hyperacute
Accelerated
Acute
Cellular
Vascular
Chronic
Humoral
+++
++
+
+++
++
Cellular
-
+
+++
+
+?
Time taken
Minutesto hours
Days
Daysto weeks
Monthsto years
Cause
Preformed antidonor antibodiesand
complement
Reactivation of sensitized T cells
Primaryactivation of T cells
Both immunologic and nonimmunologic
factors
FIGURE 9-2
Varieties of rejection (panel A) and immune mechanisms (panel B).
On the basis of the pathologic process and the kinetics of the rejection
response, rejection of renal allografts can be commonly divided
into hyperacute, accelerated, acute, and chronic types.
A B
FIGURE 9-3 (S e e Color Plate)
Histologic features of hyperacute rejection. Hyperacute rejection is
very rare and is caused by antibody-mediated damage to the graft.
The clinical manifestation of hyperacute rejection is a failure of the
kidney to perfuse properly on release of the vascular clamps just
after vascular anastomosis is completed. The kidney initially becomes
firm and then rapidly turns blue, spotted, and flabby. The presence
of neutrophils in the glomeruli and peritubular capillaries in the kidney
biopsy confirms the diagnosis. A, Hematoxylin and eosin stain of
biopsy showing interstitial hemorrhage and extensive coagulative
necrosis of tubules and glomeruli, with scattered interstitial inflam-
matory cells and neutrophils. B, Immunofluorescence stain of kidney
with hyperacute rejection showing positive staining of fibrins.
80
A B
FIGURE 9-4
Histologic features of acute accelerated rejection. A and B, Photo-
micrographs showing histologic features of acute accelerated vascular
rejection. Glomerular and vascular endothelial infiltrates and swelling
are visible. An accelerated rejection, which may start on the second
or third day, tends to occur in the previously sensitized patient in
whom preformed anti-HLA antibodies are present. This type of
rejection occurs in patients who have had a previous graft and presents
with a decrease in renal function; the clinical picture is similar to
that for hyperacute rejection.
A B
FIGURE 9-5
Histologic features of acute cellular rejection. A, Mild tubulitis.
B, Moderate to severe tubulitis. Acute rejection episodes may occur
as early as 5 to 7 days, but are generally seen between 1 and 4
weeks after transplantation. The classic acute rejection episode of
the earlier era (ie, azathioprine-prednisolone) was accompanied by
swelling and tenderness of the kidney and the onset of oliguria
with an associated rise in serum creatinine; these symptoms were
usually accompanied by a significant fever. However, in patients
who have been treated with cyclosporine, the clinical features of an
acute rejection are really quite minimal in that there is perhaps
some swelling of the kidney, usually no tenderness, and there may
be a minimal to moderate degree of fever. Because such an acute
rejection may occur at a time when there is a distinct possibility of
acute cyclosporine toxicity, the differentiation between the two
entities may be extremely difficult.
The differential diagnosis of acute rejection, acute tubular necrosis,
and cyclosporine nephrotoxicity may be difficult, especially in the
early posttransplant period when more than one cause of dysfunction
can occur together [2]. Knowledge of the natural history of several
clinical entities is extremely helpful in limiting the differential diag-
nosis. Reversible medical and mechanical causes should be excluded
first. Percutaneous biopsy of the renal allograft using real-time ultra-
sound guide is a safe procedure. It provides histologic confirmation
of the diagnosis of rejection, aids in the differential diagnosis of
graft dysfunction, and allows for assessment of the likelihood of a
response to antirejection treatment.
81
Acute rejection
Antibody deposition
Oxidized LDL
Infection
T cells
Macrophages
Platelet aggregates
Cytokines/
growth factors
Cell proliferation
Fibrosis
Reduced nephron
mass
Graft loss
Vascular injury
Arteriosclerosis
Tubulointerstitial
injury
Glomerular sclerosis
Hypothetical schema for
chronic rejection
D
C. CHRONIC ALLOGRAFT
REJECTION
Typical clinical presentation
Gradual increasein creatinine(months)
Non-nephroticrangeproteinuria
No recent nephrotoxic events
Keypathologic features
Interstitial fibrosis
Arterial fibrosisand intimal thickening
FIGURE 9-6
Features of chronic rejection. A, Arterial
fibrosis and intimal thickening. B. Interstitial
fibrosis and tubular atrophy. C, Typical
presentation and pathologic features. Chronic
rejection occurs during a span of months
to years. It appears to be unresponsive to
current treatment and has emerged as the
major problem facing transplantation [5].
Because chronic rejection is thought to be the
end result of uncontrolled repetitive acute
rejection episodes or a slowly progressive
inflammatory process, its onset may be as
early as the first few weeks after transplan-
tation or any time thereafter.
D, The likely sequence of events in chronic
rejection and potential mediating factors for
key steps. Progressive azotemia, proteinuria,
and hypertension are the clinical hallmarks
of chronic rejection. Immunologic and
nonimmunologic mechanisms are thought
to play a role in the pathogenesis of this
entity. Immunologic mechanisms include
antibody-mediated tissue destruction that
occurs possibly secondary to antibody-
dependent cellular cytotoxicity leading to
obliterative arteritis, growth factors derived
from macrophages and platelets leading to
fibrotic degeneration, and glomerular hyper-
tension with hyperfiltration injury due to
reduced nephron mass leading to progressive
glomerular sclerosis. Nonimmunologic causes
can also contribute to the decline in renal
function. Atheromatous renovascular disease
of the transplant kidney may also be
responsible for a significant number of
cases of progressive graft failure.
A B
82
BANFF CLASSIFICATION OF RENAL
ALLOGRAFT REJECTION
Normal
Patchymononuclear cell infiltrateswithout tubulitisisnot uncommon
Borderlinechanges
No intimal arteritis; mild tubulitisand endocapillaryglomerulitis
Acuterejection
GradeI: tubulitis++
GradeII: tubulitiswith glomerulitis
GradeIII: intimal arteritis, interstitial hemorrhage, fibrinoid, thrombosis
FIGURE 9-7
The Banff classification of renal allograft rejection. This schema is
an internationally agreed on standardized classification of renal
allograft pathology that regards intimal arteritis and tubulitis as
the main lesions indicative of acute rejection [6].
E
Check CsA level
High Low
Lower CsA dose
and repeat creatinine
Improved No improvement
Ultrasound
Obstruction No obstruction
Biopsy
ATN Rejection Glomerulonephritis
Recurrent GN
denovo GN
Acute
Acute
on chronic
Chronic
Adjust immunosuppressant
Steroid bolus
OKT3 or ATG
Temporizingmeasures
Control BP
Avoid nephrotoxins
Slowly risingcreatinine
Diagnostic and therapeutic approach to chronic rejection
E, Diagnostic and therapeutic approach to chronic rejection.
ATGantithymocyte globulin; ATNacute tubular necrosis; BP
blood pressure; CsAcyclosporine; LDLlow-density lipoprotein.
83
Constant (but not excessive) suction
25-G needle
Transplanted kidney
Wound
Inguinal ligament
New techniques
FIGURE 9-8
Fine-needle aspiration cytology technique for the transplanted kidney.
A 23- or 25-gauge spinal needle is used under aseptic conditions. A
20-mL syringe containing 5 mL of RPMI-1640 tissue culture medium
is connected to the needle. Ultrasound guidance may be used on
the rare occasions when the graft is not easily palpable [8].
Monitoring of other products of inflammation such as neopterin
and lymphokines continues to be explored. It has been shown that
acute rejection is associated with elevated plasma interleukin (IL)-1
in azathioprine-treated patients and IL-2 in cyclosporine-treated
patients. IL-6 is also increased in the serum and urine immediately
after transplantation and during acute rejection episodes. The major
problem, however, is that infection, particularly viral, can also elevate
cytokine levels. Recently, polymerase chain reaction (PCR) has also
been used to detect mRNA for IL-2 in fine-needle aspirate of human
transplant kidney [7,8]. Using the PCR approach, IL-2 could be
detected 2 days before rejection was apparent by histologic or clinical
criteria. Reverse transcriptasePCR has also been used to identify
intrarenal expression of cytotoxic molecules (granzyme B and perforin)
and immunoregulatory cytokines (IL-2, -4, -10, interferon gamma,
and transforming growth factor-
1
) in human renal allograft biopsy
specimens [9]. Molecular analyses revealed that intragraft display
of mRNA encoding granzyme B, IL-10, or IL-2 correlates with
acute rejection, and intrarenal expression of transforming growth
factor (TGF)-
1
mRNA is associated with chronic rejection. These
data suggest that therapeutic strategies directed at the molecular
correlates of rejection might refine existing antirejection regimens.
Treatment
IMMUNOSUPPRESSION
PROTOCOLS
Induction protocols
Maintenanceprotocols
Earlyposttransplantation
Lateposttransplantation
Antirejection therapy
FIGURE 9-9
Immunosuppressive therapy protocols. Standard immunosuppressive therapy in renal
transplant recipient consists of 1) baseline therapy to prevent rejection, and 2) short courses of
antirejection therapy using high-dose methylprednisolone, monoclonal antibodies or poly-
clonal antisera such as antilymphocyte globulin (ALG) and antithymocyte globulin (ATG).
Antilymphocyte globulin is prepared by immunizing rabbits or horses with human lymphoid
cells derived from the thymus or cultured B-cell lines. Disadvantages of using polyclonal
ALS include lot-to-lot variability, cumbersome production and purification, nonselective
targeting of all lymphocytes, and the need to administer the medication via central venous
access. Despite these limitations, ALG has been used both for prophylaxis against and for
the primary treatment of acute rejection. A typical recommended dose for acute rejection
is 10 to 15 mg/kg daily for 7 to 10 days. The reversal rate has been between 75% and
100% in different series. In contrast to murine monoclonal antibodies (eg, OKT3), ALS
does not generally induce a host antibody response to the rabbit or horse serum. As a
result, there is a greater opportunity for successful readministration.
84
CD4
CD8
CD4
CD4
CD8
CD8
CD8
CD4
ATG
OKT3
ATG
OKT3
ATG
OKT3
ATG
OKT3
ATG
OKT3
ATG
OKT3
ATG
OKT3
ATG
OKT3
Class I
HLA antigen
Pro
liferatio
n
Pro
liferatio
n
Macrophage
Steroids
Steroids
CsA
FK506
RPM
MPA
AZA
MPA
MPA
AZA
Class II
HLA antigen
IL-2
Blymphocyte
Postantigenic
differentiation
IL-1
TNF-
A
n
tib
o
d
y
IL-1
Allogeneic
cell
C
y
t
o
k
i
n
e
s
Stimulated
macrophage
IL-2
-Interferon
A
FIGURE 9-11
Mechanism of action of immunusuppressive drugs. A, The sites of
action of the commonly used immunosuppressive drugs. Immuno-
suppressive drugs interfere with allograft rejection at various sites
in the rejection pathways. Glucocorticoids block the release of
FIGURE 9-10
Induction (panel A) and maintenance (panel B) immunosuppression protocols. These
immunosuppressive protocols differ from center to center. There are numerous variations,
but the essential features are 1) the prednisone dosage is high initially and then reduced to
a maintenance dose of 10 to 15 mg/d over 6 to 9 months, and 2) the cyclosporine dosage is
8 to 12 mg/kg/d given as a single or twice daily dose, and dosage is adjusted according to
trough plasma and serum blood levels. To maintain immunosuppression provided by
cyclosporine and to reduce the incidence of cyclosporine side effects, azathioprine or
mycophenolate has also been used with lower dosages of cyclosporine. The results of this
triple therapy are excellent, with first-year graft survival greater than 85% reported in most
instances and with a substantial number of patients having no rejection at all. Although
this type of regimen was the most common, there have been a number of exceptions [2,10].
Recently, mycophenolate mofetil has been approved by the US Food and Drug
Administration for prophylaxis of renal transplant rejection [11]. This agent was devel-
oped as a replacement to azathioprine for maintenance immunosuppression. FK506 is a
new immunosuppressive agent that has been approved by the FDA. FK506 is similar to
cyclosporine in its mode of action, efficacy, and toxicity profile. The drug has been used in
kidney transplantation. FK506 may be beneficial in renal transplantation as rescue therapy
in patients taking cyclosporine who have recurrent or resistant rejection episodes [1214].
A. INDUCTION PROTOCOLS
Standard induction
Corticosteroids
Azathioprineor mycophenolate
Cyclosporineor FK506
Antibodyinduction
OKT3or antithymocytegammaglobulin
B. MAINTENANCE
IMMUNOSUPPRESSION
Cyclosporineor FK506
Mycophenolate
Prednisolone
interleukin (IL)-1 by macrophages, cyclosporine (CsA) and FK506
interfere with IL-2 production from activated helper T cells, and
azathioprine (AZA) and mycophenolate mofetil (MPA) prevent
proliferation of cytotoxic and helper T cells.
85
Cyclosporin A
FK506
Rapamycin
TCR
TCR
Cell differentiation
Cell proliferation
T lymphocyte
TCR
signal
TCR
signal
Nucleus
IL-2R
IL-2R
Il-2
IL-2R
TCRsignal
LKRsignal
TCR
TCR
LKR
signal
LKR
signal
Nucleus
Nucleus
Nucleus
B
A. ANTIREJECTION THERAPY REGIMENS
Intravenousmethylprednisolone, 0.5or 1gx 3d
OKT3
Antithymocytegammaglobulin
Rabbit antithymocyteglobulin
Humanized anti-CD25(IL-2receptor) intravenouslyevery2wk
AntiICAM-1and antiLFA-1antibodies
Acute rejection
Mild Severe
Steroid bolus
Resolves Risingcreatinine
OKT3 or polyplonal
antibodies x 10 d
Resolves
Persistent acuterejection
on repeat biopsy
EvaluateOKT3
antibody titer
High Low
ATG or OKT3 ATG
Treatment algorithm for acute rejection
B
FIGURE 9-12
Treatment of acute rejection. A, Typical antirejection therapy regimens.
B, Treatment algorithm. A biopsy should be performed whenever
possible. The first-line treatment for acute rejection in most centers
is pulse methylprednisolone, 500 to 1000 mg, given intravenously
daily for 3 to 5 days. The expected reversal rate for the first episode
of acute cellular rejection is 60% to 70% with this regimen [1517].
Steroid-resistant rejection is defined as a lack of improvement in
urine output or the plasma creatinine concentration within 3 to 4
days. In this setting, OKT3 or polyclonal antiT-cell antibodies
should be considered [18]. The use of these potent therapies should
be confined to acute rejections with acute components that are
potentially reversible, eg, mononuclear interstitial cell infiltrate with
tubulitis or endovasculitis with acute inflammatory endothelial infiltrate
[19,21]. ATGantithymocyte globulin; ICAM-1intercellular
adhesion molecule-1; LFA-1leukocyte function-associated antigen-1.
B, Mechanism of action of CsA, FK506, and rapamycin (RPM).
CsA and FK506 block the transduction of the signal from the T-
cell receptor (TCR) after it has recognized antigen, which leads
to the production of lymphokines such as IL-2, whereas RPM
blocks the lymphokine receptor signal, eg, IL-2 plus IL-2 receptor
(IL-2R), which leads to cell proliferation.
The addition of a prophylactic course of antithymocyte globu-
lin (ATG) or OKT3 with delay of the administration of CsA or
FK506 during the initial postoperative periods has been advocat-
ed by some groups. OKT3 prophylaxis was associated with a
lower rate of early acute rejection and fewer rejection episodes
per patient. Prophylactic use of these agents appears to be most
effective in high-risk cadaver transplant recipients, including
those who are sensitized or who have two HLA-DR mismatches
or a prolonged cold ischemia time [2,10]. IFN-interferon
gamma; TNF-tumor necrosis factor-.
86
Spleen
Thymus
Lymph nodes
Washed white cells
Subcutaneous injection
Horse serum Vial
Intravenous infusion
Globulin
extracted
FIGURE 9-14
The making of a polyclonal antilymphocyte preparation.
Antilymphocyte globulin (ALG) or antithymocyte globulin (ATG) are
polyclonal antisera derived from immunization of lymphocytes, lym-
phoblasts, or thymocytes into rabbits, goats, or horses. These agents
have been used prophylactically as induction therapy during the early
posttransplantation period and for treatment of acute rejection. Most
centers reduce concomitant immunosuppression (eg, stop cyclosporine
and lower azathioprine dose) to decrease infectious complications.
Antithymocyte gamma globulin (ATGAM) is the only FDA-approved
polyclonal preparation. Two rabbit immunoglobulin preparations,
raised by immunization with thymocytes or with a human lympho-
blastoid line, are scheduled for phase III multicenter testing versus
ATGAM or OKT3, respectively. Potential side effects include fever,
chills, erythema, thrombocytopenia, local phlebitis, serum sickness,
and anaphylaxis. The potential for development of host anti-ALG
antibodies has not been a significant problem because of the use of
less immunogenic preparations and probably because ALG suppresses
the immune response to the foreign protein itself [2,10].
A. MAJOR SIDE EFFECTS OF IMMUNOSUPPRESSIVE AGENTS
Nephrotoxicity
Neurotoxicity
Hirsutism
Gingival hypertrophy
?????
Hypertension
Cyclosporine
+++
+
+++
++
0
+++
FK506
++
++
0
0
+
+
Infection
Marrow suppression
Hepatic dysfunction
Megaloblastic anemia
Hair loss
?Neoplastic
Azathioprine
++
++
+
++
+
+?
Mycophenolate
mofetil
+
+
0
0
?
B
FIGURE 9-13
Side effects of immunosuppressive agents. A, The major side effects of several immuno-
suppressive agents. The major complication of pulse steroids is increased susceptibility
to i nfecti on. Other potenti al probl ems i ncl ude acute hypergl ycemi a, hypertensi on,
peptic ulcer disease, and psychiatric disturbances including euphoria and depression.
B, Vasoconstriction of the afferent arteriole (AA) caused by cyclosporine. (FromEnglish
et al. [22]; with permission.)
87
Fusewith
polyethylene glycol
Spleen cells Myelomacells
Assay hybrid cells
Select desired hybrids
Propagate desired clones
Freeze
Thaw
Antibody Antibody
Grow in
mass culture
Producein
animals
FIGURE 9-15
The making of a monoclonal antibody.
OKT3 is a mouse monoclonal antibody
directed against the CD3 molecule of the
T lymphocyte. OKT3 has been used either
from the time of transplantation to prevent
rejection or to treat an acute rejection episode.
It has been shown in a randomized clinical
trial to reverse 95% of primary rejection
episodes compared with 75% with high-dose
steroids in patients who received azathioprine-
prednisone immunosuppression. In patients
receiving triple therapy (cyclosporine-
azathioprine-prednisone), 82% of primary
rejection episodes were successfully reversed
by OKT3 versus 63% with high-dose
steroids. Like antilymphocyte globulin
(ALG), reduction of concomitant immuno-
suppression (discontinuation of cyclosporine
and reduction of azathioprine or mycophe-
nolate mofetil dose) decreases the incidence
of infectious complications. Side effects
include fever, rigors, diarrhea, myalgia,
arthralgia, aseptic meningitis, dyspnea, and
wheezing, but these rarely persist beyond
the second day of therapy.
Release of tumor necrosis factor (TNF),
interleukin-2, and interferon gamma in serum
are found after OKT3 injection. The acute
pulmonary compromise due to a capillary
leak syndrome rarely has been seen because
patients are brought to within 3% of dry
weight before initiation of OKT3 treatment.
Infectious complications, particularly infection
with cytomegalovirus, are increased after
multiple courses of OKT3.
A. RECOMMENDED PROTOCOL FOR OKT3 TREATMENT
Evaluation and treatment beforeadministration
Laboratorytestsincludingcompleteblood count
Monitor intakeand output; record weight changes
Chest radiograph
Hemodialysisor ultrafiltration for volumeoverload
Premedication on day0and 1
Methylprednisolone, 250500mgIV given 1h prior to dose
Methylprednisoloneor hydrocortisonesodiumsuccinate, 250500mgIV given
30min after thedose
Diphenhydramine, 50mgIV 30min prior to dosedaily
Acetaminophen, 650mgPO 30min prior to dose
Discontinuecyclosporine, maintain azathioprineat 25mg/d
Administer OKT3, 5mg/d IV, days013
Monitor clinical course
Check CD3level on day3
IncreaseOKT3dosageto 10mg/d if either:
Anti-OKT3antibodyishigh
OKT3level islow
CD3level isnot low
FIGURE 9-16
Treatment with OKT3. A, Recommended protocol for OKT3 treat-
ment. The development of host anti-OKT3 antibodies is a potential
problem for the reuse of this drug in previously treated patients.
About 33% to 100% of patients develop antimouse antibodies
after the first exposure to OKT3, depending on concomitant
immunosuppression. Anti-OKT3 titers of 1:10,000 or more usually
correlate with lack of clinical response. If anti-OKT3 antibodies are
of low titer, retreatment with OKT3 is almost always successful. If
retreatment is attempted with antimouse titers of 1:100 or more, then
certain laboratory parameters, including the peripheral lymphocyte
count, CD3 T cells, and trough free circulating OKT3 should be
monitored. If the absolute CD3 T-lymphocyte count is greater than
10 per microliter or free circulating trough OKT3 level is not
detected, it may be indicative of an inadequate dose of OKT3. The
dose of OKT3 can be increased from 5 to 10 mg/d [21].
88
0
0
80
70
60
50
40
30
20
10
22 16 13 9 5 2 1
%
C
D
+
c
e
l
l
s
OKT3treatment
CD3
CD4
CD8
Hours Days
AntiOKT3antibodies
B
B, Monitoring of peripheral blood T cells in a patient receiving
OKT3 treatment. The absence of CD3+ cells from the circulation
is the best parameter for monitoring the effectiveness of OKT3.
Failure of the CD-positive percentage to fall or a fall followed by
a rapid rise indicates the appearance of blocking antibodies.
Approximately 50% to 60% of patients who receive OKT3 will
produce human antimouse antibodies (HAMA), generally in low
titers (< 1:100). Low antibody titers do not affect the response to
retreatment (reversal rate almost 100%) if the rejection episode
occurs within 90 days after transplantation. Conversely, titers
above 1:100 or recurrent rejection beyond 90 days is associated
with a reversal rate of less than 25%. The reversal rate is essentially
zero when both high HAMA titers and late rejection are present.
POorally; IVintravenous.
Mouseantibody
Chimeric antibody
IgG4 nondepleting IgG1 depleting
Reshaped
antibody
Mousedeterminants
Human determinants }
A
TCR/CD3
Signal 1
MHC/Ag
CD28
B7-1
B7-2
APC T-cell
Signal 1 without signal 2
results in:
T-cell anergy
Th2>Th1
Apoptosis
X
Signal 2
CTLA41g
CTLA4
B
FIGURE 9-17
New immunosuppressive agents. New agents such as mycophenolate
mofetil, FK506, and rapamycin are currently under evaluation for
refractory acute rejection. In addition, both mycophenolate and
rapamycin prevent chronic allograft rejection in experimental animals.
Whether this important observation is reproducible in humans
remains to be determined by long-term study.
A, Humanized monoclonal antibodies. The development of
genetically engineered humanized monoclonal antibodies will largely
eliminate the anti-antibody response, thereby increasing the utility
of antiT-cell antibodies in the treatment of recurrent rejection.
Experimental antibody therapies are now being designed to directly
target the CD4 molecule, the interleukin-2 receptor, the CD3 molecule
by a humanized form of monoclonal anti-CD3, and adhesion molecules
such as intercellular adhesion molecule-1 or leukocyte function-
associated antigen-1 [23]. Humanized monoclonal antibodies are
essentially human immunoglobulin G (IgG), nonimmunologic with
a long half-life, and potentially can be administered intravenously
about every 2 weeks. Humanized anti-CD25 (IL-2 receptor
chain)
monoclonal antibodies has been shown to be effective in lowering
the incidence of acute renal allograft rejection. Its role in the treat-
ment of rejection, however, has not been explored. With increasing
specificity for lymphocytes, these new agents are likely to have fewer
toxicities and better efficacy.
B, Therapeutic application of CTLA41g to transplant rejection.
APCantigen-presenting cell; MHCmajor histocompatibility
complex; TCRT-cell receptor.
89
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in primary cadaveric renal allograft recipients. Transplantation 1995,
60:225.
12. Jordan ML, Shapiro R, Vivas SA, et al.: FK506 rescue for resistant
rejection of renal allografts under primary cyclosporine immunosup-
pression. Transplantation 1994, 57:860.
13. Woodle ES, Thistlethwaite JR, Gordon JH, et al.: A multicenter trial
of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection.
Transplantation 1996, 62:594.
14. Jordan ML, Naraghi R, Shapiro R, et al.: Tacrolimus rescue therapy
for renal allograft rejection: five year experience. Transplantation
1997, 63:223.
15. Gray D, Shepherd H, Daar A, et al.: Oral versus intravenous high
dose steroid treatment of renal allograft rejection. Lancet 1978,
1:117.
16. Chan L, French ME, Beare J, et al.: Prospective trial of high dose versus
low dose prednisone in renal transplantation. Transpl Proc 1980,
12:323.
17. Auphan N, DiDonato JA, Rosette C, et al.: Immunosuppression by
glucocorticoids: inhibition of NF-kB activation through induction of
IkBa. Science1995, 270:286.
18. Ortho Multicenter Study Group: A randomized trial of OKT3 mono-
clonal antibody for acute rejection of cadaveric renal transplants.
N Engl J Med 1985, 313:337.
19. Norman DJ, Shield CF, Henell KR, et al.: Effectiveness of a second
course of OKT3 monoclonal anti-T cell antibody for treatment of
renal allograft rejection. Transplantation 1988, 46:523.
20. Schroeder TJ, Weiss MA, Smith RD, et al.: The efficacy of OKT3 in
vascular rejection. Transplantation 1991, 51:312.
21. Schroeder TJ, First MR: Monoclonal antibodies in organ transplantation.
Am J Kidney Dis 1994, 23:138.
22. English J, et al.: Transplantation 1987, 44:135.
23. Strom TB, Ettenger RB: Investigational immunosuppressants: biologics.
In Primer on Transplantation. Edited by Norman D, Suki W.
90
10
Post-transplant Infections
A
lthough the rates are markedly decreased from previous
decades, infection is the most important cause of early mor-
bidity and mortality following transplantation. Infection is
closely linked to the degree of immunosuppression and thus to the fre-
quency and intensity of rejection and its therapy. The potential sources
of infection in the transplant patient are multiple, including organisms
from the allograft itself and from the environment. Patients should be
advised to be sensible to possible exposures and to wash their hands
thoroughly when exposed to infected individuals or human excre-
ment, specifically, exposures in daycare and occupational settings as
well as during gardening and pet care. In those taking immunosup-
pressive agents, signs and symptoms of infections are frequently blunt-
ed until disease is far advanced. Therefore, due to the unusual nature
of the infections and the lack of timely symptom development, the key
to patient survival is the prevention of infection. Infections may be
prevented by pretransplant vaccinations, along with prophylactic
medications, preemptive monitoring and behavior modification.
Currently, the most common infectious problems within the first
month following transplantation are bacterial infections of the wound,
lines, and lungs. Additionally, herpetic stomatitis is common. Beyond
1 month following transplantation, infections are related to more
intense immunosuppression and include viral, fungal, protozoal, and
unusual bacterial infections. Although hepatitis may occasionally
cause fulminate and fatal disease if acquired peritransplantation, the
manifestations of hepatitis B or hepatitis C infections occur years fol-
lowing transplantation.
Connie L. D a vis
CHA P T ER
91
FIGURE 10-1
Timetable for the occurrence of infection in the renal transplant
patient. Exceptions to this chronology are frequent. CMV
cytomegalovirus; CNScentral nervous system; EBVEpstein-
Barr virus; HSVherpes simplex virus; UTIurinary tract infec-
tion; VZVvaricella-zoster virus. (Adapted fromRubin and
coworkers. [1]; with permission.)
Hepatitis
Bacterial
Conventional Unconventional
CNS
Fungal
Viral
TB Pneumocystis
Aspergillus, nocardia, toxoplasma
Wound
Pneumonia
line-related
HepatitisB
UTI:bacteremia, pyelitis, relapse
UTI:
Cryptococcus
EBV VZV papovaadenovirus
CMV onset
HSV
CMV
chorioretinitis
Listeria
Relatively
benign
Onset of non-A, non-Bhepatitis
Time, m o
0
Transplant
1 2 3 4 5 6
CLASSIFICATION OF INFECTIONS
OCCURRING IN TRANSPLANT PATIENTS
Infectionsrelated to technical complications*
Transplantation of acontaminated allograft, anastomotic leak or stenosis, wound
hematoma, intravenouslinecontamination, iatrogenic damageto theskin,
mismanagement of endotracheal tubeleadingto aspiration, infection related
to biliary, urinary, and drainagecatheters
Infectionsrelated to excessivenosocomial hazard
A sp ergillu s species, Le gion ella species, Pseu d om on a s a eru gin osa , and other gram-
negativebacilli, N o ca rd ia a st eroid e s
Infectionsrelated to particular exposureswithin thecommunity
Systemic mycotic infectionsin certain geographic areas
Hist opla sm a ca psu la t u m , Coccid ioid es im m it is, Bla st om y ces d erm a t it id is,
St ron gyloid es st ercora lis
Community-acquired opportunistic infection resultingfromubiquitoussaphro-
phytesin theenvironment
Cry pt ococcu s n eoform a n s, A spergillu s species, N oca rd ia a st eroid es, Pn eu m ocyst is ca rin ii
Respiratoryinfectionscirculatingin thecommunity
M y cob a ct eriu m t u b ercu losis, influenza, adenoviruses, parainfluenza, respiratory
syncytial virus
Infectionsacquired bytheingestion of contaminated food/water
Sa lm on ella species, List eria m on ocy t ogen es
Viral infectionsof particular importancein transplant patients
Herpesgroup viruses, hepatitisviruses, papillomavirus, HIV
*All lead to infection with gram-negativebacilli, St a ph ylococcu s species, and/or
Ca n d id a species.
Theincidenceand severity of theseinfectionsand, to alesser extent, theother

infectionslisted, arerelated to thenet stateof immunosuppression present in
aparticular patient.
FIGURE 10-2
Classifications of infections occurring in transplant patients.
(Adapted fromRubin [2]; with permission.)
Period of prophylaxis
Timingof infection
Bacterial (mean 60days)
CMV (mean 70days)
Non-CMV viral (mean 145days)
Fungal (mean 163days)
Months after transplant
P
a
t
i
e
n
t
s
,

n
0
10
20
30
40
50
1 2 3 46 712
FIGURE 10-3
Timing of infections following kidney/pancreas transplantation
at a single transplantation center using antiviral (ganciclovir IV
followed by acyclovir) and antibacterial (trimethoprim-sul-
famethoxazole) prophylaxis. CMVcytomegalovirus. (From
Stratta [3]; with permission.)
92
10.3 Post-transplant Infections
INFECTIOUS DISEASE HISTORY TO BE TAKEN PRIOR TO TRANSPLANTATION
1. Past immunizations.
2. Past infectionsor exposuresto infections.
A.Bacterial
Rheumatic fever, sinusitis, ear infections, urinarytract infections, pyelonephritis, pneumonia, diverticulitis, tuberculosis
B. Viral
Measles, mumps, varicella, rubella, hepatitis
3. Chronic or recurrent infections, such aspneumonia, sinusitis, urinarytract infection, or diverticulitis
4. Surgical history, such assplenectomy
5. Transfusion or previoustransplant historyand dates
6. Past travel history, includingmilitaryservice
7. Past immunosuppressivedrugtreatment (eg, for asthma, renal disease, or rheumatologic disease)
8. Lifestyle
A.Smoking, drinking, illicit druguse, marijuanasmoking
B. Sexual partners, orientation, unprotected contact and date, safetypracticesused, sexuallytransmitted diseases,
genital warts
C. Food, consumption of raw fish or meat, consumption of unpasteurized products, such asmilk, cheese, fruit juices,
or tofu
D. Avocationgardeningand theuseof gloves, cleaningsheds, hiking, camping, water sources, bathingpets, cleaning
pet litter and cages, huntingpractices
E. Vocationjobsthat requireexposureto possibleinfectiousagents, such asdaycare, ministry, small closed offices,
garbagecollectionsor dump workers, construction workers, forestryworkers, health care, veterinarians, farmers
FIGURE 10-4
Infectious disease history to be taken prior
to transplantation.
Preventive Strategies
PRETRANSPLANT VACCINATIONS OR BOOSTERS TO
BE GIVEN TO ALL TRANSPLANT RECIPIENTS UNLESS
RECENT ADMINISTRATION CAN BE DOCUMENTED
1. Td (Tetanustoxoid, diphtheria)
2. Pneumococcal vaccine
3. HepatitisB
4. Influenza
PRETRANSPLANT VACCINATIONS TO BE GIVEN IF
SERONEGATIVE OR PAST INFECTION BY HISTORY
CANNOT BE DOCUMENTED
1. Measles-mumps-rubellavaccine
2. Polio
3. Varicella(0.5mL subcutaneouslyfollowed bybooster of 0.5mL in 48weeks)
4. Ha em oph ilu s in f lu en z a typeB
FIGURE 10-5
Pretransplant vaccinations or boosters to be given to all transplant
recipients unless recent administration can be documented.
FIGURE 10-6
Pretransplant vaccinations to be given if seronegative or past
infection by history cannot be documented.
93
FIGURE 10-7
Inactivated vaccines that are considered safe and may be given as
needed post-transplant for anticipated exposure.
INACTIVATED VACCINES THAT ARE CONSIDERED SAFE
AND MAY BE GIVEN AS NEEDED POST-TRANSPLANT
FOR ANTICIPATED EXPOSURE
1. Anthrax
2. Cholera
3. Rabiesvaccineabsorbed
4. Human diploid cell rabiesvaccine
5. Inactivated typhoid vaccine, capsular polysaccharideparenteral vaccine,
or heat phenol-treated parenteral vaccine
6. Japaneseencephalitisvirusvaccine
7. Meningococcal vaccine
8. Plaguevaccine
VACCINES THAT MAY NOT BE GIVEN
(LIVE ATTENUATED VACCINES)
1. BacilleCalmette-Gurin (BCG)
2. Measles
3. Mumps
4. Rubella
5. Oral polio
6. Oral typhoid
7. Yellow fever
FIGURE 10-8
Vaccines that may not be given include live attenuated vaccines.
A. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES
Vaccine
DT
Td
DTP
DTaP (Acel-Imune)
DTP-HbOC (Tetramune)
Ha em oph ilu s B, conjugatevaccine
ProHIBit (PRP-D), manufactured by
Connaught Laboratories
HibTITER (HbOC), manufactured by
PraxisBiologicals
PedvaxHib (PRP-OMP), manufactured
byMSD
HepatitisB
Infantsborn to HB
s
Ag-negative
mothersand children <y[ ]
Recombivax HB(MSD)
Engerix-B(SKF)
Dosage
0.5mL
0.5mL
0.5mL
0.5mL
0.5mL
0.5mL
0.5mL
0.5mL
0.5mL
2.5g(0.25mL)
10g(0.5mL)
Route of administration
IM
IM
IM
IM
IM
IM
IM
IM
IM
IM in theanterolateral thigh or in
theupper arm; SC in individuals
at risk of hemorrhage
Type
Toxoids
Toxoids
Diphtheriaand tetanustoxoidswith killed B. pert u ssis organisms
Diphtheriaand tetanustoxoidswith acellular pertussis
Diphtheriaand tetanustoxoidswith killed B. p e rt u ssis
organismsand Ha em oph ilu s b conjugate(diphtheria
CRM
197
protein conjugate)
Polysaccharide(diphtheriatoxoid conjugate)
Oligosaccharide(diphtheriaCRM protein conjugate)
Polysaccharide(meningococcal protein conjugate)
Yeast recombinantderived inactivated viral antigen
FIGURE 10-9
AD, General immunization guidelines. HBOChaemophilus B
influenzaediphtheria protein conjugate vaccine, oligosaccharide;
IDintradermal; IMintramuscularly; DTdiphtheria tetanus;
DTPdi phtheri a tetanus pertussi s; MMRmeasl es mumps
rubella; MRmeasles rubella; MSDMerck Sharpe & Dohme;
PRP-Dhaemophilus Bdiphtheria toxoid conjugate vaccine,
polysaccharide; PRP-OMPhaemophilus influenzae type
bmeningococcal protein conjugate vaccine; SCsubcutaneous;
SKFSmithKline and French; Tdtetanus, diphtheria. (From
Isada and coworkers [4]; with permission.)
94
B. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES
Vaccine
Recombivax HB(MSD)
Engerix-B(SKF)
Children 1119y
Recombivax HB(MSD)
Engerix-B(SKF)
Adults>19y
Recombivax HB(MSD)
Engerix-B(SKF)
Dialysispatientsand immunosuppressed patients
Recombivax HB(MSD)
Engerix-B(SKF)
Dosage
5g(0.5mL)
10g(0.5mL)
5g(0.5mL)
20g(1mL)
10g(1mL)
20g(1mL)
<11y, 20g(0.5mL); 11y, 40g, (1mL) usingspecial dialysisformulation
<11y, 20g(1mL); 11y, 40g(2mL), giveastwo 1mL dosesat different sites
C. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES
Vaccine
Influenza
Split virusonlyin pediatric patients
635mo
38y
9y
Measles
Most areas: Two doses(1st doseat 12monthswith MMR; 2nd doseat 46yearsor 1112years, dependingon local school entryrequirements).
High-risk area: Two doses(1st doseat 12monthswith MMR; 2nd doseasabove).
Children 615 months in epidemic situations: Doseisgiven at thetimeof first contact with ahealth careprovider; children<1year of ageshould receivesingleantigen measlesvaccine.
If vaccinated before1year, revaccinateat 15monthswith MMR. A 3rd doseisadministered at 46yearsor 1112years, dependingon local school entryrequirements.
Dosage
0.25mL (1or 2doses)
0.5mL (1or 2doses)
0.5mL (1dose)
0.5mL
IM (2doses4+weeksapart in children
<9yearsof agenot previously immunized;
only1doseneeded for annual updates)
SC
Type
Inactivated virussubvirion (split) (contraindicated
in patientsallergic to chicken eggs)
Livevirus(contraindicated in patientswith
anaphylactic allergyto neomycin)
Infantsborn to HB
s
Ag-positivemothers(immunization and administration of 0.5mL hepatitisBimmuneglobulin isrecommended for infantsborn to HB
s
Agmothersusingdifferent
administration sites) within 12hoursof birth; administer vaccineat birth; repeat vaccinedoseat 1and 6monthsfollowingtheinitial dose
95
D. DOSAGE AND ADMINISTRATION GUIDELINES FOR VACCINES AVAILABLE IN THE UNITED STATES
Vaccine
Meningococcal
MMR
MR
Mumps
Pneumococcal
polyvalent
Poliovirus(OPV)
trivalent
Poliovirus(IPV)
trivalent
Rabies
Rubella
Tetanus(adsorbed)
Tetanus(fluid)
Yellow fever
Dosage, mL
0.5
0.5
0.5
0.5
0.5(2y)
0.5
0.5
1
0.5(12mo)
0.5
0.5
0.5
SC
SC
SC
SC
IM or SC (IM preferred)
Oral
SC
IM
, ID
SC
IM
IM, SC
SC
Type
Polysaccharide
Livevirus
Livevirus
Livevirus
Polysaccharide
Livevirus
Inactivated virus
Inactivated virus
Livevirus
Toxoid
Toxoid
Liveattenuated virus
Children 615 months in epidemic situations: Doseisgiven at thetimeof first contact with ahealth careprovider;
children<1year of ageshould receivesingleantigen measlesvaccine. If vaccinated before1year, revaccinateat 15months
with MMR. A 3rd doseisadministered at 46yearsor 1112years, dependingon local school entryrequirements.
PRETRANSPLANT VIRAL SEROLOGIES TO CHECK
AT THE PRETRANSPLANT VISIT
Viral serology
Herpessimplex virus1, 2
Epstein-Barr virus
Varicella-zoster virus
Cytomegalovirus
HBsAg
HepatitisC virus
HIV
Treatment, work-up modification or change in post-transplant treatment
If positive, treat earlypost-transplant with acyclovir, famciclovir, or ganciclovir
If negative, consider post-transplant ganciclovir. Test donor dueto risk of post-transplant
lymphomawith primaryinfection
Consider vaccination with Okastrain liveattenuated virusif negativeor treatment with
acyclovir followingclinical exposure
If therecipient ispositiveor donor positive, consider prophylactic or preemptive
antiviral treatment
If positive, check HBeAgand HBDNA and biopsy. If HBDNA positive, consider pretransplant
antiviral treatment with interferon if biopsyallows. Consult hepatologist regardingother
treatment options
If positive, check HCV RNA statusbypolymerasechain reaction. If positivebiopsyeven
with normal transaminasevaluesand consider pretransplant treatment with interferon
Consider safetyof transplantation if truepositive. Moredataarerequired to makean
informed decision
FIGURE 10-10
Pretransplant viral serologies to check at
the pretransplant visit.
96
PRETRANSPLANT BACTERIAL SEROLOGIES
Serology
RPR(Rapid plasmareagin)
PPD
Modification
If positive, check with atreponemal specific testFluorescent treponemal antibody
absorbed test (FTA-ABS) or microhemagglutination assayfor treponemapallidum
(MHA-TP)
If positivethegeneral recommendation without documented previoustreatment after
first evaluatingachest radiograph isisoniazid 300mg/d to continuefor 6monthsor
9to 12monthspost-transplant
FIGURE 10-11
Pretransplant bacterial serologies.
EFFECT AND POSSIBLE EFFECTS OF PROPHYLACTIC ANTIVIRAL STRATEGIES
No treatment
Risk: HSV
CMV
VZV
EBV
Adenovirus
HHV6
HHV8
Acyclovir orally 3M
HSV
Slight CMV
VZV
Slight EBV
No changein adenovirus
Slight HHV6
Slight HHV8
Ganciclovir IV acyclovir PO 3M
HSV
Slight CMV
VZV
EBV
?Adenovirus
Slight HHV6
Slight HHV8
CMVIgG 5 doses
?Effect
Slight CMV
?Effect
?Effect
?Effect
?Effect
?Effect
Ganciclovir 3M PO
HSV
CMV
VZV
EBV
?Slight in adenovirus
? HHV6
? HHV8
FIGURE 10-12
Effect and possible effects of prophylactic antiviral strategies. CMV
cytomegalovirus; EBVEpstein-Barr virus; HHV6human herpes
virus 6; HHV8human herpes virus 8; HSVherpes simplex; VZV
varicella zoster. Question mark indicates question as to the effect.
PROPHYLACTIC ANTIBACTERIAL AND ANTIPROTOZOAL STRATEGIES
Type of infection
Wound
Urinarytract
Legion ella
Pneumocystis
Toxoplasmosis
Nocardia
List eria m on ocyt ogen es
Treatment perioperatively or postoperatively
Against uropathogensand staphylococci, eg, ampicillin-sulbactam, cefazolin
plusaztreonam24to 48hoursadjusted for renal function
Risk urinaryleak, hematoma, lymphocele
Common choices
Trimethoprimsulfamethoxazole
Ciprofloxacin
Cephazolin
Ampicillin
Duration of treatment varies
An important factor isthepresenceof theurinarycatheter
FIGURE 10-13
Prophyl acti c anti bacteri al /
anti protozoal strategi es.
97
PREVENTION OF RESPIRATORY INFECTIONS IN THE IMMUNOSUPPRESSED PATIENT
Infection
Pneumococcal pneumonia
Influenzaillness
Ha em oph ilu s in f lu en z a e
Tuberculosis
Mycobacteriumaviumcomplex illness
Pn eu m ocyst is ca rin ii pneumonia
CMV pneumonia
Legion ella pneumonia
Aspergillosis
Ca n d id a illness
Cryptococcosis
Histoplasmosis
Coccidioidomycosis
Strongyloidiasis
Options for prevention
Pneumococcal vaccination; oral penicillin prophylaxis; passiveprophylaxiswith immuneglobulin
Annual influenzavaccination; amantadineor rimantadineprophylaxis(for influenzaA virusonly)
H. in f lu en z a typeBvaccination
Casefindingand earlytreatment; infection control procedures; preventivetherapywith isoniazid
Rifabutin prophylaxis
Prophylaxiswith oral trimethoprim-sulfamethoxazoleor aerosolized pentamidine
Useof CMV-seronegativeorgansand blood productsfor CMV-seronegativerecipients; passiveprophylaxiswith
CMV immuneglobulin; prophylaxiswith antiviral agents(acyclovir, ganciclovir)
Identification of source; institution of control measuresassociated with potablewater, such ashyperchlorination,
maintenanceof hot water temperatureabove50C (122F)
Useof HEPA filter to minimizeairbornespores; avoidanceof decayingleavesand vegetation
Prophylaxiswith antifungal agents
Avoidanceof pigeonsand pigeon droppings; prophylaxiswith antifungal agents
Completetravel historyto identifypatientsat risk; avoidanceof areasof high exposureto Hist opla sm a ; formalin
treatment of infected soil
Completetravel historyto identifypatientsat risk; avoidanceof areasof high exposureto Coccid ioid es im m it is
Completetravel historyto identifypatientsat risk; ovaand parasiteanalysisof stool specimen in patientsat risk;
thiabendazoleprophylaxis
FIGURE 10-14
Prevention strategies for the prevention of pulmonary infection. CMVcytomegalovirus;
HEPAhigh-efficiency particulate air. (Adapted fromMaguire and Wormser [5]; with permission.)
Prevention Strategies
98
PASSIVE IMMUNIZATION AGENTSIMMUNE GLOBULINS
Immune globulin
HepatitisB(H-BIG*)
Percutaneousinoculation
Perinatal
Sexual exposure
Immuneglobulin (IG)
HepatitisA prophylaxis
HepatitisB
HepatitisC
Measles
Rabies
Tetanus(serious, contaminated, wounds;

<3previoustetanusvaccinedoses)
Varicella-zoster
(VZIG)
Dosage
0.06mL/kg/dose(within 24h) (5mL max)
0.5mL/dose(within 12h of birth)
0.06mL/kg/dose(within 14d of contact) (5mL max)
0.02mL/kg/dose(assoon aspossibleor within 2wk after exposure)
(singleexposure)
0.06mL/kg/dose(>3mo or continuousexposure) repeat every46mo
0.06mL/kg/dose(H-BIG should beused)
0.06mL/kg/dose(percutaneousexposure)
0.25mL/kg/dose(max 15mL/dose) (within 6d of exposure)
0.5mL/kg/dose(max 15mL/dose) (immunocompromised children)
20IU/kg/dose(within 3d)
250500units/dose
Within 48hoursbut not later than 96hoursafter exposure
010kg 125units=1vial
10.120kg 250units=2vials
>40kg 625units=5vials
Route
IM
IM*
IM
IM
*Deep IM in thegluteal region for largedosesonly. Deltoid muscleor theanterolateral aspect of thethigh arepreferred sitesfor injection. No greater than 5mL/sitein adultsor large
children; 13mL/sitein small children and infants. Maximumdose: 20mL at onetime.
IG prophylaxismaynot beindicated in apatient who hasreceived IGIV within 3weeksof exposure.
1/2of doseused to infiltratethewound with theremaining1/2of dosegiven IM Rabiesimmuneglobulin isnot

recommended in previouslyHDCV immunized patients.
No greater than 2.5mL of VZIG/oneinjection site. Doses>2.5mL should bedivided and administered at different sites.
FIGURE 10-15
Passi ve i mmuni zati on agents for preventi on postexposure.
HBI Ghepati ti s B i mmune gl obul i n; HDCVhuman di pl oi d
cel l rabi es vacci ne; I Gi mmune gl obul i n; I GI Vi ntravenous
i mmune gl obul i n; I Mi ntramuscul arl y; VZI Gvari cel l a
zoster i mmune gl obul i n. (FromI sada and coworkers [4];
wi th permi ssi on.)
99
FIGURE 10-16
Live virus vaccinations generally not given to
transplant patients. IGimmune globulin;
OPVpoliovirus vaccine live oral. (From
Isada and coworkers [4]; with permission.)
CH
3
COO
CH
3
COO
6H
2
O
H
2
N
N
N
N
N
(CH
3
)CH
H
2
N
HN
N
O
N
N
O
N
N
O
S
NH
2
HOCH
2
O
O
OH
OCH
2
P(OH)
2
2H
2
O
O H O
O C C
O
O
O
O
C P
NH
3
Cl
+
3Na
+
N
N
H
2
N
HN
N
O
O
HO
N
N
HN
HN
N
O
O
HO
OH
N
N
Famciclovir
Penciclovir
Phosphonoformicacid
Foscarnet Cidofuvir Lamivudine
Valacyclovir Acyclovir Ganciclovir
Acyclovir
Oral bioavailability:
Excretion:
Plasma t1/2:
Intracellular t1/2:
Antiviral spectrum:
77%
100%* R
23 h
720 h
HSV/V2V/EBV
54%
100%liver/GI
23 h
0.71 h
HSV/V2V/EBV
15%
100%* R
23 h
0.71 h
HSV/V2V/EBV
2%7%
91%unchanged urine
23 h
6 h3 wk
HHV8, CMV, adeno, HBV
Administration:
t1/2:
Tissue t1/2:
Metabolism:
IV
26 h
87.541.8 h
100%renal excretion
IV
34 h
1765 h
85%renal excretion
86%oral bioavailability
57 h
1015 h
70%90%renal excretion
A
B
FIGURE 10-17
Antiviral agents. Asterisk indicates excreted unchanged
in the urine; all antivirals are subject to changes in t1/2
wi th changi ng renal functi on. Adenoadenovi rus;
GUIDELINES FOR SPACING THE ADMINISTRATION OF
IMMUNE GLOBULIN (IG) PREPARATIONS AND VACCINES
Immunobiologic combinations
Simultaneous administration
IG and killed antigen
IG and liveantigen
First
IG
Killed antigen
IG
Liveantigen
Nonsimultaneous administration
Second
Killed antigen
IG
Liveantigen
IG
Recommended minimum interval between doses
None. Maybegiven simultaneouslyat different sitesor at anytime
between doses.
Should generallynot begiven simultaneously. If unavoidableto do so,
giveat different sitesand revaccinateor test for seroconversion in
3months. Example:MMRshould not begiven to patientswho have
received immuneglobulin within theprevious3months.
None
None
6wk, and preferably3mo
2wk
*Thelivevirusvaccines, OPV, and yellow fever areexceptionsto theserecommendations. Either vaccinemaybe
administered simultaneouslyor anytimebeforeor after IG without significantlydecreasingantibodyresponse.
CMVcytomegal ovi rus; EBVEpstei n-Barr vi rus;
HHV8human herpesvirus 8; HSVherpes simplex virus;
VZVvari cel l a-zoster vi rus.
100
Drug-P
1
GP
1
R
1
R
1
R
2
R
2
Famciclovir
viral
thymidine
kinase
DrugP
2
cell
kinase
cell
(no viral enzymes needed)
kinase
cellular
enzymes
GP
2
CP
2
cell
kinase
GP
3
cell
kinase
DrugP
3
viral
DNA
Polymerase
viral
DNA
Polymerase
cell
kinase
Cidofovir
Valacyclovir
car v UL97
gene product
autophosphorylating
protein kinase
Ganciclovir
Acyclovir
FIGURE 10-18
Antiviral activation and action (acyclovir, vala-
cyclovir, famciclovir, ganciclovir). Resistance
(R) to antivirals has been found at the level
of viral thymidine kinase (R1) and DNA poly-
merase (R2). Ganciclovir is monophosphory-
lated in cytomegalovirus (CMV)-infected cells
by the CMV UL97 gene product. Acyclovir,
valacyclovir, and famciclovir are not easily
phosphorylated in CMV-infected cells.
Cidofovir does not require viral enzymes to be
phosphorylated to the active diphosphonate.
DRUG INTERACTIONS BETWEEN ANTIVIRALS, ANTIFUNGALS,
ANTIBACTERIALS, ANTIMYCOBACTERIALS, AND ANTIPROTOZOALS
WITH CYCLOSPORINE AND FK506
Drug
Antifungals
Amphotericin B
Clotrimazoletroches(morein FK506)
Ketoconazole(keto>itra>fluconazole)
Griseofulvin
Antibacterial
Clarithromycin
Doxycycline
Erythromycin
Gentamicin
Nafcillin
Rifampin
Rifabutin
Sulfamethoxazole/trimethoprim
Ticarcillin
Antimycobacterial
Isoniazid
Pyrazinamide
Antiparasitic
Chloroquine
Effect on CSA/FK506
Nephrotoxicity of combination
FIGURE 10-19
Drug interactions between antivirals,
antifungals, antibacterials, antimycobacte-
rials, and antiprotozoals with cyclosporine
and FK506. (FromLake [6] and Yee [7];
with permission.)
INFECTIONS TRANSMITTED TO TRANSPLANT RECIPIENTS
VIA THE DONOR ORGAN
Virus
HIV, cytomegalovirus,
herpessimplex virus,
Epstein-Barr virus,
hepatitisBvirus,
hepatitisC virus,
hepatitisD virus, ?
hepatitisG virus,
adenovirus(?), parvovirus(?),
papillomavirus, rabies,
Creutzfeldt-Jakob
Bacteria
Aerobe(grampositive),
aerobe(gramnegative),
anaerobes, M ycob a ct eriu m
t u b ercu losis, atypical
mycobacteria
Fungi
Ca n d id a a lb ica n s,
Hist opla sm a ca psu la t u m ,
Cry pt ococcu s n eoform a n s,
M a rosporiu m a piosperm u m
Parasitic
Malariatoxoplasmosis,
trypanosomiasis,
strongyloidiasis
FIGURE 10-20
Infections transmitted to transplant recipients
via the donor organ.
101
FIGURE 10-21
The lifecycle of cytomegalovirus (CMV). The envelope binds with
the cell membrane, and the DNA is uncoated and transferred into
the nucleus, where cell protein synthesis machinery is used to man-
ufacture new DNA and capsid. The DNA is packaged into the cap-
sid and returns to the cytoplasm, where the tegument and envelope
are assembled around the capsid and the whole virus transported
to the cellular surface and released.
Envelope
Tegument
Capsid
Attachment and
penetration
Releaseof
viral DNA
Egress
Uncoating Cytoplasm
Nucleus
Transcription
Protein synthesis
Replication
IE
E
L
DNA
Scaffold Assembly Packaging
Cytomegalovirus
CMV is a double-stranded DNA virus that causes disease fol-
lowing transplantation after primary infection, reinfection, or reac-
tivation of latent infections. CMV disease is seen most frequently
within the first 4 to 6 months of transplantation if no antiviral
prophylaxis is used; however, in the presence of antiviral prophy-
laxis and new immunosuppressive agents, the onset of CMV dis-
ease may be shifted to longer intervals from transplantation. There
also may be a slight increase in the occurrence of CMV enteritis
with the use of some of the newer combinations of immunosup-
pressive agents. When the recipient is CMV positive and receives
an organ from a CMV-positive donor, reactivation of the latent
infection in the recipient is responsible for 15% to 30% of the
infections seen, and reinfection with the virus from the donor is
responsible for 70%.
CMV disease prevention may be accomplished by administering
prophylactic antiviral agents or by the use of routine surveillance
testing. Variables to be considered in an individuals risk of CMV
disease development are the use of antilymphocyte medications,
and the donor and recipient, CMV serostatus. The highest risk
group for CMV disease is the group at risk for primary CMV
exposure and those given antilymphocyte preparations. Specifically,
increased CMV disease is seen during situations that trigger viral
replication. High levels of tumor necrosis factor alpha, such as
levels occurring during infections or after OKT3 administration,
activate the CMV promoter, thus stimulating the conversion from
the latent to the reactivated state.
All of the prophylactic strategies for the prevention of CMV
disease have shown some benefit in different studies; currently,
however, the most effective approach is oral ganciclovir. A more
bioavailable oral ganciclovir may even increase the effectiveness
and is now under investigation. Oral ganciclovir is started when
the patient is able to take oral medications within the first week
following transplantation and is administered at a dose of 1 g 3
times a day for 3 months following transplantation adjusted for
renal function. The protective effect is also seen in those who have
received antilymphocyte preparations. The most desirable solution
would be a vaccine that induced natural immunity mechanisms.
Vaccines targeted against the structural glycoproteins of CMV are
currently continuing under development but are not yet available;
their ultimate effectiveness is not known at this time. As patients
who already have had natural infections are not immune to reinfec-
tion or reactivation, a vaccine solution may not be possible.
102
MANIFESTATIONS OF CMV DISEASE IN RENAL
TRANSPLANT RECIPIENTS
CMV disease
A. Syndrome: fever, leukopenia, malaise, lack of another cause
B. Organ specific: hepatitis, enteritisduodenum, colon; pancreatitis; pneumonitis;
interstitial nephritis, retinitis
C. Risk of CMV diseasebydonor
D/R
D
+
R
-
D
+
R
+
D
-
R
+
D
-
R
-
Infection*
70%100%
50%80%
Disease
56%80%
27%39%
0%27%
<5%
*Infection determined bynew anti-CMV antibodydevelopment or agreater than
fourfold risein anti-CMV titers.
Recipient serostatus without antiviral prophylaxis
FIGURE 10-22
Mani festati ons of cytomegal ovi rus (CMV) di sease i n renal
transpl ant reci pi ents.
A B
FIGURE 10-23 (s e e Color Plates)
Endoscopic aspects of cytomegalovirus
(CMV) infection. A, CMV esophageal
ulcers. B, CMV duodenal ulcers.
Histologic lesion in cytomegalovirus infection.
103
RANDOMIZED TRIALS EVALUATING CMV PROPHYLACTIC STRATEGIES
ADMINISTERED DURING THE TIME OF GREATEST RISK FOR CMV DISEASE
Author
Metsellar
Steinmuller
Teuschert
Snydman*
Boland
Drug
IgG
Induction or Rejection
Antilymphocyte
ATG-rej
ALG/OKT3
None
Some
None
Serostatus
All patients
R
+
D
+
R
-
D
+
R
-
D
+
R
-
n
20
18
18
35
11
CMV Disease
30%
39%
100%
60%
18%
n
19
16
18
24
11
CMV Disease
37%
13%
20%
21%
27%
Dosing
Cytotec, 6doses
Sandoglobulin, 5doses
Cytotec, 11doses
Cytotec
Cytotec, 5doses
*Antilymphocyteserumwasgiven to two globulin and eight control patientsasinduction therapyand four globulin and seven control patientsasantirejection therapy.
Balfour AcyclovirPO ALG All patients
Subgroups
D
+
R
-
D
+
R
+
51
7
8
29%
100%
38%
53
6
9
8%
17%
11%
Acyclovir
800mgpo qid x3months
Rondeau
Conti
Hibberd
Brennan
Ganciclovir ATG/OKT3
Antilymphocyte
OKT3
ATG
D+R-
R
+
R
+
D
+
or R
+
15
18
49
23
73%
56%
33%
61%
17
22
64
19
47%
9%
14%
21%
Ganciclovir 5mg/kgbid
IV d1428
Ganciclovir with antilymphocyte
drug2.5mg/kg/IV bid
Ganciclovir 2.5mg/kg/d
duringALG
Oral ganciclovir 1gtid
Squillet Valacyclovir NA R
+
204 10.8% 204 0% 2gqid
Treated Control
FIGURE 10-25
Randomized trials evaluating cytomegalovirus (CMV) prophylactic strategies
administered during the time of greatest risk for CMV disease.
104
FIGURE 10-26
The prevention of cytomegalovirus (CMV)
disease. This figure shows the different strate-
gies for the management of CMV-positive
transplant recipients or recipients of CMV-
positive organs.
Preemptive treatment
The "prevention" of CMV disease
*
Different laboratorieshavedifferent thresholdsfor clinicallysignificant positivetests.
Themost costlyapproach.
Themost convenient and effective. Both ganciclovir and acyclovir areadjusted for
renal function.
a.
No testingor
antiviral therapy
Wait for infection
b.
c.
d.
Antiviral prophylaxis
CMV antigenemia
testingor PCR
testingweekly starting
thethird or fourth
postoperativeweek
For all CMV D
+
R
,
D
+
R
+
, D
R
+
thefollowing
havebeen employed
CMV D
+
CMV R
+
po ganciclovir
1 gtid 3 months
Oral high doseacyclovir
800 mgpo qid 3 months
Pooled IV IgG or CMV
hyperimmuneglobulin
IV ganciclovir post
transplant only or followed
by oral acyclovir for 3
months
()*
or low titer
positive-depending
on the laboratory
threshold
Continue
surveillance
(+)
Treat with
IV ganciclovir
5 mg/kgbid adjusted
for renal function
1014 d
DETECTION OF CMV DISEASE AND INFECTION
Antibodies: thedevelopment of IGManti-CMV antibodies, afour fold or greater increasein IgG titers
Culture:
A. Standard culturein afibroblast monolayer
Resultsmayrequireup to 6wk
B. Shell vial culturesthebuffycoat iscentrifuged onto fibroblastsincreasingfibroblast infection. Viral infection
isdetected byapplyingamonoclonal antibodydirected against the72-Kd major immediateearlyprotein of
CMV. RBCsin thebuffycoat maybetoxic to themonolayer resultingin afalse-negativetest. Urineand BAL
specimensmaybepositivewithout predictingdisease. Resultsareavailablein 16to 36h.
Other:
A. AntigenemiaGranulocytesand monocytesareisolated and stained with amonoclonal antibodyagainst a
matrix, tegument protein pp65(structural lateprotein). Cultureisnot required, granulocytesand mono-
cytesfromthebuffycoat arestained, testingresultsareavailablein 4to 6h. It maybeargued that the
positivitymaynot bedueto replicatingvirusin theWBCsbut dueto exogenousacquisition frominfected
endothelial cells. Thenumber of antigen positivecellsper unit number of WBC counted that determines
theonset of symptomatic diseasesdependsupon theindividual laboratory; however, usuallyover 10posi-
tivecellsper 10
5
WBC precedetheonset of symptomsbyapproximately1week.
B. Polymerasechain reactionFor thedetection of CMV DNA in wholeblood or serum. CMV DNA isamplified
fromwholeblood or serum. Thesensitivityand predictivevaluedepend on thelaboratory.
FIGURE 10-27
Detection of cytomegalovirus (CMV) disease
and infection. BALbronchoalveolar
lavage; RBCred blood cell;
WBCwhite blood cell.
105
SOME ANTITUBERCULOSIS DRUGS
Drug
Primaryantituberculoustherapy
Isoniazid*
( I.N .H., a n d ot h ers)

Rifa m pin *
(Rifadin, Rimactane)
Py ra z in a m id e
Et h a m b u t ol
(Myambutol)
Other Drugs
Ca preom y cin (Capastat)
Ka n a m y cin (Kantrex, and others)
St rept om ycin **
Cycloserin e (Seromycin, and others)
Et h ion a m id e (Trecator-SC)
Ciprof lox a cin (Cipro)
Of lox a cin (Floxin)
Adult dosage (daily)
300mg
600mg
1530mg/kg
15mg/kg(about 1g)
15mg/kgIM or IV
15mg/kgIM
250500mgbid
250500mgbid
500750mgbid
200400mgq12h or
400800mg/day
Pediatric dosage (daily)
1020mg/kg(max. 300mg)
1020mg/kg(max. 600mg)
sameasadult
sameasadult
1530mg/kg
1530mg/kg
2040mg/kgIM
1520mg/kg
1520mg/kg
Not recommended
Not recommended
Main adverse effects
Hepatic toxicity
Hepatic toxicity, flu-likesyndrome
Hepatic toxicity, hyperuricemia
Optic neuritis
Auditoryand vestibular toxicity, renal damage
Auditorytoxicity, renal damage
Vestibular toxicity, renal damage
Psychiatric symptoms, seizures
Gastrointestinal and hepatic toxicity
Nausea
Nausea
*Rifamate(containingrifampin 300mgplusisoniazid 150mg) isalso available
Can begiven orallyor parenterally. Pyridoxineshould begiven to prevent neuropathyin malnourished or pregnant patientsand thosewith alcoholismor diabetes. For intermittent use
after afew weeksto monthsof dailydosage, thedosageis15mg/kgtwice/wk (max. 900mg).
Availableorallyor intravenously. For intermittent useafter afew weeksto monthsof dailydosage, thedosageis600mgtwice/wk.
For intermittent useafter afew weeksto monthsof dailydosage, thedosageis4050mg/kgtwice/wk (max. 3g).
Dailydosageshould be25mg/kg/d if organismisoniazid-resistant or duringfirst 1to 2months; decreasedosageif renal function diminished. For intermittent useafter afew weeksto
monthsof dailydosage, thedosageis50mg/kgtwice/wk.
**Temporarilynot availablein theUnited States.
For patients>40yearsold, 500to 750mg/d or 20mg/kgtwice/wk; decreasedosageif renal function isdiminished. Someclinicianschangeto lower dosageat 60rather than
40yearsof age.
Someauthoritiesrecommend pyridoxine50mgfor every250mgof cycloserineto decreasetheincidenceof adverse

psychiatric effects.
FIGURE 10-28
The treatment of tuberculosis (TB) depends on the clinical presen-
tation. Pretransplant prophylaxis for a positive purified protein
derivative, if given, is with isoniazid 300 mg/d up to, or following,
transplantation. Post-transplant treatment is more accepted, but
due to the possible high rate of hepatotoxicity, many centers have
chosen not to administer prophylaxis. Treatment of pulmonary
disease should include at least two to three drugs (depending on
resistance patterns in the area) for 6 to 9 months. Treatment of
Tuberculosis
disseminated disease or extrapulmonary disease should include
three or four drugs for 12 to 18 months. When starting treatment
with isoniazid and rifampicin, care should be taken to increase the
glucocorticoid dose twofold and the cyclosporine by threefold to
fivefold. This is because rifampicin (and somewhat isoniazid)
induces the metabolism of steroids and cyclosporine and FK506
through the P450 cytochrome system. (Adapted from Med Lett
Drugs Ther [8]; with permission.)
106
DIAGNOSTIC TECHNIQUES FOR PNEUMOCYSTISCARINII INFECTION
Technique
Routinesputum
Induced sputum
Transtracheal aspiration
Galliumscan
Bronchoalveolar lavage(BAL)
BAL/brushing
BAL/transbronchial biopsy
Open lungbiopsy
Needleaspirate
Yield
Poor
30%75%
Fair (with experience)
Nonspecific
>50%(>95%in AIDS)
Asfor BAL alone
Over 90%(all patients)
Over 95%(all patients)
Up to 60%
Complications
Rare
Rare
Common: bleeding; subcutaneousair
Injection site
Bleeding, aspiration fever, bronchospasm
Asfor BAL
SeeBAL; pneumothorax
Anesthesia, air leakage, altered respiration,
wound infection
Pneumothorax, bleeding
Comments*
Culturesneeded
First choice; excellent in AIDS
Rarelyworthwhile
Positivein >95%of infected patients
Wedged terminal BAL with immunofluorescence
Not useful for P. ca rin ii
Impression smears; cultures/pathology
Gold standardnoninfectious/infectiousprocesses;
largesample
Best in localized disease
*All samplesshould becultured and stained for bacteria(includingmycobacteria), fungi, viruses, and examined for protozoa. Optimal proceduresdepend on thelocallyavailableexpertise.
FIGURE 10-29
Diagnostic techniques for Pneumocystis carinii infection.
(Adapted fromFishman [9]; with permission.)
Protozoal/Parasitic Infections
THE TREATMENT OF PNEUMOCYSTISCARINII
Agent(s) (route)
Trimethoprim
and sulfamethoxazole
(TMP-SMZ) (IV/po)
Pentamidine
isethionate(IV)
Dapsone(po) with
TMP (po/IV)
Clindamycin (IV/po)
and primaquine
Trimetrexate(IV) with
folinic acid (po)
(leucovorin)
Pyrimethamine(po)
with sulfadiazine
Atovaquone(po)
Dose
15mg/kg/d TMP (to 20)
75mg/kg/d SMZ (to 100)
4mg/kg/d
300mg/d maximum
100mg/d
1520mg/kg/d (900mg)
600900mgq 6h
1530mgbasepo qd
3045mg/m
2
/d
80100mg/m
2
/d
Load 50mgbid x 2d,
then 2550mgqd
Load 75mg/kg, then
100mg/kg/qd
750mgpo tid
Options
Treat through rash: reduceTMP or SMZ by

onehalf; desensitize
Lower dose(23mg/kg); IM not advised
Methemoglobinemia; G6PD;
m ay betolerated in sulfadiazineallergy
Methemoglobinemia; diarrhea
(pyrimethaminefor primaquine)
Leukopenia, anemia;
thrombocytopenia; relapsecommon
Not studied fully
Maximum4gin two doses; up to 8g
Variableabsorbance, improved
with fattyfood; rash
*A d ju n ct iv e t h era pies (seetext); corticosteroids(high dosewith rapid taper); possiblyinterferon gamma;
granulocyte-macrophagecolony-stimulatingfactor.
Based on clinical judgment of physicians; someagentsarenot approved bytheFood and DrugAdministration

for thisindication.
FIGURE 10-30
The treatment of Pneumocystis carinii
infection. (Adapted fromFishman [9];
with permission.)
107
ANTIBIOTIC THERAPY FOR TOXOPLASMAGONDII INFECTION
Drug
Pyrimethamine
Sulfonamide
Clindamycin
Spiramycin
Dose
100mgpo x 2
(then) 25mg50mg
po, qd, or qod
Sulfadiazine4gpo
(then 11.5gpo qid
or tri-sulfapyridine;
(75100mg/kg/d)
6001200mgIV or
600mgpo q6h
1gpo tid or qid
Duration
Load
36wk
36wk
36wk
36wk
Comments
Bonemarrow suppression;
maygivefolinic acid 5mgpo/im
qod except leukemia
Decreasedosefor neutropenia;
sulfaallergycommon
Slower resolution than
with sulfa; C. d if f icile colitis
In pregnancyor sulfaallergywith
pyrimethamine; CNSdatalimited
*Activeinfection: twiceweeklyblood countsarenecessaryto detect bonemarrow suppression resultingfromtherapy.
Lifelongprophylaxisafter acuteinfection isrecommended in transplant and AIDSpatients.
Investigational: trimetrexate, atovaquone, macrolides, gammainterferon.

FIGURE 10-31
Antibiotic therapy for Toxoplasma gondii
i nfecti on. (Adapted fromFi shman [9];
wi th permi ssi on.)
FIGURE 10-32
(s e e Color Plate)
Candida esophagitis
seen on esopha-
gogastroduo-
denoscopy.
Yeast and Fungal Infections
FIGURE 10-33
(s e e Color Plate)
Endoscopic view of
severe esophagitis.
108
Displayed are Aspergillus as fungus balls, which are proliferating
masses of fungal hyphae. The hyphae are septute, 5 to 10 m
thick, and branch at acute 40 angles. Aspergillus frequently
invades blood vessels, causing hemorrhage and necrotizing
inflammation with downstream infarction. This image shows
three fungus balls in the lung (Gomori-Ammon stain for fungi).
TREATMENT OF FUNGAL INFECTIONS IN THE SOLID-ORGAN
TRANSPLANT RECIPIENT BY CATEGORY OF INFECTION
Category of infection
Mucocutaneouscandidiasis
Candiduria
Invasivecandidiasis
Life-threatening
Catheter-associated
Less-ill, sensitiveorganism
Aspergillosis
Mucormycosis,
Phaeohyphomycosis,
Hyalohyphomycosis
Cryptococcosis
Histoplasmosis,
Coccidioidomycosis,
Blastomycosis
Pn eu m ocyst is ca rin ii
Prophylactic
Nystatin (oral)
?Itraconazole
TMP/SMX
Preemptive
Fluconazole*
Itraconazole
Fluconazole
Itraconazole
Definitive
Fluconazole
Amphotericin Bbladder irrigation;
Fluconazole
Amphotericin B(0.51.0mg/kg)
+/ flucytosine
Amphotericin B
Fluconazolein selected cases
Fluconazole
Amphotericin B(1.01.5mg/kg)**
Amphotericin B(1.0-1.5mg/kg)**
Amphotericin B+flucytosinex 2wk,
then Fluconazolex 410wk if
clinical and microbiologic response
Amphotericin B;
itraconazolemaybeuseful as
primarytherapy
TMP/SMX
*Asymptomatic candiduriain renal transplant recipients
Not T. gla b ra t a or other resistant species
Removal of catheter
Lessill, sensitiveorganism, nephrotoxicityowingto amphotericin Band proven microbiologic and clinical response
Pulmonarycolonization immediatelybeforeor after transplantation

**Surgical dbridement wherepossible
Excision of focal pulmonarynoduledueto C. n eoform a n s or H. ca psu la t u m
For coccidioidomycosisin endemic areas

FIGURE 10-35
Treatment of fungal infections in the solid-
organ transplant recipient by category of
i nfecti on. TMP/SMXtri methopri m-
sulfamethoxazole. (Adapted fromHadley
and Karchmer [10]; with permission.)
109
FIGURE 10-36
Survival of hepatitis B virus (HBV)infected patients with end-stage
renal disease treated with either dialysis or transplantation. Patients
infected with HBV (hepatitis B surface antigen [HBsAg] positive)
on hemodialysis were matched for age with 22 previously trans-
planted HBsAg-positive patients. This study shows the reason for
concern and investigation as to the safety of transplantation in
HBV-infected patients. Although there are other studies showing a
significantly decreased survival in patients transplanted with HBV
infection, most currently show equivalent survival of over 10 years.
The cause of death in the HBV-infected group, however, may more
often be from infection and liver failure than from cardiac disease.
Dialysis
Transplant
31
22
19
18
15
13 13
11
9 9
6
24
20
17
12 9 7
6 5
1
Years followingdetection of HBsAg
C
u
m
u
l
a
t
i
v
e

s
u
r
v
i
v
a
l
,

%
0
10
20
30
40
50
60
70
80
90
100
2 0 4 6 8 10
Hepatitis B
The safety of transplantation in HBsAg-positive patients has
been debated for over 25 years. Increased mortality, if seen, is usually
seen beyond 10 years following transplantation and is often sec-
ondary to liver failure or sepsis. The acquisition of hepatitis B infec-
tions post-transplant, however, does carry a worse prognosis.
Virtually all patients with severe chronic active hepatitis, and 50%
to 60% of those with mild chronic active hepatitis on liver biopsy
prior to transplantation, will progress to cirrhosis. Patients with
chronic persistent hepatitis usually do not show histologic progres-
sion over 4 to 5 years of follow-up, although mild lesions do not
guarantee preservation of hepatic function over longer periods. The
complete natural history of hepatitis B following transplantation is
not known, as biopsies have been performed largely in those who
have abnormal liver function tests; however, one recent study, that
included analyses of all individuals who were HBsAg positive
around the time of transplantation, has shown histologic progres-
sion in 85.3% of those who were rebiopsied with the development
of hepatocellular carcinoma in eight of 35 patients who developed
cirrhosis. A key to management of patients who were HBsAg posi-
tive following transplantation is to periodically monitor the liver by
ultrasound and to perform a serum alpha-fetoprotein level to detect
hepatocellular carcinoma at the earliest possible stage. The key to
minimizing the effects of hepatitis B infections following transplan-
tation, however, is to administer the hepatitis B vaccine as early as
possible in the treatment for end-stage renal disease. It is noted that
60% will develop antihepatitis B titers when vaccinated while on
dialysis compared with only 40% of those who have already been
transplanted. Co-infection with hepatitis C may result in more
aggressive liver disease but so far has not led to a marked decrease
in patient survival. Because of the high risk of acute renal failure or
rejection with the use of interferon post-transplant, treatment of
hepatitis B with interferon following renal transplantation is not
advised. Lamivudine or other experimental antihepatitis agents may
be used pretransplant for patients with hepatitis B infection. (Figure
adapted fromHarnett and coworkers. [11]; with permission.)
110
POST-TRANSPLANT SURVIVAL IN HEPATITIS BINFECTED PATIENTS
Author
Pirson
Hillis
Touraine
Dhar
Roy
Pfaff
HBsAg +
61
16
140
51
85
781
Year
1977
1979
1989
1991
1994
1997
HBsAg +
94
55
94
92
100
88.8
+HBsAgpositive; HBsAgnegative.
Later studieshaveusuallyshown comparablepatient and graft survival in HBsAg-positivepatientscompared with HBsAg-negativepatients. Theremayonlybeaslight 3%to 4%difference
overall in long-termgraft and patient survival in favor of HBsAg-negativepatients.
HBsAg +
28
HBsAg +
60
91
88
75
77.6
FIGURE 10-37
Post-transplant survival in hepatitis Binfected patients. Later stud-
ies have shown comparable patient and graft survival in hepatitis B
surface antigen (HBsAg)positive patients compared with HBsAg-
negative patients. There may only be a slight 3% to 4% difference
overall (in favor of HBsAg-negative patients) in long-term graft and
patient survival. (Data fromPirson and coworkers [12], Hillis and
coworkers [13], Touraine and coworkers [14], Dhar and coworkers
[15], Roy and coworkers [16], and Pfaff and Blanton [17].)
CHRONIC HEPATITIS B INFECTION IN HBsAg-POSITIVE RENAL
TRANSPLANT RECIPIENTS: RESULTS OF LIVER BIOPSIES PERFORMED
PERITRANSPLANT AND A MEDIAN OF 66 MONTHS LATER
Histology
Normal
Chronic persistent
Chronic active
Cirrhosis
Miscellaneous
First Biopsy
n =131
%
39%
25%
25%
0%
11%
66months
Second biopsy
n =101
%
6%
18%
42%
28%
6%
Histologic deterioration wasseen in 85.3%of thoserebiopsied with hepatocellular carcinomaseen in 8/35 with
cirrhosis. Patientshad not been treated with anti-HBV agents. 151 patientswereHBsAgpositive, median age46,
35 females, 116 males. Immunosuppression in 124 wasprednisoneand azathioprineand in 27 cyclosporine,
azathioprine, and prednisone. Themedian follow-up was125 months(range1 to 320). Median timeof HBsAg
positively was176 monthswith 20%acquiringHBV infection post-transplant.
FIGURE 10-38
Chronic hepatitis B infection in hepatitis B
surface antigen (HBsAg)positive renal
transplant recipients. Results of liver biop-
sies performed peritransplant and a median
of 66 months later in 131 of 151 HBsAg
+
patients. Histologic determination was seen
in 85.3% of patients rebiopsied, with hepa-
tocellular carcinoma seen in eight of 35
patients with cirrhosis. Patients had not
been treated with anti-hepatitis B virus
agents. With a median age of 46, 151
patients were HBsAg positive (35 female,
116 male). Immunosuppression in 124
patients was with prednisone and azathio-
prine, and in 27 patients was with
cyclosporine, azathioprine, and prednisone.
(FromFornairon and coworkers [18];
with permission.)
1 y, %
HBsAg
95
90
93
98
100
91.8
3 y, % 5 y, %
HBsAg +
87
66
61.6
10 y, %
HBsAg
80
HBsAg
80
88
93
75
80.6
HBsAg
82
68(8y)
65.8
Patients evaluated, n
HBsAg
60
149
869
541
172
13,287
111
FIGURE 10-41
Patient survival in 235 hepatitis C virus (HCV)-positive patients.
Patients coinfected with HCV and hepatitis B virus (HBV) had
comparable survival 12 years after transplant as those infected
with HCV alone although fibrosis was more common in dually
infected patients. Results were based on 27 biopsies in patients
who were both HCV positive and HBV positive and 81 biopsies
in patients who were both HCV positive and HBV negative. Over
time, liver failure occurred more frequently in patients who were
both HCV and HBV positive (17%) than in patients who were
both HCV positive and HBV negative (7%). (FromPouteil-Noble
and coworkers [19]; with permission.)
HCV+HBV (n =189)
HCV+HBV+(n =46)
Months
C
u
m
u
l
a
t
i
v
e

s
u
r
v
i
v
a
l
,

%
0.5
0.6
0.7
0.8
0.9
1.0
24 12 36 0 48 60 72 84 96 108 120
CHRONIC HEPATITIS B INFECTION: CAUSES OF DEATH
IN 151 HBSAG-POSITIVE PATIENTS OVER 125 MONTHS
Liver related (n=15)
Spontaneousbacterial peritonitis 6
Hepatocellular carcinoma 4
Liver failure 5
Fibrosingcholestatic hepatitis 2
Not liver related (n=26)
Cancer 6
Sepsis 8
Cardiovascular 5
Stroke 3
Other 4
FIGURE 10-39
Chronic hepatitis B infection. Causes of death in 151 hepatitis B
surface antigen (HBsAg)positive patients over 125 months. Death
following transplantation is more frequently due to sepsis and liver
failure in patients with hepatitis than in patients without chronic
hepatitis. (FromFornairon and coworkers [18]; with permission.)
Death followingtransplantation in patientswith hepatitisismorefrequentlycaused
bysepsisand liver failurethan in patientswith chronic hepatitis.
Hepatitis B virus screening in renal transplant candidates
()
No further testing
except by routine
dialysis schedule
No renal transplant alone
Referral to Liver transplant
center (if appropriate)
that transplants
HBV DNA(+) candidates
Hepatitis Bvirus
Screen by HBsAg
(+) DNA/eAg(+)
Biopsy
In trials
Cirrhosis
() DNA
indicates lack of
viral replication
Mild to
severehepatitis
(CPH, CAH)
?Biopsy
?Useantiviral
Consult hepatology
Lamividine
Famacyclovir
Labucovir
Adefovir
(+) eAg
HBV DNA
Consider
treatment
FDA approved
interferon
FIGURE 10-40
Hepati ti s screeni ng i n renal transpl ant candi dates. CAH
chroni c acti ve hepati ti s; CPHchroni c persi stent hepati ti s;
HBsAghepati ti s B surface anti gen; HBVhepati ti s B vi rus.
112
FIGURE 10-42
Risk factors associated with reported cases of acute hepatitis C in the United States (1991 to
1995). Hepatitis C transplant infection prior to transplantation has not been definitively
shown in most studies to markedly affect survival for at least 5 years following renal trans-
plantation. Furthermore, hepatitis Cpositive individuals who are otherwise good transplant
candidates appear to have increased survival when transplanted, compared with staying on
dialysis. Liver biopsies performed prior to transplantation have usually shown mild histologi-
cal changes or chronic persistent hepatitis, but sequential biopsies have not been performed
for a long enough period of time and compared with survival to outline the natural history.
Transaminase levels do not help to predict histology or outcome. Death in hepatitis Cpositive
individuals is more often related to infection than in hepatitis Cnegative transplant recipients.
Post-transplant treatment with interferon alpha has led to an unacceptably high rate of both
rejection and acute renal failure secondary to severe interstitial edema without tubulitis.
Additionally, except for a few individuals, interferon has not resulted in long-term viral clear-
ance. Most studies show the return of hepatitis C viremia within 1 month following cessation
of interferon. At this point it appears that hepatitis G infections (also caused by an RNA
virus) in renal transplant recipients, although occasionally associated with slight increases in
chronic hepatitis, are not associated with decreased survival.
Hepatitis C
Injection
druguse43%
Unknown 1%
Household 3% Occupation/hemodialysis4%
Transfusions4%
Sexual 15%
Other high risk 30%
16%Drug-related
4%STD history
1%Prison
9%Low SES
Lipoprotein
envelope
E2/NS1 glycoprotein
E1 glycoprotein
33 nmcore 55 nm RNA
Hepatitis C virus screening in renal transplant candidates
HCV Ab ()
no further testing
unless high-risk behavior
Hepatitis C virus
Screen for HCV by EIA-2 or 3
Liver biopsy
Transplant
PCR
Cirrhosis
Cleared infection
Repeat PCR in high-risk
group in 6 months
Mild changes
CPH (mild hepatitis)
CAH (moderateto
severehepatitis)
Monitor clinically
for the onset of
cirrhosis
Monitor carefully
for infection
Referral for liver
and kidney
transplant
Transplant
HCV (Ab) (+)
+
Interferon treatment
Currently unknown
sustained response
Referral for
FIGURE 10-43
Proposed structure of the hepatitis C virus.
FIGURE 10-44
Hepatitis screening in renal transplant candidates. CAHchronic
active hepatitis; CPHchronic persistent hepatitis; HCV(ab)
hepatitis C virus antibody; PCRpolymerase chain reaction.
113
FIGURE 10-45
The survival of hepatitis C virus (HCV)infected patients after
transplant group 1 or while awaiting transplantation group 2.
Patients who are transplanted have an increased survival. A small
biopsy study of dialysis (n = 14) and transplant (n = 14) patients
showed no difference in histologic progression in transplant recipi-
ents. The amount of fibrosis, however, was slightly increased.
(Adapted fromKnoll and coworkers. [20]; with permission.)
Group I
Group II
Time, m o
F
r
a
c
t
i
o
n

o
f

p
a
t
i
e
n
t
s

s
u
r
v
i
v
i
n
g
0.5
0.6
0.7
0.8
0.9
1.0
12 0 24 36 48
HCV +
HCV
S
u
r
v
i
v
a
l
,

%
0
20
40
60
80
100
MCW Miami UCSF
LRD
UCSF
CAD
NEOB UW
3 yr
HCV +
HCV
S
u
r
v
i
v
a
l
,

%
0
20
40
60
80
100
MCW Miami UCSF
LRD
UCSF
CAD
NEOB UW
3 yr
FIGURE 10-46
Five-year patient (panel A) and graft (panel B) survival in hepatitis C
virus (HCV)positive and HCV-negative patients from recent reports
from United States centers. There is no significant difference over
5 years in patient or kidney graft survival. MCWMedical College
of Wisconsin; MiamiUniversity of Miami; NEOBNew England
Organ Bank; UCSF CAD University of California, San Francisco
with cadaveric donors; UCSF LRDUniversity of California, San
Francisco, with living related donors; UWUniversity of Washington.
114
FIGURE 10-47
Renal and hepatic outcome in patients
treated with interferon alpha post-renal
transplant for hepatitis C virus (HCV)
infection. Interferon treatment results in a
high rate of transplant acute renal failure or
rejection. Transplant biopsies in those with
acute renal failure show severe diffuse
edema. Acute renal failure is not very
responsive to steroids. Virologic clearing is
rare, as HCV-RNA is detectable, on aver-
age, 1 month after discontinuing interferon
if the polymerase chain reaction (PCR)
became negative during treatment. ALT
alanine aminotransferase; SCsubcuta-
neously; TIWthree times a week. (Data
fromThervet and coworkers [21],
Magnone and coworkers [22], Rostaing
and coworkers [23,24], and Yasumura and
coworkers [25].)
RENAL AND HEPATIC OUTCOME IN PATIENTS TREATED WITH INTERFERON
ALPHA FOLLOWING RENAL TRANSPLANT FOR HCV INFECTION
Author
Year
Number treated
HCV +HBV +
DosemU, SC, TIW
Normalization of ALT
Discontinued treatment
Number with cirrhosis
PCR +PCR
RelapsePCR +
Acuterenal failure
Rejection
Lost transplant
New proteinuria
Thervet
1994
13
4
35
1
7
8
NA
NA
2
0
0
NA
Magnone
1995
11
1
1.55
NA
7
NA
NA
NA
0
7
6
NA
Rostaing
1995
14
0
3
10
7
1
4
4
5
0
1
2
Rostaing*
1996
16
NA
3
NA
9
NA
NA
NA
6
0
3
NA
Yasumura
1997
6
0
6
6
0
0
2
0
0
1
0
1
*Most areoverlappingpatientswith the1995study.
Hepatitis G
FIGURE 10-48
Hepatitis G virus (HGV) in renal transplantation: prevalence of
infection and associated findings. Hepatitis G virus is an RNA
virus of the flaviviridae family. Hepatitis G virus was isolated inde-
pendently by two different groups of investigators and called
hepatitis GB viruses by Simmons and colleagues, and hepatitis G
virus by Lenin and colleagues. It now appears that GB virus-A and
GB virus-B are tamarin viruses and GBV-C is a human virus with
sequence homology of more than 95% with the hepatitis GV
sequence. The virus has been shown to be transmitted by transfu-
sions, including plasma products, by frequent parenteral exposure,
including intravenous (IV) drug abuse, by sexual exposure, and by
mother to child transmission. In the United States, the prevalence
of hepatitis G virus is 1.7% among healthy volunteer blood
donors, 8.3% among cadaveric organ donors, and 33% among IV
drug abusers. Among chronic hemodialysis patients, the prevalence
of hepatitis G virus RNA has been variable, ranging from 3.1% in
Japan to 55% in Indonesia and some areas in France. Likewise, the
reported incidence of co-infection with hepatitis B virus (HBV) and
hepatitis C virus (HCV) is extremely variable.
Hepatitis G virus RNA is detected by reverse transcriptase poly-
merase chain reaction (PCR). The development of reliable serologic
assays for hepatitis G has been difficult due to the lack of linear
epitopes expressed by hepatitis G virus. The risk for pretransplant
hepatitis G infection is associated with increasing numbers of
blood transfusions and with longer duration of dialysis. Post-trans-
plantation, most patients with hepatitis G virus remain viremic;
however, patients have been shown to clear the virus post-trans-
plant. At this time, hepatitis G virus does not appear to invoke a
poor outcome after transplantation, either in the form of severe
liver disease or increased mortality; however, the long-term studies
needed to provide a firm conclusion about this have not been per-
formed. The question of transmission of hepatitis G virus via trans-
plantation is still under investigation. NAnot available; NEOB
New England Organ Bank. (Data fromDussol and coworkers [26],
Murthy and coworkers [27], and Fabrizi and coworkers [28].)
HEPATITISG VIRUSIN RENAL TRANSPLANTATION:
PREVALENCE OF INFECTION AND ASSOCIATED FINDINGS
Author
Year
Location
%infection
%with HCV infection
%with chronic ALT elevation
Rejection rate
%with HBsAg
Survival versusHGV negative
Dussol
1997
Marseille
28%
12.5%
12.5%
Unchanged
8%
NA
Murthy*
1997
NEOB
18%
28%
35%
Unchanged
NA
Unchanged
Fabrizi
1997
Milan
36%
91%
18%
NA
18%
NA
*Onepatient mayhaveacquired HGV through thedonor organ. Fiveof 10pretransplant
positivepatientsbecameHGV RNA negativepost-transplant.
115
FIGURE 10-49
Kaplan-Meier estimate of graft survival among recipients with
GBV-C RNA and without GBV-C RNA before transplantation.
Death with a functioning graft is included as a cause of graft loss.
The relative risk of graft loss among recipients with pretransplanta-
tion GBV-C RNA (and 95% CI of the risk) was calculated using a
proportional hazards model. The number of patients at risk at the
beginning of each 12-month interval is provided. (Adapted from
Murthy and coworkers [27]; with permission.)
GBV-C negative
GBV-C positive
GBV-C neg.
GBV-C pos.
Relativerisk: 0.88(0.37, 2.09)
P
r
o
b
a
b
i
l
i
t
y

o
f

g
r
a
f
t

s
u
r
v
i
v
a
l
0.0
0 12 24 36 48
Time, m o
60 72 84 96 108
79 63 58 54 50 46 35 26 14 0
16 12 10 10 10 10 9 9 4 0
0.2
0.4
0.6
0.8
1.0
Value of Pretransplant Liver Biopsy
FIGURE 10-50
Liver biopsy in the evaluation of hemodialysis patients who are
renal transplant candidates. Seventy-four patients were biopsied.
Forty-six percent of patients had normal or nonspecific changes in
their liver biopsies, 30% CAH, 11% CPH, and 3% cirrhosis. Liver
enzymes are poor predictors of histology in ESRD. Although with
current management HBV-positive and HCV-positive recipients can
enjoy comparable 10-year survival to noninfected patients, those
with moderate to severe hepatitis more frequently progress histolog-
ically and may develop sepsis or liver failure. Liver biopsy aids in
the long-term plan for the individual patients immunosuppression
and hepatic and infection monitoring. Furthermore, pretransplant
antiviral medications may be beneficial, especially interferon, where
post-transplant administration is not advisable because of markedly
increased rates of acute renal failure and rejection.(Adapted from
zdogan and coworkers. [29]; with permission.)
Hepati ti s A i nfecti ons are associ ated wi th acute hepati ti s
and, on occasi on, wi th acute renal fai l ure. Hepati ti s A i nfec-
ti ons can be prevented by ei ther usi ng i mmunogl obul i n i njec-
ti ons or, more currentl y, a hepati ti s A vacci ne that i s gi ven as
a two-dose seri es. Thi s i s an i nacti vated vi rus that i s produced
i n human fi brobl ast cel l cul ture and i s gi ven to adul ts as an
i ni ti al and second dose 6 to 12 months l ater. The effecti veness
of thi s vacci nati on has not yet been tested i n renal transpl ant
reci pi ents, nor are there speci fi c gui del i nes on the admi ni stra-
ti on pri or to transpl antati on, but gi ven the l ack of toxi ci ty, i t
may very wel l be advi sed i n the future to gi ve thi s to pati ents
wi th end-stage renal di sease and, speci fi cal l y, to pati ents who
are consi deri ng transpl antati on. CAHchroni c acti ve hepati ti s;
CPHchroni c persi stent hepati ti s; CI RHci rrhosi s; HSTAS
hepati c steatosi s.
HEPATITIS MARKERS AND HISTOPATHOLOGIC DIAGNOSIS FROM LIVER BIOPSIES PRIOR TO TRANSPLANT
HbsAg(+)
Anti-HCV (+)
HBsAgand anti-HCV (+)
Anti-HBsand anti-HCV (+)
Anti-HBs(+)
Total
CAH
2
11
1
8
22
CPH
2
4
8
CIRH
1
2
Normal
1
10
1
9
13
34
HSTAS
3
Other
1
3
5
Total
7
30
2
22
13
74
116
FIGURE 10-52
The occurrence of AI DS i n HI V-i nfected transpl ant reci pi ents
accordi ng to i mmunosuppressi ve treatment. I mmunosuppressi on
i ncl uded cycl ospori ne i n 40 i ndi vi dual s and no cycl ospori ne i n
13 i ndi vi dual s.
The precise natural history of HIV infection following renal
transplantation is still not well delineated. The largest single series
from Pittsburgh analyzed 11 patients who were HIV positive prior
to transplantation and 14 patients who developed HIV infections
following transplantation. Of the 11 patients infected before trans-
plantation, six were alive an average of 3.3 years following trans-
plantation. Five patients had died, however; three of AIDS-related
complications. Of the 14 patients infected peritransplantation,
seven patients were alive at follow-up an average of 4.8 years later.
There had been seven deaths, three due to AIDS. Complications
seemed to correlate with increased immunosuppression for rejec-
P=0.001
No cyclosporinetreatment (n =13)
Cyclosporinetreatment (n =40)
P
r
o
p
o
r
t
i
o
n

o
f

p
a
t
i
e
n
t
s

w
i
t
h

A
I
D
S
0.0
0 6 12 18 36 48 30
Months sincetransplantation-related HIV-1 infection
60 54 42 24 66
0.1
0.3
0.5
0.6
0.2
0.4
0.7
0.8
0.9
1.0
FIGURE 10-51
Viruses that cause interstitial nephritis in renal transplant recipi-
ents. Consider this condition when nonspecific inflammation is
seen on biopsy or unexplained rejection occurs. Viruses may cause
renal disease by direct infection of the glomerular and/or tubular
cells or by the immune response directed against virally infected
cells. Most commonly nonspecific interstitial inflammation is seen
but severe tubular injury by mononuclear cells, peritubular inflam-
mation, and interstitial fibrosis may also be seen. The presentation
of virally mediated interstitial nephritis may be acute or subacute.
In addition to routine light microscopy, occasionally evaluation by
immunofluorescence, electron microscopy, or special stains for light
microscopy are necessary to make the diagnosis.
Viral Interstitial Nephritis
VIRAL INTERSTITIAL NEPHRITIS
Adenovirus
BK virus
Cytomegalovirus
Epstein-Barr virus
Herpessimplex virus1, 2, 6
Varicella-zoster virus
Hantavirus
HepatitisC viruspossible
HIV
HIV
tion. Another report evaluating 53 patients infected with HIV
around the time of transplantation found that patients treated with
cyclosporine appeared to have a better long-term prognosis than
those who were treated with prednisone and azathioprine.
In summary, although there are no firm conclusions, it appears
that there is not much difference between pre- or post-transplant
acquisition of HIV infection, although some authors, based on
small numbers of patients, have concluded that the age of the
patient and the duration of the infection are both prognostic fac-
tors. It also appears that approximately 25% of HIV-infected indi-
viduals do poorly within the first 6 months of transplantation,
especially following antirejection treatment (Rubin, unpublished
data). Another 25% of individuals appear to do very well 6 years
and beyond following transplantation. The remainder of the indi-
viduals seem to develop AIDS within 3 to 3.5 years after transplan-
tation, with an average survival of about 3 months after the onset
of AIDS. It has also been noted that cytomegalovirus or other
infections that may increase HIV proliferation may influence this
outcome, and that prophylactic antimicrobial strategies may alter
the natural history.
Currently, it is advised that all transplant candidates be
screened for the presence of HIV antibody and counseled about
the possible consequences of further immunosuppression, but
not be categorically denied transplantation if they are otherwise
asymptomatic. Patient management following transplantation
should be focused on the avoidance of large increases in immuno-
suppression and opportunistic infections, with special attention to
the viral, pneumocystic, and mycobacterial infections that these
individuals may develop. Antiretroviral strategies in transplanta-
tion require study. (Adapted fromSchwarz and coworkers [30];
with permission.)
117
Linear esophageal ulcers caused by herpes simplex virus (HSV) and
Candida. Infection with HSV-1 and -2 leads to stomatitis and
esophagitis post-transplantation without acyclovir prophylaxis.
Additionally, paronychia, corneal ulcers, encephalitis, genital
lesions, disseminated involvement of the gastrointestinal tract, pan-
creas, and liver, and interstitial nephritis has been seen. HSV-6
causes exanthem subitum in children, mononucleosis, and hepati-
tis. There has been some evidence that reactivation infections may
be associated with rejection in transplant recipients. Both reactiva-
tion and reinfection may occur. HSV-8 is associated with Kaposis
sarcoma. Prevention of these infections has been achieved using
prophylactic acyclovir following transplantation. If clinical symp-
toms occur from HSV, they usually are treated with acyclovir
adjusted for renal function.
Herpes Simplex Virus
Varicella-zoster virus (VZV) infection. Primary VZV infections usu-
ally result in typical vesicular eruptions of generalized onset with-
out dermatomal localization. Reactivation infection of the virus
from the dorsal root ganglion usually causes a dermatomally local-
ized vesicular eruption. By the time of renal transplantation, over
94% of adults have evidence of a prior VZV infection. In those
patients previously infected, antibody titers increase following
transplantation. Pretransplant screening is recommended to advise
the patient on treatment of post-transplant exposures. Post-trans-
plant exposures to zoster or chickenpox in the nonimmune individ-
ual should be treated with acyclovir, famcyclovir, or varicella-zoster
immune globulin. Immune globulin is rarely required at this time.
Patients with the new onset of varicella infection following trans-
plantation or with diffuse zoster should be treated with intra-
venous acyclovir, 10 mg/kg, three times per day, or famcyclorir
depending on renal function. Infection in the transplant recipient,
particularly in those who are primarily infected, can result in
encephalitis, disseminated intravascular coagulation, pneumonia,
bowel involvement, pancreatitis, dermatitis, and hepatitis.
The attack rate in nonimmune individuals of household contacts
with varicella infections is 80% to 90%. Therefore, if individuals
have not previously had varicella infections at the time of transplant
evaluation, vaccination with a live attenuated strain could be consid-
ered. Recently this strategy has been used in children prior to renal
transplantation. Attack rates in vaccinated individuals may be up to
31%, but the disease that develops is much milder compared with
those susceptible individuals not previously vaccinated. Should resis-
tant strains of varicella develop, foscarnet has been effective.
Foscarnet is associated with a renal decline in renal function.
(Adapted fromFriedman-Kien [31]; with permission.)
118
FIGURE 10-55
Adenovirus infection of the colon. Adenovirus infections normally
cause asymptomatic infections, coryza, or pharyngitis. Infection in the
first decade of life usually protects individuals from future infection as
long as the immune system is intact; however, in transplant recipients,
adenovirus types 11, 34, and 35 have been shown to cause interstitial
pneumonia, conjunctivitis, hemorrhagic cystitis, hepatitic necrosis,
interstitial nephritis and gastroenteritis, and disseminated disease.
Adenovirus infection may be latent prior to transplant and reac-
tivate post-transplant, or a primary infection may be acquired.
Adenovirus has been shown to infect the bladder, uroepithelial
cells, renal tubular cells (distal greater than proximal), the
endothelium of the glomeruli and peritubular capillaries, and,
occasionally, mesangial cells. The outcome of adenovirus infection
is related to the type of immunosuppression and the recipient age.
The death rate during active infection in renal transplantation may
be as high as 18% but may be even higher in younger patients.
The onset of disease after transplantation is usually within 6
months of the transplant.
Clinically, the most frequent symptoms of an adenovirus infec-
tion involve difficult micturition, including gross hematuria, fever,
and, occasionally, renal dysfunction. The diagnosis is suspected
when bacterial cultures are negative but there is gross hematuria.
The urinary symptoms usually last 2 to 4 weeks. The diagnosis is
made by urine culture or by electron microscopy or light
microscopy, where adenoviruses are seen as intranuclear
basophilic viral inclusions with a narrow halo between the inclu-
sions and the nuclear membrane. Treatment has been somewhat
successful using ganciclovir. Interferon therapy is difficult because
of the risk of acute renal failure or rejection in transplant recipi-
ents. Furthermore, efficacy is questionable because of the virus
ability to inhibit the mode of action of interferon. Ribavirin has
successfully cleared the virus in several immunosuppressed
patients. The use of IVIG has not been associated with reliable
results. In the future, cidofovir may also be used for the treatment
of adenovirus infections, but renal insufficiency and proteinuria
may limit use.
CENTRAL NERVOUS SYSTEM INFECTION IN THE TRANSPLANT RECIPIENT
Incidence5%; mortalityup to 85%for CNSinfections
Acuteto subacute
L. m on ocy t ogen es
Subacuteto chronic
Cry pt ococcu s n eoform a n s
M y cob a ct eriu m t u b ercu losis
Coccid iod es im m it is
Focal brain infection
A spergillu s
T. gon d ii
N . a st eroid es
Ca n d id a a lb ica n s
Cry pt ococcu s
Progressivedementia
Polyomavirus, HSV, CMV, HIV
Symptoms
Headachemaybemild, mayhavelittlemeningismus
Fevermaybemild
altered consciousness
Cerebrospinal fluid
Lymphocytic pleocytosis
(viral/fungal/MTB)
Hypoglycorrhaia
Neutrophilic pleocytosis(bacterial)
Over three-fourthsof central nervoussysteminfection
isaccounted for by
C. n eoform a n s
A . f u m iga t u s
Timing
Early
List eria
N oca rd ia
Tox opla sm a
A spergillu s
Lateasaboveand dueto chronic enhanced immuno-
suppression plusCry pt ococcu s and tuberculosis
Diagnosis
CT scan identifieshypodensering-enhancinglesions
CSFexamination
Directed lesional aspirates
FIGURE 10-56
Central nervous system infection in the
transplant recipient. CNScentral nervous
system; CSFcerebrospinal fluid; MTB
mycobacterium tuberculosis.
119
FIGURE 10-57
Causes of headache in the transplant recipient. ACEangiotensin-
converting enzyme; CNScentral nervous system; ATGantithy-
mocyte globulin.
CAUSES OF HEADACHE IN THE TRANSPLANT RECIPIENT
Medications
OKT3(aseptic meningitis)
ATG
IVIgG
Cyclosporine
Tacrolimus
Antihypertensives
Calciumchannel blockers
ACEinhibitors
Nitrates
Hydralozine
Minoxidil
Hypertension
Neck tension,musclepulls, ligamental irritation
Sinusitis
Ocular abnormalities
Excessivevomiting
Migraineheadachesexacerbated bycyclosporine, tacrolimus, and
calciumchannel blockers
Stroke
Infection of thecentral nervoussystem
FIGURE 10-58
Work-up of an unexplained headache.
WORK-UP OF AN UNEXPLAINED HEADACHE
History
Character, pattern, positional relationships
Fever, duration of headacheand fever
Location of headache
Visual, movement, sensoryimpairment
Bowel or bladder incontinence
Trauma
Medicationsold and new
Timeof medicationsand relationshipsto headache
Eye
Neurological
Completetherest of theexamination
If no papilledemaor focal neurological deficitlumbar puncture
If papilledemaor focal deficitCT first if no masslesionlumbar puncture
Cerebrospinal fluid issent for
Cell count and differential
Protein
Glucose
Gramsstain
Fungal stains
Acid fast stain
Fungal culture
Mycobacterial cultures
Bacterial cultures
Cryptococcal antigen
Savecerebrospinal fluid in addition for other testsincluding
Hist opla sm a ca psu la t u m or Coccid iod es im m it is antibodytiters
FIGURE 10-59
Epstein-Barr virus (EBV). EBV is associated with asymptomatic infection, mononucleosis,
hepatitis, and, rarely, interstitial nephritis. In transplant recipients, posttransplant lympho-
proliferative disorder (PTLD) is also associated with EBV. EBV promotes B-cell prolifera-
tion, if left unchecked by immunosuppressive agents targeting the T-cell system. This chest
radiograph shows multiple pulmonary nodules of PTLD. Symptoms vary from no symp-
toms to diffuse organ involvement causing dysfunction. Any area of the body may be
involved, with frequent sites being the gums, chest, abdomen, and central nervous system.
PTLD occurs during the first posttransplant year in approximately 50% of those devel-
oping PTLD. It is seen in 1% to 2% of renal transplant recipients. Primary EBV infection
following transplantation and antilymphocyte agent use is associated with an increased
risk. Increasing quantitative blood EBV DNA levels may predict the onset of PTLD.
120
VIRAL MENINGITIS
Causal agents
Enterovirus
Coxsackie*
ECHO*
Poliovirus
Adenovirus
Mumps
Arbovirus
Herpesgroup
Cytomegalovirus*
Herpessimplex virus1and 2*
HHV-6*
HHV-8*
Varicella-zoster virus*
Epstein-Barr virus*
Coronavirus
HIV
InfluenzaA, B
Lymphocytic choriomeningitisvirus
Parainfluenzavirus
Rabiesvirus
Rhinoviruses
Rotavirus
Japaneseencephalitisvirus*
Tick borneencephalitisvirus
PML (JC) virus(in development)*
BK virus(in development)*
FIGURE 10-60
Viruses causing meningitis in transplant
recipients. The presentation is usually with
fever and headache alone or in conjunction
with headache may be the initial symptom.
Nuchal rigidity is rare in the transplant
patient. Cerebrospinal fluid samples should
be saved for viral analysis and analysis
should be requested if the diagnosis is not
rapidly available from standard studies.
Viral Meningitis
Black hairy tongue is the result of hypertrophy of filiform papillae
of the tongue, often seen in transplant patients after antibiotic
treatment. The origin is unknown but is associated with topical or
systemic antibiotics, poor oral hygiene, smoking, alcohol, and the
use of mouthwashes. Most often there are no symptoms; however,
nausea, gagging, taste alteration, or halitosis are reported by some
patients. Treatment includes brushing with a soft brush and, occa-
sionally, topical vitamin B, salicylic acid, gentian violet, or surgical
removal. This entity is not to be confused with hairy leukoplakia,
which is composed of white corrugated plaques on the lateral sur-
face of the tongue. These lesions may be small and flat or exten-
sive and hairy. Microscopic evaluation shows epithelial cells with
herpetic viral inclusions, specifically Epstein-Barr virus. Treatment
is oral acyclovir.
Black Hairy Tongue
* Cerebrospinal fluid polymerasechain reaction availableto makethediagnosisbut locationsvary
Increased in transplant patients

121
Tinea versicolor (pityriasis versicolor) is a chronic superficial fungal
disease caused by Malassezia furfur, a yeast normally found on the
skin. It is in yeast form in the unaffected skin areas and in the
mycelial phase on affected skin. The disease usually is located on
the upper trunk, neck, or upper arms. Symptoms may include scal-
ing, erythema, and pruritis. It may appear as slightly scaly brown
macules or whitish macules. Treatment options include oral or topi-
cal terbinafine (1% cream or gel), oral or topical ketoconazole, oral
fluconazole, or topical treatments, such as ciclopiroxolamine, piroc-
toneolamine, zinc pyrithione, or sulfur-containing substances, such
as selenium sulfide; the most common treatment is selenium.
Patients are asked to wet themselves in the shower, turn off the
water, apply the selenium and let it sit for 10 minutes, and then
rinse. Also, oral fluconazole, 200 mg, once or repeated once a week
later is a simple and effective treatment. Of note, oral terbinafine,
250 mg, daily for 12 weeks is associated with slightly decreased
cyclosporine levels. Terbinafine is an allylamine that binds to a
small subfraction of hepatic cytochrome P450 in a type I fashion.
Side effects seen during terbinafine use include gastrointestinal dis-
tress in up to 5% of patients and skin rashes in 2% of patients.
Tinea Versicolor
Kaposis Sarcoma
Kaposis sarcoma of the lower leg in a male transplant recipient.
Kaposis sarcoma is a tumor, perhaps of lymphatic endothelial origin,
that presents as purple papules or plaques that advance to nodules of
the extremities, oral mucosa, or viscera. In transplant recipients it pre-
sents on average by 21 months post-transplant, with the largest num-
ber (46%) within the first post-transplant year. It is seen most often in
men (3:1) and in those of Arabic, black, Italian, Jewish, and Greek
ancestry. It accounts for 5.7% of the malignancies reported to the
Cincinnati Transplant Tumor Registry (nonmelanoma skin cancers
and in situ carcinomas of the uterine cervix excluded). Transplant
programs in Italy and Saudi Arabia have reported higher rates of
post-transplant Kaposis sarcoma. Visceral involvement is less com-
mon in the transplant recipient than in the AIDS patient, but it must
be remembered that it may be seen in the liver, lungs, gastrointestinal
tract, and nodes. Mortality is increased with visceral involvement
(57% versus 23%). HHV-8 has been proposed as the causal agent
of this tumor; however, not all investigators feel the evidence is con-
clusive. Of note, the occurrence in AIDS patients is decreased in those
who receive foscarnet, cidofovir, and ganciclovir, but not acyclovir.
Treatment includes decreasing immunosuppression, local radiation,
excision, interferon, or chemotherapy.
122
FIGURE 10-64
Mucormycosis is caused by fungi of the order Mucorales, including
Rhizopus, Absidia, and Mucor. Mucorales are ubiquitous sapro-
phytes found in the soil and on decaying organic material, including
bread and fruit. Human infection is believed to be caused by the
inhalation of spores that initially land on the oral and nasal
mucosa. Direct inoculation into tissues, however, has been reported.
Mucormycosis
Most of the spores, once in the tissue, are contained by the phago-
cytic response. If this fails, as it often does in patients with diabetes
mellitus and those otherwise immunosuppressed, germination
begins and hyphae develop. The hyphae, as shown in the micro-
graph, are large, nonseptate, rectangular, and branch at right angles.
Infection begins with the invasion of blood vessels, which causes
necrosis and dissemination of the infection. The most common site
of involvement is the rhino-orbital-cerebral area, accounting for
approximately 70% of cases; however, pulmonary, cutaneous, gas-
trointestinal, and disseminated infection may be seen. The chest
radiograph during pulmonary infections may show an infiltrate,
nodule, cavitary lesion, or pleural effusion. Gastric involvement may
range from colonization of peptic ulcers to infiltrative disease with
vascular invasion causing perforation. Although classic for
mucormycosis, a black eschar of the skin, nasal mucosa, or palate is
present in only about 20% of patients early in the course of the dis-
ease and cannot be relied on for assistance in early diagnosis.
Survival is dependent on early diagnosis. Diagnosis is by biopsy
with classic histologic findings and by culture of tissue. Treatment
includes amphotericin B, surgical removal of the lesion, packing of
the sinus areas with amphotericin Bsoaked packs, and perhaps
hyperbaric oxygen. Liposomal amphotericin B has also been effec-
tive. Treatment must include both surgery and amphotericin B.
A B
FIGURE 10-65
Condyloma acuminata (anogenital/venereal warts) are caused by
infection with human papillomavirus 6 or 11. In transplant recipi-
ents they may become extremely extensive. Treatment has included
fluorouracil, podophyllin, podophyllotoxin, intralesional interfer-
on, topical interferon, systemic interferon, and, more recently,
imiquimod, which causes the induction of cytokines, especially
interferon alpha. Lesions have responded in 50% of nontransplant
patients receiving the 5% cream. Invasive treatments have included
surgical excision, cryotherapy, electrocautery, and carbon dioxide
laser. Recurrences are common. A, Condyloma acuminata in a
male transplant recipient. B, Condyloma acuminata in a female
transplant recipient.
Condyloma Acuminata
123
FIGURE 10-66
Verruca vulgaris (common warts) are caused by human papillo-
maviruses 1, 2, 3, 4, 5, 8, 11, 16, and 18, as well as others, with
the highest percentage by type 4. Warts are found most often on
the fingers, arms, elbows, and knees and are much more numerous
in the immunosuppressed patient. Treatment modalities have been
the same as for condyloma acuminata, with the addition of topical
cidofovir and hyperthermia. Therapy should be planned based on
the location, extent, and size of the lesions. Not all lesions need
treatment. Early dermatologic referral is needed for those lesions
that appear to be advancing rapidly as certain papilloma viruses
(16, 18, 31, 51, 52, 56) have been associated with squamous cell
carcinomas of the skin and cervix. A and B, Verruca vulgaris of the
finger and knee. Note the large size and multiple warts. C, Verruca
planae, flat warts at multiple locations of the hand, also often seen
on the face.
Verruca Vulgaris
A
C
B
124
FIGURE 10-67
Molluscum contagiosum is an infection of
the skin caused by the molluscum contagio-
sum virus, a member of the pox virus family.
Molluscum does not grow in culture or
infected laboratory animals. Manifestations
are pearly, pink, dome-shaped, glistening,
firm lesions; in immunosuppressed patients,
however, they may be over 1 cm in diameter
and multiple lesions may occur together. The
infection usually lasts up to 2 months in
immunocompetent patients, but a chronic,
recalcitrant, and disfiguring infection may
occur in immunosuppressed patients. The
virus is contracted and spreads via close con-
tact with an infected person, fomites, or via
autoinoculation. The incubation period is 2
weeks to 6 months. The diagnosis is made
visually or by direct examination of curet-
tings from the center of the lesion showing
molluscum intracytoplasmic inclusion bod-
ies. Treatment is started for the prevention of
spreading, to relieve symptoms, and for cos-
metic reasons. Treatment includes cryothera-
py, curettage, podophyllin, cantharidin,
trichloroacetic acid, phenol, salicylic acid,
strong iodine solutions, lactic acid, tretinoin,
silver nitrate, and interferon alpha topical or
intralesional, and possibly oral cimetidine,
with adhesive tape occlusion. None of the
available treatments result in a rapid or defi-
nite clearance in the immunosuppressed
patient. Treatment of the underlying retro-
virus infection has been shown to help in
AIDS patients, and perhaps reviewing the
degree of immunosuppression in the trans-
plant patient will help. A, Molluscum conta-
giosum papule. Note pearly umbilicaled
appearance. B, Histologic slide of molluscum
showing a cross section of the papule.
C, Close-up view of the molluscum bodies.
Molluscum Contagiosum
A
B
C
125
Intestinal Protozoa
SIMILARITIES AMONG THE INTESTINAL SPORE-FORMING PROTOZOA
History
Identified ashuman pathogensin recent decades
Onceconsidered rarepathogens; now known to commonlycauseinfections
TheAIDSepidemic increased awarenessand recognition
Biology
Protozoa
Intracellular location in epithelial cellsof theintestine
Sporeor oocyst formisshed in stool
Pathogenesisof diarrhea
Unknown; possibleabnormalitiesof absorption, secretion, and motility
Intenseinfection of small bowel associated with denseinflammatoryinfiltrate
Maybeassociated with villusbluntingand crypt hyperplasia
Nonulcerativeand noninvasive*
Gut function and morphologyrelated to number of organisms
Epidemiology
Common in tropical regionsand placeswith poor sanitation
Transmission isthrough fecal-oral route, person-to-person contact, and
water or food
Endemic diseaseof children
Common sourceof epidemicsin institutionsand communities
Maycausetravelersdiarrhea
Clinical manifestations
Asymptomatic infection
Self-limited diarrhea, nausea, and abdominal discomfort in healthychildren and adults
Prolonged (subacute) diarrheain someimmunocompetent patients
Chronic diarrheain immunodeficient patients

Diagnosis
Microscopic stool examination should beinitial approach
Detection of cystsor sporesin stool requiresexpertiseand proper stains
Antibiotic treatment
Not usuallyindicated in healthypersonswith acuteinfection
Indicated for chronic infection in immunodeficient patients
*Septataintestinalismayinvadethemucosa.
Probablytruefor all; conclusivelyshown onlyfor cryptosporidia.
Not proven for microsporidia.

FIGURE 10-68
Cryptosporidia, I sospora, cyclospora, and microsporidia are
intestinal spore-forming protozoa that infect enterocytes predomi-
nately of the small intestine. Infection occurs by ingesting the
spores (oocytes) by person-to-person contact or ingesting contami-
nated food or water, including city or swimming pool water [32].
Infections in immunocompetent individuals may be asymptomatic
or self-limited and associated with mild to moderate diarrhea and,
less frequently, nausea, abdominal cramping, vomiting, and fever.
In immunodeficient patients, especially those with T-cell impair-
ment, the infections may cause severe persistent diarrhea. The most
common infection among the intestinal protozoas is cryptosporidi-
um. The general prevalence of cryptosporidia in stool specimens in
Europe and North America is 1% to 3%, and in Asia and Africa is
5% to 10%. Antibodies to cryptosporidia, however, have been
found in 32% to 58% of adults. (Adapted fromGoodgame [33];
with permission.)
126
FIGURE 10-69
Histoplasmosis is caused by the thermal dimorphic fungus
Histoplasma capsulatumthat exists in its mycelial phase in nature
and in the yeast form in the human body. It is found in the soil
enriched with bird or bat droppings in the Ohio and Mississippi
River Valleys and in Texas, Virginia, Delaware, and Maryland.
Disease is caused by primary infection or by reactivation of latent
infection. Primary infection is acquired by inhalation of infectious
microconidia, by direct inoculation into the skin, or via an infected
allograft. Once the microconidia is lodged in the alveolar and
Histoplasmosis
interstitial spaces, it becomes a yeast, multiplies intracellularly, and
disseminates until cell-mediated immunity develops (2 to 10 weeks).
Organisms that disseminate concentrate in the reticuloendothelial
system. Disseminated disease is marked by fever, weight loss, weak-
ness, fatigue, and mild respiratory symptoms. There may also be
organ-specific symptoms, including those of urinary tract obstruc-
tion. Histoplasma may be found in the glomerular capillary macro-
phages or macrophages within the interstitium and be associated
with focal medullary necrosis or papillary necrosis. The most com-
mon symptom of infection is fever, and often there are skin lesions,
as shown in this figure, but central nervous system involvement is
rare in transplant patients, as are abnormal chest radiographs.
When present, chest radiographic findings include diffuse, nodular,
patchy, or miliary infiltrates; hilar adenopathy is uncommon.
Diagnosis is made by identification of the yeast on a smear,
histopathologic detection of intracellular organisms in viable pul-
monary tissue, a fourfold rise in antibody titers (only seen in about
50% of immunosuppressed patients), culture of the blood or tissue,
or a urine antigen assay. Identification of the organism causing
culture growth of a white, fuzzy mold (Histoplasma, Blastomyces,
Coccidioides) is now performed by DNA hybridization. The bone
marrow may be the most reliable source for sampling and staining
for organisms. Treatment is amphotericin B occasionally, with
long-term oral intraconazole after completing amphotericin.
Resolution of infection may be monitored by following the
Histoplasma urinary antigen.
FIGURE 10-70
Cutaneous cryptococcosis, multiple lesions on the arm. Cryptococcus
neoformans is an encapsulated yeast that exists worldwide, pre-
dominately in the soil contaminated by bird and other animal
droppings. Infection is through inhalation with dissemination to
the central nervous system (CNS), skin, mucous membranes, bone,
bone marrow, and genitourinary tract. Infection has also occurred
through the renal allograft. The most common disease site is the
Cryptococcosis
CNS, where patients present with headache, fever, mental confu-
sion, seizures, papilledema, long tract signs, or, uncommonly,
meningismus. The onset of infection is anywhere from 6 months
to years following transplantation. The onset may be very insidi-
ous, with nausea and headache occurring for weeks to months
before the fever develops. Pulmonary involvement presents asymp-
tomatically or with dyspnea and cough. The chest radiograph
shows wide variability in that circumscribed pulmonary nodules,
alveolar infiltrates, interstitial infiltrates with or without effusions,
and cavitation may be seen. Cutaneous disease may be the first
sign of dissemination in up to 30% of cases. Diagnosis is made by
the identification of the yeast in the cerebrospinal fluid (CSF) or
pulmonary secretions, the detection of cryptococcal antigen in the
CSF or blood, or culture. Amphotericin B is the most common
agent used for treatment, with some also favoring the use of flucy-
tosine and perhaps azole therapy for maintenance to prevent
relapse. Specific patients may be treated with fluconazole alone.
Serial determinations of the serum cryptococcal antigen, which is
positive in over 95% of patients with cryptococcal meningitis, may
help to follow and modify the course of therapy. Patients should
be treated until the cryptococcal antigen is negative, and then for
another 2 to 4 weeks for added safety.
127
Primary oral herpes simplex, mucosal membrane showing vesicles
and ulceration.
Primary herpes simplex stomatitis.
Herpes Simplex
FIGURE 10-73
Cutaneous herpes simplexherpetic whitlow. This condition may be
confused with a bacterial infection.
128
Central Nervous System Infections
CEREBROSPINAL FLUID FINDINGS BY TYPE OF MENINGITIS
Type
Viral
Fungal
Tuberculous
Bacterial
WBC Count (per mm)
5.500
40400
1001000
400100,000
Differential, %
>50lymphocytes
>50lymphocytes
>80lymphocytes
>90PMNs
Protein Level, mg/dL
30150
40150
40150(mayexceed 400)
80500
Glucose level, mg/dL
Normal to low
Normal
Normal to low
<35
Stain used
Grams
Indiaink and cryptococcal antigen
Acid-fast
Grams
FIGURE 10-74
Cerebrospinal fluid findings in patients with bacterial meningitis.
(Adapted fromMaxon and Jacobs [34]; with permission.)
References
1. Rubin RH, Wolfson JS, Cosimi AB, et al.: Infection in the renal trans-
plant recipient. Am J Med 1981, 70:405411.
2. Rubin RH: Infectious disease complications of renal transplantation.
Kidney I nt 1993, 44:221236.
3. Stratta R: International Congress on Immunosuppression, Orlando,
FL, 1998.
4. Isada CM, Kastan BL, Goldman MD, et al.: Infectious Disease
Handbook, edn. 2. Lexi Comp, Inc., 19971998.
5. Maguire GP, Wormser GP: Preventing infections in the immunocom-
promised: Part 2. J ournal of Respiratory Diseases 1994, 15:408.
6. Lake KD: Management of drug interactions with cyclosporine.
Pharmacotherapy 1991, 11:110S118S.
7. Yee GC: Pharmacokinetic interactions between cyclosporine and other
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8. Drugs for tuberculosis [letter]. Med Lett Drugs Ther 1992, 24:1012.
9. Fishman JA: Pneumocystis carinii and parasitic infections in trans-
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10. Hadley S, Karchmer AW: Fungal infections in solid organ transplant
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11. Harnett JD, Zeldis JB, Parfrey PS, et al.: Hepatitis B disease in dialysis
and transplant patients: further epidemiologic and serologic studies.
12. Pirson Y, Alexandre GPJ, van Ypersele de Strihou C: Long-term effect
of HB
s
antigenemia on patient survival after renal transplantation.
N Engl J Med 1977, 296:194196.
13. Hillis WD, Hillis A, Walker WG: Hepatitis B surface antigenemia in renal
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14. Touraine JL, Traeger J: Renal TX at the University of Lyon. Clin
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15. Dhar JM, Al-Khader AA, Al-Sulaiman MH, Al-Hasani MK: The sig-
nificance and implications of hepatitis B infection in renal transplant
recipients. Transplant Proc 1991, 23:1785-1786.
16. Roy DM, Thomas PP, Dakshinamurthy KV, et al.: Long-term survival
in living related donor renal allograft recipients with hepatitis B infec-
tion. Transplantation 1994, 58:118119.
17. Pfaff WW, Blanton JW: Hepatitis antigenemia and survival after renal
transplantation. Clin Transplant 1997, 11:476479.
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pathologic impact of renal transplantation on chronic hepatitis B virus
infection. Transplantation 1996, 62:297299.
19. Pouteil-Noble C, Tardy JC, Chossegros P, et al.: Co-infection by
hepatitis B virus and hepatitis C virus in renal transplantation: mor-
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20. Knoll GA, Tankersley MR, Lee JY, et al.: The impact of renal trans-
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21. Thervet E, Pol S, Legendre C, et al.: Low-dose recombinant leukocyte
interferon- treatment of hepatitis Cpositive end-stage renal disease
patients: a pilot study. Transplantation 1994, 58:625627.
22. Magnone M, Holley JL, Shapiro R, et al.: Interferon--induced acute
renal allograft rejection. Transplantation 1995, 59:10681070.
23. Rostaing L, Izopet J, Baron E, et al.: Treatment of chronic hepatitis C
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24. Rostaing L, Modesto A, Baron E, et al.: Acute renal failure in kidney
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25. Yasumura T, Nakajima H, Hamashima T, et al.: Long-term outcome
of recombinant INF- treatment of chronic hepatitis C in kidney
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29. Histopathological impacts of hepatitis virus infection in hemodialysis
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130
11
Immunosuppressive
Therapy and Protocols
T
he 1990s have seen major steps in the dissection of basic mecha-
nisms of allorecognition, and renal graft survival has achieved
unprecedented clinical results. Transplantation has turned into a
widespread modality of therapy for patients with chronic renal failure
that benefits thousands worldwide. Combinations of immunosuppres-
sive agents have proved to be an effective strategy to inhibit diverse
pathways of the multifaceted immune system, allowing the reduction of
both dosage and adverse effects of each individual drug. As under-
standing of the molecular basis of the immune response has expanded
rapidly, so have the possibilities for designing therapeutic interventions
that are more effective, more specific, and safer than are current treat-
ment options. As we reach the end of the century, several different and
innovative approaches will add to this fascinating and complex therapy.
A ngel o M . d e M a t t os
CHA P T ER
131
Calcineurin
Csa/Cyp
DNA DNA
RNA
P
Ca
IL-2
X
NF-AT box
NF-ATc
Tac/FK-BP
p p
Rapa/FKBP
eIF-4F
PHAS-1
PHAS-1
IL-2 receptor
IL-2
m-TOR
G
1
G
0
M G
2
S
FIGURE 11-1
Mechanism of action for cyclosporine (Csa) and tacrolimus (Tac).
The common cytoplasmic target for cyclosporine and tacrolimus is
calcineurin. After binding to cyclophillin (Cyp), cyclosporine inter-
acts with calcineurin, inhibiting its catalytic domain. Thus dephos-
phorylation of transcription factors is prevented, as exemplified by
the nuclear factor of activated T lymphocyte (NF-AT). Despite hav-
ing a different ligand called FK-binding protein (FK-BP), tacrolimus
inhibits calcineurin in a similar way. Because phosphorylated tran-
scription factors cannot cross the nuclear membrane, the production
of key factors for lymphocyte activation and proliferation (ie, inter-
leukin-2, tumor necrosis factor-, interferon, c-myc, and others) is
inhibited [1]. NF-ATcnuclear factor of activated T-lymphocyte-
cytoplasmic form; Pphosphorus; Cacalcium.
FIGURE 11-2
Proposed mechanism of action for rapamycin (rapa). Rapamycin
binds to FK-binding protein (FK-BP). However, the immunosup-
pressive properties of rapamycin are not due to inhibition of cal-
cineurin. Rapamycin blocks the activating signal delivered by
growth factors (exemplified by the interleukin-2 [IL-2] receptor)
by blocking the translation of the coding of messenger RNA
(mRNA) for key proteins required for progression through the
G
1
phase of the cell cycle. In this model the mammalian target of
rapamycin (m-TOR, also called FRAP or RAFT1), phosphorylates
the translational repressor PHAS-I. Arrest of the cell cycle results,
and the proliferation of lymphocytes is thereby inhibited. The full
understanding of the mechanism(s) of action of rapamycin is the
focus of intense research at this time [2]. elF-4translation initia-
tion factor belonging to the Ets family; G
(0,1, and 2)
quiescent;
Mmitosis; Ssynthesis.
132
11.3 Immunosuppressive Therapy and Protocols
PRPP
IMP
AMP
ATP
GMP
GTP
HGPRT
HGPRT
Energy, signaling
Guanine+PRPP
A z a t h ioprin e
6-m -M P 6-M P
Th iou ric a cid
M y coph en ola t e , m iz orib in e
Energy RNA, DNA Glycoproteins
A llopu rin ol
HGPRT
T IM P
PRPP +Adenine
Hypoxanthine+PRPP
I
M
P
D
FIGURE 11-3
Mechanism of immunosuppression of
azathioprine and mycophenolate mofetil
(MMF). Azathioprine and MMF prevent
lymphocyte proliferation by way of inhibi-
tion of purine base synthesis, thus resulting
in decreased production of the building
blocks of nucleic acids (ie, DNA and RNA).
Azathioprine is metabolized to 6-mercap-
topurine (6-MP), which is further converted
to 6-ionosine monophosphate. This mole-
cule inhibits key enzymes in the de novo
pathway of purine synthesis (adenosine
monophosphate [AMP] and guanosine
monophosphate [GMP]). MMF is metabo-
lized to mycophenolic acid, which is a non-
competitive inhibitor of the enzyme that
converts inosine monophosphate (IMP) to
GMP. The depletion of GMP may have
effects other than inhibition of nucleic acid
production. Some events of T-lymphocyte
activation are independent of guanosine
triphosphate (GTP), as is the assembling of
certain adhesion molecules. ATPadenosine
triphosphate; HGPRThypoxanthine-gua-
nine phosphoribosyl transferase; IMPD
inosine-monophosphate dehydrogenase;
PRPPphosphoribosyl pyrophosphate;
6-m-MP6-methyl-mercaptopurine; TIMP
thioinosine monophosphate. (Adapted from
de Mattos and coworkers [3,4].)
}
}
}
}
1 week 1 month
Csaor FK-506
Csaor FK-506
Csaor FK-506
Csaor FK-506
Csaor FK-506
Csaor FK-506
Azaor MMF
Azaor MMF
Azaor MMF
Azaor MMF
Steroid
Steroid
Steroid
Steroid
Antilymphocytic
Antilymphocytic
Monotherapy
Dual therapy
Tripletherapy
Quadruple
therapy
(induction versus
sequential)
FIGURE 11-4
Summary of strategies for combining immunosuppressive agents.
Currently, monotherapy (usually cyclosporine [Csa]) is not used in
the United States. Dual therapy (involving cyclosporine or tacrolimus)
is used commonly in Europe. Most centers in the United States use
triple or quadruple therapy (induction or sequential). Some centers
continue the induction with the antilymphocytic biologic agent for
a predetermined period (usually 1014 days), overlapping with the
initiation of cyclosporine (or tacrolimus). Alternatively, the biologic
agent is discontinued and cyclosporine (or tacrolimus) begun as soon
as the graft function reaches a determined threshold, resulting in no
overlap of these two agents. In living donor transplants, azathioprine
(Aza) is commonly begun a few days before surgery. [5]. FK-506
tacrolimus; MMFmycophenolate mofetil.
133
A
B
Humanized-grafted Humanized-chimeric Murine
Monoclonal
antibody
Type Target
CD3
IL-2R (CD25)
IL-2R (CD25)
TCR
TCR
CD3
CD54
IL-2R (CD25)
Murine
Murine
Murine/Human
Murine
Murine
Murine
Murine
Rat
Muromonab OKT3
Anti-Tac
SDZ-CHIB
T10B9
BMA 031
WT 32
Anti-ICAM 1
33B3-1
FIGURE 11-5
Evolution of monoclonal antilymphocytic antibodies. Monoclonal
antibodies are the result of complex genetic engineering techniques.
A, Differences among murine, chimeric, and humanized antibod-
ies. Attempts to reduce side effects, improve efficacy, and decrease
xenosensitization are the main reasons for development of these
modifications on the murine molecule. B, The different monoclonal
antibodies, their classification regarding the molecular structure, and
their targets. Muromonab OKT3 (Ortho Pharmaceutical, Raritan,
NJ) is the only monoclonal antibody commercially available at this
time [6]. CD3 monomorphic membrane co-receptor present in
T-lymphocytes; IL-2Rinterleukin-2R; TCRT-cell receptor.
A B
FIGURE 11-6
Experimental model of the vasoconstrictive
effect of cyclosporine. Some of the acute
nephrotoxicity of cyclosporine is due to the
significant yet reversible vasoconstrictive
effect of the drug. A, Scanning electron
micrograph of glomerulus of a rat not
exposed to cyclosporine. Arrow indicates
glomerular capillary loop. AAafferent
artery. B, After 14 days of cyclosporine
treatment, the entire length of an afferent
arteriole shows narrowing (magnification
500). Arrow indicates afferent artery. (From
English and coworkers [7]; with permission.)
134
AGENTS USED IN RENAL TRANSPLANTATION
Drug
Cyclosporine
Sandimmune
(Sandoz Pharmaceuticals, East Hanover, NJ)
Neoral
(Sandoz Pharmaceuticals, East Hanover, NJ)
Azathioprine
Imuran
(Glaxo Wellcome, Research TrianglePark, NC)
Azathioprine
(RoxaneLaboratories, Columbus, OH)
Azathioprinesodium(injectable)
(Bedford Laboratories, Bedford, OH)
OKT3
(Ortho Pharmaceutical, Raritan, NJ)
Muromonab-cd3
Antithymocyteglobulin
Atgam
(Upjohn Co, Kalamazoo, MI)
Prednisone
(variousmanufacturers)
Deltasone
(Upjohn Co, Kalamazoo, MI)
FK-506, tacrolimus
Prograf
(FujisawaUSA, Inc, Deerfield, IL)
Mycophenolatemofetil
CellCept
(RocheLaboratories, Nutley, NJ)
Daclizumab
(RocheLaboratories, Nutley, NJ)
Simulect
(NovartisPharmaceuticalsInc.,
East Hanover, NJ)
Dosage
Startingdose: 710mg/kg/d in
2divided doses
Maintenance: based on blood levels
Startingdose: 710mg/kg/d in
2divided doses
IV Csaequalsonethird of oral Csa; IV
cyclosporineisgiven bycontinuous
infusion over 24h
Startingand maintenancedose:
13mg/kg/d;IV doseequalshalf of oral dose
Decreasedosebyhalf for 50%decrease
in leukocytecount
Hold dosefor leukocytecount of <3000
Induction: 2mg/d (low-dose)
5mg/d (standard)
Rejection treatment: 5mg/d
Hold (delay) dosefor weight gain >3%or
temperature>39C
Increasedosebased on CD3+cell count
and CD3density(suggested)
Discontinueif anti-OKT3antibodytiter
>1:1000
Startingdose: 1530mg/kg/d
Decrease(or hold) dosefor leukocytes
<3000or platelets<100,000
Startingdose: 500to 1000-mginfusion
for 35d
Maintenance: taper schedule(variable)
Startingdose: 0.150.3mg/kg/d in
2divided doses
Avoid IV (0.050.1mg/kg/d asa
continuousinfusion over 24h)
Startingdose: 23g/d orallyin 2divided
doses(IV preparation in clinical trials)
Maintenance: based on GI and bone
marrow toxicities
1mg/kg/d every2wk for atotal of 5doses
20mg/d, given on days0and
4post transplant
Adverse reactions
Nephrotoxicity, hypertension, gingival over-
growth, hirsutism, hepatotoxicity, neurotoxicity,
hypomagnesia, hyperkalemia
Same
Leukopenia, anemia, thrombocytopenia,
hepatitis, pancreatitis, alopecia, skin cancer,
aplastic anemia(rare)
Cytokinereleasesyndrome: fever, chills, chest
pain, dyspnea, wheezing, noncardiogenic
pulmonaryedema, nausea, vomiting, diarrhea,
headache, aseptic meningitis, seizures, skin rash
Leukopenia, thrombocytopenia, fever, chills, skin
rash, back pain, headache, nausea, vomiting,
diarrhea, horseserumsickness
Fat redistribution, increased appetite, weight gain,
hyperlipidemia, hypertension, peripheral edema,
hyperglycemia, skin atrophy, poor healing, acne,
night sweats, insomnia, mood changes, blurred
vision, cataractsglaucoma, osteoporosis
Nephrotoxicity, hypertension, hepatotoxicity,
pancreatitis, diabetes, seizures, headache,
insomnia, tremor, paresthesia
Nausea, vomiting, diarrhea, leukopenia,
anemia, thrombocytopenia
Reported sameasplacebo
Reported sameasplacebo
Cost
Gelcaps: $1.61/25mg;
$6.42/100mg
Liquid: $6.41/100mg, orally
Gelcaps: $1.44/25mg;
$5.77/100mg
Liquid: $6.38/100mg, orally
$113.32/100mg, IV
$1.29/50-mgtablet
$101.18/100-mgvial, IV
$1.16/50-mgtablet
$81.60/100-mgvial, IV
$672.00/5-mgvial
$262.24/250-mgvial
$0.02$0.05/5-mgtablet
Methylprednisolone, IV
$17.88$35.50/500-mgvial
$2.39/1-mgcaplet
$11.97/5-mgcaplet
$222.00/5-mgampule, IV
$2.04/250-mgcaplet
$4.08/500-mgtablet
$102.00/500-mg, IV
$418.20/25mg, IV
$1224.00/20mg, IV
Cost to thepharmacist based on theaveragewholesalepricelistingin Red Book , 1997[8].
CD3monomorphic membraneco-receptor present in T-lymphocytes; Csacyclosporine; GIgastrointestinal.
A d a pt ed f rom deMattosand coworkers[3,4].
FIGURE 11-7
A summary of the immunosuppressive agents currently used in human renal
transplantation is given. Dosages and costs are subject to local variation.
135
CLINICALLY RELEVANT DRUG INTERACTIONS WITH IMMUNOSUPPRESSIVE DRUGS
Drug
Cyclosporin A and tacrolimus
Diltiazem
Nicardipine
Verapamil
Erythromycin
Clarithromycin
Ketoconazole
Fluconazole
Itraconazole
Methylprednisolone(high doseonly)
Carbamazepine
Phenobarbital
Phenytoin
Rifampin
Aminoglycosides
Amphotericin B
Cimetidine
Lovastatin
Azathioprine
Allopurinol
Warfarin
ACEinhibitors
Mycophenolatemofetil
Acyclovir-ganciclovir (high dosesonly)
Antiacids
Cholestyramine
Effect
Increased blood levels
Decreased blood levels
Increased renal dysfunction
Increased serumcreatinine
Decreased metabolism
Increased bonemarrow toxicity
Decreased anticoagulation effect
Increased bonemarrow toxicity
Increased levelsof acyclovir-ganciclovir
and mycophenolatemofetil
Decreased absorption
Decreased absorption
Mechanism
Decreased metabolism(inhibition of cytochromeP-450-IIIA 4)
Unknown
Increased metabolism(inhibition of cytochromeP-450-IIIA 4)
Additivenephrotoxicity
Competition for tubular secretion
Myositis, increased creatinephosphokinase, rhabdomyolysis
Inhibitingxantineoxidase
Increased prothrombin synthesisor activity
Not established
Competition for tubular secretion
Bindingto mycophenolatemofetil
Interfereswith enterohepatic circulation
ACEangiotensin-convertingenzyme.
A d a pt ed f rom deMattosand coworkers[3,4].
FIGURE 11-8
Clinical relevant drug interactions with immunosuppressive agents.
Close monitoring of drug levels is required periodically with concomi-
tant use of drugs with potential interaction. Drug level monitoring is
clinically available for cyclosporin A and tacrolimus. Monitoring of
non-immunosuppressive drug level is also important when used with
potential interacting immunosuppressive agents.
136
NEW IMMUNOSUPPRESSIVE AGENTS UNDERGOING CLINICAL TRIALS
Agent
Rapamycin
Leflunomide
Brequinar
Deoxyspergualin
SKF-105685
Mizoribine
CTLA-4Ig
Mechanism of action
Inhibition of cytokineaction (downstreamof interleukin-2receptor and other growth factors)
Inhibition of cytokineaction (expression of or signalingbywayof interleukin-2receptor)
Inhibition of DNA and RNA synthesis(pyrimidinepathway)
Inhibition of DNA and RNA synthesis(pyrimidinepathway)
Unknown (related to heat-shock proteins?)
Unknown (stimulation of suppressor cells?)
Inhibition of DNA and RNA synthesis(d e n ov o purinepathway)
Blockageof T-cell co-stimulatorypathway
FIGURE 11-9
Proposed mechanisms of action of new
immunosuppressive drugs currently under-
going clinical or preclinical trials in organ
transplantation [9].
1. Clipstone NA, Crabtree GR: Calcineurin is the key signaling enzyme
in T lymphocyte activation and the target of the immunosuppressive
drug.Ann NY Acad Sci USA 1993, 696:2030.
2. Brunn GJ, Hudson CC, Sekulic A, et al.: Phosphorylation of the transla-
tional repressor PHAS-I by the mammalian target of rapamycin.Science
1997, 277:99101.
3. de Mattos AM, Olyaei AJ, Bennet WM: Pharmacology of immuno-
suppressive medications used in renal diseases and transplantation.Am
J Kid Dis 1996, 28:631637.
4. de Mattos AM, Olyaei AJ, Bennet WM: Mechanism and risks of
immunosuppressive therapy. In I mmunologic Renal Disease. Edited
by Neilson EG, Couser WG. Philadelphia: Lippincott-Raven;
1996:861885.
5. Barry JM: Immunosuppressive drugs in renal transplantation: a review
of the regimens. Drug1992, 44:554566.
6. Powelson JA, Cosimi AB: Antilymphocyte globulin and monoclonal
antibodies. In Kidney Transplantation: Principles and Practice, edn 4.
Edited by Morris PJ. Philadelphia: WB Saunders Co; 1994.
7. English J, Evan A, Houghton DC, Bennett WM: Cyclosporine-
induced acute renal dysfunction in the rat.Transplantation 1987,
44:135141.
8. Red Book: Drug Topics
. Montvale, NJ: Medical Economics

Company, Inc., 1998.
9. First MR: An update on new immunosuppressive drugs undergoing
preclinical and clinical trials: potential applications in organ trans-
plantation.Am J Kid Dis1997, 29:303317.
References
Acknowledgments
The author would like to thank Ali Olyaei, Pharm D., for his assistance with the
preparation of this manuscript.
137
12
Evaluation of Prospective
Donors and Recipients
A
ll patients should be considered for transplantation when it is
determined that renal replacement therapy will someday be
required. In some cases, the evaluation can be completed and the
patient can receive transplantation before initiating chronic maintenance
dialysis. Prospective candidates for transplantation must be carefully
screened for potentially fatal cancers and infections that are made worse
by immunosuppression. Hepatic, pulmonary, cardiovascular, and gas-
trointestinal disorders all may increase the risks of surgery and chronic
immunosuppression. Patients must be carefully screened for these disor-
ders. In many cases, intervention before transplantation may help reduce
the recipients risks of transplantation. Detailed guidelines have been
established to evaluate prospective candidates for transplantation [1].
Living donors offer the recipient optimal graft survival, reduced wait-
ing time, and an opportunity for preemptive transplantation (ie, before
initiating dialysis). The evaluation of prospective living donors must
ensure that the donation is safe for both donor and recipient. However,
the primary focus of this evaluation must always be on protecting the
well-being of the prospective donor. Both the short-term surgical risks
and the long-term risks of having a single kidney must be carefully
defined. The evaluation also must ensure the donor has no disease that
could be transmitted with the kidney. Guidelines have been developed
for the evaluation of living prospective donors [2].
When no suitable living donors are available, the prospective recipient
can be placed on the waiting list for a cadaveric kidney. Unfortunately,
because the number of patients needing cadaveric kidneys has grown
much faster than has the number of available kidneys, the median
waiting time is now over 2 years. This shortage has led many trans-
plantation centers to use cadaveric kidneys, which are associated with
reduced graft survival. In particular, graft survival is affected by the
age of the kidney donor. Many centers are expanding the age limits of
acceptability to reduce waiting times. A detailed discussion of the
selection, retrieval, preservation, and allocation of cadaveric kidneys
is beyond the scope of this review.
Ber t r a m L. Ka siske
CHA P T ER
138
Evaluation of Prospective Transplantation Recipients
Irreversible
renal failure
Currently on
dialysis?
Monitor rate
GFR decline
Dialysis likely in
6 months?
Prospective
livingdonor?
Evaluatepotential
recipient
Evaluateprospective
livingdonor
Yes
Yes
Yes
No
No
No
Initial evaluation of recipients
FIGURE 12-1
Initiating the evaluation. Before transplantation it must be clearly
established that renal failure in the patient is irreversible. When the
prospective recipient is not already on chronic maintenance dialysis,
however, preemptive transplantation (ie, transplantation before
initiating dialysis) should be considered. Because the waiting time
for a cadaveric kidney is generally long, preemptive transplantation
usually is possible only when a prospective living donor is available.
In any case, the rate of decline in the glomerular filtration rate (GFR)
must be monitored closely in patients with progressive renal disease.
The evaluation process should begin when it is anticipated that
transplantation may be required within 6 months. (FromKasiske
and coworkers. [1]; with permission.)
Screen for cancer
Current or past
evidenceof cancer?
Appropriate
disease-free
interval?
Proceed with
evaluation
Yes
No
Cancer screeningin recipients
FIGURE 12-2
Screening for cancer. An active malignancy is an absolute contraindication to transplantation.
Effective screening measures for patients at risk include chest radiograph, mammogram,
PAP test, stool Hemoccult, digital rectal examination, and flexible sigmoidoscopy exami-
nation. Patients who have had a life-threatening malignancy but are potentially cured may
be candidates for transplantation when there has been an appropriate disease-free interval.
This interval generally is at least 2 years, and longer in the case of some malignancies.
(FromKasiske and coworkers [1].)
139
12.3 Evaluation of Prospective Donors and Recipients
Activeinfection?
Appropriate treatment
and disease-freeinterval
HIV positive? Discouragetransplantation
History of TBor
positivePPD
without adequate
therapy?
Consider prophylactic
treatment
Assess risk for
other infections
Yes
Yes
Yes
No
No
No
Screeningfor infection in recipients
0 1 2 3 4
0
10
20
30
40
50
60
70
80
90
100
5
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
n
n/n 4670
n/p 5970
p/n 7299
p/p 11,257
Yearsafter transplantation
CMV r/d
FIGURE 12-3
Screening for infection. An active potentially life-threatening infection
is a contraindication to transplantation. Patients with human immun-
odeficiency virus (HIV) are usually not candidates for transplantation.
Patients with a history of tuberculosis (TB) or a positive purified
protein derivative (PPD) skin test who have not been adequately
treated should generally receive prophylactic therapy. (From
Kasiske and coworkers [1].)
FIGURE 12-4
Assessing the risks of cytomegalovirus (CMV) infection after trans-
plantation. CMV is a major cause of morbidity and mortality after
transplantation. The incidence and severity of CMV are associated
with the serologic status of the donor (d) and recipient (r), the risks
generally being the following: recipient negativedonor negative
less than recipient positivedonor negative less than recipient negative
donor positive less than recipient positivedonor positive. As shown
in these data from the United Network for Organ Sharing Scientific
Registry, the rate of graft survival tends to be less in recipients of
kidneys from donors who test positive for CMV infection. The
serologic status of both the donor and recipient is often used to
determine which patients are candidates for prophylactic or pre-
emptive anti-CMV therapy after transplantation. (FromCecka [3];
with permission.)
Renal disease
with potential
to recur?
Proceed with
evaluation
Wait until
quiescent
Risk acceptable?
Avoid
transplantation
Yes
Yes
No
No
Assessment for recurrent renal
disease in recipients
FIGURE 12-5
Assessing the risk of renal disease recurrence. Although the risk for recurrence of the
underlying renal disease is rarely great enough to preclude transplantation, patients and
physicians must be aware of this risk. In some cases it may be prudent to delay transplan-
tation until the underlying disease is quiescent. (FromKasiske and coworkers [1].)
140
0
100
90
80
70
60
50
40
30
20
10
Alport's
syndrome
PKD FSGS MPGN HUS IgA Scleroderma Oxalosis HSP Diabetes
typeII
Can recur in transplant organ
Cannot
recur
3
-
y
e
a
r

g
r
a
f
t

s
u
r
v
i
v
a
l
,

%
411
3072
1058
134
101
685 31
39
41 5421
Symptoms or
enzymes
suggestingliver
disease?
MeasureHBsAg
and HCV antibody
Consider
cholecystectomy
for gallstones
Toxic drugor
alcohol
Elevated TIBC
or ferritin
Discontinue
Consider biopsy
and treatment
Yes
Yes
Yes
No
No
No
Evaluation for liver diseasein recipients
PositiveHBeAg
or HCV?
Antibody or
HBeAg?
Elevated
enzymes?
Elect
biopsy?
Severedisease
on biopsy?
Consider
avoiding
transplantation
Proceed with
evaluation
Moderate
diseaseon
biopsy?
Acceptable
risk?
Yes Yes
Yes
Yes Yes
Yes
No
No
No
No
No
No
No
Evaluation for viral hepatitis in recipients
FIGURE 12-7
Evaluation of patients with signs and symptoms of liver disease.
Patients with cholecystitis should be considered for cholecystectomy.
For other patients with signs and symptoms of liver disease, poten-
tial hepatic toxins should be considered. The incidence of liver dis-
ease from iron deposition has declined with the diminishing use of
blood transfusions in dialysis patients, but may be seen occasionally
in patients with a high total iron binding capacity (TIBC) or ferritin.
All prospective candidates for transplantation must be screened for
hepatitis B and C by testing for the presence of hepatitis B surface
antigen (HBsAg) and hepatitis C virus (HCV) antibodies. Both
viruses can cause potentially fatal liver disease after transplantation.
Fortunately, the incidence of hepatitis B is declining among patients
with renal disease, largely as a result of the use of effective vaccina-
tion programs. (FromKasiske and coworkers [1]; with permission.)
FIGURE 12-8
Viral hepatitis. Patients whose test results are positive for anti-
bodies or hepatitis e-antigen (HBeAg) are at high risk for succumb-
ing to liver disease and most likely are not candidates for transplan-
tation. A liver biopsy should be considered for all patients with
hepatitis C virus (HCV) antibodies or hepatitis B surface antigen.
Patients with severe chronic active hepatitis or cirrhosis on biopsy
generally are not candidates for renal transplantation unless simul-
taneous liver transplantation is being considered. Whether antiviral
therapy before transplantation can increase the number of patients
who are candidates for transplantation is unclear. (FromKasiske
FIGURE 12-6
The influence of underlying renal disease on
graft survival. As shown in these data from
the United Network for Organ Sharing
Scientific Registry, 3-year graft survival rates
in groups of patients with different underly-
ing causes of renal failure vary substantially.
The 3-year graft survival rates for recipients
with renal diseases that do not recur (eg,
Alports syndrome and polycystic kidney dis-
ease [PKD] were about 80%. Graft survival
rates for patients with diseases that may recur
in the transplanted kidney varied from 60%
to 83%. Of course, most of these differences
in graft survival may be due to factors associ-
ated with the underlying cause of renal failure
(eg, cardiovascular disease) and not disease
recurrence itself. Focal segmental glomeru-
losclerosis (FSGS), hemolytic uremic syn-
drome (HUS), Henoch-Schnlein purpura
(HSP), and hereditary oxalosis can cause graft
failure relatively soon after transplantation.
Membranoproliferative glomerulonephritis
(MPGN), scleroderma, IgA nephropathy, and
diabetes generally cause graft failure only
after several years. Numbers above barsindi-
cate number of patients who had that disease.
(FromCecka [3]; with permission.)
141
0 2 4 6
0
1.0
0.8
0.6
0.4
0.2
8
78 59 52 47 45 34 20 2
21 16 13 10 9 7 6 1
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
AntiHCV positive
AntiHCV negative
A
0 2 4 6
0
1.0
0.8
0.6
0.4
0.2
8
79 69 67 62 57 45 29 5
22 17 15 12 11 8 6 1
P
a
t
i
e
n
t

s
u
r
v
i
v
a
l
,

%
AntiHCV positive
AntiHCV negative
B
FIGURE 12-9
Effects of pretransplantation hepatitis C virus (HCV) serology
results on survival of the graft (A) and patient (B). Numbers
above (antiHCV negative) and below (antiHCV positive)
survival curves indicate the number of patients at risk during
that time interval. The relative risk after transplantation associat-
ed with the patient testing positive for HCV antibodies before
transplantation also is shown, along with 95% confidence inter-
vals. Although no statistically significant effect of HCV on graft
survival was seen, patient survival was significantly diminished
among those who tested positive for HCV after transplantation.
Not all investigators have confirmed these findings. (FromPeriera
Dyspneaon
exertion or
smokinghistory?
Currently
smoking?
Smoking
cessation
program
Severelung
diseaseon
function tests?
Wait until adequate
resolution with therapy
Proceed with
evaluation
Evaluation of effects of smokingin recipients
Yes
Yes
Yes
No
No
No
Past
history of
IHD?
High
risk for
IHD?
Active
angina?
Stress test
positive?
Evaluate
for CHF
Risk factor
intervention
Imaged coronary
lesions severe?
Revascularization
successful?
Reconsider
transplantation
candidacy
Evaluation of IHD in recipients
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
No
FIGURE 12-10
Lung disease. Few studies exist that address the effects of cigarette
smoking on outcome after renal transplantation. Because the risks of
transplantation surgery no doubt are increased by cigarette smoking,
candidates for transplantation should be referred to smoking cessa-
tion programs. (FromKasiske and coworkers [1]; with permission.)
FIGURE 12-11
Ischemic heart disease (IHD). The incidence of IHD is several fold
higher in renal transplantation recipients compared with the general
population. Patients with IHD before transplantation are at high risk
to develop IHD events after transplantation. Therefore, angiography
should be considered in candidates for transplantation who have
angina pectoris. Candidates with currently asymptomatic IHD and
those at high risk for IHD should undergo a stress test. Patients with
severe coronary artery disease on angiography must be considered
for a revascularization procedure before transplantation. Aggressive
management of risk factors is appropriate for all patients, with or
without IHD. (FromKasiske and coworkers [1]; with permission.)
142
0 3 6 9 12 15 18 21
0
10
20
30
40
50
60
70
80
90
100
24
Follow-up, m o
F
r
e
e

o
f

c
a
r
d
i
a
c

e
v
e
n
t
s
,

%
(9)
(13)
(7)
(10)
(4)
(2)
Medicallytreated
Revascularized
Signs and
symptoms of
CHF?
Proceed with
evaluation
Adequateresponse
to medical
management?
Reconsider
transplant
candidacy
Excludesecondary
causes
Evaluation of CHF in recipients
No
No
Yes
Yes
FIGURE 12-12
Effects of surgical versus medical management of coronary disease
before renal transplantation in candidates who have insulin-depen-
dent diabetes. In this study, 26 patients with insulin-dependent dia-
betes who were found to have over 75% stenoses in one or more
coronary arteries were randomly allocated to either medical man-
agement or a revascularization procedure before transplantation.
Ten of the 13 patients who were managed medically and 2 of the
13 who had revascularization performed had a cardiovascular dis-
ease end point within a median of 8.4 months after transplantation
(P < 0.01). These findings suggest that transplantation candidates
who have diabetes should be screened for silent coronary artery
disease because revascularization decreases morbidity and mortality
after transplantation. The numbers in parentheses indicate the num-
ber of patients being followed at that time. (FromManske and
FIGURE 12-13
Congestive heart failure (CHF). Myocardial performance has
been shown to improve in some patients after renal transplanta-
tion. Thus, a low ejection fraction alone does not automatically
exclude patients from transplantation. In contrast, patients with
severe irreversible myocardial disease may not be good candidates
for transplantation. Occasionally, patients may be candidates for
simultaneous heart and kidney transplantation. (FromKasiske
History of
strokeor TIA?
Recent
symptoms?
Carotid bruit?
High-risk
ADPKD patient?
Large
intracranial
aneurysmon
imaging?
Consider carotid
ultrasonography
Risk factor
intervention
Consider prophylactic
surgery
Refer to
neurologist
Proceed with evaluation
Yes
Yes
Yes
Yes
Evaluation of CVD in recipients
Yes
No
No
No
No
No
FIGURE 12-14
Cerebral vascular disease (CVD). Patients must not undergo
surgery within 6 months of a stroke or transient ischemic attack
(TIA). Asymptomatic patients with a carotid bruit should be con-
sidered for carotid ultrasonography because patients with severe
carotid disease may be candidates for prophylactic surgery. Patients
with autosomal dominant polycystic kidney disease (ADPKD) and
either a previous episode or a positive family history of a ruptured
intracranial aneurysm must be screened with computed tomogra-
phy or magnetic resonance imaging. Patients found to have an
aneurysm over 7 mm in diameter may benefit from prophylactic
surgery. (FromKasiske and coworkers [1]; with permission.)
143
PVD unresponsive
to conservative
management?
Consider
invasive
intervention
Aortoiliac vascular
disease?
Consider repair
beforeor at
transplantation
Proceed
with
evaluation
Yes
Yes
No
No
Evaluation of PVP in recipients
Psychosocial
evaluation
Freeof limiting
cognitive
impairment?
Recent alcohol or
drugabuse?
Supervised
abstinence?
Refer until
resolved
Proceed with
evaluation
Freeof limiting
psychiatric illness?
History of limiting
medication
noncompliance?
Psychosocial evaluation of recipients
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
FIGURE 12-15
Peripheral vascular disease (PVD). Peripheral vascular disease is commonly associated
with coronary artery disease, cerebral vascular disease, or both. However, PVD itself may
require intervention before transplantation to prevent infection and sepsis after transplan-
tation. In addition, some patients may have aortoiliac disease severe enough to require
intervention before transplantation. Rarely, vascular disease is severe enough to make it
difficult to find an artery suitable for the anastomosis of the allograft renal artery. (From
Kasiske and coworkers [1]; with permission.)
FIGURE 12-16
Psychosocial evaluation. Patients must be free of cognitive impairments and able to give
informed consent. Most transplantation centers require patients with a history of alcohol
or drug abuse to demonstrate a period of supervised abstinence, generally 6 months or
more [6]. Similarly, patients with a past history of medication adherence poor enough
to suspect that the immunosuppressive regimen will be compromised may need to delay
transplantation until reasonable adherence can be demonstrated [6]. (FromKasiske and
144
BMI >35 kg/m
2
Age >65?
Hypertension
unresponsiveto
medical
management?
Additional risk
acceptable?
Consider weight
reduction
program
No further
evaluation
Nativekidney
nephrectomy
Proceed with
evaluation
Yes
Yes
Yes
Yes
No
No
No
No
Assessment of themedical risks to recipients
*
* * *
* * *
*
*
0
0
10
20
30
40
50
60
70
80
90
100
24 21 18 15 12 9 6 3
Obesepatients
Nonobesepatients
Obesepatient grafts
Nonobesepatient grafts
Time, m o
S
u
r
v
i
v
a
l
,

%
0 1 2 3 4
0
10
20
30
40
50
60
70
80
90
100
5
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
Age n t1/2
05 198 15.1
618 1144 8.7
1945 14994 9.4
4660 10933 9.9
>60 3908 8.0
FIGURE 12-17
Assessing the medical risks of transplantation surgery. Obesity
increases the risks of surgery, and a weight reduction program
before transplantation must be considered for very obese patients.
Older age is a relative contraindication to transplantation; however,
it is difficult to precisely define an upper age limit for all patients.
Rather, age and overall medical condition must be considered
together. Hypertension should be controlled before transplantation.
When control of hypertension is difficult, bilateral nephrectomy
should be considered before transplantation. BMIbody mass
index. (FromKasiske and coworkers [1]; with permission.)
FIGURE 12-18
Effects of obesity on patient and graft survival. In this case-control
study, 46 obese (body mass index > 30 kg/m
2
) recipients of cadav-
eric renal transplantation were compared with nonobese controls
matched for the following after transplantation: age, gender, dia-
betes, panel reactive antibody status, graft number, cardiovascular
disease, date of transplantation, and immunosuppression. Survival
of patients and grafts was significantly less among obese patients
compared with controls (P < 0.01 and P < 0.05, respectively). The
following occurred more often in obese versus nonobese patients:
delayed graft function, postoperative complications, wound com-
plications, and new-onset diabetes. (FromHolley and coworkers
FIGURE 12-19
Effects of the recipients age on renal allograft survival. Data from the
United Network for Organ Sharing Scientific Registry indicate that
recipients over the age of 60 have slightly less allograft survival com-
pared with younger recipients. t1/2graft survival half-life (in years)
the first year after transplantation. (FromCecka [3]; with permission.)
145
Difficult to
control
diabetes?
Symptomatic
hyperparathyroidism
or uncontrolled
hypercalcemia?
Need for
medication that
may jeopardize
recipient or graft?
Consider simultaneous
kidney-pancreas
transplantation
Consider
parathyroidectomy
Discontinue or
reduce risk
Proceed with
evaluation
Evaluation of diabetes and hyperparathyroidismin recipients
Yes
Yes
Yes
No
No
No
0.25 1.0 2.0 3.0 4.0
0
20
40
60
80
100
5.0
84.7
77.4
69.0
39.4
61.8
27.7
22.6
27.7
39.2
52.5
71.4
73.5
54.4
73.2
46.0
P
a
n
c
r
e
a
s

g
r
a
f
t

s
u
r
v
i
v
a
l
,

%
Simultaneouskidney
transplantation(n =3336)
No previouskidney
transplantation
Previouskidney
transplantation (n=273)
FIGURE 12-20
Diabetes and hyperparathyroidism. Patients with difficult to control
diabetes may be candidates for simultaneous kidney-pancreas trans-
plantation. However, patients with diabetes who have a living donor
are generally better off undergoing transplantation with the living
donor kidney alone. Patients with symptomatic hyperparathyroidism
or uncontrolled hypercalcemia should be considered for parathy-
roidectomy before transplantation. Medications that interfere with
the metabolism of immunosuppressive agents such as cyclosporine
should be substituted with appropriate alternatives, if possible, before
transplantation. (FromKasiske and coworkers [1]; with permission.)
FIGURE 12-21
Pancreas graft survival in recipients of pancreatic transplantation
with simultaneous, no previous, and previous kidney transplantation.
Survival rates of pancreatic grafts are best when pancreatic and
kidney transplantations are performed at the same time. (Data from
the United Network for Organ Sharing Scientific Registry [8].)
Signs or
symptoms of
bladder
dysfunction?
History of
recurrent
UTIs?
VCUG
normal?
Ultrasonography,
cystoscopy, and/or
retrograde
pyelogramnormal?
Proceed with
evaluation
Indications for
nativekidney
nephrectomy?
Consider ureteral
diversion or
intermittent
self-catheterization
Consider native
kidney
nephrectomy
Bladder
insufficiency?
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No No
No
No
Urologic evaluation in recipients
FIGURE 12-22
Urologic evaluation of transplantation
recipients. Patients without signs and symp-
toms of bladder dysfunction generally do not
need additional urologic testing. However,
patients with bladder dysfunction must be
evaluated to ensure that the bladder is func-
tional after transplantation and that poten-
tial sources of urinary tract infection (UTI)
are eliminated. Such patients can be screened
initially with voiding cystourethrography
(VCUG). (FromKasiske and coworkers [1];
with permission.)
146
History of
diverticulitis?
Severediverticular
diseaseon barium
enema?
Other activecolonic
disease?
Consider partial
colectomy
Proceed with
evaluation
Defer transplantation
until quiescent
Yes
Yes
Yes
No
No
No
Evaluation of active colonic disease in recipients
Signs or symptoms
of activePUD?
Endoscopic or
radiographic
confirmation?
Adequateresponse
to medical
management?
History of
pancreatitis?
Consider
pretransplantation
surgical treatment
Delay transplantation
until evaluation and
treatment
Proceed with
evaluation
Yes
Yes
Yes
Yes
No
No
No
No
PUD and pancreatitis
FIGURE 12-23
Diverticulitis and inflammatory bowel disease. Patients with a history
of symptomatic diverticulitis must be evaluated for partial colectomy
before transplantation. Inflammatory bowel disease generally
should be quiescent at the time of transplantation. (FromKasiske
FIGURE 12-24
Peptic ulcer disease (PUD) and pancreatitis. Patients with PUD
or pancreatitis must undergo evaluation and treatment before
transplantation. Both conditions may be exacerbated by corticos-
teroids used after transplantation. (FromKasiske and coworkers
Potential living
donor?
Consider
cadaveric
donor
Blood and tissue
typing
ABO compatible?
T-cell CDC
X-match negative?
Assess
likelihood of
false-positive
results
HLA identical?
Presenceof
autoantibodies?
Proceed with
evaluation
Transplantation
Consider other
donor
Evaluation of transplantation froma livingdonor
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
FIGURE 12-25
Immunologic evaluation for living donor transplantation. Generally,
transplantation donors and recipients must have compatible blood
groups. Tissue typing is also carried out, and the degree of human
leukocyte antigen (HLA) matching may be taken into account in
selecting the best living donor when more than one donor is available.
Just before transplantation, the recipients serum is tested against
donor cells to be certain no preformed antibodies are present in the
recipient that may cause a hyperacute rejection. A positive cross-
match (X-match) generally precludes transplantation from that
donor. CDCcell-dependent cytotoxicity. (FromKasiske and
147
No
No
No
Yes
Yes
Yes
First transplantation?
Consider DST
NegativeX-match, flow
cytometry, or antiglobulin?
X-match negative? Transplantation
Consider other
donor
Donor-specific transfusions in recipients
0 1-5 6-10 >10 0 1-5 6-10 >10
0
40
50
60
70
80
90
100
P=0.02 P=0.04
Number of pretransplantation transfusions
A
d
j
u
s
t
e
d

g
r
a
f
t

s
u
r
v
i
v
a
l
,

%
84%
76.4%
1y 5y>1y
2
6
,
5
8
5
1
9
,
1
8
7
4
1
7
2
3
1
6
4
2
0
,
4
6
1
1
5
,
0
8
7
3
3
0
3
2
4
4
4
FIGURE 12-26
Donor-specific transfusion (DST). When the living donor is non
human leukocyte antigen identical and it is the recipients first trans-
plantation, some centers use donor-specific blood transfusions before
transplantation to enhance graft survival. Unfortunately, donor-spe-
cific transfusions may induce the formation of antibodies against the
donor that will preclude the transplantation. Most centers have
abandoned the use of random blood transfusions as part of the
preparation of recipients for cadaveric transplantation. X-match
cross-match. (FromKasiske and coworkers [1]; with permission.)
FIGURE 12-27
Effects of random blood transfusions on first cadaveric renal allo-
graft survival. Blood transfusions before transplantation had a
small but statistically significant beneficial effect on 1-year graft
survival. However, a small reduction occurred in 5-year graft sur-
vival (among patients who survived at least 1 year with a function-
ing kidney) that was attributable to random donor blood transfu-
sions before transplantation (FromGjertson [9]; with permission.)
No living
donor
First
transplantation?
Waitinglist
PRA 11%
Review typingfrom
previous grafts
Identify HLA
specificities
Increasing
PRA?
Final CDC
X-match
negative?
Transplantation
Autologous
X-match positive?
PRA after DTT or
analogous cell
adsorption
Periodic
antibody
screening
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
Immunologic evaluation for cadaveric transplantation
FIGURE 12-28
Immunologic evaluation for cadaveric transplantation. Donors and
recipients must have compatible blood groups. Tissue typing is car-
ried out, and the degree of matching is used in the allocation of
cadaveric organs. Some data suggest that the presence of human
leukocyte antigen (HLA) mismatches that were also mismatched in
a previous graft (especially at the DR locus) may lead to early graft
loss. Thus, it may be wise to avoid these mismatches. When the
percentage of panel reactive antibodies (PRA) is over 10%, tests
may be carried out to determine whether some of the antibodies
are autoreactive rather than alloreactive. Autoreactive antibodies
may not increase the risk for graft loss as do alloreactive antibodies.
The presence of high titers of alloreactive antibodies usually is due
to previous pregnancies, transplantations, and blood transfusions.
Determining antibody specificities may be useful in avoiding certain
HLA antigens. In the highly sensitized patient (PRA > 50%) it may
be difficult to find a complement-dependent cytotoxicity (CDC)
cross-matched (X-match) negative donor. Avoiding blood transfu-
sions may help the titer decrease over time. DTT1, 4-dithiothre-
itol (DTT). (FromKasiske and coworkers [1]; with permission.)
148
Evaluation of Prospective Living Donors
0 1 2
0
100
90
80
70
60
50
40
30
20
10
3
HLA-identical siblingdonor (n =1984)
Spousal donor (n =368)
Parental donor (n =3368)
Livingunrelated donor (n =129)
Cadaveric graft (n =43,341)
Cadaveric graft, urineflow 1st day, no dialysis(n =32,281)
Cadaveric graft, no urine1st day, dialysisrequired
in 1st week (n =11,060)
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
0 1 2 3 4
0
100
90
80
70
60
50
40
30
20
10
5
P<0.025
Graft: n t1/2
HLA-identical 2288 25.5
1-haplotype 3082 16.0
Zero-haplotype 808 11.9
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
FIGURE 12-29
Effects of donor source on renal allograft survival. Data from the
United Network for Organ Sharing Scientific Registry were used to
compare 3-year graft survival rates between recipients of kidneys
from different donor sources. The best graft survival was seen in
recipients of human leukocyte antigen (HLA)identical sibling
donors. Grafts from spouses and other living unrelated donors,
however, survived just as well as did grafts from parental donors
and better than grafts from cadaveric donors. These data have
encouraged centers to use emotionally related donors to avoid
the long waiting times for cadaveric kidneys. (FromTerasaki and
FIGURE 12-30
Effects of human leukocyte antigen (HLA) matching on living related
graft survival. Graft survival is best for HLA-identical grafts from sib-
lings and next best for one-haplotype mismatched grafts. Importantly,
the half-life (t1/2) of grafts that survived at least 1 year is proportional
to the degree of matching. This information can be used along with
other factors to select the most suitable among two or more living
prospective donors. (FromCecka [3]; with permission.)
Candidatefor renal
transplantation
Evaluatefor cadaveric
transplantation
Willingto
accept living
donor?
Willingand available
ABO-compatible
livingrelated donor?
Willingand available
ABO-compatible
emotionally related donor?
Cross-match
negative?
Proceed with
evaluation
Yes
Yes
Yes
Yes
No
No
No
No
Choiceof livingdonor versus cadaveric transplantation
FIGURE 12-31
Use of living donors. A suitable living donor is better than a cadaveric
donor because graft survival is better and preemptive transplantation
is possible. The best donor usually is a family member. Psychosocial
and biological factors must be taken into account when choosing
among two or more living prospective donors. Every effort must
be made to ensure that the donation is truly voluntary. Caregivers
should tell prospective donors that if they do not wish to donate,
then friends and relatives will be told the donor was not medically
suitable. (FromKasiske and coworkers [2]; with permission.)
149
Economic risk
acceptable?
Psychosocial
evaluation
Voluntarism
reasonably
certain?
Financial
incentive?
Risk
acceptable?
Consider
alternative
donor
Preliminary
medical
evaluation
HIV, hepatitis,
or pregnancy
test positive?
CMV titer
positiveor
history of
tuberculosis?
Proceed with
evaluation
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
No
Preliminary evaluation for alivingdonor
Ageand renal
function
acceptable?
Surgical risk
acceptable?
Risk
acceptable?
Long-termrisk
acceptable?
Screeningfor
diabetes
negative?
Consider
alternative
donor
Risk of
recurrent
disease?
Risk of
diabetes?
Proceed with
evaluation
Risk assessment for livingdonor
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
No
No
FIGURE 12-32
Preliminary evaluation of a living prospective donor. The
prospective donor must be made aware of the possible costs
associated with donation, including travel to and from the
transplantation center and time away from work. The prospective
donor must undergo a psychological evaluation to ensure the
donation is voluntary. A preliminary medical evaluation should
assess the risks of transmitting infectious diseases with the kid-
ney, eg, infection with human immunodeficiency virus (HIV)
and cytomegalovirus (CMV). (FromKasiske and coworkers [2];
with permission.)
FIGURE 12-33
Assessing risks. Older age may place the living prospective donor at
greater surgical risk and may be associated with reduced graft sur-
vival for the recipient. The prospective donor must be informed of
both the short-term surgical risks (very low in the absence of car-
diovascular disease and other risk factors) and the long-term conse-
quences of having only one kidney. With regard to long-term risks,
it should be considered whether there is a familial disease that the
living donor may be at risk to acquire and whether having only one
kidney would alter the natural history of renal disease progression.
These questions are often most pertinent for relatives of patients
with diabetes. (FromKasiske and coworkers [2]; with permission.)
No age
exclusion
55 60 65 70 7580 No policy
or do not
know
0
30
20
10
27
6
22
13
15
3
13
T
r
a
n
s
p
l
a
n
t
a
t
i
o
n

c
e
n
t
e
r
s
,

%
Excludeif agein years is greater than:
FIGURE 12-34
Donor age restrictions used by transplantation centers. Results of
an American Society of Transplantation survey of the United
Network for Organ Sharing centers showed that many centers
either use no specific age exclusion criteria or have no policy.
Among those that use an upper age limit, there appears to be a
bell-shaped curve, with 65 years of age at the median. (FromBia
150
0
10
20
30
40
50
60
70
80
90
100
Mildly
elevated
FBS
Normal FBS
but abnormal
GTT
Mild type
II diabetes
<50y
Mild type
II diabetes
<30y
T
r
a
n
s
p
l
a
n
t
a
t
i
o
n

c
e
n
t
e
r
s
,

%
61
46
90
88
5.0
0 25 50 75
0 1.0 2.0 3.0 4.0
100
-20 5 0 -5 -10 -15
Glomerular filtration rate, m L/ m in
Proteinuria, m g/ d
Systolic blood pressure, m m Hg
Progressiveeffect
(each 10y)
(0.3) (1.4) (2.5)
Static effect
(20.2) (17.1) (14.0)
Progressiveeffect (each 10y)
Progressiveeffect (each 10y)
(52)
(1.1) (2.2) (0)
(76) (101)
Static effect
(0.3) (2.4) (5.1)
FIGURE 12-35
Screening living prospective donors for diabetes. Results of the sur-
vey of the United Network for Organ Sharing centers showed that
most centers exclude patients with a mildly elevated fasting blood
sugar (FBS) and patients with normal FBS but an abnormal glucose
tolerance test (GTT). Most centers exclude donors with mild type
II diabetes. (FromBia and coworkers [11]; with permission.)
FIGURE 12-36
Long-term risks of kidney donation. In a meta-analysis combining
48 studies of the long-term effects of reduced renal mass in humans,
no evidence was found of a progressive decline in renal function
after a 50% reduction in renal mass. Indeed, a small but statistically
significant increase occurred over time in the glomerular filtration
rate. A small increase in urine protein excretion occurred; however,
the rate of increase per decade was less than that generally considered
an abnormal amount of protein excretion, eg, 150 mg/d. A small
increase in systolic blood pressure was noted; however, it was not
enough to lead to an increase in the incidence of hypertension. Thus,
it appears that the long-term risks of kidney donation are very small.
Shown are multiple linear regression coefficients and 95% confidence
intervals. Failure of the confidence interval to include zero indicates
P < 0.05. (FromKasiske and coworkers [12]; with permission.)
0
70
60
50
40
30
20
10
T
r
a
n
s
p
l
a
n
t
a
t
i
o
n

c
e
n
t
e
r
s
,

%
Controlled
on oneBP
medication
Persistently
130/90 mmHg
Occasionally
130/90 mmHg
130/90 mmHg
in doctor's
officeonly
No policy
or do not
know
64
54
20
12
9
FIGURE 12-37
Blood pressure (BP) criteria for excluding
living prospective donors. Results of the
survey of the United Network for Organ
Sharing centers showed that most exclude
prospective donors who require antihyper-
tensive medication or whose BP is persistent-
ly elevated over 130/80 mm Hg. However,
most centers do not exclude living prospec-
tive donors who occasionally have BP read-
ings over 130/80 mm Hg or patients with
so-called white coat hypertension. (From
Bia and coworkers [11]; with permission.)
151
Proteinuria
or pyuria?
Evaluation
indicates low risk?
Consider alternative
donor
Hypertension?
Blood pressure
high normal?
Risk acceptable?
Risk acceptable?
History of
kidney stones
Evaluate
Proceed with
evaluation
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
No
No
Evaluation of prospectivedonors with
proteinuria, hypertension, or kidney stones
Relativewith
ADPKD?
Normal renal
imagingand low
risk for ADPKD?
Malewith
hematuria?
Malewith no
hematuria?
Femalewith
acceptablelow
risk?
Relativewith
hereditary
nephritis?
Evaluation indicates
low risk?
Proceed with
evaluation
Isolated
hematuria
Evaluation of donor risks in recipients
with familial renal diseases
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
No
No
No
Consider
alternative
donor
FIGURE 12-38
Proteinuria, hypertension, or kidney stones in living prospective
donors. Prospective donors with pyuria must be evaluated for possible
infection and other reversible abnormalities. Proteinuria is generally
a contraindication to donation. Hypertension also must be considered
at least a relative contraindication to donation. Patients with a history
of nephrolithiasis but no current or recent stones may be considered
for donation after first undergoing urologic and metabolic evaluations
for stones. (FromKasiske and coworkers [2]; with permission.)
FIGURE 12-39
Risks to the related donor when the recipient has familial renal dis-
ease. Donors for relatives with autosomal dominant polycystic kidney
disease (ADPKD) may be permitted to donate if over 25 years old and
results on renal imaging are negative for cysts. Some younger persons
may be permitted to donate if genetic studies indicate that the risk for
subsequent ADPKD is very low. Male relatives of individuals with
hereditary nephritis can be donors if they do not have hematuria.
Male relatives with hematuria cannot be donors. Female relatives
without hematuria may donate; however, women of child-bearing age
who might be carriers must consider the possibility of someday donat-
ing a kidney to a child of their own with the disease. Female relatives
with hematuria should not donate when other evidence of renal dis-
ease exists; however, in the absence of such evidence the exact risk of
donation is unknown. Occasionally, donors with isolated microhema-
turia (not hereditary) and a negative evaluation may be suitable
donors. (FromKasiske and coworkers [2]; with permission.)
Donor-specific
transfusion?
Cross-match
negative?
Consider
alternative
donor
Angiography
results
acceptable?
Schedule
transplantation
surgery
No
No
No
Yes
Yes
Yes
Final evaluation of prospectivelivingdonors
FIGURE 12-40
Final steps in evaluating a living prospective donor. Renal artery
angiography is performed to define the anatomy of the renal artery
system and exclude other previously undetected abnormalities.
Recent studies have shown that spiral computerized tomography
can replace angiography without loss of sensitivity or specificity
and with less risk and inconvenience to the prospective donor.
(FromKasiske and coworkers [2]; with permission.)
152
0 1 2 3 4
0
10
20
30
40
50
60
70
80
90
100
5
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
Age n t1/2
618 6652 10.9
1930 7354 11.7
3145 7532 9.8
4660 6476 6.9
>60 1928 5.2
FIGURE 12-41
Donor age. When there are no suitable living donors, recipients are
placed on the cadaveric waiting list. The transplantation center
must always decide whether a particular cadaveric kidney being
offered for transplantation is suitable for the individual recipient.
The shortage of organs and long waiting times have caused many
centers to accept kidneys from older donors and kidneys that may
be damaged. Data from the United Network for Organ Sharing
clearly demonstrate the decreased graft survival rates of kidneys
from older donors. As a compromise, some advocate using kidneys
from older donors for older recipients. In any case, so-called marginal
kidneys should be offered to recipients with appropriate informed
consent. (FromCecka [3]; with permission.)
Use of Marginal Cadaveric Donor Kidneys
References
1. Kasiske BL, Ramos EL, Gaston RS, et al.: The evaluation of renal
transplant candidates: clinical practice guidelines. J Am Soc Nephrol
1995, 6:134.
2. Kasiske BL, Ravenscraft M, Ramos EL, et al.: The evaluation of living
renal transplant donors: clinical practice guidelines. J Am Soc Nephrol
1996, 7:22882313.
3. Cecka JM: The UNOS Scientific Renal Transplant Registry. In Clinical
Transplants 1996. Edited by Cecka JM, Terasaki PI. Los Angeles:
UCLA Tissue Typing Laboratory, 1997:114.
4. Periera BJG, Wright TL, Schmid CH, Levey AS: The impact of pre-
transplantation hepatitis C infection on the outcome of renal trans-
plantation. Transplantation 1995, 60:799805.
5. Manske CL, Wang Y, Rector T, et al.: Coronary revascularisation in
insulin-dependent diabetic patients with chronic renal failure. Lancet
1992, 340:9981002.
6. Ramos EL, Kasiske BL, Alexander SR, et al.: The evaluation of candi-
dates for renal transplantation: the current practice of U.S. transplant
centers. Transplantation 1994, 57:490497.
7. Holley JL, Shapiro R, Lopatin WB, et al.: Obesity as a risk factor follow-
ing cadaveric renal transplantation. Transplantation 1990, 49:387389.
8. 1996 Annual Report of the U.S. Scientific Registry for Transplant
Recipients and the Organ Procurement and Transplantation Network
Transplant Data: 19881995. UNOS, Richmond, VA, and the Division
of Transplantation, Bureau of Health Resources Development, Health
Resources and Services Administration, U.S. Department of Health
and Human Services; 1996.
9. Gjertson DW: A multi-factor analysis of kidney graft outcomes at one
and five years posttransplantation: 1996 UNOS Update. In Clinical
Transplants 1996. Edited by Cecka JM, Terasaki PI. Los Angeles:
UCLA Tissue Typing Laboratory. 1997: 343360.
10. Terasaki PI, Checka M, Gjertson DW, Takemoto S: High survival
rates of kidney transplants from spousal and living unrelated donors.
N Engl J Med 1995, 333:333336.
11. Bia MJ, Ramos EL, Danovitch GM, et al.: Evaluation of living renal
donors. the current practice of US transplant centers. Transplantation
1995, 60:322327.
12. Kasiske BL, Ma JZ, Louis TA, Swan SK: Long-term effects of reduced
renal mass in humans. Kidney I nt 1995, 48:814819.
153
13
Medical Complications of
Renal Transplantation
W
ith long-term function of allografts increasingly the norm,
detecti on and management of medi cal compl i cati ons
assume greater importance in the care of renal transplanta-
tion recipients. At least two trends in transplantation seem likely to
make medical surveillance even more crucial. First, better control of
adverse immunologic events early after transplantation has signifi-
cantly reduced graft loss caused by rejection; the impact of later events
(especially death with a functioning organ and chronic rejection) on
graft and patient survival is proportionately larger. Second, with suc-
cessful transplantation now fairly routine, it is being offered to a
broader spectrum of candidates, including increasingly older patients
with multiple coexisting medical problems. Because more patients
with immunosuppression are now being cared for over increasingly
longer periods of time, the impact of comorbid events on outcomes
must be reduced.
Medical complications in the renal allograft recipient represent the
often overlapping impact of several variables. At the time of transplan-
tation, significant comorbidity may already be present and can be of
immediate concern. Other problems may have originated in the milieu
of chronic renal failure, such as hyperparathyroid bone disease or
hypertension, but may evolve differently after transplantation. Finally,
new complications may result from specific toxicities of pharmaceutical
agents, reflecting the overall impact of immunosuppression. In many
cases, all of these elements contribute to overt clinical illness. For
instance, cardiovascular disease is now the most common cause of death
in renal allograft recipients [1]. Coronary disease may have predated
transplantation (indeed, coronary disease is a common cause of death
among all patients with end-stage renal disease). After transplantation,
hypertension and hyperlipidemia, perhaps exacerbated by administration
of cyclosporine and corticosteroids, result in accelerated atherosclerosis,
further potentiating preexisting cardiac problems. To intervene appropri-
ately requires a comprehensive understanding of all the variables involved:
any decision to lessen the impact of one risk factor (eg, withdrawing
steroids) may result in unintended consequences (eg, acute rejection).
Rober t S. Ga st on
CHA P T ER
154
An obvious prerequisite to caring for transplant recipients is a
thorough understanding of immunosuppressive therapies [2].
Although acute rejection can occur at any time, the greatest risk
is during the first 90 days after transplantation. Accordingly,
immunosuppression is most intense during this time, and the
chances of suffering its consequences are great (eg, drug toxici-
ties, infection, and some malignancies [lymphoma]). In general,
tapering to a less arduous regimen over time is done, with
resulting reduction in the risks of toxicity and infection. With
long-term survival, however, the duration rather than the inten-
sity of immunosuppression becomes more critical and strongly
influences the risks of other complications, including malignan-
cies (skin), bone disease, and atherosclerosis.
Current maintenance immunosuppressive therapy involves
multidrug regimens (including azathioprine or mycophenolate
mofetil [MMF] and corticosteroids) built around a cornerstone,
the calcineurin-inhibitor (either cyclosporine or tacrolimus) [2].
Therapeutic considerations in treating patients on either of the
calcineurin inhibitors are remarkably similar in terms of both
adverse effects and drug interactions (Figs. 13-1 and 13-2)
[35]. Common azathioprine toxicities include bone marrow
suppression and alopecia. Because azathioprine is metabolized
by xanthine oxidase, concomitant use with allopurinol is prob-
lematic. MMF causes less bone marrow suppression than does
azathioprine and does not interact with allopurinol, facilitating
therapy of gout. However, gastrointestinal complaints (usually
dose-related nausea, bloating, or diarrhea) are common. In
addition, MMF may exacerbate the gastrointestinal toxicity of
tacrolimus. Corticosteroid toxicities are well described; protocols
designed to minimize corticosteroid exposure of transplantation
recipients remain the ideal pursued by many physicians who
treat these patients.
FIGURE 13-1
Despite differing structures, both
cyclosporine and tacrolimus bind to intra-
cellular receptors in T cells, forming a com-
bination that then inhibits calcineurin-
dependent pathways of cell activation.
Although slight differences exist in side-
effect profiles between the two drugs, their
overall impact is remarkably similar. In
many cases, dose reduction may ameliorate
the toxic effect; however, the benefit of dose
reduction must be weighed against increas-
ing the risk of acute rejection in each
patient. CyAcyclosporine; FKtacrolimus.
ADVERSE EFFECTS OF CYCLOSPORINE AND TACROLIMUS
Renal
Hypertension
Nephrotoxicity
(azotemia)
Gastrointestinal
Hepatotoxicity(abnormal
transaminaselevels)
Nausea, vomiting, diarrhea
(FK >CyA)
Metabolic
Glucoseintolerance(FK >CyA)
Hyperkalemia
Hyperlipidemia(CyA >FK)
Hyperuricemia
Hypomagnesemia
Cosmetic
Gingival hypertrophy
(CyA only, especially
in combination with
calciumantagonists)
Hirsutism(CyA >FK)
Neurologic
Headache
Paresthesias
Seizures
Tremor
COMMON DRUG INTERACTIONS
WITH CYTOKINE INHIBITORS
Drugsthat commonlyincreaseblood levelsof
cyclosporineand tacrolimus
Bromocryptine
Cimetidine
Clarithromycin
Clotrimazole
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Mefredil
Methylprednisolone
Nicardipine
Verapamil
Drugsthat commonlydecreaseblood levelsof
cyclosporineand tacrolimus
Carbamazepine
Phenobarbital
Phenytoin
Rifampin
FIGURE 13-2
Cyclosporine and tacrolimus are subject to remarkably similar interactions, owing in part
to a common pathway of metabolic degradation, the cytochrome P-450 enzyme system.
Although the drugs listed here predictably alter blood levels of the calcineurin inhibitors,
other interactions may also occur.
155
13.3 Medical Complications of Renal Transplantation
Months posttransplant
12 0 4 2 6 8 10
R
i
s
k

m
o
n
t
h
0.8
1.0
0.6
0.4
0.0
0.2
FIGURE 13-3
Risk of acute rejection in cadaver kidney transplantation. This graph, derived from the para-
metric analysis techniques of Blackstone and coworkers [6], depicts the risk of acute rejec-
tion over time. Using an immunosuppressive protocol including cyclosporine, mycopheno-
late mofetil, and prednisone, the risk of acute rejection is greatest during the first 2 months
after transplantation, diminishing significantly afterward. Because the risk of rejection is
greatest, immunosuppressive therapy is most intense during this period. Correspondingly,
complications related to immunosuppressive therapy (including infections and specific
drug toxicities) also are most likely during this time.
Tacrolimus level (whole blood), n g/ m L
0.8
1.0
0.6
0.4
0.2
0
I
n
c
i
d
e
n
c
e

r
a
t
e
25 22.5 20 17.5 15 12.5 10 7.5 5
Rejection
Toxicity
FIGURE 13-4
Relationship between blood levels of tacrolimus, immunosuppressive
efficacy, and toxicity [7]. As tacrolimus levels diminish, particularly
during the early period after transplantation, the risk of toxicity is
reduced accordingly. However, the risk of acute rejection increases.
Toxicity still can occur at very low drug levels, as can rejection at
high levels. The relationship between these variables beyond the
first 6 to 12 months after transplantation is not well established.
A similar plot could be constructed for cyclosporine. (Adapted
fromKershner and Fitzsimmons [7].)
Complications of Immunosuppression
Kaposi's
(6%)
Lymphomas
(24%)
Other
(36%)
Skin and lip
(34%)
FIGURE 13-5
Types and distribution of malignancies among renal transplant recipients in the current era of
cyclosporine use. In these patients the risk of malignancy is increased approximately fourfold
when compared with the general population [8]. Malignancies likely to be encountered in the
transplantation recipient differ from those most common in the general population [9,10].
Lymphomas and Kaposis sarcoma may evolve as a consequence of viral infections. Women
are at an increased risk for cervical carcinoma, again related to infection (human papilloma
virus). Surprisingly, the solid tumors most commonly seen in the general population (eg, of
the breast, lung, colon, and prostate) do not occur with significantly greater frequency among
transplant recipients. Nonetheless, long-term care of these patients should involve standard
screening for these malignancies at appropriate intervals. (FromPenn [9]; with permission.)
Malignancy
156
FIGURE 13-6
Pri mary basal cel l carci noma. Cutaneous carci nomas (pri mari l y
basal cel l and squamous cel l ) compri se the greatest percentage
of tumors i n transpl ant reci pi ents. They tend to be most prob-
l emati c i n fai r-ski nned persons whose l i festyl e i ncl udes si gni fi -
cant sun exposure; the ri sk i ncreases wi th durati on of i mmuno-
suppressi on. I n i mmunocompetent pati ents the ri sks of these
l esi ons usual l y are l i mi ted; however, i n transpl ant reci pi ents
these l esi ons can be very aggressi ve and metastasi ze l ocal l y or
even systemically. The best management is aggressive prevention:
exposure to ul travi ol et radi ati on from the sun shoul d be mi ni -
mi zed through di l i gent use of protecti ve cl othi ng, hats, and
sunscreen. When suspi ci ous l esi ons devel op, earl y recogni ti on
and removal are of utmost i mportance.
FIGURE 13-7
Posttransplantation lymphoproliferative disease (PTLD): histologic
appearance of a renal allograft infiltrated by a monoclonal proliferation
of B lymphocytes. Non-Hodgkins lymphomas, of which PTLD is
a variant, occur in 1% to 3% of transplant recipients and in many
cases are linked to an infectious cause. PTLD can be of either
polyclonal or monoclonal B-cell composition, with lymphocytes
driven to proliferate by infection with the Epstein-Barr virus
[1113]. Development of PTLD is strongly linked to the intensity
of immunosuppression and may regress with its reduction.
However, most often in the setting of splanchnic involvement
and monoclonal proliferation, as depicted, PTLD can follow a
more aggressive unrelenting course despite withdrawal of immuno-
suppressive therapy.
Days after transplantation
S
e
r
u
m

e
r
y
t
h
r
o
p
o
i
e
t
i
n

l
e
v
e
l
,

U
/
L
80 0 10 20 30 40 50 60 70
200
150
1st peak 2nd peak
100
50
25
0
is the range of serum erythropoietin levels in normal persons with-
out anemia.
Anemia is a common complication. Many patients leave the dialy-
sis population with diminished iron stores and are unable to respond
to erythropoietin produced by the successful allograft. Iron replace-
ment therapy successfully restores erythropoiesis in these patients.
Another common cause of anemia after transplantation is bone
marrow suppression owing to drug therapy with azathioprine or
mycophenolate mofetil (MMF), an effect that is usually dose-relat-
ed [15,16]. Other drugs, notably angiotensin-converting enzyme
inhibitors and angiotensin receptor antagonists, may also inhibit
erythropoiesis [17].
Neutropenia also is a common complication after transplantation.
It can reflect dose-related bone marrow suppression owing to drug
therapy with azathioprine or MMF or an idiosyncratic response to a
number of drugs commonly used in this population (acyclovir, ganci-
clovir, sulfa-trimethoprim, H
2
blockers). Alternatively, neutropenia
can be a manifestation of systemic viral, fungal, or tubercular infec-
tions. The approach to the patient with neutropenia usually involves
reducing the dose or discontinuing the potential offending agents,
along with a careful search for infections. In some settings of refrac-
tory neutropenia, administration of filgrastim (granulocyte colony-
stimulating factor, Neupogen
) reduces the duration and severity of

neutropenia. (FromSun and coworkers [14]; with permission.)
Hematologic Complications
FIGURE 13-8
The course of normal erythropoiesis after renal transplantation
showing mean serum erythropoietin levels of 31 recipients [14].
An initial burst of erythropoietin (EPO) secretion at the time of
engraftment does not result in erythropoiesis. As excellent graft
function is achieved, a second burst of EPO secretion is normally
followed by effective production of erythrocytes. The hatched area
157
Months on enalapril (mean 74.5 mo)
15 12 9 6 5 4 3 2 1 PRE
62
60
58
56
54
52
50
48
46
44
42
40
H
e
m
a
t
o
c
r
i
t
,

%
FIGURE 13-9
Posttransplant erythrocytosis (PTE). PTE (a hematocrit of >0.52)
affects 5% to 10% of renal transplantrecipients, most commonly
male recipients with excellent allograft function [17]. PTE usually
occurs during the first year after transplantation. Although it may
resolve spontaneously in some patients, PTE persists in many. It has
been linked to an increased risk of thromboembolic events; howev-
er, our own experience is that such events are uncommon. Previous
management involved serial phlebotomy to maintain the hematocrit
at 0.55 or less (dashed line). More recently, hematocrit levels have
been found to normalize in almost all affected patients with a small
daily dose of angiotensin-converting enzyme inhibitor (ACEI) or
angiotensin II receptor antagonist. The pathogenetic mechanisms
underlying PTE and its response to these therapies remain poorly
understood; although elevated serum erythropoietin levels decrease
with ACEI use, other pathways also appear to be involved.
Cardiovascular Complications
D
e
a
t
h

r
a
t
e

p
e
r

1
0
0
0

p
a
t
i
e
n
t

y
e
a
r
s
Causeof death in patients with functioningtransplants
Cardiac Infectious Stroke
Diabetic
Nondiabetic
Malignancy
8
7
6
5
4
3
2
1
0
FIGURE 13-10
Causes of death in renal allograft recipients. Cardiovascular dis-
eases are the most common cause of death, largely reflecting the
high prevalence of coronary artery disease in this population [1].
The risks are particularly high among recipients who have dia-
betes, as many as 50% of whom, even if asymptomatic, may have
significant coronary disease at the time of transplantation evalua-
tion [18]. Effective management of cardiac disease after transplan-
tation mandates documentation of preexisting disease in patients
at greatest risk [19].
DEMOGRAPHIC VARIABLES HIGHLY PREDICTIVE OF CORONARY DISEASE
IN RENAL TRANSPLANTATION CANDIDATES WITH INSULIN-DEPENDENT
DIABETES MELLITUS
Age>45y
Electrocardiographic abnormality: nonspecific ST-T wavechanges
Historyof cigarettesmoking
Duration of diabetes>25y
FIGURE 13-11
Demographic variables highly predictive of coronary disease in renal transplantation candidates
with insulin-dependent diabetes mellitus. Most transplant centers screen potential candi-
dates, particularly persons with diabetes, for
coronary disease before transplantation. In
patients with diabetes who have end-stage
renal disease with none of the demographic
characteristics listed, the risk for coronary
disease is low. Conversely, in patients who
are insulin-dependent and have any of these
risk factors, the prevalence of coronary disease
is sufficiently high to justify angiography.
A randomized study of medical therapy
versus revascularization in transplantation
candidates who have insulin-dependent
diabetes and coronary disease showed superior
outcomes with prophylactic revascularization,
even in the absence of overt symptomatol-
ogy [20]. (Adapted fromManske and
coworkers [18].)
158
0
40
32
24
16
8
0
50
40
30
20
10
100 400 200 300 70 310 130 190 250
100 400 200 300 0 35 95 50 65 80
0
75
60
45
30
15
0
75
60
45
30
15
74% 63%
29%
10%
n=429 n=591
n=430 n=588
LDL, m g/ d L
HDL, m g/ d L
Cholesterol, m g/ d L
Triglycerides, m g/ d L
,
,
FIGURE 13-12
Hypercholesterolemia and hypertriglyc-
eridemia. Hypercholesterolemia and hyper-
triglyceridemia are common after kidney
transplantation. Approximately two thirds
of transplant recipients have low density
lipoprotein (LDL) or total cholesterol levels
signifying increased cardiac risk; 29% have
elevated triglyceride levels 2 years after
transplantation (Kasiske, Unpublished
data). Not only is hyperlipidemia a clear
risk factor for coronary disease (seeFigs.
13-13 and 13-14), but it may also contribute
to the progressive graft dysfunction associated
with chronic rejection [21,22]. HDLhigh
density lipoprotein. (FromBristol-Myers
Squibb [23]; with permission.)
RISK FACTORS FOR CORONARY MORBIDITY
IN RENAL ALLOGRAFT RECIPIENTS
Positive
Age:
Male 45y
Female 55yor prematuremenopause
Familyhistoryof prematurecoronary
heart disease
Smoking
Hypertension
HDL cholesterol <35mg/dL
Diabetesmellitus
Negative
HDL cholesterol 60mg/dL
FIGURE 13-13
Risk factors for coronary morbidity in renal allograft recipients. In
addition to elevated low density lipoprotein (LDL) cholesterol levels,
risk factors known to contribute to coronary morbidity often are
present in renal allograft recipients. About 40% of recipients are
over 45 years old, and 23% have diabetes. Smoking, hypertension,
and hyperlipidemia are among the risk factors most amenable to
long-term modification. (For guidelines in instituting lipid-lowering
therapy see Figure 13-14 [24].)
GUIDELINES FOR LIPID-LOWERING THERAPY
Goal
<160
<130
100
Diet therapy
LDL cholesterol, mg/dL
No CHD and <2risk factors
No CHD and 2risk factors
CHD
Initiation
160
130
100
LDL cholesterol, mg/dL
No CHD and <2risk factors
No CHD and 2risk factors
CHD
Diet plus drug therapy
Initiation
190
160
130
Goal
<160
<130
100
FIGURE 13-14
The indications for lipid-lowering therapy and its goals are based
on the clinical history, risk factor profile (seeFig. 13-13), and low
density lipoprotein (LDL) cholesterol level in individual patients.
CHDcoronary heat disease. (From Grundy [24]; with permission.)
159
Cholesterol Triglycerides
p<0.001 P<0.05
193.9
229.8
165.4
198.6
0
125
250
L
i
p
i
d

l
e
v
e
l
,

m
g
/
d
L
Prograf
CyA
FIGURE 13-15
Cyclosporine (CyA) and corticosteroid therapies clearly contribute to hyperlipidemia in
renal allograft recipients. Although dose reduction can reduce lipid levels, it may also
increase the risk of acute rejection. As depicted, early experience in a large multicenter
trial indicates that tacrolimus may have a less adverse impact on lipid metabolism than
does cyclosporine [25]. (FromFujisawa USA [26]; with permission.)
THERAPEUTIC OPTIONS IN LIPID-LOWERING THERAPY
Control groups
Diet
HMG CoA
inhibitors
Fibrates
Fish oil
Probucol
Niacin
LDL cholesterol
-1522
-5925
-4918
-6924
-8680
Cholesterol
16
-2115
-516
-369
-49
111
-2814
-569
-3812
2343
-6621
-4828
Triglycerides
24
58
3.54.5
36
-13.512
1010
mg/dL changes95%CI.
HDL cholesterol
FIGURE 13-16
A recent meta-analysis of published trials in renal transplant
recipients demonstrated these benefits of the various treatments.
Pharmacologic therapy should be instituted at low doses with
cautious surveillance for potential adverse effects, especially liver
dysfunction or rhabdomyolysis. These adverse events may occur
more frequently in transplant recipients owing to the effect of
cyclosporine on drug disposition. Levels of 3-hydroxy-3-methylglutaryl
coenzyme A (HMG CoA) reductase inhibitors are substantially higher
in patients receiving both drugs [27]. HDLhigh density lipoprotein;
LDLlow density lipoprotein. (Adapted fromMassy and coworkers
CAUSES OF HYPERTENSION AFTER TRANSPLANTATION
Intrinsic
Delayed graft function
Acuterejection
Chronic rejection
Cyclosporinenephropathy, chronic
Recurrent primaryrenal disease
(glomerulonephritis, hemolytic uremic
syndrome, and so on)
Extrinsic
Nativekidneys
Immunosuppression:
Cyclosporine
Tacrolimus
Corticosteroids
Transplantation renal arterystenosis
Hypercalcemia
FIGURE 13-17
In the current era of immunosuppressive therapy, hypertension
affects roughly two thirds of transplant recipients. Unlike hyperten-
sion in the general population, posttransplant hypertension often
reflects the impact of readily definable (and potentially treatable)
factors on systemic blood pressure [2830]. These may be grouped
conveniently into those originating within the allograft (intrinsic)
and those originating elsewhere (extrinsic).
160
Diagnosisand treatment of hypertension
in therenal transplant recipient
Evaluateallograft function
Consider salt restriction
and/or diuretic
Intervention fails to
normalizeBP
Adequateresponse
to therapy?
ECF volumestatus
acceptable?
Adequateresponse
to therapy?
Acceptableside
effect profile?
StableGFR?
Yes
Yes
Yes
No
No
No
No
Yes
Yes
Yes No
Reducedoseof
cyclosporineor
tacrolimus
Multidrugregimen:
add agents of different
classes as necessary
Re-evaluateallograft
function and drugtherapy
Consider TRAS
Optimal blood levels
of cyclosporine
or tacrolimus?
Continue
antihypertensivetherapy
Reassess periodically
Administer
antihypertensiveagent
(CA, ACEI, or other)
Blood pressure140/90
FIGURE 13-18
Hypertension in the renal transplant recipient. In these patients
it may be possible to approach diagnosis and therapy in a fairly
standardized fashion. In transplant recipients with blood pressure
readings consistently over 140/90 mm Hg, intervention is warranted.
The initial approach includes assessment of allograft function,
extracellular fluid volume (ECF) status, and immunosuppressive
dosing. If these variables are stable, it is reasonable to proceed with
antihypertensive therapy. Calcium antagonists (CA) are effective
agents and may offer the added benefit of attenuating cyclosporine-
induced changes in renal hemodynamics. Verapamil, diltiazem,
nicardipine, and mibefradil increase blood levels of cyclosporine
and tacrolimus and should be used with caution. Common problems
with CAs that may limit their use include cost, refractory edema,
and gingival hyperplasia. Angiotensin antagonists (ACEIs and
receptor antagonists) are also effective; their use requires close
monitoring of renal function, serum potassium levels, and hematocrit
levels. Diuretics frequently are useful adjuncts to therapy in recipients
owing to the salt retention that often accompanies cyclosporine
use. Other antihypertensive medications offer no particular benefits
or drawbacks and can be employed as needed. The rationale of
multidrug therapy is to employ agents that block hypertensive
responses via interruption of differing pathogenetic pathways.
As antihypertensive drugs are added, this consideration should
remain paramount [31,32]. GFRglomerular filtration rate;
TRAStransplanted renal artery stenosis.
FIGURE 13-19
Transplant renal artery stenosis (TRAS). TRAS accounts for less than 5% of cases of
hypertension after transplantation. Nonetheless, TRAS should always be considered in
patients with refractory hypertension who develop renal insufficiency after addition of an
ACEI to the therapeutic regimen. Although noninvasive studies (such as a renal scan with
captopril) may be helpful in diagnosing TRAS, angiography remains the gold standard for
diagnosis. Revascularization of the allograft by either surgical or angioplastic techniques
may improve renal function and ameliorate hypertension [33,34].
161
GASTROINTESTINAL TRACT COMPLICATIONS IN
RENAL TRANSPLANTATION RECIPIENTS
Other complications
Hepatotoxicity, constipation
Hepatotoxicity, constipation
Constipation, dyspepsia
Hepatotoxicity, pancreatitis
Diarrhea
3
32
31
Rare
Nausea and
vomiting
4
30
20
12
Drug
Cyclosporine
Tacrolimus
MMF
Azathioprine
FIGURE 13-20
Complications affecting the gastrointestinal (GI) tract remain rela-
tively common in transplant recipients. Both tacrolimus and
mycophenolate mofetil (MMF) cause bloating, nausea, vomiting,
and diarrhea in a dose-dependent manner, particularly when used
in combination [15,16,25]. Some authors have noted that this rather
nonspecific GI toxicity occurs more commonly with Neoral
than
with Sandimmune
(both from Sandoz Pharmaceuticals, East

Hanover, NJ).
Gastrointestinal Complications
A B
FIGURE 13-21 (S e e Color Plate)
Endoscopic image of candida esophagitis
with diffuse white exudate (panel A) and
colitis induced by cytomegalovirus infection
with submucosal hemorrhage, ulcers, and
diffuse mucosal edema (panel B). The avail-
ability and common use of effective prophy-
laxis against acid-peptic disease (eg, H
2
block-
ers, omeprazole, and antacids) have signifi-
cantly reduced the frequency of upper
gastrointestinal bleeding. However, infectious
agents such as cytomegalovirus and candida
continue to be problematic, particularly in
the setting of the more intense immunosup-
pression afforded by drugs such as mycophe-
nolate mofetil (MMF) and tacrolimus.
FIGURE 13-22
Histologic image of chronic active hepatitis secondary to infection
with the hepatitis C virus (HCV). Note the periportal distribution
of the lymphocytic infiltrate. Recent identification of HCV has caused
intense reevaluation of the causes, frequency, and natural history of
liver disease in renal allograft recipients. As the percentage of patients
with end-stage renal disease who are infected with the hepatitis B
virus has diminished, HCV has become the most problematic cause
of liver disease. In recipients with HCV antibodies, immunosup-
pressive therapy may potentiate liver injury from the virus and
accelerate the course of time over which cirrhosis develops.
Nonetheless, in patients who desire transplantation and have well-
preserved liver function, little evidence exists of better longevity on
dialysis. HCV can be transmitted easily from donor to recipient in
solid organ transplantation. Because kidney transplantation is not a
life-saving procedure, most transplant centers choose not to use
kidneys from donors who are infected with HCV.
Previously, liver disease was thought to be a common cause of
death in renal allograft recipients. As blood transfusions have
become less common in the dialysis population and hepatitis B
virus less prevalent, the risk of death owing to hepatic disease
seems to have diminished. Unfortunately, therapies for HCV-related
hepatitis (interferon-) have proved to be of questionable efficacy
and may stimulate rejection of the renal allograft [3537].
162
0 6
*
*
*
*
*
*
18
12
9
6
3
0
C
h
a
n
g
e

i
n

d
e
n
s
i
t
y
,

%
Males
Females
Both genders
FIGURE 13-23
Mean percentage changes in bone mineral
density of the lumbar spine after transplan-
tation. Substantial bone loss can occur quite
early after transplantation. Metabolic bone
disease in this setting is usually multifactorial.
Most often, patients who had end-stage
renal disease before transplantation already
have some degree of renal osteodystrophy,
exacerbated in some cases by the impact of
aluminum toxicity or
2
-microglobulin
amyloidosis. Patients with diabetes are
particularly at risk for low-turnover bone
disease. Administration of corticosteroids
and cyclosporine also contributes to bone
loss. Although biochemical evidence of
secondary hyperparathyroidism usually
resolves during the first year after transplan-
tation, some patients may have persistent
parathyroid-driven bone resorption, with
or without hypercalcemia, and may require
surgical parathyroidectomy. Asterisk
values significantly different from those at
the time of transplantation. (FromJulian
Musculoskeletal and Metabolic Complications
FIGURE 13-24
Bone densitometry. Bone densitometry
offers a noninvasive method to quantitate
bone mass. Here, a renal transplant
recipient demonstrates marked osteoporosis,
with bone density greater than 2 standard
deviations below age- and gender-matched
controls. In recent years, new therapeutic
options (including bisphosphonates, estrogens,
and thiazides) have offered hope of preserving
or even increasing bone mass [38,39].
BMDbone mass density.
FIGURE 13-25
Magnetic resonance imaging of osteonecrosis.
Osteonecrosis most commonly affects the
femoral head but can affect any weight-
bearing bone. The most debilitating compli-
cation of renal transplantation, its incidence
seems to be decreasing (<10% of transplant
recipients). This decrease reflects better
management of calcium and bone homeostasis
during long-term dialysis and less intense
steroid use after transplantation. The
pathogenesis of osteonecrosis remains poorly
understood, and therapeutic options are
limited (pain management while awaiting
progression to the need for joint replacement).
Magnetic resonance imaging is a sensitive
diagnostic method, allowing detection of
osteonecrosis at a very early stage [39].
FIGURE 13-26
Photograph of gouty inflammation of joints (tophus). Gout is
the clinical manifestation of hyperuricemia. After transplantation,
cyclosporine can exacerbate hyperuricemia, and severe gout can
be problematic even in the presence of chronic immunosuppression.
Management of gouty arthritis usually involves some combination
of colchicine and judicious use of short courses of nonsteroidal
anti-inflammatory drugs. Concomitant administration of allopurinol
and azathioprine can cause profound bone marrow suppression
and is avoided by most physicians who treat transplant recipients.
Because the metabolism of mycophenolate mofetil (MMF) is not
dependent on xanthine oxidase, use of allopurinol in patients
treated with MMF is relatively safe [39,40].
163
INCIDENCE OF POST-TRANSPLANT
DIABETES MELLITUS
Initial
At 1year
At 18mo
*Patientswithout historyof diabetes.
FIGURE 13-27
Photograph of gingival hyperplasia. Gingival hyperplasia occurs
in approximately 10% of transplant recipients treated with
cyclosporine. Its severity reflects the interaction of effective dental
hygiene, cyclosporine dose, and concomitant administration of calcium
antagonists (particularly dihydropyridines). This complication does
not seem to occur with use of tacrolimus, and complete resolution
of gingival hyperplasia has been noted with conversion from
cyclosporine-based therapy [25,41].
FIGURE 13-28
Post-transplantation diabetes mellitus (PTDM). PTDM complicates
the course of treatment in 5% to 10% of patients on cyclosporine-
based immunosuppressive therapy. It is more common in blacks
and in patients with a family history of glucose intolerance.
PTDM often reflects the substantial steroid-related weight gain
that sometimes occurs after transplantation. The severity of PTDM
can be attenuated by weight loss and corticosteroid withdrawal,
although the latter may not be advisable owing to the risk of
rejection. In a multicenter trial, PTDM occurred with greater
frequency among patients treated with tacrolimus, particularly
blacks. Although PTDM resolved over time in almost half of
affected patients (as doses of tacrolimus and corticosteroids were
gradually reduced), PTDM remained more common in patients
receiving tacrolimus [25,42,43]. CyAcyclosporine. (From
Fujisawa USA [26]; with permission.)
Acknowledgments
The author thanks his colleagues at the University of Alabama at
Birmingham for contributing many of the illustrations used in this
chapter: Drs. Ralph Crowe, Bruce Julian, Catherine Listinsky,
Brendan McGuire, Klaus Monckemuller and Colleen Shimazu.
PTDM (defined as requiring insulin 30 d)
n
30
25
18
%
15.9
18.5
12.0
Prograf *
(n=151)
CyA
(n=151)
n
8
5
0
%
4.0
3.3
3.3
Pvalue
>0.001
>0.001
References
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11. Randhawa PS, Jaffe R, Demetris AJ, et al.: Expression of Epstein-Barr
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-based therapy vs.

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after renal transplantation: pathogenesis and treatment. Am J Kidney
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165
14
Technical Aspects of
Renal Transplantation
R
enal transplantation is the preferred treatment method of end-
stage renal disease (ESRD). It is more cost-effective than is
maintenance dialysis [1] and usually provides the patient with
a better quality of life [2]. Adjusted mortality risk ratios indicate a sig-
nificant reduction in mortality for kidney transplantation recipients
when compared with that for patients receiving dialysis and patients
receiving dialysis who are on a waiting list for renal transplantation
(Fig. 14-1) [3].
The indication for renal transplantation is irreversible renal failure
that requires or will soon require long-term dialytic therapy. The eval-
uation of candidates for renal transplantation is discussed in Chapter
12. Generally accepted contraindications are noncompliance, active
malignancy, active infection, high probability of operative mortality,
and unsuitable anatomy for technical success [4]. The technical
aspects of kidney transplantation are discussed, primarily through the
illustrations of kidney preparation and of a living donor renal trans-
plantation.
Kidneys from living donors require little preparation by the trans-
plantation team because most of the dissection has already been done
during the nephrectomy. Further separation of the renal artery or
arteries from the renal vein(s) will allow separation of the arterial and
venous suture lines in the recipient and will prevent the technical
inconvenience of side-by-side anastomoses. The right kidney from a
living donor usually has a cuff of the inferior vena cava attached to
the renal vein. This provides the recipient team with maximum renal
vein length and a wide lumen for anastomosis. The renal arteries in a
kidney graft from a living donor are not attached to aortic patches as
they usually are in the cadaveric kidney. The technical aspects of living-
donor harvesting are not illustrated here.
John M . Ba r r y
CHA P T ER
166
ADJUSTED MORTALITY RISK RATIOS FOR END-STAGE
RENAL DISEASE BY TREATMENT MODALITY
Treatment modality
All patientson dialysis
Patientson dialysiswho areon awaitinglist
Cadaveric kidneytransplantation recipients
Living-donor related kidneytransplantation recipients
Da t a f rom USRenal DataSystem[3].
Risk ratio
1.0
0.48
0.32
0.21
TECHNICAL CONSIDERATIONS FOR RECIPIENTS
OF KIDNEY TRANSPLANTATION
Kidney graft
Right or left
Grossappearanceand size
Arterial anatomy
Venousanatomy
Ureteral anatomy
Recipient
Abdominal wall anatomy
Size
Arterial anatomy
Venousanatomy
Urinarytract anatomyand function
Gender
FIGURE 14-1
The adjusted mortality risk ratio for patients on dialysis placed on
the renal transplantation waiting list is greater than that for kidney
transplantation recipients, suggesting transplantation itself results
in a reduced mortality risk for patients with end-stage renal disease
who are treated [3].
FIGURE 14-2
A number of factors concerning the kidney graft and recipient
determine the technique of renal transplantation in each recipient.
Placement of the kidney graft in the contralateral iliac fossa is
preferable because the renal pelvis becomes the most medial of the
vital renal structures and thus readily available for future recon-
struction if ureteral stenosis occurs. Areas of previous abdominal
surgery such as ileostomy, colostomy, renal transplantation, or a
peritoneal dialysis exit site are avoided, if possible. A kidney too
large for the recipients iliac fossa is usually placed in the right
retroperitoneal space and revascularized with the aorta or common
iliac artery and interior vena cava or common iliac vein. Pelvic vas-
cular disease and previous renal transplantation determine whether
the aorta or internal iliac, external iliac, common iliac, native renal
or splenic artery will be selected for renal artery anastomosis. The
use of both internal iliac arteries in serial renal transplantations in
men is avoided to prevent impotence [5]. The method of urinary
tract reconstruction depends primarily on the status of the recipi-
ents bladder, continent reservoir, or incontinent intestinal conduit.
Cadaveric Kidney Graft
FIGURE 14-3
Instrument setup for cadaveric kidney graft preparation. The towel
prevents renal movement during dissection.
167
14.3 Technical Aspects of Renal Transplantation
FIGURE 14-4
Preparation of a left
cadaveric kidney
graft. The kidney
and its vital struc-
tures are surround-
ed by other tissues.
The cadaveric
kidney graft can
require an hour of
preparation time
because the specimen
usually includes a
portion of the inferior
vena cava, an aortic
cuff, the adrenal
gland, variable
amounts of peri-
nephric tissue,
sometimes pieces of
muscle, and occa-
sionally damaged
renal vessels.
FIGURE 14-5
Renal vein dissection. The adrenal and gonadal veins have been
isolated. They will be divided between ligatures.
FIGURE 14-6
Renal artery dissection. In this posterior view, the aortic patch and
main renal artery have been separated from the surrounding tissues.
FIGURE 14-7
Left cadaver kidney
graft after prepara-
tion. The adrenal
gland and excess
perinephric tissue
have been removed.
Fibrofatty tissue is
left around the renal
pelvis and ureter to
ensure blood supply
to the ureter. The
aortic patch, renal
vein, and ureter will
be further modified
to provide a best
fit in the recipient.
168
Preparation of Kidney Graft Vessels
A
B
C
D
A
B or
C
D
E
FIGURE 14-8
Venoplasties for
right renal vein
extension of a
cadaveric kidney
graft [68]. AC,
Use being made of
the inferior vena
cava. D,Use being
made of the external
iliac vein of the
cadaveric donor.
FIGURE 14-9
Preparation of the
renal allograft with
multiple renal arteries
[9]. A and B, The
use of aortic patches
when the kidney is
from a cadaveric
donor is demon-
strated. C and D,
The possibilities that
exist when an aortic
patch is not part of
the specimen, such
as when the kidney
is from a living
donor. E, The
segmental renal
artery also can be
anastomosed to the
inferior epigastric
artery using an end-
to-end technique.
The Kidney Transplantation Operation
DIVISION OF OPERATING ROOM RESPONSIBILITIES
FOR RECIPIENTS OF KIDNEY TRANSPLANTATION
Anesthesiologist
Anesthetic induction
Placement of central venousaccessline
Administration of antibiotics
Administration of immunosuppressants
Administration of heparin
Assuranceof conditionsfor diuresis
Surgeon
Patient position
Bladder catheterization
Initial skin preparation
Incision and exposureof operativesite
Renal revascularization
Urinarytract reconstruction
Wound closure
FIGURE 14-10
After the induction of anesthesia, the anesthesia team places a dou-
ble- or triple-lumen central venous access catheter, usually via the
internal jugular vein. While that is taking place, the surgical team
places a retention catheter (usually 20F with a 5-mL balloon), fills
the bladder to 30 cm H
2
pressure or 250 mL (whichever occurs
first), connects the catheter to a three-way system or clamped uri-
nary drainage system, and places the clamp(s) within reach of the
anesthesiologist for control during the operation. The preoperative
antibiotic is administered by the anesthesia team. The surgical team
shaves both sides of the patients abdomen from just above the
umbilicus to the distal edge of the mons pubis. The skin is wiped
with alcohol, and the nursing team completes the skin preparation.
The skin over both iliac fossae is prepared in the event an unex-
pected vascular contraindication is detected on the chosen side. If
immunosuppressant therapy has not been administered, the anes-
thesia team begins that protocol.
169
Adult Recipient
FIGURE 14-11
Surgeons view of the right iliac fossa operative site. In this procedure,
a 40-year-old man will be receiving his brothers left kidney, which
has a single artery, single vein, and single ureter. The renal vessels
will be anastomosed to his right external iliac artery and vein, and
urinary tract reconstruction will be by extravesical ureteroneocys-
tostomy [10,11]. The patient is positioned with the head slightly
down, supine, and rotated toward the surgeon, who is standing
on the patients left side.
Exposure of the right iliac fossa. The contents of the iliac fossa are
exposed by incising the skin, subcutaneous tissues, anterior rectus
sheath, external and internal oblique muscles, and the transversalis
muscle and fascia. The inferior epigastric artery is divided between
ligatures, the spermatic cord is preserved (in women, the round lig-
ament is divided between ligatures), and the rectus muscle and
peritoneum are retracted medially. This exposes the genitofemoral
nerve (white umbilical tape), the external iliac vein (blue tape), and
the external and internal iliac arteries (red tapes).
FIGURE 14-13
Determining best fit. The kidney graft is placed in the wound
and the renal vessels stretched to the recipient vessels to determine
the best sites for the arterial and venous anastomoses.
FIGURE 14-14
Isolation of the arteriotomy site. Heparin (3050 U/kg) is adminis-
tered intravenously, and vascular clamps are placed on the external
iliac artery. The distal clamp is applied first so that the arterial
pressure will distend the targeted artery. The external iliac artery is
incised longitudinally, the lumen is irrigated with heparinized
saline, and fine monofilament vascular sutures are placed in four
quadrants to receive the spatulated renal artery. When the recipient
artery has significant arteriosclerosis, an endarterectomy can be
done or a 5- or 6-mm aortic punch can be used to create a smooth
round arteriotomy.
170
FIGURE 14-15
Completed end-to-side renal arterytoexternal iliac artery anasto-
mosis. Many surgeons perform the arterial anastomosis first because
it is smaller than is the venous anastomosis. Thus, the kidney can
be moved about more easily to expose the arterial anastomosis
when it is not tethered by a previously completed venous anasto-
mosis. An ice-cold electrolyte solution is periodically dripped onto
the kidney graft to keep it cold during vascular reconstruction.
FIGURE 14-16
Isolation of the right external iliac vein. The kidney is retracted
medially, and a segment of the external iliac vein is isolated
between Rumel tourniquets. The cephalad tourniquet is applied
first so that increased venous pressure will dilate the vein.
FIGURE 14-17
Renal vein anastomotic setup. The renal vein is anastomosed to the
side of the external iliac vein with the same suture technique that
was used for the arterial anastomosis.
FIGURE 14-18
Completed venous and arterial anastomoses.
171
FIGURE 14-19
Revascularized kidney transplantation. The usual clamp release
sequence is as follows: proximal vein, distal artery, proximal artery,
and distal vein. Arterial spasm is treated by subadventitial injection
of papaverine.
FIGURE 14-20
Urinary tract reconstruction [1011]. Unstented parallel incision
extravesical ureteroneocystostomy requires a bladder full of antibiotic
solution, clearance of fat from the superolateral surface of the bladder,
and placement of the ureter under the spermatic cord to prevent
ureteral obstruction. Parallel incisions are made 2 cm apart in the
seromuscular layer of the bladder to expose the bladder mucosa.
FIGURE 14-21
Submucosal tunnel creation. A right-angle clamp is used to develop
the tunnel and to pull the transplantation ureter through it.
FIGURE 14-22
Bladder mucosa incision. After the ureter is spatulated on its ventral
surface, single-armed 5-0 absorbable sutures are placed in the heel
and in each of the dog-ears of the ureter. A double-armed hori-
zontal mattress suture of the same material is placed in the toe
of the ureter so that the needles exit on the mucosal side. The bladder
is drained by unclamping the catheter tubing, and the bladder
mucosa is incised.
172
FIGURE 14-23
Partially completed ureteral anastomosis. The heel and dog-ears
of the spatulated ureter have been sutured to the bladder mucosa.
The horizontal mattress suture will be passed through the full thick-
ness of the bladder wall and tied distal to the seromuscular incision.
This will close the toe and anchor the ureter to the bladder.
FIGURE 14-24
Completed ureteroneocystostomy. The distal seromuscular incision has
been closed over the ureter, which now lies in a submucosal tunnel.
FIGURE 14-25
Deep wound closure. A suction drain has been placed around the
kidney graft deep in the wound, and the musculofascial interrupted
sutures are ready to be tied.
FIGURE 14-26
Completed wound closure. Scarpas fascia has been closed over the
musculofascial sutures, and the skin has been closed with a 4-0
absorbable subcuticular suture. This procedure accurately approximates
the skin and eliminates subsequent staple or skin suture removal.
173
FIGURE 14-27
Artists depiction of the completed kidney transplantation.
DIURESIS ENHANCEMENT IN
KIDNEY TRANSPLANTATION
Living-donor kidney transplantation
Maintain CVP 510cmH
2
O
Maintain MAP 60mmHg
Maintain SBP 90mmHg
Mannitol, 0.20g/kg, IV over 1h, start
with first vascular anastomosis
Furosemide, 0.20mg/kg, IV duringsecond
half of second vascular anastomosis
Cadaveric kidney transplantation
Same
Same
Same
Increasemannitol doseto 1g/kg
(maximum50g) IV
Increasefurosemidedoseto 1mg/kgIV
Albumin, 1g/kg(to 50g), IV over 23h
Verapamil, 010mg, into renal artery
based on blood pressureand weight
CVPcentral venouspressure; IVintravenous; MAPmean arterial pressure;
SBPsystemic blood pressure.
M od if ied f rom Dawidson and ArRajab [12].
FIGURE 14-28
Maneuvers for diuresis enhancement [12]. Several intraoperative
maneuvers can be used to promote diuresis.
Child Recipient
FIGURE 14-29
Transplantation of a kidney from an adult
into a small child. The technique is modi-
fied for transplantation of a large kidney
into a small recipient. The renal artery is
anastomosed to the distal aorta or common
iliac artery, and the shortened renal vein is
anastomosed to the interior vena cava or
common iliac vein.
174
Postoperative Care
POSTOPERATIVE CARE DURING HOSPITALIZATION
AFTER KIDNEY TRANSPLANTATION
Removeon 5th postoperativeday, administer doseof antibiotic
Remove612wk postoperativelyin clinic
Removewhen 30mL/24h or in 3wk if volume>30mL/24h
Discontinuein 2448h (check intraoperativecultureresultsfirst)
Patient-controlled analgesia
Livingdonor: fixed rateof 125200mL/h of D5W in 0.45%
normal saline
Cadaveric donor: replaceinsensiblelosswith D5W, replace
urineoutput mL for mL with 0.45%normal saline
Protocol (covered in Chapter 11)
Foleycatheter
Ureteral stent, if used
Suction drain(s)
Antibiotics
Pain control
Intravenousfluids
Immunosuppressants
Infection prevention
Peptic ulcer prevention
IVintravenous.
FIGURE 14-30
Postoperative clinical pathway.
Urologic Complications
Hydronephrosis
Nephrostomy drainage
plus serial serum
creatininelevels
Radioisotopevenogram
+
furosemide wash-out
T1/2 1020 min T1/2 <1020 min
Nephrostogram
Whitaker test
Repair No repair
Obstruction ?
Nephrostogram
Percutaneous nephrostomy
T1/2 >1020 min
Percutaneous nephrostomy
Yes No
or
Evaluation of kidney transplantation hydronephrosis
FIGURE 14-31
Algorithm for evaluation of kidney trans-
plantation hydronephrosis [9]. The generally
accepted criterion for exclusion of upper
urinary tract obstruction is a washing out
of half of the radioisotope from the renal
pelvis in less than 10 minutes. Obstruction
is considered to be present when this value is
over 20 minutes. Percutaneous nephrostomy
allows anatomic definition of the obstruction
and temporary drainage of the hydronephrotic
kidney. A generally accepted criterion for
the diagnosis of obstruction with the percu-
taneous pressure-flow Whitaker test is fluid
infusion into the pelvis at the rate of 10
mL/min, resulting in a renal pelvic pressure
over 20 cm H
2
O.
175
CAUSES OF KIDNEY
TRANSPLANTATION
URETERAL OBSTRUCTION
Late
X
X
X
X
X
Early
X
X
X
X
Cause
Blood clot
Edema
Technical error
Lymphocele
Ischemia
Periureteral fibrosis
Stone
Tumor
FIGURE 14-32
Causes of renal transplantation ureteral obstruction. Hydronephrosis owing to ureteral
obstruction is one of the two most common urologic complications for which invasive
therapy is required, the other being perigraft fluid collection. Early causes of ureteral
obstruction are usually apparent within the first few days after renal transplantation.
Late causes become apparent weeks to years later.
Perigraft fluid collection
>50 mL ?
Hydronephrosis ?
Decreased renal function ?
Ipsilateral legswelling?
Fever ?
Pain ?
"No" to all
Serum Lymph Urine Blood
Serum Lymph Urine Blood
Repair Explore
Pus
Drain
Restudy as necessary
"Yes" to any
Aspirate
Repeat ultrasound
Significant recurrence?
Yes
No
Evaluation of treatment of perigraft fluid collection
FIGURE 14-33
Algorithm for evaluation and treatment of
perigraft fluid collection [9]. Perigraft fluid
collection is one of the two most common
urologic complications for which invasive
therapy is required, the other being hydro-
nephrosis owing to ureteral obstruction.
Serum, urine, lymphatic fluid, blood, and
pus can be differentiated by creatinine and
hematocrit determinations and by micro-
scopic examination of the fluid. Urine has a
high creatinine level, serum and lymphatic
fluid have low creatinine levels, and blood
has a relatively high hematocrit level.
Lymphocytes are present in lymphatic fluid,
and polymorphonuclear leukocytes with or
without organisms are present in pus. Open
surgical drainage is usually necessary for
fluid collections showing infection. Significant
lymphoceles have been successfully treated
with percutaneous sclerosis or by marsupi-
alization into the peritoneal cavity by either
a laparoscopic or open surgical technique.
Persistent urinary extravasation often
requires open surgical repair. Significant
bleeding requires exploration and control
of bleeding.
176
Results of Renal Transplantation
US KIDNEY GRAFT SURVIVAL RATES FOR
TRANSPLANTATIONS DONE FROM 1991 TO 1995
Donor
Cadaver
Living
Number
36,417
13,771
1 y, %
84
92
5 y, %
60
75
10 y (projected), %
43
62
FIGURE14-34
The 5-year patient survival rates for recipients of cadaveric and living-
donor kidney transplantations were 81% and 90%, respectively
[13]. Kidney transplantation survival rates have steadily improved
since the 1970s because of the following: careful recipient selection
and preparation, improvement in histocompatibility techniques and
organ sharing, contributions from our colleagues in government
and the judiciary, improvements in immunosuppressive therapy and
infection control, careful monitoring of recipients, and refinement of
surgical techniques. What we accomplish today as a matter of routine
was only imagined by a few just decades ago.
References
1. United Network for Organ Sharing: The UNOS Statement of
Principles and Objectives of Equitable Organ Allocation. UNOS
Update1994, 10:20.
2. Evans RW, Manninea DL, Garrison LP, et al.: The quality of life of
patients with end-stage renal disease. N Engl J Med 1985, 312:553.
3. US Renal Data System, USRDS 1997 Annual Data Report, National
Institutes of Health, Bethesda, MD: National Institute of Diabetes and
Digestive and Kidney Diseases, 1997:7273.
4. Nohr C: Non-AIDS immunosuppression. In Care of the Surgical
Patient, Vol. 2. Edited by Wilmore DW, Brennan MF, Harken AH,
et al. New York: Scientific American; 1989:118.
5. Gittes RF, Waters WB: Sexual impotence: the overlooked complication
of a second renal transplant. J Urol 1979, 121:719.
6. Barry JM, Fuchs EF: Right renal vein extension in cadaver kidney
transplantation. Arch Surg1978, 113:300.
7. Corry RJ, Kelly SE: Technique for lengthening the right renal vein of
cadaver donor kidneys. Am J Surg1978, 135:867.
8. Barry JM, Hefty TR, Sasaki T: Clam-shell technique for right renal vein
extension in cadaver kidney transplantation. J Urol 1988, 140:1479.
9. Barry JM: Renal transplantation. In Campbells Urology. Edited by
Walsh PC, Retik AB, Vaughan ED, Wein AJ. Philadelphia: WB
Saunders Co, 1997:505530.
10. Barry JM: Unstented extravesical ureteroneocystostomy in kidney
transplantation. J Urol 1983, 129:918.
11. Gibbons WS, Barry JM, Hefty TR: Complications following unstented
parallel incision extravesical ureteroneocystostomy in 1000 kidney
transplants. J Urol 1992, 148:38.
12. Dawidson IJA, ArRajab A: Perioperative fluid and drug therapy
during cadaver kidney transplantation. In Clinical Transplants 1992.
Edited by Terasaki PI, Secka JM. Los Angeles: UCLA Tissue Typing
Laboratory; 1993:267284.
13. Cecka JM: The UNOS Scientific Renal Transplant Registry. In Clinical
Transplants 1996. Edited by Terasaki PI, Cecka JM. Los Angeles:
UCLA Tissue Typing Laboratory; 1997:114.
Da t a f rom Cecka[13].
177
15
Kidney-Pancreas
Transplantation
I
n the United States, diabetes mellitus is the third most common
disease and fourth leading cause of death from disease. Diabetes is
the leading cause of blindness, the number one cause of amputa-
tions and impotence, and one of the most frequently occurring chron-
ic childhood diseases. Diabetes is also the leading cause of end-stage
renal disease in the United States, with a prevalence rate of 31% com-
pared with other renal diseases. Diabetes is also the most frequent
indication for kidney transplantation, accounting for 22% of all
transplantation operations.
Increasingly, pancreas transplantation is being offered to patients
who would benefit from kidney transplantation (called simultaneous
pancreas-kidney transplantation) or who have had a previously suc-
cessful kidney transplantation (called sequential pancreas after kidney
transplantation). Relatively few transplantation centers are performing
pancreas transplantation alone in patients with severe life-threatening
complications of diabetes. Pancreas transplantation has been criticized
because of the increased morbidity associated with the procedure and lack
of controlled trials demonstrating significant benefit to the secondary
complications of diabetes. However, many of these criticisms have
been overcome with improvement in surgical techniques and pancreas
transplantation preservation and with more potent immunosuppressive
regimens. The relative frequency of pancreas transplantation, common
surgical procedures, and outcomes of patients undergoing pancreas
transplantation are discussed.
John D . Pir sch
Jon S. O dor ico
H a ns W. Sol l i nger
CHA P T ER
178
Urologic
2%
PCKD
5%
GN
19%
HTN
26%
Other
11%
Unknown
6%
DM
31%
Nephritis
8%
PCKD
8%
GN
26%
HTN
12%
Other
18%
Unknown
6%
Diabetes
22%
FIGURE 15-1
Disease prevalence resulting in end-stage renal disease (ESRD)
from the United States Renal Data Service (1993 to 1995). In the
continental United States at the end of 1995, 257,266 patients had
ESRD. Diabetes mellitus (DM) accounts for nearly one third of all
patients newly diagnosed with ESRD who require kidney trans-
plantation. GNglomerulonephritis; HTNhypertensive
nephropathy; PCKDpolycystic kidney disease.
FIGURE 15-2
Kidney transplantations by diagnosis (October 1987 through
December 1994). Approximately 10,000 patients receive kidney
transplantations in a given year. Of the primary renal diseases
requiring transplantation, diabetes accounted for 22% of all kidney
transplantations performed in the United States. GNglomeru-
lonephritis; HTNhypertensive nephropathy; PCKDpolycystic
kidney disease.
1200
800
600
400
200
1000
0
Pre-
78
78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96
32
66
6
9
11
8
19
20
30
24
36
38
85
50
112
51
111
112
147
170
218
146
213
249
201
417
201
528
181
530
200
557
157
774
167
842
130
1027
115
1022
Year
Total
US
NonUS
n=9012
n =6640
n =2372
FIGURE 15-3
Pancreas transplantations per year. The number of pancreas transplantations performed per year in
the United States has been increasing. In 1995 and 1996, over 1000 pancreas transplantations were
performed in the United States. A smaller number were performed outside of the United States.
179
15.3 Kidney-Pancreas Transplantation
8000
7000
6000
5000
4000
3000
2000
1000
0
1988 1989 1990 1991 1992 1993 1994 1995
Year
R
e
c
i
p
i
e
n
t

n
u
m
b
e
r
FIGURE 15-4
Relative proportion of simultaneous pancreas-kidney (SPK) transplantations versus cadaveric
kidney transplantations in the United States. Despite an increasing number of SPK transplan-
tations over the past 7 years, pancreas transplantation is a less common procedure than is
cadaveric kidney transplantation alone.
INCLUSION CRITERIA FOR
PANCREAS TRANSPLANTATION
TypeI diabetesmellitus
Abilityto undergo theprocedure
Emotional and psychological stability
Agelessthan 60y
Secondarycomplicationsof diabetes
Financial resources
FIGURE 15-5
The inclusion criteria for pancreas transplan-
tation are relatively few. Patients usually have
type I diabetes mellitus and must have the
physical stamina to undergo a major abdomi-
nal operation. The patients age is important,
with 60 years of age usually being the cutoff.
In some transplantation centers, the cutoff
age is 50 years. The patient should demon-
strate emotional and psychological stability,
and significant secondary complications of
diabetes must be present. Because Medicare
does not pay for pancreas transplantations,
recipients must use either private insurance or
personal funds.
EXCLUSION CRITERIA FOR
PANCREAS TRANSPLANTATION
Significant cardiac disease
Substanceabuse
Psychiatric illness
Historyof noncompliance
Extremeobesity
Activeinfection or malignancy
No secondarycomplicationsof diabetes
FIGURE 15-6
The exclusion criteria for pancreas trans-
plantation include significant cardiac disease,
substance abuse, psychiatric illness, and a
history of noncompliance. Extreme obesity,
active infection, and malignancy are relative
contraindications to transplantation. Patients
with few or very mild secondary complica-
tions of diabetes may be candidates for kidney
transplantation alone.
1000
800
600
400
200
0
1988 1989 1990 1991 1992 1993 1994 1995 1996
Year
SPK
PTA
PAK
N
u
m
b
e
r

o
f

t
r
a
n
s
p
l
a
n
t
s
FIGURE 15-7
Types of pancreas transplantation procedures and relative frequency per year (January 1988
through December 1996). Three different indications for pancreas transplantation exist.
Patients with type I insulin-dependent diabetes who require kidney transplantation may
undergo a simultaneous pancreas-kidney (SPK) transplantation or receive a kidney transplan-
tation followed by a pancreas transplantation during a separate operation (called pancreas
after kidney [PAK] transplantation). Patients without significant renal disease may undergo
pancreas transplantation alone (PTA). The relative proportion of the types of transplantations
is shown. Most pancreas transplantations performed in the United States are of the SPK type,
followed by PAK transplantations. Presently, few PTA transplantations are performed. 180
or external iliac artery. The portal vein of the allograft is anastomosed
to the common iliac vein or distal inferior vena cava. Likewise, on the
left side the renal artery and vein are anastomosed to the common
iliac artery and vein, respectively. To restore the continuity of the
urinary tract, a standard ureteroneocystostomy is constructed to the
dome of the bladder.
Because the pancreas has dual endocrine and exocrine functions,
it is necessary to perform another anastomosis to handle exocrine
secretions. A variety of techniques to manage pancreatic exocrine
secretions have been proffered over the years with less than satisfac-
tory results. These include duct occlusion, open drainage into the
peritoneal cavity, and creation of a button of duodenum and anasto-
mosing this or the pancreatic duct directly to the bladder. Currently,
the most commonly performed technique in the United States is
drainage of pancreatic exocrine secretions into the bladder (bladder
drainage, BD), as depicted [1]. The BD technique involves fashioning
a short segment of donor duodenum, which is transplanted along
with the pancreas. Then the donor duodenum is anastomosed to
the dome of the recipient bladder in a side-to-side manner. In this
way exocrine secretions, including enzymes, proenzymes, water,
and sodium bicarbonate, are diverted into the urinary tract. This
technique is safe, reliable, and well tolerated; however, it is associated
with a number of specific urinary tract complications.
As a consequence of implantation into the iliac fossa, the pancreatic
allograft is drained into the systemic venous circulation, as depicted.
This results in systemic venous, rather than portal venous, insulin
release and peripheral hyperinsulinemia. An alternative approach
practiced by some surgeons is portal venous drainage. In this
approach the portal vein of the allograft is anastomosed to the supe-
rior mesenteric vein of the recipient in an end-to-side fashion. This
technique establishes drainage of insulin into the portal venous
blood flow, perhaps a more physiologic situation (procedure not
shown). The results of the two techniques are largely comparable.
Fortunately, patients have suffered no adverse effects of systemic
venous drainage and hyperinsulinemia.
Solitary pancreaticoduodenal allografts are implanted into either
iliac fossa, at whichever point the iliac vessels permit vascular anas-
tomoses. This procedure is done, usually and preferentially, on the
right side. Otherwise, the operative sequence duplicates that of the
combined procedure.
Transplantation Operation
FIGURE 15-8
Simultaneous pancreas-kidney allograft procedure. Most pancreas
transplantations performed in the United States are whole organ
pancreaticoduodenal allografts from cadaveric donors transplanted
simultaneously with the kidney from the same donor [1]. Because
the pancreas from a patient with diabetes still subserves digestive
function, it is not removed. Therefore, the pancreaticoduodenal
allograft is transplanted to an ectopic location, usually the right
iliac fossa. Similarly, the kidney allograft is transplanted ectopically
to the contralateral iliac fossa. The reconstructed arterial supply to
the pancreas, as shown in Figure 15-9, is anastomosed to the common
181
Ligated
splenic A and V
Iliac Y graft
Ligated SMA and SMV
Ligated CBD
Splenic A
SMA
FIGURE 15-9
Preparation of the pancreaticoduodenal allograft and arterial recon-
struction. The donor pancreas, duodenum, and spleen are perfused in
situ with cold University of Wisconsin solution and harvested en bloc
with the liver. The pancreaticoduodenal graft is separated from the
liver graft and prepared on the surgical back table at 4
o
C. The spleen
is first removed by ligating the splenic artery and vein. The duodenal
segment is shortened to approximately 10 cm, and the suture lines are
reinforced. The common bile duct (CBD) and the superior mesenteric
artery and vein (SMA and SMV) have been ligated previously in the
donor. A variety of techniques exist to reconstruct the dual arterial
blood supply to the pancreas. In our experience, the most favorable
approach entails using an iliac artery bifurcation graft harvested from
the same donor. As shown, the external iliac arterial limb of the graft
is anastomosed to the SMA, and the hypogastric arterial limb is anas-
tomosed to the splenic artery. This technique is reliable and associated
with a very low thrombosis rate. The venous anastomosis (portal vein
to iliac vein or inferior vena cava) can be performed without tension
by complete mobilization of both the donor portal vein and the recip-
ient iliac vein. A venous extension graft is rarely necessary and proba-
bly increases the risk of thrombosis.
FIGURE 15-10
Enteric drainage (ED) technique. An alternative approach to bladder
drainage, ED is, perhaps, a more physiologic method of handling
pancreatic exocrine secretions. ED is the preferred method in Europe
and is rapidly gaining popularity in the United States [1]. Most
commonly, it is performed as depicted without a Roux-en-Y
anastomosis. The donor duodenal segment is anastomosed in a
side-to-side fashion to the ileum or distal jejunum. Long-term graft
survival, thrombosis rates, and primary nonfunction rates are no
different when comparing the two techniques [13]. Performed
with expertise, both techniques should yield excellent results.
Several significant advantages of the ED technique over bladder
drainage make ED our technique of choice.
182
COMPARISON OF BLADDER DRAINAGE VERSUS ENTERIC DRAINAGE TECHNIQUES
Bladder drainage (BD)
Advantages
Abilityto monitor urinaryamylaselevelsasan indicator of rejection [6]
?Decreased risk of perioperativeintra-abdominal infections
Disadvantages
Risksof developingurologic complicationsin up to 25%of patients, includingurethritis,
urethral disruption, and hematuria
Risk of recurrent UTIsgreater for BD than for ED [3]
Prolonged urinarycatheter drainageneeded to decompressbladder anastomosis
for healing
Frequent postoperativeadmissionsfor dehydration and metabolic acidosisand need for
bicarbonatereplacement
Enteric drainage (ED)
Advantages
No need for enteric conversion in up to 25%of patientswho haveurologic
complications
Lessmetabolic acidosisand chronic dehydration [3]
Shorter length of hospital staysecondaryto lessdehydration
Earlyremoval of urinarycatheter and fewer UTIs
Abilityto performportal venousdrainage, if desired
Disadvantages
?Increased risksof perioperativeperipancreatic infections
Difficult to diagnosepancreatic enzymeleaks
UTIsurinarytract infections.
FIGURE 15-11
Early attempts using enteric drainage (ED) techniques resulted in
prohibitively high rates of intra-abdominal abscesses, wound infections,
and mycotic aneurysms threatening both graft and patient. Thereafter,
bladder drainage (BD) via a duodenocystostomy evolved in the
United States as the safest and most frequently performed exocrine
drainage procedure. It has been suggested that BD affords the ability
to monitor urinary amylase levels as an indicator of rejection, which
may be useful in the setting of a solitary pancreas transplant. However,
in recipients of simultaneous pancreas-kidney (SPK) transplant in
whom kidney function serves as a marker of rejection monitoring of
urinary amylase levels is not necessary to achieve excellent long-term
graft survival.
As experience grew with BD, however, it was found that up to
25% of patients with BD developed a significant urologic or metabolic
complication requiring surgical conversion of exocrine secretions to
ED [4,5]. Renewed interest in primary ED has resulted. Several
recent retrospective studies have compared BD pancreas transplants
to ED transplants. These studies have demonstrated equivalent
short-term graft survival rates without increased risks of infectious
complications and pancreatic enzyme leaks [13]. ED is associated
with fewer urinary tract infections (UTIs) and no hematuria.
Patients who have ED experience less dehydration and metabolic
acidosis and, as a result, a reduced need for fluid resuscitation and
bicarbonate supplementation [3]. Finally, in patients who have ED
the Foley catheter can be removed within several days, whereas
patients who have BD require prolonged drainage (up to 14 days)
to permit healing of the duodenocystostomy. Consequently, with
ED, patients are able to leave the hospital sooner. ED has proved
to be more physiologic and results in less morbidity compared
with BD. Therefore, ED is rapidly gaining popularity as the
method of choice for handling graft exocrine secretions in
pancreas transplantation.
183
Immunosuppression and Monitoring
IMMUNOSUPPRESSIVE PROTOCOLS
SPK
ATGAM (20mg/kg/d for 10d)
MMF (3g/d)
Neoral
(8mg/kg/d)
Prednisone(500mgintraoperatively; 250
mgon postoperativedays1and 2; 30
mg/d thereafter)
PAK and PTA
ATGAM (20mg/kg/d for 10d) or
OKT3(510mg/d for 10d)
MMF (2g/d)
FK506(8mg/d)
Prednisone(500mgintraoperatively; 250
mgon postoperativedays1and 2; 30
mg/d thereafter)
ATGAMantithymocyteglobulin, polyclonal serum; FK506 tacrolimus, Prograf
(FujisawaUSA, Inc., Deerfield, IL); MMFmycophenolatemofetil, RS-61443, CellCept
(RocheLaboratories, Nutley, NJ); OKT3muromonab, murineantihuman CD3mono-
clonal antibody;PAKpancreasafter kidneytransplantation;PTApancreastransplan-
tation alone; SPKsimultaneouspancreas-kidneytransplantation.
inhibitor of inosine monophosphate dehydrogenase (IMPDH).
IMPDH is an essential enzyme in the de novo purine synthetic
pathway upon which lymphocyte DNA synthesis and proliferation
are strictly dependent. Compared with AZA, MMF has no associa-
tion with pancreatitis and has less association with leukopenia.
Moreover, whereas AZA is not useful in treating ongoing rejection,
MMF can salvage refractory acute renal allograft rejection in up to
half of patients. By virtue of this mechanism of action, MMF provides
more effective and specific immunosuppression with less risk com-
pared with AZA.
Similarly, Neoral, a microemulsified formulation of cyclosporine
(CsA) has replaced standard CsA therapy with Sandimmune (both
drugs from Sandoz Pharmaceuticals, East Hanover, NJ). Because of
gastroparesis and autonomic dysfunction, patients with diabetes exhibit
unpredictable absorption of CsA. The new formulation of CsA
has an increased rate and extent of drug absorption with lower
inter- and intra-individual pharmacokinetic variability than does
Sandimmune, particularly in patients with diabetes. Improved
bioavailability and more reliable pharmacokinetics may translate
into fewer rejection episodes and improved graft survival. Experience
with tacrolimus (FK506) in pancreas transplantation for induction,
maintenance, and rescue therapy has demonstrated that it is safe,
well tolerated, and has a low risk of glucose intolerance. Moreover,
particularly for solitary pancreas transplants, strikingly improved
short-term graft survival results have been reported [9,10]. The
mechanism of action of FK506 as a calcineurin inhibitor is similar
to that of CsA. FK506 has a better side-effect profile compared
with CsA, causing less hirsutism, less hyperlipidemia, but some-
what more neurotoxicity. Unlike CsA, FK506 can rescue patients
with refractory rejection and treat ongoing rejection. One caveat
when using FK506 in combination with MMF is the risk of over-
immunosuppression. Several studies have highlighted the fact that
FK506 may increase blood levels of the active metabolite of MMF,
mycophenolic acid, in a clinically relevant manner [11]. By reducing
the incidence of rejection, these modern immunosuppressants have
resulted in improved short- and long-term graft survival. Fewer
rejection episodes will likely translate into an overall reduction in
the glucocorticoid dosage being given in the perioperative period.
This reduction may favorably impact short-term infectious compli-
cations and long-term steroid-related adverse side effects.
FIGURE 15-12
Because the best treatment of rejection is prevention, the most effi-
cacious regimen of immunosuppressive drugs should be used first.
Quadruple-drug immunosuppressive regimens, including the use
of antithymocyte globulin (ATGAM) or OKT3, have been accepted
as standard at most pancreas transplant centers. Recent data from
the United Network for Organ Sharing and several smaller retro-
spective comparative trials provide evidence that antiT-cell antibody
induction therapy may lessen the severity and delay the onset of
rejection and may improve short-term graft survival in recipients of
simultaneous pancreas-kidney (SPK) transplants [1,7,8]. This is the
current practice. The development of newer more specific immuno-
suppressive agents, however, recently has changed the face of mod-
ern immunosuppression in solid organ transplantation and raises
the possibility of successful pancreas transplantation without
induction therapy. Mycophenolate mofetil (MMF) has recently
replaced azathioprine (AZA) as maintenance immunosuppressive
therapy in kidney transplantation alone, SPK, and pancreas trans-
plantation alone. MMF is a potent noncompetitive reversible
184
A
B
C
Pancreas transplantation biopsy. Pancreas allograft biopsy is the
gold standard for evaluating pancreas allograft dysfunction and for
diagnosing acute rejection. In a pancreas transplantation recipient,
indications for the need of a biopsy to rule out rejection include
elevated amylase or lipase levels, unexplained fever, and glucose
intolerance. In patients with simultaneous pancreas-kidney (SPK)
transplantation, pancreas rejection most commonly (about 90%)
occurs simultaneously with kidney rejection. As a result, a diagnosis
of rejection relies almost entirely on serum creatinine,
2
-microglobulin,
and renal allograft biopsy. However, in the setting of sequential
pancreas after kidney transplantation or pancreas transplantation
alone (PTA) in which isolated pancreas rejection occurs, predicting
rejection with a serologic or urinary marker is more difficult. To date,
no marker has been identified that can predict rejection accurately
enough to warrant treatment without first performing a biopsy. Thus,
the ability to perform pancreas allograft biopsy is essential in the
postoperative care of recipients of PTA. In addition to a biopsy, radio-
logic evaluation of the allograft with ultrasonography (to evaluate
vascular flow) and computed tomography (CT) scan (to rule out pan-
creatic enzyme leaks and fluid collections) are complementary studies
that deserve consideration for all episodes of allograft dysfunction.
Percutaneous core biopsies of the pancreas allograft with real-
time ultrasonography or CT guidance have been shown to be safe
and reliable [1214]. A and B, After the gland is assessed for vascu-
lar patency an appropriate portion of the pancreas is identified that
is free of major vessels and overlying viscera (usually the body or
tail). C, A 20-gauge automated biopsy needle is advanced into the
pancreas graft under real-time ultrasonography, and a biopsy is
obtained. In pancreaticoduodenal grafts with bladder drainage (BD)
a cytoscopic transduodenal biopsy offers the opportunity to obtain
biopsy specimens from both the pancreas and duodenum. Success
rates for obtaining tissue for pathologic review in both techniques
are 85% to 95%. Firm adherence of the pancreas to surrounding
structures and use of real-time ultrasonography reduce the risks of
complications related to biopsy. Overall, complications occur in 5%
to 10% of patients, which can include bleeding, pancreatic duct
leak, hematuria (in BD pancreas transplants), and asymptomatic
transient hyperamylasemia. Rarely does a complication require a
repeat operation or result in graft loss.
185
Management of Complications
A
C
B
approach that balances aggressive immunosuppression against risks
of infection. A diagnosis of rejection is dependent on biopsy of
either the kidney or pancreas allograft in recipients of SPK trans-
plantation or of the pancreas allograft in pancreas transplantation
alone. Because of the double-edged sword of aggressive antirejection
treatment, an episode of graft dysfunction should not be treated
without biopsy-proven histopathologic evidence of immunologic
graft injury. Ruling out infectious and anatomic causes of graft
dysfunction with appropriate radiologic studies is equally important.
Drachenberg and coworkers [15] and Nakhleh and Sutherland [16]
have defined histologic criteria for grading pancreas allograft rejection
that are practical from the standpoint of being able to prognosticate
outcome and response to therapy. Serial histologic studies of pancreas
rejection (as in this case) have shown that lymphocytic infiltrates
initially involve the exocrine portion of the gland and that islet cell
tissue becomes involved later [12]. As a result, exocrine dysfunction
is frequently the first clinical sign of rejection (manifested by either
elevated serum amylase or decreased urinary amylase levels).
Consequently, early rejections without evidence of islet cell involve-
ment usually can be treated successfully. On the contrary, the success
of antirejection treatment is far less successful when initiated after
the development of hyperglycemia [17].
A, Normal pancreas allograft core biopsy demonstrating an acinar
lobule and preserved individual islet of Langerhans without inflam-
matory infiltrate (magnification 200). B, Needle core biopsy
demonstrating glandular architecture with fibrous septae interdigi-
tating between acinar lobules. An infiltrate is present that can be
described as mononuclear, predominantly lymphocytic, perivascular,
and septal. Endothelialitis is seen in a medium-sized vein at the
upper central edge of the biopsy specimen. These features are con-
sistent with mild acute cellular rejection (magnification 200).
C, Needle core biopsy demonstrating intense septal inflammation
with activated lymphocytes. Early acinar inflammation is present
in the right upper lobule. Eosinophils also are present in the dense
septal infiltrate. These findings also are consistent with mild acute
cellular rejection (magnification 200). Moderate rejection is
characterized by significant acinar inflammation and arteritis.
Severe rejection is suggested when, in addition to the features listed
above, confluent acinar necrosis with extensive acinar inflammation
and ductal epithelial necrosis are present.
Features indicating a poor prognosis include arteritis, confluent
acinar necrosis, islet inflammation and necrosis, ductal epithelial
necrosis, and fibrosis. Mild acute rejection usually is reversible
with bolus corticosteroid therapy. In contrast to renal allograft
rejections, however, most mild pancreas allograft rejections are
somewhat recalcitrant to bolus steroid immunotherapy. Steroids
may worsen potentially compromised glycemic control, thus com-
plicating treatment. Therefore, significant rejection of the pancreas
allograft may be best treated with antibody therapy, although a
randomized control trial comparing the two treatment options
has not been carried out. FK506 is commonly employed as rescue
therapy in pancreas transplant episode recipients who are experi-
encing a significant acute rejection episode while on cyclosporine
or Neoral (Sandoz Pharmaceuticals, East Hanover, NJ). Irreversible
allograft rejection was a frequent occurrence several years ago.
Today, it is unusual, occurring in less than 5% of patients.
FIGURE 15-14
Pancreas allograft rejection. Rejection occurs with greater frequency
after pancreas and simultaneous pancreas-kidney (SPK) transplan-
tation than after kidney transplantation alone, predictably in 75%
to 85% of patients. This difference requires a strategically different
186
Metabolic
acidosis
2%
Indications for enteric conversion
Hematuria
19%
Urethritis
23%
Recurrent
urinary
tract
infections
11%
Reflux
pancreatitis
3%
Leak
42%
FIGURE 15-15
Indications for enteric conversion (EC). A set of complications unique to pancreas trans-
plantation arise as a consequence of urinary diversion of graft exocrine secretions. The
development of one of these complications is the most frequent cause for re-admission to
the hospital after pancreas transplantation with BD. These include the following: persistent
gross hematuria, recurrent or chronic urinary tract infections (UTIs), urethritis, urethral
stricture or disruption, urinary or pancreatic enzyme leak, graft (reflux) pancreatitis, and
excessive bicarbonate loss and acidosis [18]. Surgical conversion to ED is indicated when these
complications are incapacitating or refractory to conservative therapy. Except for leaks
and pancreatitis, these complications are largely avoided in ED pancreas grafts.
Hematuria in the immediate postoperative period is usually mild and self-limited, occa-
sionally requiring irrigation, cytoscopic fulguration, or both. Hematuria occurring late
after transplantation (ie, months to years) may be caused by UTIs, suture granulomas,
bladder stones, or ulceration of the duodenal segment. In total, hematuria occurs in 17%
of patients. Conversion to ED is indicated when hematuria persists despite appropriate therapy
and is required in up to a third of patients who present with late or chronic hematuria.
Pancreatic enzyme or urinary leaks also can occur in the early postoperative period or as
late as several years after transplantation. Early leaks usually occur at the bladder-duodenum
suture line, whereas late leaks occur most commonly at the lateral duodenal staple line or
at the location of a duodenal ulcer. The cause is unclear. Whereas some early leaks may be
technically related, late leaks are more likely a result of rejection, cytomegalovirus infection,
ischemia, or a combination of all these. Patients usually present with sudden-onset lower
abdominal pain, fever, leukocytosis, increased serum amylase and slightly increased creatinine.
Diagnosis is confirmed by cystogram (seeFig. 15-17). Fortunately this complication is
unusual, occurring in 10% to 15% of patients.
The most common infectious complication after pancreas transplantation is UTI, occurring
in 63% of pancreas transplant recipients with BD. These recipients may be more predisposed
to UTIs than are kidney transplant recipients because of the additive effect of several factors.
These factors include alkalinization of the urine secondary to bicarbonate exocrine secretion,
presence of a diabetic neurogenic bladder with incomplete emptying, mucosal injury at the
bladder anastomosis, and prolonged catheter drainage. Occasionally, a cause for therapy-
resistant or recurrent infections is found on cystoscopy and study of the upper tracts also
is indicated. When no source is found, EC is indicated.
If persistent, urethritis may result in urethral stricture, disruption, or both. Although its
exact cause is unclear, urethritis is most likely caused by the digestive action of pancreatic
enzymes on the urothelium. Urethritis usually is manifested as perineal pain and discomfort
during urination and seems to occur almost exclusively in males. Initially, conservative
treatment with Foley catheter drainage for several weeks is recommended. When perforation
occurs, it usually is in the membranous portion of the urethra and presents with perineal
and testicular swelling. To avoid complications of urethral stricture and disruption, early
enteric conversion is recommended when urethritis fails to respond to an initial short
course of conservative treatment. Fortunately, these complications are unusual, occurring
in only 5% of simultaneous pancreas-kidney (SPK) transplantation recipients.
Early postoperative hyperamylasemia, thought to be caused by preservation injury, is not
uncommon and, fortunately, usually is asymptomatic and improves rapidly. Persistent or
marked elevations of amylase indicate possible technical errors, including ductal ligation
or leak. Graft pancreatitis (sometimes referred to as reflux pancreatitis) presents in a manner
similar to that of a leak. Graft pancreatitis is further defined by absence of a leak on radi-
ologic study; evidence of gland edema on CT scan, without evidence of abscess or fluid
collections; and; most important, resolution of symptoms within 48 hours of Foley catheter
drainage. Treatment with Foley catheter drainage for several days is usually successful. When
an infection is found in the patients urine at this time, appropriate parenteral antibiotics
may be beneficial.
Metabolic acidosis is present postoperatively in about 80% of patients after pancreas
transplantation with BD and usually is due to excessive urinary loss of bicarbonate-containing
exocrine fluids. Because urinary bicarbonate loss is accompanied by an obligate loss of
fluid, low serum levels are associated with dehydration. Oral fluid replacement should be
instituted to maintain a serum bicarbonate level of at least 20 to 25 mg/dL, and dehydration
is treated appropriately. Fortunately, this problem usually stabilizes over time and infrequently
requires conversion from bladder to enteric drainage.
187
A
F
r
a
c
t
i
o
n

o
f

p
a
t
i
e
n
t
s

c
o
n
v
e
r
t
e
d
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0
Years
Kaplan-Meier rate=28%
P
e
r
c
e
n
t
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
8 7 6 5 4 3 2 1 0
Years
Timeto EC
B
Duodenum
Bladder
Sideto side
duodeno-
enterostomy
FIGURE 15-16
Incidence and procedure in enteric conversion (EC). A, Surgical
conversion of pancreatic exocrine secretions from bladder drainage
to enteric drainage is necessary in many patients. Whereas half of
patients receive EC within the first postoperative year, a significant
percentage must undergo EC up to 5 years after transplantation.
B, EC involves taking down the duodenocystostomy, repairing the
bladder, and performing a simple side-to-side duodenoenterostomy.
In our experience of performing 95 ECs over a 14-year period in
480 simultaneous pancreas-kidney (SPK) transplant recipients, only
one graft was lost within 3 months of EC [5]. No differences were
found in patient, kidney, or pancreas graft survival when compar-
ing SPK transplant recipients who underwent EC with those who
did not. The frequency of urologic complications and need for EC
have prompted a changing trend toward performing primary
enteric drainage; however, neither of these problems appears to
impact negatively on graft survival.
A
FIGURE 15-17
Pancreatic enzyme and urinary leaks. A leak of urine, activated pancreatic enzymes, or both,
is one of the most devastating and life-threatening infectious complications after pancreas
transplantation. Patients exhibit sudden-onset lower abdominal pain, fever, leukocytosis,
increased serum amylase levels, and increased serum creatinine levels. Diagnosis is confirmed
by cystogram. When no leak is identified, voiding cystourethrography (VCUG) with gastrograf-
fin (panel A) or a VCUG using technetium (Tc
99m
) in normal saline is performed (panelsBE).
188
B
D E
C
In our opinion, a Tc
99m
-VCUG is the most sensitive test, because
extravasation may occur only during the high-pressure phase of void-
ing [19]. B, This gastrograffin-VCUG demonstrates duodenal segment
and anastomosis in the region of the dome of the bladder in an
oblique anteroposterior projection. A leak of contrast is identified at
the lateral duodenal segment staple line. Band C, Normal Tc
99m
-
VCUG scintigraphy is shown. Radioactive tracer is seen within the
confines of the intact urinary tract, refluxing into the duodenal seg-
ment (large black arrow) and renal transplantation collecting sys-
tem (small black arrow). D and E, Tc
99m
-VCUG demonstrates spill
of radioactive tracer outside of the bladder and duodenal segment
(large white arrowhead). Later, radioactive tracer is also present in
the pelvis and between loops of bowel throughout the peritoneal
cavity (small white arrowheads).
For small leaks that are contained early, treatment consists of
bladder decompression with a urinary catheter for 2 to 3 weeks.
Large leaks and those that recur after conservative therapy require
exploration, repair of the involved suture line, and enteric conversion.
Careful inspection of the duodenal segment is essential, and biopsy
of the duodenal mucosa to search for rejection or cytomegalovirus
pathology may be revealing in determining the cause. In most cases,
however, the exact cause remains enigmatic despite careful investi-
gation. In some cases, simultaneous diversion of the fecal stream
with a Roux-en-Y anastomosis or proximal ileotransverse colosto-
my is advocated. Rarely is a urinary leak secondary to disruption
of the ureteroneocystostomy. Enzyme leaks are more difficult to
diagnose in enterically drained pancreata. A diagnosis in this setting
relies on contrast-enhanced computed tomography (CT) scan, which
usually demonstrates peripancreatic fluid collections. When drained
percutaneously, these fluid collections reveal infection with enteric
organisms and an elevated fluid amylase level. Surgical treatment
of leaks in ED pancreata requires an individualized approach that
usually involves repair, drainage, and diversion of the fecal stream.
An expeditious diagnosis, depending on a high index of suspicion,
and aggressive surgical intervention are essential to manage these
life-threatening complications.
189
FIGURE 15-18
Urethral disruption. When left untreated, urethritis usually progresses to urethral disruption.
Retrograde urethrography in a recipient of a simultaneous pancreas-kidney transplant with
bladder drainage demonstrates perforation of the membranous urethra with extensive
extravasation of contrast. Immediate treatment is placement of a suprapubic cystostomy
or, if possible, a Foley catheter. Enteric conversion follows, which is 100% successful.
Sequelae of this process include stricture and bladder outlet obstruction.
C
%
100
90
80
70
60
50
40
60 54 48 42 36 30 24 18 12 6 0
Months posttransplantation
SPK kidney graft function by era
UScadaveric pancreas transplantations 10/1/19877/31/1997
P =0.004
Years
8789
9091
9293
9497
n Txs
532
908
1125
2387
1Yr surv.
86%
84%
86%
89%
B
%
100
80
60
40
20
0
60 54 48 42 36 30 24 18 12 6 0
SPK pancreas graft function by era
P =0.0001
Years
8789
9091
9293
9497
n Txs
532
908
1125
2387
1Yr surv.
74%
75%
79%
82%
A
%
100
90
80
70
60
50
40
60 54 48 42 36 30 24 18 12 6 0
SPK patient survival by era
P =0.002
Years
8789
9091
9293
9497
n Txs
532
908
1125
2387
1Yr surv.
90%
91%
92%
94%
FIGURE 15-19
Patient and graft survival rates for simultaneous pancreas-kidney
(SPK) transplantations in the United States. The survival rates have
improved over the past 10 years. The current 1-year patient survival
rate for SPK is 94% (panel A), with an 89% kidney graft survival
rate (panel B) and 82% pancreas graft survival rate (panel C). The
differences over time are highly significant between all eras.
190
B
%
100
90
80
70
60
50
40
60 54 48 42 36 30 24 18 12 6 0
PAK graft function by era
P 0.008
Years
8789
9091
9293
9497
n Txs
77
76
84
209
1Yr surv.
56%
51%
52%
70%
A
%
100
80
60
40
20
0
60 54 48 42 36 30 24 18 12 6 0
PAK patient survival by era
P =NS
Years
8789
9091
9293
9497
n Txs
77
76
84
209
1Yr surv.
90%
96%
90%
95%
B
%
100
90
80
70
60
50
40
60 54 48 42 36 30 24 18 12 6 0
PTA patient survival by era
Years
8789
9091
9293
9497
n Txs
46
49
72
92
1Yr surv.
93%
90%
90%
93%
A
%
100
80
60
40
20
0
60 54 48 42 36 30 24 18 12 6 0
PTA graft function by era
P =NS
Years
8789
9091
9293
9497
n Txs
46
49
72
92
1Yr surv.
46%
51%
56%
74%
P 0.0001
FIGURE 15-20
Patient (panel A) and graft (panel B) survival rates for sequential
pancreas after kidney (PAK) transplantations. For patients with
PAK, the survival rate is similar to simultaneous pancreas-kidney
transplantations but graft survival has been poorer until very
recently. The 1-year PAK graft survival rate has improved from
52% to nearly 70%. NSnot significant.
FIGURE 15-21
Graft (panel A) and patient (panel B) survival rates for pancreas
transplantation alone (PTA). A much smaller number of PTAs
have been performed in the United States compared with sequential
pancreas after kidney (PAK) transplantations and simultaneous
pancreas-kidney (SPK) transplantations. The patient survival rate
for PTA is similar to those of SPK and PAK transplantation; howev-
er, the PTA graft survival rate has been closer to that of the PAK rate
until the most recent transplantation era. Advancements in immuno-
suppressive therapy have improved the 1-year graft survival rate of
PTA transplantations from 56% to 74%. NSnot significant.
EFFECTS OF PANCREAS TRANSPLANTATION ALONE
ON SECONDARY COMPLICATIONS OF DIABETES
Maintenanceof normoglycemia
Neuropathy
Prevention of recurrent nephropathy
Qualityof life
Retinopathy
Vascular disease
Beneficial
Stabilization and improvement
Beneficial
Major
None
Minimal
FIGURE 15-22
Multiple studies have been performed on the effects of pancreas
transplantation on the secondary complications of diabetes.
Unfortunately, most of these studies were performed with small
numbers of patients and were not randomized controlled studies.
There are four major benefits of pancreas transplantation for the
secondary complications of diabetes: 1) Normoglycemia has been
demonstrated for an extended period of time as long as the pan-
creas is functioning; 2) nephropathy has been shown to improve;
3) pancreas transplantation appears to prevent recurrent diabetic
nephropathy in the transplanted kidney; and 4) quality of life.
Complete freedom from insulin injections, appears to be the
major benefit of pancreas transplantation. Unfortunately, pancreas
transplantation does not appear to reverse established diabetic
nephropathy in patients with their own kidneys, and established
retinopathy and vascular disease do not appear to improve.
191
H
e
m
o
g
l
o
b
i
n

A
1
,
%

o
f

t
o
t
a
l

h
e
m
o
g
l
o
b
i
n
16
14
12
10
8
6
4
124 mo 266 mo
Before
transplantation
After
transplantation
FIGURE 15-23
Glycosylated hemoglobin before and after pancreas transplantation. All patients have an
abnormal hemoglobin A1 value before pancreas transplantation. Most patients, however,
maintain a normal hemoglobin A1C after successful pancreas transplantation. (From
Morel and coworkers [20]; with permission).
Kidney pancreas
Control
A
u
t
o
n
o
m
i
c

i
n
d
e
x
2.5
2.0
1.5
1.0
0.5
42 24 12 0
Months
S
e
n
s
o
r
y

i
n
d
e
x
2.5
2.0
1.5
1.0
0.5
42 24 12 0
M
o
t
o
r

i
n
d
e
x
2.5
2.0
1.5
1.0
0.5
42 24 12 0
*
*
A
B
C
P
e
r
c
e
n
t

e
y
e
s

w
i
t
h

s
t
a
b
l
e
r
e
t
i
n
o
p
a
t
h
y

g
r
a
d
e
100
75
50
25
0
0 12 24 36 48 60 72
Timefollowingpancreas transplantation, m o
Pancreas transplant
Control
FIGURE 15-24
Effects of pancreas transplantation on diabetic neuropathy. Careful
studies of motor index (panel A), sensory index (panel B), and
autonomic index (panel C) show a general trend of improvement
over 42 months in patients who received pancreas transplantation
compared with patients in the control group. In patients with pan-
creas transplantation, 70% had improved results on motor nerve
tests, nearly 60% on sensory tests, and 45% on autonomic tests.
In patients in the control group, only 30% had improved results
on motor and sensory tests, 12% had improved autonomic tests,
and nearly 50% had deterioration of neurologic function. (From
Kennedy and coworkers [21]; with permission).
FIGURE 15-25
Effects of pancreas transplantation on diabetic retinopathy.
Retinopathy does not appear to improve after pancreas trans-
plantation. A similar rate of deterioration was observed in both
patients who had successful pancreas transplantation compared
with patients with diabetes who had kidney transplantation alone.
(FromRamsay and coworkers [22]; with permission).
192
2p =0.02
0
1
2
3
4
5
Kidney alone Kidney/ pancreas
G
l
o
m
e
r
u
l
a
r

v
o
l
u
m
e
A
0.0
0.1
0.2
0.3
0.4
0.5
B Kidney alone Kidney/ pancreas
2p =0.004
M
e
s
a
n
g
i
u
m

v
o
l
u
m
e
FIGURE 15-26
Effects of pancreas transpl antati on on
recurrent di abeti c nephropathy. Pancreas
transpl antati on appears to prevent the
subsequent devel opment of di abeti c
nephropathy in renal allografts [23]. Both
mean gl omerul ar vol ume (panel A) and
mesangi al vol ume (panel B) were si gni fi -
cantl y l ower i n pati ents wi th successful
pancreas transpl antati on compared wi th
reci pi ents wi th di abetes who had unsuc-
cessful pancreas transpl antati on.
M
e
a
n

g
l
o
m
e
r
u
l
a
r

v
o
l
u
m
e
,

1
0
6

m
3
T
o
t
a
l

m
e
s
a
n
g
i
u
m

p
e
r

g
l
o
m
e
r
u
l
u
s
,

1
0
6

m
3
M
e
s
a
n
g
i
a
l

f
r
a
c
t
i
o
n
a
l

v
o
l
u
m
e
0.7
0.6
0.5
0.4
0.3
0.2
0
1.8 3.5
3.0
2.5
2.0
1.5
1.0
0
1.5
1.2
0.9
0.6
0.3
0
Baseline 5 y Baseline 5 y
Pancreastransplant
recipients
Comparison group
Pancreastransplant
recipients A B C
Comparison group
Pancreastransplant
recipients
Comparison group
FIGURE 15-27
Effects of pancreas transpl antati on on establ i shed di abeti c
nephropathy. Al though there appears to be a benefi t i n the
prevention of diabetic nephropathy, there does not appear to be
a benefi t i n pati ents who undergo pancreas transpl antati on i n
reversi ng establ i shed di abeti c gl omerul ar l esi ons. I n thi s study,
mesangi al fracti onal vol ume i ncreased (panel A) and mean
glomerular volume decreased (panel B) in pancreas transplantati on
reci pi ents but no si gni fi cant change i n total mesangi al vol ume
(panel C) occurred over a 5-year fol l ow-up. (FromFi oretto and
coworkers [24]; wi th permi ssi on).
A B
FIGURE 15-28 (s e e Color Plates)
Effects of pancreas transplantation on
microvascular disease. The benefits of
pancreas transplantation on vascular
disease have been variable. A, In this study,
thermography demonstrated a clear-cut
improvement in diabetic microvascular
disease after successful pancreas transplan-
tation [25]. B, However, no evidence exists
that successful pancreas transplantation
results in the regression of established
macrovascular disease.
193
References
1. Gruessner A, Sutherland DER: Pancreas transplantation in the United
States (US) and Non-US as reported to the United Network for Organ
Sharing (UNOS) and the International Pancreas Transplant Registry
(IPTR). In Clinical Transplants 1996. Edited by Cecka JM, Terasaki
PI. Los Angeles: UCLA Tissue Typing Laboratory; 1996:4767.
2. Kuo PC, Johnson LB, Schweitzer EJ, Bartlett ST: Simultaneous pancreas/
kidney transplantation: a comparison of enteric and bladder drainage
of exocrine pancreatic secretions. Transplantation 1997, 63:238243.
3. Odorico JS, Becker YI, Van der Werf WJ, et al.: Advances in pancreas
transplantation: the University of Wisconsin experience. In Clinical
Transplants 1997. Edited by Terasaki PI, Cecka JM. Los Angeles:
UCLA Tissue Typing Laboratory; 1998:157166.
4. Sollinger HW, Messing EM, Eckhoff DE, et al.: Urological complications
in 210 consecutive simultaneous pancreas-kidney transplants with
bladder drainage. Ann Surg1993, 218:561570.
5. Van der Werf WJ, Odorico JS, DAlessandro AM, et al.: Enteric
conversion of bladder drained pancreas allografts: experience in 95
patients. Transplantation Proc 1998, 30:441442.
6. Prieto M, Sutherland DER, Fernandez-Cruz L, et al.: Experimental and
clinical experience with urine amylase monitoring for early diagnosis of
rejection in pancreas transplantation. Transplantation 1987, 43:7379.
7. Brayman KL, Egidi MF, Naji A, et al.: Is induction therapy necessary
for successful simultaneous pancreas and kidney transplantation in the
cyclosporine era? Transplantation Proc 1994, 26:25252527.
8. Wadstrom J, Brekke B, Wramner L, et al.: Triple versus quadruple
induction immunosuppression in pancreas transplantation.
Transplantation Proc 1995, 27:13171318.
9. Bartlett ST, Schweitzer EJ, Johnson LB, et al.: Equivalent success of
simultaneous pancreas kidney and solitary pancreas transplantation.
A prospective trial of tacrolimus immunosuppression with percuta-
neous biopsy. Ann Surg1996, 224:440449.
10. Gruessner RW, Burke GW, Stratta R, et al.: A multicenter analysis of
the first experience with FK506 for induction and rescue therapy after
pancreas transplantation. Transplantation 1996, 61:261273.
11. Zucker K, Rosen A, Tsaroucha A, et al.: Augmentation of mycophe-
nolate mofetil pharmacokinetics in renal transplant patients receiving
Prograf
and CellCept
in combination therapy. Transplantation Proc

1997, 29:334336.
12. Allen RDM, Wilson TG, Grierson JM, et al.: Percutaneous biopsy
of bladder-drained pancreas transplants. Transplantation 1991,
51:12131216.
13. Gaber AO, Gaber LW, Shokouh-Amiri MH, Hathaway D: Percutaneous
biopsy of pancreas transplants. Transplantation 1992, 54:548550.
14. Bernardino M, Fernandez M, Neylan J, et al.: Pancreatic transplants:
CT-guided biopsy. Radiology 1990, 177:709711.
15. Drachenberg CB, Papadimitriou JC, Klassen DK, et al.: Evaluation of
pancreas transplant needle biopsy. Transplantation 1997, 63:15791586.
16. Nakhleh RE, Sutherland DER: Pancreas rejection: significance of
histopathologic findings with implication for classification of rejection.
Am J Surg Pathol 1992, 16:10981107.
17. Stratta RJ, Taylor RJ, Weide LG, et al.: A prospective randomized
trial of OKT3 vs. ATGAM induction therapy in pancreas transplant
recipients. Transplantation Proc 1996, 28:927928.
18. Sollinger HW, Odorico JS, Knechtle SJ, et al.: Experience with 500
simultaneous pancreas-kidney transplants. Ann Surg1998, 228:
284296.
19. Rayhill SC, Odorico JS, Heisey DM, et al.: A comparison of the sensi-
tivities of contrast and isotope voiding cystourethrograms for the
detection of pancreas transplant bladder leaks. Transplantation Proc
1995, 27:31433144.
20. Morel P, Goetz FC, Moudry-Munns K, et al.: Long-term glucose
control in patients with pancreatic transplants. Ann I ntern Med 1991,
115:694699.
21. Kennedy WR, Navarro X, Goetz FC, et al.: Effects of pancreatic
transplantation on diabetic neuropathy. N Engl J Med 1990,
322:10311037.
22. Ramsay RC, Goetz FC, Sutherland DER, et al.: Progression of diabetic
retinopathy after pancreas transplantation for insulin-dependent diabetes
mellitus. N Engl J Med 1988, 318:208214.
23. Bilous RW, Mauer SM, Sutherland DER, et al.: The effects of pancreas
transplantation on the glomerular structure of renal allografts in patients
with insulin-dependent diabetes. N Engl J Med 1989, 321:8085.
24. Fioretto P, Mauer SM, Bilous RW, et al.: Effects of pancreas trans-
plantation on glomerular structure in insulin-dependent diabetic
patients with their own kidneys. Lancet 1993, 342:11931196.
25. Abendroth D, Landgraf R, Illner W-D, Land W: Evidence for
reversibility of diabetic microangiopathy following pancreas trans-
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194
1 6
Transplantation
in Children
R
enal transplantation in children has been considered the treat-
ment of choice for end-stage renal disease for many years [1].
Successful transplantation allows for improved physical,
social, and psychological rehabilitation, enabling a child to have a
qual i ty of l i fe that usual l y i s not attai nabl e wi th di al ysi s.
Improvements in technology in pediatric transplantation have been
significant in the 1990s; however, owing to the inherent potential risks
and benefits, the optimal timing for transplantation needs to be indi-
vidualized to the child. Currently, dialysis and transplantation need to
be viewed as complementary parts of each childs lifelong treatment
plan. Renal transplantation in children carries with it special issues
and problems that vary somewhat from those in adult transplanta-
tion. Because children are constantly growing and developing, techni-
cal, metabolic, immunologic, and psychological factors exist that are
unique to children and must be considered.
The current status of pediatric renal transplantation is reviewed,
summarizing immunosuppressive regimens, outcomes, and complica-
tions. Because of the low incidence of end-stage renal disease in chil-
dren, much of the information available about current practices and
trends regarding pediatric renal transplantation has been collected by
national registries. To supplement the United States Renal Data
Source, the North American Pediatric Renal Transplant Cooperative
Study (NAPRTCS) was initiated in 1987 in an effort to capture infor-
mation to improve the care of pediatric renal allograft recipients.
Current NAPRTCS data include information collected voluntarily
from 123 centers on 3066 children who received renal transplantation
on or after January 1, 1987 [2]. This registry has been helpful in pro-
viding a mechanism through which the clinical course of a large num-
ber of children can be evaluated.
Jea nne A . M ow r y
CHA P T ER
195
End-Stage Renal Disease
0
20
25
30
15
10
5
R
a
t
e

p
e
r

m
i
l
l
i
o
n

p
o
p
u
l
a
t
i
o
n

p
e
r

y
e
a
r
04
7
4
59 1014
Age,y
1519
24
21
10
11
6
4
Male
Female
Total 019
12
10
Frequency
FIGURE 16-1
The incidence of pediatric end-stage renal disease per million
population by age and gender and adjusted for race is depicted,
as reported by the United States Renal Data Source. This graph
shows the average rate per year, 1993 to 1995. (FromUnited
States Renal Data System [3]; with permission.)
Etiology
DISEASES CAUSING END-STAGE RENAL DISEASE
Disease category
Urologic malformations
Renal dysplasia
Other congenital causes
Focal segmental glomerulosclerosis
Other glomerulonephritidesand
immunologic diseases
Hypertensivenephropathy
Diabetic nephropathy
All other causes
Children <18 years, %*
26
17
15
11
14
0
0.1
17
Adults 2064 years, %
,
4
0.3
5
2
17
22
40
10
FIGURE 16-2
Different diseases causing end-stage renal
disease in children and adults. The leading
causes of chronic renal failure in young
children are inherited disorders or congeni-
tal abnormalities of the urinary tract, espe-
cially obstructive uropathy and reflux
nephropathy. Focal segmental glomeru-
losclerosis and other glomerular disorders
are seen more often in older children.
Almost no children develop end-stage renal
disease as a result of diabetic nephropathy
and hypertension, the leading causes of
end-stage renal disease in adults. (From
Harmon [4]; with permission.)
0
40
50
30
20
10
E
a
c
h

a
g
e

g
r
o
u
p
,

%
Glomerulo-
nephritis
17
37
Cystic,
hereditary,
and
congenital
diseases
Interstitial
nephritisand
pyelonephritis
Hypertension
5
6
13 13
44
21
Agegroup 04(n =715)
Agegroup 519(n =4052)
Collagen
and vascular
disease
5
11
Other and
unknown
diseases
15
13
FIGURE 16-3
Data from the United States Renal Data Source of the incident
pediatric cases by disease group and age group (04 vs 519 years),
as a percentage of total pediatric end-stage renal disease within
each age group. The numbers on top of the bars indicate the per-
centage within each age group over 5 years, 1991 to 1995. (From
*Da t a f rom North American Pediatric Renal Transplant CooperativeStudy.
Da t a f rom United StatesRenal DataSource.

196
16.3 Transplantation in Children
FIGURE 16-4
Voiding cystourethrogram in a child with
posterior urethral valves showing gross
dilation of the posterior urethra with an
abrupt change in caliber at the level of the
external sphincter. Obstructive uropathy
is reported to be the cause of end-stage
renal disease in 16.5% of pediatric trans-
plantation recipients (the primary cause
along with aplastic, hypoplastic, and dys-
plastic kidneys) in the North American
Pediatric Renal Transplant Cooperative
Study 1995 Annual Report. (Courtesy of
Philip Silberberg, MD.)
FIGURE 16-5
Voiding cystourethrogram in grade 5 reflux
nephropathy showing gross dilation of the
collecting system and blunting of the fornices.
Renal parenchymal scarring and destruction
usually occur before the age of 5 years but
may occur in older age groups. Intrarenal
reflux extends the vesicoureteric reflux into
the collecting tubules and nephrons, allowing
urinary access to the renal parenchyma that
can lead to renal scarring. (Courtesy of Philip
Silberberg, MD.)
FIGURE 16-6
Plain radiograph of a child with prune-belly
syndrome showing a markedly protuberant
abdomen. This syndrome, also referred to as
Eagle-Barrett syndrome or triad syndrome,
occurs almost exclusively in males. The three
classic physical findings are the deficiency of
the abdominal wall musculature, urinary
tract anomalies characterized by an extremely
dilated urinary tract, and bilateral intra-
abdominal testes. A wide spectrum in the
severity of abnormalities is seen, with most
children having some degree of renal dyspla-
sia, along with bladder and ureteric dys-
plasias (partial or complex lack of smooth
muscle). (Courtesy of Philip Silberberg, MD.)
0
40
50
30
20
10
R
a
t
e

o
f

p
e
d
i
a
t
r
i
c

r
e
n
a
l

t
r
a
n
s
p
l
a
n
t
a
t
i
o
n
s
p
e
r

1
0
0

d
i
a
l
y
s
i
s

p
a
t
i
e
n
t
-
y
e
a
r
s
04
28
16
59 1014
Recipient age
1519
22
24
31
33
43
28
Livingrelated donor
Cadaveric donor
Total
019
27
26
2044
(adult)
5
11
Transplantation Rates
FIGURE 16-7
Data from the United States Renal Data Source showing the 1995
rates of pediatric renal transplantations per 100 dialysis patient-
years by recipient age. The rate of kidney transplantation varies
inversely with recipient age group. Emphasis is placed on living
related donors in the pediatric group with end-stage renal disease.
(FromUnited States Renal Data System [3]; with permission.)
197
0
80
100
60
40
20
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
0 10 20 30
Follow-up, m o
40 50 60
Living donor
Cadaveric donor
FIGURE 16-9
The estimated graft survival probabilities by
allograft source from the 1995 North
American Pediatric Renal Transplant
Cooperative Study Annual Report. The over-
all median follow-up for patients with func-
tioning grafts is 29 months. The estimated
graft survival probabilities have improved by
approximately 1 percentage point for cadav-
eric donor grafts compared with the data in
the 1994 report. For living related donor
grafts the estimated graft survival probabilities
are similar to those in the previous report at 1
and 2 years, and 1 percentage point higher at
4 years. (FromWarady and coworkers [5];
with permission.)
Renal Allograft Outcome
0
80
100
60
40
20
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
0 12 24 36
Timeposttransplantation, m o
Livingdonors
48 60
Primary
First repeat
A
0
80
100
60
40
20
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
0 12 24 36
Cadaveric donors
48 60
Primary
First repeat
B
FIGURE 16-10
Graft loss in young infants and children often caused by irreversible acute rejection
episodes. Rejection is, perhaps, a result of heightened immune response in this age group
[7]. Despite an improvement in graft survival in children over the past 5 years, the half-life
of renal grafts in pediatric patients remains around 10 years [8]. This half-life means that
many of these children will need a second transplantation in their lifetime. Depicted are the
North American Pediatric Renal Transplant Cooperative Study data stratifying the analysis
of the percentage of graft survival by donor source. A, Graft survival rates for living donor
transplantations, primary and first repeat. B, Survival rates for cadaveric donor source
transplantations. Graft survival rates for repeat transplantations did not correlate with
early or late failure of the primary graft. (FromTejani and Sullivan [9]; with permission.)
NUMBER OF PATIENTS ON
TRANSPLANTATION WAITING LIST
Age groups, y
05
610
1117
1849
5064
65+
Total
Number, %
78
0.21
124
0.33
421
1.13
20,971
56.07
12,784
34.18
3026
8.09
37,404
FIGURE 16-8
The national renal transplantation waiting list as of September
30, 1997. (FromUnited Network for Organ Sharing Bulletin [6];
with permission.)
198
Factors Affecting Outcome
Donor Age and Source
50
90
100
110
80
70
60
Livingdonors
01 years
25 years
612 years
>12 years
50
90
100
110
80
70
60
C
a
l
c
u
l
a
t
e
d

c
l
e
a
r
a
n
c
e
,

m
L
/
m
i
n

p
e
r

1
.
7
3
m
2
6 12 18 24
Cadaveric donors
30 36
Follow-up, m o
42 48 54 60
1.0
0.4
0.2
0.0
0.6
0.8
I
n

(
r
e
l
a
t
i
v
e

r
i
s
k
)
0 10 20 30
Cadaveric donor age, y
40 50
FIGURE 16-11
Data from the North American Pediatric Renal Transplant Cooperative Study for pedi-
atric kidney allograft function, measured as calculated creatinine clearance values for
both cadaveric and living donors. Regardless of the donor source, younger recipients
begin with higher calculated creatinine clearance values with a more rapid decline in
function. Older recipients have more stable calculated creatinine clearance values with
less of a decline in function.
FIGURE 16-12
The relationship between cadaveric donor
age and the logarithm of the relative risk
of graft loss from all causes for pediatric
recipients of cadaver-donor renal transplan-
tations. The perfect donor is 21 years of
age. The risk of graft loss is higher when the
grafts used are from either younger or older
donors. An equivalent risk of graft loss exists
from donors who are 6 and 55 years of age.
(FromHarmon [10]; with permission.)
RISK FACTORS ASSOCIATED WITH GRAFT FAILURE
Cadaveric donor
Recipient age(<2y)
Donor age(<6y)
Previoustransplantation
ATG, ALG, OKT3earlyadministration (none)
Morethan 5lifetimetransfusions
No DR matches
Annual cohort (1992v s 1987)
Living related donor
Recipient age<2y
Black race
Morethan 5previoustransfusions
Relative risk increase
2.03
1.47
1.36
1.36
1.37
1.23
1.29
1.4
1.9
1.7
P
0.001
0.001
0.004
0.001
0.001
0.01
0.04
0.08
<0.001
<0.001
FIGURE 16-13
Risk factors associated with graft failure in a proportional hazards model for recipients of
donor grafts. ATGantithrombocytic globulin; ALGantilymphocytic globulin. (From
Warady and coworkers [5]; with permission.)
199
0.4
0.7
0.9
0.8
1.0
0.6
0.5
R
e
l
a
t
i
v
e

r
i
s
k
0 2 4 6
Recipient age, y
8 10 12 14 16 18
50
90
100
80
70
60
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
0 0.5 1 1.5
Time,y
2 2.5
No A, no B, no DR
No A, no B, DRmatch
A and Bmatch, no DR
A and Band DRmatch
30
70
100
90
80
60
50
40
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
0 10 20 30
40
A
50
Preemptive
Prior dialysis
Livingdonor
30
70
100
90
80
60
50
40
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
0 10 20 30
40
B
50
Preemptive
Prior dialysis
Cadaveric donor
FIGURE 16-14
Relationship between recipient age and the relative risk of graft loss for children who
receive cadaveric donor transplantation. A strong inverse relationship exists between the
risk of graft loss and recipient age, particularly in the group under 2 years of age. (From
Human Leukocyte Antigen Matching
Recipient Age
FIGURE 16-15
Results of 4 years of experience monitoring outcomes by the North American Pediatric
Renal Transplant Cooperative Study. These results suggest a statistically significant benefi-
cial effect of donor-related matching (P 0.05) when analyzing this allele with other
effects unique to pediatric patients with regard to age. This figure displays the subgroup
with a match at both the A and the B locus, or at neither, and compares that with the
effect of adding a donor-related (DR) antigen on the percentage of renal allografts
surviving after transplantation. Owing to the relatively short follow-up, small sample
size (1558 patients), and nonimmunologic factors pertinent to pediatric transplantation,
it is difficult to determine separate time-varying effects of class I versus class II matching.
However, it does seem clear that no antigen matching has a worse prognosis at 1 year
(72% graft survival) versus 1 or more antigen matching at each locus (1-year 81%
survival, 2-year 69% survival). (FromMcEnery and Stablein [11]; with permission.)
FIGURE 16-16
Percentage of graft survival of initial living
(panel A) and cadaveric donor (panel B)
grafts in recipients with and without (pre-
emptive) dialysis, indicating better survival
rates in those who did not receive dialysis
previously. The survival probabilities in the
preemptive group are significantly better
until adjustments are made for recipient
age (01 years vs others) and number of
previous transplantations (>5 vs 05) in
a proportional hazards model. (FromFine
Preparation for Transplantation
Preemptive versus Previous Dialysis
200
Hepatitis B(Hep B) Hep B-1
Hep B-2 Hep B-3
Hep B
Diptheriatetanus
pertussis (DPT)
H. in f lu en z a e
typeb (Hib)
Varicella(Var)
Measles-mumps-
rubella(M-M-R)
Polio
DTaP
or DTP
DTaP
or DTP
DTaP
or DTP
DTaP
or DTP
DTaP or DTP
Hib Hib Hib Hib
Polio Polio Polio Polio
M-M-R M-M-R M-M-R
Var Var
Age, m o Age, y
Birth 1 2 4 6 12 15 18 4-6 11-12 14-16
Td
or
FIGURE 16-17
Infection remains a major cause of morbidity and mortality in pedi-
atric transplantation recipients. Many infections can be successfully
prevented by immunization. The recommended US immunization
schedule for children (JanuaryDecember 1997) before transplanta-
tion is outlined. Diphtheria-tetanus-pertussis vaccine, Haemophilus
influenzatype b vaccine, inactivated poliovirus vaccine, and hepatitis
B immunizations can be given after transplantation but their efficacy
may be suboptimal. The live attenuated vaccines, oral polio vaccine
(OPV), measles-mumps-rubella (M-M-R) vaccine, and varicella virus
vaccine, usually are recommended to be given only after immunosup-
pressive therapy has been discontinued for 3 months. Influenza A vac-
cines also should be administered yearly in the fall to pediatric trans-
plantation recipients. The advent of the varicella virus vaccine may
decrease the chances of pediatric transplantation recipients developing
severe chickenpox and the incidence of zoster [13]. A recent survey
by the North American Pediatric Renal Transplant Cooperative Study
found that almost 90% of centers recommend the use of influenza
vaccine, whereas only 60% of centers recommend pneumococcal
Vaccinations
vaccine for children with renal disease. Between 5% and 12% of
centers recommend live viral vaccines, including OPV, M-M-R vaccine,
and varicella virus vaccine, for immunosuppressed patients after renal
transplantation. (FromFurth and coworkers [14]; with permission.)
Vaccines are listed under the routinely recommended ages. Barsindi-
cate the range of acceptable ages for vaccination. Shaded barsindicate
catch-up vaccination: at 11 to 12 years of age, hepatitis B vaccine
should be administered to children not previously vaccinated, and vari-
cella virus vaccine should be administered to children not previously
vaccinated who lack a reliable history of having had chickenpox. This
schedule indicates the recommended age for routine administration of
currently licensed childhood vaccines. Some combination vaccines are
available and may be used whenever administration of all components
of the vaccine is indicated. Providers should consult the manufacturers
package inserts for detailed recommendations. Approved by the
Advisory Committee on Immunization Practices (ACIP), American
Academy of Pediatrics (AAP), and American Academy of Family
Physicians (AAFP). (SeeRed Book [13] for more information.)
201
Immunosuppression
IMMUNOSUPPRESSIVE THERAPY AND FUNCTIONING GRAFTS
Prednisone
Livingdonor
Cadaveric donor
Cyclosporine
Livingdonor
Cadaveric donor
Azathioprine
Livingdonor
Cadaveric donor
Month 6 (n=2999)
Treated, %
96
96
97
93
90
95
88
87
89
MMD*
0.28
0.27
0.29
6.81
6.94
6.73
1.69
1.69
1.69
Month 24 (n=1915) Month 12 (n=2606)
Treated, %
95
94
97
92
90
94
88
86
90
MMD*
0.22
0.21
0.22
6.15
6.26
6.06
1.67
1.67
1.66
Treated, %
95
94
96
90
87
93
88
87
90
MMD*
0.19
0.18
0.19
5.49
5.37
5.58
1.66
1.69
1.62
Month 36 (n=1358)
Treated, %
95
95
95
89
86
92
88
87
89
MMD*
0.17
0.17
0.17
4.99
4.88
5.08
1.64
1.67
1.58
Month 48 (n=890)
Treated, %
95
96
94
88
85
90
89
89
87
MMD*
0.16
0.16
0.16
4.69
4.28
4.89
1.68
1.73
1.64
Month 60 (n=543)
Treated, %
96
97
95
87
81
92
88
86
90
MMD*
0.15
0.15
0.16
4.52
4.29
4.65
1.64
1.76
1.57
FIGURE 16-18
Data from the North Ameri can Pedi atri c Renal Transpl ant
Cooperative Study on immunosuppressive therapy and function-
ing grafts at selected times. The median daily dose of prednisone
decreased from 0.28 mg/kg at 6 months to 0.17 mg/kg at
36 months, and then to 0.15 mg/kg at 5 years after transpl anta-
ti on. Al ternate-day predni sone was prescri bed to 9% of reci pi -
ents at 6 months, 17% at 12 months, 24% at 24 months, and
27% at 48 months after transplantation. The daily dose of
azathi opri ne di d not change over ti me. The mean dose of
cycl ospori ne has i ncreased over the years i n the most recent
reported study: the mean 1-year dosages after transpl antati on
were 6.5, 7.0, 7.7, and 8.0 mg/kg/d for transpl antati ons occur-
ring in 1987, 1989, 1991, and 1993, respectively. (FromWarady
and coworkers [5]; wi th permi ssi on.)
Cyclosporine
0
8
20
4
6
2
16
18
12
14
10
M
e
a
n

(

u
p
p
e
r

9
5
%

C
I
)
1
6 12 18
A
24 30 36 42 48
01
Recipient age, y
25
612
>12
Cadaveric donor
FIGURE 16-19
Data from the North American Pediatric Renal Transplant Cooperative
Study of the maintenance dose of cyclosporine by donor source, recipi-
ent age, and time after transplantation. The dosage for the first month
for 0- to 1-year-old cadaveric donor graft recipients (panel A) is
15.0 mg/kg/d, which is similar to the 14.4 mg/kg/d the living related
donor graft recipients (panel B) receive.
*MMDmedian dailydoses, in mg/kg.
202
0
8
20
4
6
2
16
18
12
14
10
M
e
a
n

(
+
u
p
p
e
r

9
5
%

C
I
)
1
6 12 18
B
24 30 36 42 48
01
Recipient age, y Livingrelated donor
25
612
>12
By 4 years after transplantation the mean doses of all age groups are similar
(mean and upper 95% CIs). (FromTejani and Sullivan [15]; with permission.)
LATE FIRST REJECTION RATES
CsA dosage, mg/kg/d*
0
>0and 4.0
>4.0and 5.9
>5.9and 8.6
>8.6
N
80
185
186
188
184
Number of rejections
9
41
44
46
29
Rejecting, %
11.3
22.2
23.7
24.5
15.8
Mean year-1 CsA dosage, mg/kg/d
Rejection
(SD)
0.0
2.9(0.8)
4.9(0.6)
6.9(0.8)
11.7(2.7)
Nonrejection
(SD)
0.0
3.1(0.7)
5.0(0.6)
7.3(0.8)
12.6(4.1)
FIGURE 16-20
Data from the North American Pediatric
Renal Transplant Cooperative Study on late
first rejection rates by quartiles of mainte-
nance cyclosporine dose at 1 year. The first
acute rejection occurred over 1 year after
transplantation. Patients not receiving
cyclosporine (human leukocyte antigeniden-
tical or those receiving tacrolimus [FK-506])
form a small group. The difference between
the rejection rates for the other four groups
are not statistically significant. The lowest
rate of late first rejection, however, is
observed in those patients receiving dosages
of cyclosporine over 8.6 mg/kg/d. CsA
cyclosporine; SDstandard deviation. (From
Tejani and Sullivan [15]; with permission.)
*Chi-squared test of percentagerejectingamongfour nonzero dosegroups(P =0.163).
203
COMPARISON OF TACROLIMUS AND CYCLOSPORINE
Major advantages of tacrolimus
Steroid sparing
Lesshypertension
Rescueof cyclosporine-resistant
rejections
Minor advantages of tacrolimus
Better graft survival
Lesshirsutism
Lessgingival hypertrophy
Lessneurologic dysfunction
Lessmetabolic acidosis
Lesshyperlipidemia
Major disadvantages of tacrolimus
Increased viral infections
Cytomegalovirus
Epstein-Barr virus
Increased lymphoproliferativedisease
Minor disadvantages of tacrolimus
Increased acuterejection?
Morediabetogenic?
Hyperkalemia?
Hypomagnesemia?
Similarities of tacrolimus and
cyclosporine
Nephrotoxicity
FIGURE 16-21
The experience at Childrens Hospital of Pittsburgh using
tacrolimus has been that 14% of 43 pediatric patients managed
with tacrolimus for a mean period of 25 months developed post-
transplantation lymphoproliferative disease (PTLD). This occur-
rence is very high compared with PTLD reported by the North
American Pediatric Renal Transplant Cooperative Study in only
six of 1550 (0.39% or 0.10%/y) children managed with various
cyclosporine regimens [16]. Epstein-Barr virus (EBV) has a primary
role in the development of PTLD, and an even higher rate of EBV-
related PTLD has been reported in children receiving tacrolimus
for liver transplantation or rescue [17,18]. Children seem to have a
greater predisposition to PTLD than do adults. Therefore, children
need closer monitoring for this disorder when being managed with
tacrolimus. The major advantages of tacrolimus over cyclosporine
are a reduced severity of hypertension and an improved cosmetic
appearance that, in turn, may improve patient compliance with
medications. (FromEllis [19]; with permission.)
Tacrolimus
Mycophenolate Mofetil
0
30
50
40
20
10
A
c
u
t
e

r
e
j
e
c
t
i
o
n

e
p
i
s
o
d
e
,

%
Living
donor
Azathioprine
26%
48%
19%
Cadaveric
donor
Mycophenolate
mofetil
FIGURE 16-22
Initial studies at the University of California, Los Angeles Medical Center (UCLA), using
mycophenolate mofetil along with cyclosporine and prednisone, instead of azathioprine.
In 37 pediatric renal transplantation recipients, an overall incidence of first acute rejection
of just 19% was found (only 13% were clinically significant). This is a decrease compared
with the historical incidence at UCLA (19871994) of acute rejection episodes in living
related and cadaveric donor transplantations, which is 26% and 48%, respectively. The
researchers saw a moderate increase in the incidence of infection after transplantation
(mostly caused by cyclomegalovirus) and gastrointestinal side effects. (FromEttenger and
204
Transplantation versus Dialysis
Growth in End-Stage Renal Disease
0.0
10.0
3.0
2.0
1.0
4.0
7.0
6.0
9.0
8.0
5.0
G
r
o
w
t
h

r
a
t
e
,

c
m
/
y
0 2 4 6 8 10 12 14 16 18
Age, y
Kidney
transplantation
(n =724)
USgeneral population
Averagefollow-up for calculating
ESRD growth rate=10.4mo
Dialysis
(n =578)
P<0.01
Averageage, 12.7y
01 years
Age group, y
25 years
612 years
1317 years
155
6
441
1023
1112
99
24
312
716
625
48
48
160
374
235
1.0
0.5
0
H
e
i
g
h
t

Z
0 12 18 24 30 36
Follow-up, m o
Samplesizesfor height Z at
follow-up months:
42 48 54 60
FIGURE 16-24
Data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)
on the mean change from baseline in standardized height scores in patients with graft
function. The height standard deviation score (SDS), or Z score, is the current accepted
measurement used to evaluate accelerated growth. The Z score is an attempt to standardize
the height deficit of children with renal failure to the height of healthy children. A positive
change in Z score (+ Z), for example, indicates a reduction in height deficit (ie, an accelera-
tion of growth). At transplantation the mean height deficit (Z score or SDS) for all patients
was -2.16 standard deviations (SD) below the appropriate age- and gender-adjusted levels.
Recipients under 6 years of age at the time of transplantation showed acceleration in linear
growth after transplantation at 4 years follow-up. Children 6 years of age or older at time
of transplantation showed no improvement in height deficit at 4 years follow-up. Z score
patients height - height at 50% for age and standard deviation of height for age. (From
Warady and coworkers [5]; with permission.)
FIGURE 16-23
Chronic renal insufficiency and end-stage renal disease (ESRD)
resulting in physical growth and sexual development well below
the potential for age and gender [21]. One of the benefits of trans-
plantation in children has been to improve the growth rate; however,
this may not occur in all patients [16,22,23]. Depicted is the overall
comparison between adjusted annualized growth rates by age for
prevalent pediatric transplantation and dialysis patients (1990
USRDS data) [24] and the US general population (19761980 data
from the National Center for Health Statistics) [25]. Shown are the
results of a linear regression analysis of growth rates for 578 patients
on dialysis and 724 transplantation recipients. Growth rates were
adjusted to reflect the average characteristics of patients with ESRD
at each age with regard to gender, race, ethnicity, baseline height,
and duration of ESRD. At almost all ages, growth rates were higher
for transplantation recipients compared with patients on dialysis;
however, the degree of advantage declined with age. No pubertal
growth spurt was seen in either treatment group. Although growth
rates in adolescents between 15 and 18 years of age were higher than
expected for both the dialysis and transplantation groups, the aver-
age height achieved at the end of the study was still lower than
expected. (FromTurenne and coworkers [26]; with permission.)
205
Alternate-Day Corticosteroids
0.2
0.6
0.8
0.4
0.2
0 C
h
a
n
g
e

i
n

h
e
i
g
h
t

S
D
S
12 24 36
Timeposttransplantation,m o
48
Daily
Alternateday
Significant differencebetween dailyand
alternatedaygroup
*
*
*
60
*
*
*
FIGURE 16-25
Corticosteroids are an integral part of pediatric renal transplanta-
tion immunosuppressive protocols. In addition to hypertension and
hyperlipidemia, one of the main adverse effects of daily steroid dos-
ing in children is growth retardation. A review of North American
Pediatric Renal Transplant Cooperative Study data, looking at the
change in the height standard deviation score (SDS) from 30 days
after transplantation to 12 to 60 months after transplantation ana-
lyzed the difference between the 1477 children treated continuously
on a daily or alternate-day steroid regimen. The mean change in
SDS was significantly greater for the alternate-day group at each
12-month interval (P < 0.05). Of note is the fact that at 12 months,
those children on alternate-day steroids had a mean serum creati-
nine of 1.06 0.04 mg/dL as compared with 1.28 0.02 mg/dL for
those on daily steroids (P < 0.001). Alternate-day therapy also was
more common in children without a rejection episode in the first
12 months after transplantation, recipients of living donor grafts,
white recipients, and children 2 to 12 years of age at the time of
transplantation. (FromJabs and coworkers [27]; with permission.)
50
A
80
100
90
70
60
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
10 20 30 40
Time, m o
Livingdonor
Daily
Alternateday
50 60
50
B
80
100
90
70
60
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
10 20 30 40
Time, m o
Cadaveric donor
50 60
Daily
Alternateday
FIGURE 16-26
Renal Transplant Cooperative Study
(NAPRTCS) evaluating the effects of
alternate-day steroids on graft survival.
Patients receiving alternate-day steroids
at 12 months were compared with those
receiving daily steroids. The NAPRTCS
found that the survival of living donor
(panel A) and cadaveric (panel B) grafts
subsequent to 12 months did not differ
between the steroid treatment groups.
Because a number of factors contribute
to graft survival and the patients were not
randomly delegated to steroid treatment
groups, a proportional hazards regression
model for graft survival after 12 months
also was developed. Again, the use of
alternate-day steroids had no adverse effect
on graft survival for recipients of either
living or cadaveric donor grafts. (From
Jabs and coworkers [27]; with permission.)
206
Recombinant Human Growth Hormone After Transplantation
HEIGHT VELOCITY AND HEIGHT STANDARD DEVIATION SCORES
Pubertal status
Prepubertal
Enteringpuberty
Pubertal
Change in height velocity, cm/y
Control
0.31.6
(n =30)
0.61.8
(n =11)
0.72.1
(n =18)
Treated
3.71.6*
(n =28)
4.93*
(n =9)
4.32.2*
(n =29)
Change in height SDS
Control
+0.10.3
(n =30)
0.10.4
(n =11)
+0.10.5
(n =18)
Treated
+0.60.3*
(n =28)
+0.60.6*
(n =9)
+0.70.5*
(n =29)
FIGURE 16-27
Because growth often remains poor despite a functioning renal graft, a large multicenter
controlled study was initiated to evaluate the effectiveness of recombinant human growth
hormone in stimulating growth in children with a kidney allograft. In all three groups a
significantly different growth velocity
and change in height SDS occurred during
the first year of treatment with growth
hormone (P < 0.0001) compared with a
control group. Preliminary data from the
second year of treatment also show a con-
tinued improvement in growth velocity
compared with baseline; however, not of
the magnitude seen during the first year.
The mean glomerular filtration rate did
not change significantly in the group
receiving growth hormone. Acute rejection
episodes were noted more frequently
during treatment with growth hormone,
especially for patients with a history of
more than one episode. However, other
factors, such as noncompliance with
immunosuppressive medications, were
not analyzed and cannot be excluded.
Values are expressed as mean standard
deviation. SDSstandard deviation score.
(FromBroyer [28]; with permission.)
Interstitium
0 1 2 4 5 6 3
Mean semiquantitativescore(06) Mean score
Growth hormone
treated recipients
Nontreated recipients
P <0.05between groups
Growth hormone
treated (SD)
Nontreated
(SD)
Focal inflammation (lymphocytes)
Diffuseinflammation
Focal fibrosis
Diffusefibrosis
Mesangial cell proliferation
Mesangial matrix increase
Endothelial swelling
Endothelial proliferation
Intimal proliferation
Dilation
Atrophy
Casts
1.6(1.7)
1.1(1.9)
2.6(1.8)
1.7(1.7)
1.3(1.5)
1.7(1.4)
0.3(0.8)
0.6(1.0)
1.6(1.6)
1.0(0.8)
2.1(0.7)
1.1(1.2)
1.4(0.8)
0.9(0.9)
2.1(0.4)
0.7(1.0)
1.4(0.8)
2.7(1.0)
0.6(1.1)
0.3(0.8)
0.9(1.1)
1.1(1.2)
0.7(0.8)
0.4(0.5)
Interstitium
Glomeruli
Arterioles
Proximal tubules
FIGURE 16-28
A Finnish study investigating the possible
association between growth hormone treat-
ment and acceleration of chronic rejection
and late allograft dysfunction in prepubertal
children. The most common histologic find-
ings between the eight growth hormone
treated and eight nontreated renal transplan-
tation recipients are scored and compared
(matched for age, donor age, human leuko-
cyte antigen, immunosuppression, and renal
function) 36 months after transplantation.
Improvement in growth was clear during
administration of growth hormone, without
a negative influence on allograft survival.
No significant difference in the amount of
lymphocyte infiltration of the allografts
between patients and the control group was
seen. No acute rejection episodes occurred
in the recipients treated with growth hor-
mone but one occurred in the control group.
SDstandard deviation. (FromLaine and
*P <0.0001compared with control groups.
207
Complications after Transplantation
SAFETY AND EFFICACY OF GROWTH HORMONE TREATMENT
Reference
Bartosh et a l.
Benfield et a l.
Fineet a l.
Ingulli and Tejani
Tonshoff et a l.
Van Dop et a l.
Van Eset a l.
Prepubertal
Pubertal
Patients, n
5
11
13
17
10
9
17
19
Glomerular filtration rate,
mL/min/1.73 m
2
*
Before
51+6.8
75+20
67+27
59
(23- 118)
71
(25- 150)
67
(29- 152)
After
58+29
60+18
63+25
49
(19- 102)*
72
(4.4- 172)
83
(24- 121)
Serum creatinine,
mg/dL
Before
1.4+0.1
1.5
1.6+0.6
After
1.6+0.6
1.6*
2.1+0.9*
FIGURE 16-29
Analysis of the safety and efficacy of growth
hormone in pediatric renal transplantation
recipients. Overall, a catch-up in growth
was reported in each study, with changes in
height standard deviation score from 0.2 to
1.0. These results were not as favorable as
those reported when growth hormone was
used in patients with chronic renal failure,
perhaps owing to the use of corticosteroids
after transplantation. In three studies, renal
function was significantly decreased after
administration of growth hormone. Twelve
acute rejection episodes and four graft losses
occurred; however, a causal relationship is
unclear [30]. A controlled trial using growth
hormone after transplantation is currently
underway by the North American Pediatric
Renal Transplant Cooperative Study to help
establish the efficacy and safety of growth
hormone in pediatric transplantation recipi-
ents. Calculated clearance according to the
Schwartz formula, except for Tonshoff
(inulin clearance) [31]. (FromTonshoff
DIAGNOSIS OF ACUTE REJECTION
Clinical picture
Fever, weight gain, enlargement and tendernessof graft, hypertension, reduced urinaryoutput, decreased renal
function, reduced urinarysodiumexcretion, and increased proteinuria
Cyclosporine trough blood level
When theselevelsarehigher than expected, cyclosporinenephrotoxicityissuspected; however, thisdoesnot ruleout
rejectionverylow levels, in thepresenceof elevated serumcreatinine, suggest acuterejection, perhapsasaresult of
noncompliance
Radionuclide renal studies
Provideinformation about blood flow and theexcretion index, and aid in excludingextravasation and obstruction
Renal sonography with Doppler ultrasonography
Providesinformation about kidneysize, renal blood flow, corticomedullarydifferentiation, pyramid shape, and thecol-
lectingsystem; establishesthediagnosisof obstruction, extravasation, and renal arterystenosis
Renal arteriogram
Establishesthediagnosisof major renal vessel stenosisor occlusion
Magnetic resonance imaging
Establishesthediagnosisof obstruction, renal vessel stenosis, or occlusion; aidsin evaluatingthecorticomedullaryjunc-
tion and pyramid shape
Fine-needle aspiration biopsy
Identifiesinflammatorycellsin thegraft, tubular damage, cyclosporinetoxicity, and cytomegalovirusinfection; aidsin
differentiatingrejection, acutetubular necrosis, cytomegalovirusinfection, and cyclosporinenephrotoxicity
Renal biopsy
Remainsthegold standard for determiningrejection and cyclosporinenephrotoxicity
Acute Rejection
FIGURE 16-30
When impaired graft function occurs in
pediatric renal transplantation recipients,
rejection is the most common cause. A num-
ber of other conditions exist that also can
result in an increase in serum creatinine and
blood urea nitrogen, a decrease in urine out-
put, or both, which must be differentiated
from rejection. In small children with large
allografts, the most sensitive indication of
rejection is hypertension. It is important to
remember that in small children, a small
increase in serum creatinine can reflect a sig-
nificant decrease in the glomerular filtration
rate. Several methods to establish the cause
of renal allograft dysfunction are described;
however, the diagnostic gold standard is the
allograft core biopsy. Biopsy can easily be
performed percutaneously in most children
and should not be postponed once other
variables have been eliminated and rejection
is likely. (FromYadin and coworkers [32];
with permission.)
*P value significant.
Median values.
208
0
60
100
80
40
20
R
e
j
e
c
t
i
o
n
,

%
0 12 24 36
Follow-up, m o
48 60
Livingdonor
Cadaveric donor
FIGURE 16-31
Data from the 1995 North American Pediatric Renal Transplant Cooperative Study showing
that the cumulative risk for first rejection is similar for living donor (LD) and cadaveric
donor (CD) recipients in the first few weeks after transplantation. After the first month,
however, the cumulative risk for a first rejection is higher for recipients of a CD graft. By the
end of the 48th month, 56% of LD recipients and 71% of CD recipients have had at least
one rejection episode. Rejections were completely reversed (return to baseline creatinine) in
53% of LD graft recipients, partially reversed (improved graft function but no return to
baseline creatinine) in 40%, and resulted in graft failure or death in 4% of cases. In CD,
rejection episodes were completely reversed in 49%, partially reversed in 45%, and resulted
in graft failure or death in 6%. (FromWarady and coworkers [5]; with permission.)
PREDICTORS OF GRAFT FAILURE
FROM CHRONIC REJECTION
Acuterejection
2acuterejections
Late(>365d) initial acuterejection
Cadaveric donor source
Black recipient
Relative risk
increase
3.1
4.3
2.3
1.6
1.6
P value
<0.001
<0.001
<0.001
0.001
0.003
Chronic Rejection
FIGURE 16-32
Multivariate analysis of data from the North American Pediatric
Renal Transplant Cooperative Study evaluating predictors of graft
failure from chronic rejection. A proportional hazards analysis of
time to chronic rejection failure, eliminating other failures, is used
to evaluate predictors of graft failure from chronic rejection. A 3.1-
fold increased risk of failure from chronic rejection was seen after
a single rejection episode. A second rejection increased the risk to
over 13 times that of children who did not experience rejection.
(FromTejani and coworkers [33]; with permission.)
CAUSES OF GRAFT FAILURE
Cause
Primarynonfunction
Vascular thrombosis
Miscellaneoustechnical
Hyperacuterejection, <24h
Accelerated rejection, 27d
Acuterejection
Chronic rejection
Renal arterystenosis
Infection/discontinued medication
Cyclosporinetoxicity
De n ov o kidneydisease
Patient discontinued medication
Malignancy
Recurrenceof original disease
Death
Other
Index graft failures
n=881 (%)
28(3.2)
107(12.2)
16(1.8)
9(1.0)
26(3.0)
167(19.0)
239(27.1)
10(1.1)
17(1.9)
9(1.0)
4(0.5)
18(2.0)
9(1.0)
56(6.5)
98(9.0)
67(7.6)
Second graft failures*
n=104 (%)
2(1.9)
20(19.2)
2(1.9)
2(1.9)
5(4.8)
16(15.4)
28(26.9)
0(0.0)
2(1.9)
0(0.0)
2(1.9)
1(1.0)
1(1.0)
10(9.6)
9(8.7)
4(3.8)
Total graft failures
n=985 (%)
30(3.0)
127(12.9)
18(1.8)
11(1.1)
31(3.1)
183(18.6)
267(27.1)
10(1.0)
19(1.9)
9(0.9)
6(0.6)
19(1.9)
10(1.0)
67(6.8)
107(10.9)
71(7.2)
FIGURE 16-33
Renal Transplant Cooperative Study show-
ing causes of graft failure. Chronic rejection
has become the most common cause of
graft failure (27.1%). Acute rejection causes
up to 18.6% of graft failures. Recurrence
of primary disease (focal segmental glomeru-
losclerosis) accounts for 6.8% of all fail-
ures. Vascular thrombosis continues to
cause a significant number of graft failures
(12.9%). (FromWarady and coworkers
*Four patientshavehad threegraft failures.
209
0
60
100
80
40
20
A
l
l

t
h
r
o
m
b
o
s
i
s
,

%
Livingdonor
n =38
Cadaveric donor
n =100
Day>15
Day after transplantation
Day614
Day35
Day2
Day1
Day0
Vascular Thrombosis
FIGURE 16-34
Data from the North American Pediatric Renal Transplant Cooperative Study showing
vascular thrombosis is the third most common cause of graft failure in pediatric transplan-
tation recipients. The incidence varies between centers and has been reported to be as high
as 20% in children under 2 years of age [34]. This figure depicts the timing of thrombotic
graft failure by donor source. Most of the thromboses occurred soon after transplantation.
(FromSingh and coworkers [35]; with permission.)
UNIVARIATE ANALYSIS OF RISK FACTORS
All
Recipient age
01y
25y
612y
>12y
Donor age
05y
510y
>10y
Cold ischemiatime
<24h
>24h
Day0/1
Antilymphocytetherapy
No
Yes
Day0/1cyclosporinetherapy
No
Yes
Previoustransplantation
No
Yes
Nativenephrectomy
No
Yes
Previousdialysis
No
Yes
Persistent ATN with >7d of
function
No
Yes
Living donor, n
38/2060
6/172
12/341
5/732
15/783
28/1187
10/873
29/1115
9/945
30/1886
8/174
26/1440
12/617
11/680
27/1380
10/1929
3/79
%
1.8
3.5*
3.4
0.7
1.9
2.4
1.2
2.6*
1.0
1.6*
4.6
1.8
1.9
1.6
2.0
0.5*
3.8
Cadaveric donor, n
100/2334
7/78
19/343
36/827
38/1086
32/386
11/245
54/1667
44/1363
51/909
61/990
39/1344
66/1682
34/652
66/1723
34/611
82/1790
18/540
13/319
87/2015
22/1844
13/365
%
4.3
9.0
5.5
4.4
3.5
8.3*
4.5
3.2
3.2*
5.6
6.2*
2.9
3.9
5.2
3.8
5.6
4.6
3.3
4.1
4.3
1.2*
3.6
FIGURE 16-35
Recent univariate analysis of risk factors
by the North American Pediatric Renal
Transplant Cooperative Study. Although
the mechanisms that lead to thrombosis are
unclear, numerous factors have been impli-
cated, whether they be by direct or indirect
means. In cadaveric donor kidney recipients,
children less than 2 years of age had a sig-
nificantly higher rate of thrombosis, as did
children who received kidneys from donors
who were under 5 years of age. Recipients
of cadaveric donor kidneys with prolonged
cold ischemia time had a higher rate of
thrombosis than did those with a cold
ischemia time under 24 hours. ATNacute
tubular necrosis. (FromSingh and coworkers
*P <0.01, test for trend.
P =0.01, test for trend.

210
Hypertension
EVALUATING HYPERTENSION
Pretransplantation
230
11
23
1
264
14
26
6
262
16
13
12
261
16
10
24
257
9
9
FIGURE 16-36
Data from the North American Pediatric Renal Transplant
Cooperative Study evaluating hypertension. Hypertension is com-
mon in children after renal transplantation. The definition of
hypertension used was taken from the Report of the Second Task
Force on Blood Pressure Control in Children [15]. The percentage
of children exceeding age-adjusted blood pressure standards
decreased considerably over the 2-year period. (FromBaluarte and
CYCLOSPORINE DOSAGES IN RECIPIENTS WITH AND
WITHOUT HYPERTENSION
Degree of hypertension
Normotensive
Significant
Severe
1 mo
n
161
36
69
CsA dosage, mg/kg
8.2
9.4
10.0
P =0.11
2 y
n
213
22
22
CsA dosage, mg/kg
3.9
4.8
4.7
P =0.23
FIGURE 16-37
North American Pediatric Renal Transplant
Cooperative Study evaluating cyclosporine
dosages in recipients with and without hyper-
tension. CsAcyclosporine. (FromBaluarte
GRAFT FAILURE FROM RECURRENT DISEASE
Disease
FSGS
MPGN typeI
MPGN typeII
SLE
HSP
HUS
Classical
Atypical
Recurrence rate, %
2530
70
100
540
5585
1220
25
Clinical severity
High
Mild
Low
Low
Low to mild
Moderate
High
Those with recurrence whose graft failed, %
4050
1230
1020
5
520
010
4050
FIGURE 16-38
Recurrence rates and graft failure from
recurrent disease. Some primary renal dis-
eases may recur in the allograft, making the
underlying disease an important considera-
tion when evaluating a child for renal trans-
plantation. Focal segmental glomerular scle-
rosis and atypical hemolytic uremic syn-
drome recur in roughly 25% of cases.
These diseases are severe clinically and lead
to the highest percentage of graft failures,
ie, 40% to 50%. In contrast, membra-
noproliferative glomerulonephritis type II
recurs in all cases; however, it is not very
severe clinically and leads to graft failure in
only 10% to 20% of patients. FSGSfocal
segmental glomerulosclerosis; HSP
Henoch-Schnlein purpura; HUShemolyt-
ic-uremic syndrome; MPGNmembra-
noproliferative glomerulonephritis; SLE
systemic lupus erythematosus. (FromFine
and Ettenger [37]; with permission.)
Recurrent Disease
Patients, n
Significant hypertension, %
Severehypertension, %
211
Other Causes of Renal Allograft Loss
30
A
60
100
70
80
90
50
40
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
0 10 20 30
Months
40 50
Congenital and structural
Glomerulonephritis
Congenital nephrotic syndrome
30
B
60
100
70
80
90
50
40
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
0 10 20 30
Months
40 50
Hemolytic uremic syndrome
Renal infarction
Cystinosis
Familial nephritis
FIGURE 16-39
Data from the North American Pediatric Renal
Transplant Cooperative Study showing that
those patients receiving living donor kidneys
who have congenital nephrotic syndrome
(CNS), focal segmental glomerulosclerosis (FSG)
(panel A) or hemolytic uremic syndrome (HUS)
(panel B) had the lowest 2-year graft survival
rates. These rates range from 74.3% to 80.6%.
In patients with focal segmental glomerular
sclerosis, graft failure was attributed to disease
recurrence in 13 of 39 (33%) patients who
received kidneys from living related donors.
B, The patients with familial nephritis or cysti-
nosis had the highest graft survival rates (88.9%
and 92.9%, respectively). (FromKashton and
30
A
60
100
70
80
90
50
40
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
0 10 20 30
Months
40 50
Congenital and structural
Glomerulonephritis
Congenital nephrotic syndrome
30
B
60
100
70
80
90
50
40
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
0 10 20 30
Months
40 50
Renal infarction
Cystinosis
Familial nephritis
FIGURE 16-40
Data from the North American Pediatric Renal
Transplant Cooperative Study for cadaveric
donor renal allografts showing that the lowest
graft survival rates occurred in children with
focal segmental glomerular sclerosis or congeni-
tal nephrotic syndrome (panel A), or hemolytic
uremic syndrome (panel B). These rates range
from 40% to 58.9%. In patients with focal
segmental glomerular sclerosis, graft failure
was attributed to disease recurrence in 14 of
81 (17%) patients who received cadaveric
donor kidneys. A, The highest graft survival
rate correlated with the diagnosis of congenital
and structural disease and glomerulonephritis
(72.2% and 73.5%, respectively). (From
Kashton and coworkers [38]; with permission.)
Mortality in Recipients
0
15
10
5
1
-
y
e
a
r

K
a
p
l
a
n
-
M
e
i
e
r

d
e
a
t
h

r
a
t
e
s
,

%
04 59 1014
Agegroups
1519
Dialysis
CD Tx
LRD Tx
FIGURE 16-41
Data from the United States Renal Data Source on pediatric patient 1-year death rates by
age group and treatment mortality. Survival follow-up began on day 91 after onset of end-
stage renal disease for patients on dialysis incident in 1994, and from the date of trans-
plantation for patients receiving transplantations in 1994 [3]. CD Txcadaveric donor
transplant; LRD Txliving related donor transplant. (FromUnited States Renal Data
System [3]; with permission.)
212
0
20
30
10
D
e
a
t
h
s
,

%
Cardiac
arrest
13
Total deaths=290
Percentagesadd to 100
Acute
myocardial
infarction
4
Other
cardiac
causes
12
Cardio-
vascular
disease
6
Infection
24
Malignancy
7
Hemorrhage
4
Other
known
causes
25
Unknown
causes
6
FIGURE 16-42
Data from the United States Renal Data
Source regarding distribution of causes of
death in children aged 0 to 19, 1993 to
1995. (FromUnited States Renal Data
System [3]; with permission.)
CAUSES OF DEATH BY AGE GROUP
Cause of death
All causes
Viral infection
Bacterial infection
Other infections
Malignancy
Cardiopulmonary
Hemorrhage
Recurrenceof original disease
Dialysis-related complications
Other
Unknown
Recipient age
01
n(%)
27(100.0)
5(18.5)
3(11.1)
4(14.8)
1(3.7)
5(18.5)
3(11.1)
1(3.7)
1(3.7)
4(14.8)
0(0.0)
25
n(%)
33(100.0)
1(3.0)
6(18.1)
5(15.2)
2(6.1)
7(21.2)
4(12.1)
1(3.0)
0(0.0)
5(15.2)
2(6.1)
612
n(%)
33(100.0)
6(18.2)
5(15.2)
3(9.1)
2(6.1)
10(30.3)
3(9.1)
0(0.0)
0(0.0)
3(9.1)
1(3.0)
1317
n(%)
43(100.0)
8(18.6)
6(14.0)
3(7.0)
4(9.3)
6(14.0)
6(14.0)
1(2.3)
3(7.0)
5(11.6)
1(2.3)
FIGURE 16-43
Data from the North American Pediatric Renal Transplant
Cooperative Study on causes of death by age group. This study
revealed a high rate of attrition among pediatric transplantation
recipients under the age of 5 years. It is unclear whether this high
rate is due to a higher rate of infection. (FromTejani and cowork-
ers [39]; with permission.)
70
85
100
95
90
80
75
P
a
t
i
e
n
t

s
u
r
v
i
v
a
l
,

%
0 12 24 36
Follow-up, m o
48 60
Livingdonor
Numbersat risk at:
Livingdonor
Cadaveric donor
Baseline
1800
1873
12
1393
1362
24
1033
1080
12
1393
1362
36
815
774
48
535
536
Cadaveric donor
FIGURE 16-44
Data from the 1995 North American Pediatric Renal Transplant Cooperative Study show-
ing a total of 214 deaths. Infection was the leading cause of death, occurring in 74
patients. This graph depicts the survival distribution estimates by donor source. Infants
aged under 2 years at the time of transplantation have a mortality rate of 14%. This rate
is significantly higher (P < 0.001) than in other age groups, with a mortality rate between
4.7% and 8.0%. (FromWarady and coworkers [5]; with permission.)
213
0
20
30
25
15
10
5
C
u
m
u
l
a
t
i
v
e

m
o
r
t
a
l
i
t
y
,

%
0 10 20 30
40
01(n =154)
25(n =413)
612(n =926)
1317(n =964)
Recipient age
FIGURE 16-45
Data from the North American Pediatric Renal Transplant Cooperative Study of patient
mortality by recipient age. A significant difference (P < 0.001) in 1-year mortality rates by
age groups occurred: 13.6% (21 of 154) for 0- to 1-year-old recipients; 8.0% (33 of 413)
for 2- to 5-year-old recipients; 3.6% (33 of 926) for 6- to 12-year-old recipients; and 4.5%
(43 of 964) for 13- to 17-year-old recipients. Mortality also is increased for recipients of
kidneys from young cadaveric donors. A dramatic increase in cumulative mortality is seen,
with increasing concordance between young donor and recipient ages. (FromTejani and
0
20
30
25
15
10
5
C
u
m
u
l
a
t
i
v
e

m
o
r
t
a
l
i
t
y
,

%
0 10 20 30
40
No (n =2140)
Yes(n =310)
Acutetubular necrosis
FIGURE 16-46
The effect of acute tubular necrosis (ATN) on patient survival. The development of ATN
leads to a significantly higher (P = 0.0001) mortality rate of 13.2% (risk ratio of 3.1) for
the 310 patients reported on in the registry. A 25% mortality rate and 6.4 risk ratio were
noted for the 188 patients who developed graft failure within 30 days after transplantation
(P < 0.001). (FromTejani and coworkers [39]; with permission.)
References
1. Ettenger RB: Renal transplantation. In Renal Disease in Children.
Edited by Barakat AY. New York: Springer-Verlag; 1990:371384.
2. Warady BA, Hebert D, Sullivan EK, et al.: Renal transplantation,
chronic dialysis and chronic renal insufficiency in children and
adolescents: 1995 Annual Report of the North American Pediatric
Renal Transplant Cooperative Study. Pediatr Nephrol 1997,
11:4964.
3. United States Renal Data System: USRDS 1997 Annual Data Report.
Am J Kidney Dis 30:S128144.
4. Harmon WE: Treatment of children with chronic renal failure. Kidney
I nt 1995, 47:951961.
5. Warady BA, Hebert D, Sullivan EK, et al.: Renal transplantation,
chronic dialysis and chronic renal insufficiency in children and
adolescents: 1995 Annual Report of the North American Pediatric
11:4964.
6. UNOS Bull 1997, 2(10), October.
7. Tejani A, Stablein D, Alexander S, et al.: Analysis of rejection out-
comes and implications. Transplantation 1995, 59:502.
8. Stablein DM, Tejani A: Five-year patient and graft survival in North
American children. Kidney I nt 1995, 44:516.
9. Tejani A, Sullivan EK: Factors that impact on the outcome of second
renal transplants in children. Transplantation 1996, 62:606611.
10. Harmon WE: Treatment of children with chronic renal failure. Kidney
I nt 1995, 47:951961.
11. McEnery P, Stablein DM: Does human lymphocyte antigen matching
improve the outcome in pediatric renal transplants? J Am Soc
Nephrol 1992, 2:S234S237.
12. Fine RN, Tejani A, Sullivan EK: Pre-emptive renal transplantation in
children: report of the North American Pediatric Renal Transplant
Cooperative Study. Clin Transplantation 1994, 8:474478.
13. Red Book: Report of the Committee on I nfectious Diseases, edn 24.
Edited by Georges Peter. Elk Grove: American Academy of Pediatrics;
1997:1819.
14. Furth SL, Neu AM, Sullivan EK, et al.: Immunization practices in
children with renal disease: a report of the North American Pediatric
11:443446.
15. Tejani A, Sullivan EK: Higher maintenance cyclosporine dose
decreased the risk of graft failure in North American children: a
report of the North American Pediatric Renal Transplant Study. J Am
Soc Nephrol 1996, 7:550555.
16. McEnery PT, Stablein DM, Arbus G, Tejani A: Renal transplantation
in children: a report of the North American Pediatric Renal
Transplant Cooperative Study. N Engl J Med 1992, 326:17271732.
17. Tzakis AG, Reyes J, Todo S, et al.: Two-year experience with FK-506
in pediatric patients. Transplant Proc 1993, 25:619621.
18. Reding R, Wallemacq PE, Lamy ME, et al. Conversion from
cyclosporine to FK-506 for salvage of immunocompromised pediatric
liver allografts. Transplant 1994, 57:93100.
214
19. Ellis D. Clinical use of tacrolimus (FK-506) in infants and children
with renal transplants. Pediatr Nephrol 1995, 9:487494.
20. Ettenger R, Cohen A, Nast C, et al.: Mycophenolate mofetil as main-
tenance immunosuppression in pediatric renal transplantation.
Transplant Proc 1997, 29:340341.
21. Rees L, Rigden SPA, Ward GM: Chronic renal failure and growth.
Arch Dis Child 1989, 64:573577.
22. Tejani A, Fine R, Alexander S, et al.: Factors predictive of sustained growth
in children after renal transplantation: The North American Pediatric Renal
Transplant Cooperative Study. J Pediatr 1993, 122:397402.
23. Harmon WE, Jabs K: Factors affecting growth after renal transplanta-
tion. J Am Soc Nephrol 1992, 2:S295S303.
24. United States Renal Data System: USRDS 1995 Annual Data Report.
Bethesda, MD, The National Institutes of Health, The National
Institute of Diabetes and Digestive and Kidney Diseases, 1995. Am J
Kidney Dis 1995, 26:S1S186.
25. Najjar MF, Rowland M: Anthropometric reference data and the
prevalence of overweight. Vital Health Stat 1987, 11:1073.
26. Turenne MN, Port FK, Strawderman RL, et al.: Growth rates in pedi-
atric dialysis patients and renal transplant recipients. Am J Kidney Dis
1997, 30:193203.
27. Jabs K, Sullivan EK, Avner ED, Harmon WE: Alternate day steroid
dosing improves growth without adversely affecting graft survival or
long-term graft function. Transplantation 1996, 61:3136.
28. Broyer M: Results and side-effects of treating children with growth
hormone after kidney transplantation: a preliminary report. Acta
Paediatr Suppl 1996, 417:7679.
29. Laine J, Krogerus L, Sarna S, et al.: Recombinant human growth hor-
mone treatment: its effect on renal allograft function and histology.
30. Ingulli E, Tejani A: An analytical review of growth hormone studies in
children after renal transplantation. Pediatr Nephrol 1995,
9:S61S65.
31. Tonshoff B: Efficacy and safety of growth hormone treatment in short
children with renal allografts: 3-year experience. Kidney I nt
44:199207.
32. Yadin O, Grimm PC, Ettenger RB: Renal transplantation in children.
Pediatr Ann 1991, 20:662667.
33. Tejani A, Cortes C, Stablein D: Clinical correlates of chronic rejection
in pediatric renal Transplantation: a report of the North American
Pediatric Renal Transplant Cooperative Study. Transplantation 1996,
61:10541058.
34. Palleschi J, Novick AC, Braun WE: Vascular complications of renal
transplantation. Urology 1990, 16:61.
35. Singh A, Stablein D, Tejani A: Risk factors for vascular thrombosis in
pediatric renal transplantation. Transplantation 1997, 63:12631267.
36. Baluarte HJ, Gruskin AB, Ingelfinger JR, et al.: Analysis of hyperten-
sion in children post-renal transplantation: a report of the North
American Pediatric Renal Transplant Cooperative Study (NAPTRCS).
Pediatr Nephrol 1994, 8:570573.
37. Fine RN, Ettenger R: Renal transplantation in children. Kidney
Transplantation: Principles and Practice, edn 4. Edited by Morris PJ.
Philadelphia: WB Saunders Company; 1994:418.
38. Kashton CE, McEnery PT, Tejani A, Stablein DM: Renal allograft sur-
vival according to primary diagnosis: a report of the North American
Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1995,
9:679684.
39. Tejani A, Sullivan EK, Alexander S, et al.: Post-transplant deaths and
factors that influence the mortality rate in North American children.
215
17
Recurrent Disease in the
Transplanted Kidney
M
any patients receiving renal allografts become identified simply
as recipients of kidney transplantation. All subsequent events
involving changes in renal function are attributed to the
process and natural history of transplantation itself: acute and chronic
rejection, immunosuppressive drug nephrotoxicity, graft vasculature
thrombosis or stenosis, ischemia, infection, and lymphoproliferative
disorders. However, it is important to remember the nature of the
underlying disease that caused the initial renal failure, even if the disease
occurred many years previously. Recurrence of the primary disease
often causes pathologic changes within the allograft; clinical manifes-
tations such as proteinuria and hematuria; and less commonly, renal
failure. Thus, focal segmental glomerulosclerosis (FSGS) frequently
causes recurrent proteinuria after transplantation, which may begin as
early as minutes after the graft is vascularized [1]. All patients with
diabetes develop recurrent basement membrane and mesangial pathology
within their allografts [2], and recurrent oxalate deposition can cause
rapid renal allograft failure in patients with oxalosis [3]. Identifying
patients at particular risk of primary disease recurrence allows
consideration of therapeutic maneuvers that may minimize the incidence
of recurrence.
Living-related transplantation poses additional dilemmas. For many
nephritides good evidence exists for an increased incidence of recurrent
primary disease in related as opposed to cadaveric grafts. Data from
the Eurotransplant Registry suggests a fourfold increased incidence of
recurrence of glomerulonephritis, causing graft loss in grafts from living
related donors (16.7% vs 4%) [4].
Finally, the recurrence of glomerulonephritis after transplantation,
in particular, can cause specific diagnostic problems. It may be caused
by recurrent disease, development of de novo glomerulonephritis in the
transplanted organ, or transplanted glomerulonephritis from a donor
with unrecognized disease. Glomerulonephritis after transplantation
must be distinguished from chronic rejection causing glomerulopathy
and cyclosporine-induced glomerulotoxicity. Each of the following
diseases can present diagnostic dilemmas and cause graft failure:
Jer em y B. Levy
CHA P T ER
216
recurrence of FSGS, mesangial immunoglobulin A disease,
hemol yti c uremi c syndrome, mesangi ocapi l l ary gl omeru-
lonephritis, and antiglomerular basement membrane disease.
Overall, three groups of diseases recur in patients with
transplantations: metabolic disorders, especially primary hyper-
oxaluria and diabetes; systemic diseases, including systemic
lupus erythematosus, sickle cell disease, systemic sclerosis,
hepati ti s C vi rusassoci ated nephropathi es and systemi c
vasculitis; and a variety of glomerulonephritides. For immune-
medi ated systemi c di seases the standard transpl antati on
immunosuppressive regimens often prevent recurrence of primary
disease, which also may be true for the glomerulonephritides.
Some evidence exists that in the glomerulonephritides there is a
reduced incidence of recurrence with the use of cyclosporine.
Confirmed recurrence of all the glomerulonephritides causes
graft loss in 4% of adults and 7% of children receiving allografts
[4,5]. Although few data exist on the treatment of most forms
of recurrent nephritis, plasma exchange or immunoadsorption
are proving beneficial at reducing nephrotic range proteinuria
in recurrent FSGS [6,7], and recurrent renal oxalate deposition
often can be abrogated after transplantation in patients with
primary hyperoxaluria [8,9].
DISEASES THAT RECUR AFTER
Metabolic
Diabetesmellitus
Oxalosis
Amyloidosis
Fabrysdisease
Systemic
Systemic lupus
erythematosus
Systemic vasculitis
Sicklecell disease
HepatitisC virus
associated nephropathy
Systemic sclerosis
Glomerulonephritis
Immunoglobulin A nephropathy
Henoch-Schonlein purpura
Membranousnephropathy
MCGN
Antiglomerular basement
membranedisease
DIFFERENTIAL DIAGNOSIS OF
RECURRENT DISEASE AFTER
De n ov o glomerulonephritis
Transplanted glomerulonephritis
Chronic rejection
Acuteallograft glomerulopathy
Chronic allograft glomerulopathy
Cyclosporinetoxicity
Acuterejection
Allograft ischemia
Cytomegalovirusinfection
FIGURE 17-1
Many diseases can recur in transplanted kidneys, although fewer
cause graft failure. Those disorders that can cause loss of allografts
include oxalosis (primary hyperoxaluria) and some glomerulonephri-
tides, particularly mesangiocapillary glomerulonephritis (MCGN),
focal segmental glomerulosclerosis, and sometimes hemolytic uremic
syndrome. Diabetes recurs almost universally in isolated renal grafts
but rarely causes graft failure. Histologic recurrence of diabetic
vascular pathology and glomerular pathology is much more infrequent
in patients receiving combined pancreas and kidney transplantations
[10,11]. Hepatitis C virus is now recognized as a cause of a number
of problems after transplantation, including an increased risk of
recurrent and de novo glomerulonephritis (MCGN and membranous)
and allograft glomerulopathy [12].
FIGURE 17-2
Acute cellular rejection and cyclosporine toxicity usually can be distinguished easily from
recurrent glomerular disease. Recurrent hemolytic uremic syndrome, however, can cause a
microangiopathy similar to cyclosporine toxicity, with erythrocyte fragments visible both
in blood films and within glomerular capillary loops. The major diagnostic difficulty lies
with chronic rejection, especially in the form of transplantation glomerulopathy, and de
novo or transplanted glomerulonephritis. Chronic transplantation glomerulopathy occurs
in 4% of renal allografts and usually is associated with proteinuria of more than 1 g/d,
beginning a few months after transplantation. Chronic glomerulopathy shares some features
with both recurrent mesangiocapillary glomerulonephritis type I and hemolytic uremic
syndrome: glomerular capillary wall thickening, mesangial expansion, and double contour
patterns of the capillary walls with mesangial cell interposition [13]. Thus, a definitive
diagnosis of recurrent nephritis may require histologic characterization of the underlying
primary renal disease and a graft biopsy before transplantation.
217
17.3 Recurrent Disease in the Transplanted Kidney
A
B
FIGURE 17-3
Biopsy showing rejection (panel A) and membranous changes (panel B) in a woman
8 months after transplantation. The patient initially had idiopathic membranous
nephropathy that progressed to end-stage renal failure over 5 years. She subsequently
received a cadaveric allograft but developed proteinuria and renal dysfunction after
8 months. The biopsy shows recurrent membranous disease, with thickened glomerular
capillary loops (and spikes on a silver stain), and features of acute interstitial rejection,
with a pronounced cellular infiltrate and tubulitis. Additional sections also showed evi-
dence of chronic cyclosporine toxicity. In many patients, transplantation biopsies have
features of several pathologic processes. Recurrent nephritis can be overlooked in a
biopsy showing evidence of chronic rejection, cyclosporine toxicity, or both.
INVESTIGATING RECURRENT DISEASE
Renal biopsywith immunofluorescenceand electron microscopy
Cyclosporin A level
Urinemicroscopyand culture
24-h urineprotein
Renal ultrasonography
Antiglomerular basement membraneautoantibodyand antineutrophil cytoplasmantibody
Cytomegalovirusserologyand viral antigen detection
HepatitisC virusserologyand RNA detection
FIGURE 17-4
Confirming a diagnosis of recurrent disease requires a renal biopsy.
Features that favor recurrence include an active urine sediment
with erythrocytes and erythrocyte casts, heavy proteinuria, and
normal cyclosporine levels. Serologic testing for antiglomerular
basement membrane antibody is important in patients with
Alports or Goodpastures syndrome, and blood film examination
for patients with previous hemolytic uremic syndrome. Immuno-
fluorescence and electron microscopic studies are rarely performed
routinely on transplantation biopsies but can be vital in making a
diagnosis of recurrent nephritis.
218
HISTOLOGIC AND CLINICAL RECURRENCE OF RENAL
DISEASE AFTER KIDNEY TRANSPLANTATION
Disease
Diabetesmellitus
Primaryhyperoxaluria
MesangiocapillaryglomerulonephritistypeI
MesangiocapillaryglomerulonephritistypeII
Antiglomerular basement membranedisease
Systemic lupuserythematosus
Vasculitis
Amyloidosis
Histologic recurrence rate, %
50100
40100
1015without risk factors
50100with risk factors
2575
3075
970
3040
357
510
<1
045
116
2033
Clinical recurrence rate, %
10, after 10years
32100
50
140
145
50100
1020
50
25
Rare
1050
040
2060
FIGURE 17-6
Accurate data for recurrence rates are difficult
to obtain, especially because transplantation
biopsies often are not performed routinely
after transplantation without a specific indi-
cation. Thus, some recurrence rates may be
overrepresented in failing grafts, with
asymptomatic recurrence being undetected.
Many recurrent diseases do not cause urinary
abnormalities or symptoms. Diseases that
are slowly progressive also may be under-
represented in studies with only a short fol-
low-up time (eg, immunoglobulin A disease).
RECURRENT DISEASES AFTER KIDNEY TRANSPLANTATION
Recurrent diseases that commonly cause graft failure
PrimaryhyperoxaluriatypeI
MesangiocapillaryGN typeI (and lesscommonly, typeII)
Immunoglobulin A disease?
Histologic recurrence only, graft failure uncommon
Diabetesmellitus
Immunoglobulin A disease
MembranousGN
MesangiocapillaryGN typeII
Systemic vasculitis(antineutrophil cytoplasmantibodyassociated)
Fabrysdisease
Histologic recurrence rare
Systemic lupuserythematosus
Systemic vasculitis
Idiopathic rapidlyprogressiveGN
MembranousGN
FIGURE 17-5
The prevalence and incidence of recurrent disease after transplanta-
tion is difficult to ascertain. Certainly, system lupus erythematosus
and idiopathic rapidly progressive glomerulonephritis rarely recur
in grafts, whereas in some groups of patients recurrence of focal
segmental glomerulosclerosis is universal [4]. There is much debate
as to the frequency of recurrence of immunoglobulin A disease and
whether there is any association of recurrence with graft dysfunction
[14,15]. Recurrence of an underlying primary renal disease may
cause changes within the allograft and predispose patients to acute
rejection and graft failure, eg, upregulation of human leukocyte
antigens in parenchymal tissue. Proteinuria and dyslipidemia also
can lead to changes in the expression of cell surface proteins critical
for antigen presentation and immune regulation.
219
0 5 10 15 20 25
0
100
80
60
40
20
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
Grafted before1983,y A
Patientswith glomerulonephritis
Patientswithout glomerulonephritis
0 5 10
0
100
80
60
40
20
G
r
a
f
t

s
u
r
v
i
v
a
l
,

%
Grafted since1983,y B
Patientswith glomerulonephritis
Patientswithout glomerulonephritis
FIGURE 17-7
Actuarial cadaveric survival curves in patients with or without
glomerulonephritis (GN) as the primary disease. A Significantly
worse renal graft survival in patients receiving grafts before 1983
if their underlying disease was GN, rather than any other disease
(P < 0.015; diabetes excluded). B, Since the introduction of
cyclosporine (in transplantations after 1983), graft survival curves
are the same for patients with or without GN. For patients receiv-
ing a living related graft, however, GN still carries an excess risk of
recurrent disease causing graft failure [4]. (Adapted fromfrom
Michielsen [16].)
RECURRENCE OF ORIGINAL GLOMERULONEPHRITIS CAUSING GRAFT FAILURE
01
12
23
34
45
Total
All LRD transplantation failures
from recurrent GN, %
1.9
0.7
1.5
0
0.8
4.4
Living related donor (LRD) kidney transplantations
LRD graft failures from
recurrent GN, %
25
9
33
0
14
16.7
Cadaveric kidney transplantations
Cadaveric graft failures
from recurrent GN, %
1.5
8.7
5.8
4.8
6.6
4
All cadaveric transplantation
failures from recurrent GN, %
0.2
0.5
0.3
0.25
0.3
1.3
FIGURE 17-8
Several studies have reported an increased incidence of recurrent
glomerulonephritis (GN) after renal transplantation in grafts from
living related donors. In one study with histologic data available on
both donors and recipients, GN recurred in 8.7% of 149 cadaveric
grafts compared with 25.8% of 124 living donor grafts [16,17]. The
data shown here are from the Eurotransplant Registry. These data
demonstrate a substantial excess of recurrent GN causing graft failure
in living donor grafts compared with cadaveric grafts from the same
centers over the same time period [4]. Up to one third of all the graft
failures in grafts from living related donors were due to recurrent
disease compared with less than 1 in 10 graft failures in cadaveric
transplantations. No difference in recurrence rates was seen in any
of the first 5 years after transplantation. GNglomerulonephritis.
(Adapted fromKotanko and coworkers [4].)
220
CAUSE OF GRAFT LOSS IN RENAL GRAFT
RECIPIENTS WITH DIABETES DURING THE
FIRST AND SECOND DECADES
Cause
Deathswith functioninggrafts:
Cardiovascular disease
Sepsis
Malignancy
Other
Rejection
Recurrent diabetic nephropathy
Technical
Other
First decade, %
(No. of patients)
56(104)
16
14
2
24
31(62)
0(0)
8(14)
5(9)
Second decade, %
(No. of patients)
76(19)
40
4
16
16
16(4)
8(2)
0(0)
0(0)
13 4 3 2 0
Transplant
Glomerular capillary
basement membrane
thickening
Mesangial
expansion,
microalbuminuria
Hyalinevasculopathy
almost universal
18%of patients have
severe
mesangial expansion
(Kimmelsteil-Wilson
nodules)
Years
FIGURE 17-10
Recurrence of diabetes in renal allografts is a common histologic
finding but a rare cause of graft loss. The most frequent cause of
death in the second decade after transplantation was cardiovascular
disease, and the most common cause of graft loss was the death of
a patient with a functioning graft. Only 2 of 100 patients surviving
more than 10 years suffered graft loss from recurrent diabetic
nephropathy, occurring at 12.6 and 13.6 years after transplantation
[2]. The incidence of vascular complications and the need for ampu-
tations, however, are substantially increased in patients with diabetes
receiving transplantations. In most centers, overall graft survival rates
are lower for recipients with diabetes than for those without diabetes.
(Adapted fromNajarian and coworkers [2].)
FIGURE 17-11
Diabetic changes in renal allografts transplanted into patients with
diabetes. Diabetic changes (especially glomerular capillary wall
thickening and hyaline vasculopathy) probably occur in all these
recipients [2,10]. Diabetic changes occur slowly, however, and rarely
are severe enough to cause graft dysfunction. The serum creatinine
at 10 years in 95 patients from Minnesota with renal allografts
functioning for more than 10 years was 1.5 0.1 mg/dL (mean
standard error of the mean) and in 10 patients with allograft function
for 15 or more years was 1.6 0.3 mg/dL [2]. Classic nodular
glomerulosclerosis is much rarer. Recurrence of diabetic nephropathy
can be prevented by simultaneous pancreatic and renal transplanta-
tion. At 2 years, most patients receiving a combined pancreatic and
kidney graft have no histologic changes on renal biopsy and normal
basement membrane thickness on electron microscopy of glomerular
tissue [10,11]. Intensive insulin treatment with good glycemic control
after transplantation also prevents the development of recurrent
glomerular and arteriolar lesions.
0 5 10 15
0
5
10
15
20
25
30
35
40
45
20
R
e
c
u
r
r
e
n
c
e
,

%
Timeof follow-up, y
A
P<0.02
Nephx
No Nephx
0 5 10 15
0
5
10
15
20
25
30
35
40
20
G
r
a
f
t

l
o
s
s

f
r
o
m

r
e
c
u
r
r
e
n
c
e
,

%
Timeof follow-up, y
B
P<0.01
Nephx
No Nephx
FIGURE 17-9
Bilateral pretransplantation native nephrectomy has been advocated
to reduce the likelihood of recurrence of nephritis in renal trans-
plantations. The data shown here indicate that of 364 transplanta-
tions in patients with a diagnosis of primary glomerulonephritis,
an increased recurrence rate exists in those 61 patients with bilateral
pretransplantation nephrectomies compared with the 303 patients
without nephrectomy (24.6% vs12.2%; P < 0.02) [18]. Overall,
14% of patients having transplantation developed recurrent
glomerulonephritis (panel A), and 52% of grafts in these patients
failed (panel B). Thus, pretransplantation nephrectomy has no
place in preventing recurrent nephritis. (FromOdorico and
coworkers [18].)
221
Glyoxylate
Oxalate
Alanine: glyoxylate
aminotransferase
(AGT)
Cofactor: pyridoxine
Glyoxylate
reductase
Glycolate
Glycine
Lactate dehydrogenase
L--hydroxy acid oxidase
Glycolateoxidase
FIGURE 17-12
Primary hyperoxaluria type I in renal failure. Primary hyperoxaluria
type I is an autosomal recessive inborn error of metabolism resulting
from a deficiency (or occasionally incorrect subcellular localization)
of hepatic peroxisomal alanineglyoxylate aminotransferase [8].
Patients excrete excess oxalate as a result of the increased glyoxylate
pool. In many patients, renal disease is manifested by chronic renal
failure. Once the glomerular filtration rate has decreased below 25
mL/min the combination of oxalate overproduction and reduced
urinary excretion leads to systemic oxalosis, with calcium oxalate
deposition in many tissues. Renal transplantation alone has yielded
poor results in the past, with 1-year graft survival rates of only
26% [3]. Combined hepatorenal transplantation simultaneously
replaces renal function and corrects the underlying metabolic defect.
The 1-year liver graft survival rate is 88%, with patient survival of
80% at 5 years. Of 24 renal grafts from the European experience
of hepatorenal transplantation, 17 were still functioning at 3 months
to 2 years after transplantation [19].
FIGURE 17-13
Histologic slide of a patient who received an isolated renal allograft
for primary hyperoxaluria type I in which oxylate crystals are seen
clearly within the tubules and interstitium. The major hazards for
the renal graft after transplantation include early acute nephrocal-
cinosis caused by rapid mobilization of the systemic oxalate deposits.
Acute tubular obstruction by calcium oxalate crystals also can
occur. Late nephrocalcinosis leads to progressive loss of renal function
over several years. Rejection episodes are less common in patients
receiving combined liver and kidney grafts than in those receiving
kidney transplantation alone [3,19]. Acute rejection with renal
dysfunction, however, causes additional episodes of acute calcium
oxalate deposition in the kidney. Recurrent oxalosis can be seen as
early as 3 months after transplantation.
PATIENT MANAGEMENT IN RENAL OR HEPATORENAL
TRANSPLANTATIONS FOR PRIMARY HYPEROXALURIA
Aggressivepreoperativedialysis(and possiblycontinued postoperatively)
Maintenanceof high urineoutput
Low oxalate, low ascorbic acid, diet low in vitamin D
Phosphatesupplements
Magnesiumglycerophosphate
High-dosepyridoxine(500mg/d)
Thiazidediuretics
FIGURE 17-14
Daily hemodialysis for at least 1 week before transplantation
depletes the systemic oxalate pool to some extent. Some centers
continue aggressive hemodialysis after transplantation, regardless
of the renal function of the transplanted organ. In patients receiving
combined hepatorenal grafts, dietary measures to reduce oxalate
production are not as important as they are in patients receiving
isolated kidney grafts. In these patients, excess production of
oxalate from glyoxylate still occurs. Magnesium and phosphate
supplements are powerful inhibitors of calcium oxalate crystallization
and should be used in all recipients, whereas thiazide diuretics may
reduce urinary calcium excretion. Pyridoxine is a cofactor for alanine
glyoxylate aminotransferase and can increase the activity of the enzyme
in some patients. Pyridoxine has no role in combined hepatorenal
transplantation. For most patients the ideal option is probably a
combined transplantation when their glomerular filtration rate
decreases below 25 mL/min [8,9].
222
A B
FIGURE 17-16
Microradioangiography comparing the
vasculature of the kidney in a patient with
no disease (panel A) and a patient with
homozygous sickle cell disease (panel B)
[22]. Despite the frequency of renal damage
in sickle cell disease, only 4% of patients
progress to end-stage renal disease, and little
experience exists with renal transplantation.
Three patients have been reported with
recurrent sickle cell nephropathy. In one
case, a patient developed renal dysfunction
3.5 years after transplantation; a biopsy
showed glomerular sclerosis, tubular
atrophy, and interstitial fibrosis, without
features of rejection. A second study reported
recurrent sickle cell nephropathy leading to
graft failure in two of eight patients receiving
transplantation [23]. Concentration defects
were observed within 12 months of grafting.
Patients also suffered an increased incidence
of sickle cell crises after renal transplantation,
possibly associated with the increase in
hematocrit.
AMYLOIDOGENIC AND RELATED DISEASES CAUSING RENAL FAILURE
Disease
Nonhereditary
Systemic amyloidosisassociated with chronic inflammatorydisorders(especiallyrheumatoid arthritis)
Systemic amyloidosisassociated with immunedyscrasia: multiplemyeloma, monoclonal gammopathy,
occult immunedyscrasia, lymphoma
Hereditary
Familial Mediterranean fever
Ostertag-type(autosomal dominant, earlyhypertension, and renal impairment)
Muckle-Wellssyndrome(deafness, nephropathy, urticaria, and limb pain)
Hereditaryrenal amyloidosis
Familial nephropathic systemic amyloidosis
Light chain deposition disease
Fibril protein
Amyloid A
AL
Amyloid A
Not known
Not known
Fibrinogen
Apolipoprotein A
AL or immunoglobulin light chains
Precursor protein
Serumamyloid A
Monoclonal immunoglobulin
light chain
Serumamyloid A
Not known
Not known
Fibrinogen
Apolipoprotein A
Immunoglobulin light chains
FIGURE 17-15
The most common cause of amyloidosis leading to renal failure is
rheumatoid arthritis [20]. However, increasing numbers of patients
with myeloma and AL amyloid, or primary amyloidosis, are now
receiving peripheral blood stem cell transplantations or bone mar-
row allografts. Thus, these patients are surviving long enough to
consider renal transplantation. Over 60 patients with renal failure
resulting from systemic amyloid A (AA) amyloidosis have been
reported to have received renal allografts. Graft survival in these
patients is the same as that of a matched population. Histologic
recurrence of renal amyloid has been reported in 20% to 33% of
these grafts within 2 years of transplantation [20,21]. Patient survival
is reduced, owing to infections and vascular complications, to 68% at
1 year and 51% at 2 years. Recurrence is characterized by proteinuria
11 months to 3 years after transplantation. Recurrent light chain
deposition disease is found in half of patients receiving allografts, with
graft loss in one third despite plasmapheresis and chemotherapy [4].
Heavy proteinuria is seen at the onset of recurrence. ALprimary
amyloidosis.
223
FEATURES OF RECURRENT
SYSTEMIC LUPUS
ERYTHEMATOSUS
Rash
Arthralgia
Proteinuria(usuallynonnephrotic)
Increasinganti-DNA antibodytiters
Increasingantinuclear antibodytiters
Decreasingcomplement levels(C3and C4)
FIGURE 17-17
Nephritis caused by systemic lupus erythe-
matosus (SLE) rarely recurs in transplanta-
tions. SLE accounts for approximately 1%
of all patients receiving allografts, and less
than 1% of these will develop recurrent
renal disease. Time to recurrence has been
reported as 1.5 to 9 years after transplanta-
tion [24,25]. Cyclosporine therapy does not
prevent recurrence. It is reasonable to
ensure that serologic test results for SLE are
minimally abnormal before transplantation
and certainly that patients have no evidence
of active extrarenal disease. Patients with
lupus anticoagulant and anticardiolipin
antibodies are at risk of thromboembolic
events, including renal graft vein or artery
thrombosis. These patients may require
anticoagulation therapy, or platelet inhibi-
tion with aspirin.
RELAPSE RATE IN ANTINEUTROPHIL CYTOPLASM
ANTIBODYASSOCIATED SYSTEMIC VASCULITIS
Series
Hammersmith Hospital
19741997[26]
Habitz and coworkers
19801995[26]
Schmitt and coworkers
19821993[26]
Patients, n
59
18
18
Relapse rate on dialysis,
relapses/patient/y
0.088
0.24
0.3
Relapse rate after transplantation,
relapses/patient/y
0.018
0.06
0.1
FIGURE 17-18
Recurrence of Wegeners granulomatosis or microscopic polyangiitis has been reported
after transplantation, with overall renal and extrarenal recurrence rates of up to 29% and
renal recurrences alone of up to 16% [27]. Graft loss has been reported in up to 40% of
patients with renal recurrence. In the most recent data from the Hammersmith Hospital,
however, renal recurrences were rare, with only 0.018 relapses per patient per year after
transplantation [26]. These patients have often been on long courses of immunosuppres-
sive therapy before receiving a graft. Extrarenal recurrence of Wegeners granulomatosis
can involve the ureter, causing stenosis and obstructive nephropathy. Serial monitoring of
antineutrophil cytoplasmic antibodies after transplantation is important in all patients
with vasculitis because changes in titer may predict disease relapse [28,29]. (Adapted from
Allen and coworkers [26].)
RENAL COMPLICATIONS OF HEPATITIS C VIRUS
Clinical:
Proteinuria
Nephrotic syndrome
Microscopic hematuria
Histologic and laboratoryfindings
Mesangiocapillaryglomerulonephritiswith or without cryoglobulinemia,
hypocomplementemia, rheumatoid factors
Membranousnephropathy: normal complement, no cryoglobulinemia
or rheumatoid factor
Acuteand chronic transplantation glomerulopathy
FIGURE 17-19
Recurrence of both mesangiocapillary glomerulonephritis (MCGN)
and, less frequently, membranous nephropathy is well described
after transplantation. Nineteen cases of de novo or recurrent
MCGN after transplantation have been described in patients with
hepatitis C virus (HCV) [12]. Almost all had nephrosis and exhibited
symptoms 2 to 120 months after transplantation. Eight patients
had demonstrable cryoglobulin, nine had hypocomplementemia,
and most had normal liver function test results. Membranous GN
is the most common de novo GN reported in allografts, and it is
possible that HCV infection may be associated with its development
[12]. Twenty patients with recurrent or de novo membranous GN
and HCV viremia have been reported. In one study, 8% of patients
with membranous GN had HCV antibodies and RNA compared
with less than 1% of patients with other forms of GN (excluding
MCGN) [30]. Prognosis in these patients was poor, with persistent
heavy proteinuria and declining renal function.
224
RISK FACTORS FOR RECURRENT FOCAL SEGMENTAL
GLOMERULOSCLEROSIS AFTER TRANSPLANTATION
Recurrence rate, %
50
80100
7585
1015
Risk factor
Age<5y
Age<15ywith progression to end-stagerenal disease
within 3y
First graft lost fromfocal segmental glomerulosclerosis
Adultswithout risk factors
Graft lossoccursin half of all patientswith recurrent focal segmental glomerulosclerosis
and nephrotic syndrome.
FIGURE 17-20
Focal segmental glomerulosclerosis accounts for 7% to 10% of
patients requiring renal replacement therapy. The overall recurrence
rate is approximately 20% to 30% [1,4,31]. These numbers, however,
may be an underestimate because of biopsy sampling errors. Patients
at high risk for recurrence can be identified, particularly children
with rapid evolution of their original disease and mesangial expansion
on biopsy [1,32]. Recurrence manifests with proteinuria (often
1040 g/d), developing hours to weeks after transplantation. In
children the mean time to recurrence is 14 days. Recurrence is not
benign and leads to graft loss in up to half of patients. Patients at
highest risk for recurrence should not receive grafts from living
related donors.
A. RECURRENT FOCAL SEGMENTAL GLOMERULOSCLEROSIS
AND ACUTE RENAL FAILURE AFTER TRANSPLANTATION
Acuterenal failure(23)
No acuterenal failure(50)
Patients with no recurrence, n
7
40
Patients with recurrence, n
16
10
FIGURE 17-21
Patients with recurrent focal segmental
glomerulosclerosis are at substantially
increased risk of developing both acute
renal failure (panel A) after transplantation
and acute rejection episodes (panel B). In
one study, 23 of 26 patients with recurrence
developed one or more episodes of rejec-
tion, compared with only 11 of 40 patients
without recurrence [31]. Although the mecha-
nism for the increased rate of acute dysfunc-
tion and rejection is unclear, proteinuria and
dyslipidemia may alter the expression of cell
surface immunoregulatory molecules and
major histocompatibility complex antigens.
(Adapted fromKim and coworkers [31].)
B. ACUTE REJECTION EPISODES AMONG ACUTE RENAL FAILURE CASES
>1acuterejection episode
No rejection
Patients with recurrence
Acute renal failure
16
0
No acute renal failure
7
3
Patients with no recurrence,
no acute renal failure
11
29
225
55
0
10
4
3
2
1
8
6
4
2
155
S
e
r
u
m

c
r
e
a
t
i
n
i
n
e
,

m
g
/
d
L
U
r
i
n
a
r
y

p
r
o
t
e
i
n

e
x
c
r
e
t
i
o
n
,

g
/
d
A
6 3
500 540 520
0
10
12
10
6
8
2
4
8
6
4
2
580 560
S
e
r
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m

c
r
e
a
t
i
n
i
n
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,

m
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i
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p
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o
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i
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e
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c
r
e
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i
o
n
,

g
/
d
C
4
400 500
0
10
5
4
3
2
1
8
6
4
2
600
S
e
r
u
m

c
r
e
a
t
i
n
i
n
e
,

m
g
/
d
L
U
r
i
n
a
r
y

p
r
o
t
e
i
n

e
x
c
r
e
t
i
o
n
,

g
/
d
D
3
60 110 160 210
0
10
10
8
6
4
2
8
6
4
2
260
S
e
r
u
m

c
r
e
a
t
i
n
i
n
e
,

m
g
/
d
L
U
r
i
n
a
r
y

p
r
o
t
e
i
n

e
x
c
r
e
t
i
o
n
,

g
/
d
B
5 5 2
FIGURE 17-22
Serum creatinine concentrations and urinary protein excretion in four patients (AD) with
recurrent nephrotic syndrome after transplantation treated by protein adsorption. Each
bar indicates one cycle of treatment and the numbers above the bars indicate the sessions
of treatment in that cycle. A number of studies have demonstrated that both plasma
exchange and protein adsorption (using protein A sepharose), can decrease urinary protein
excretion in recurrent focal segmental glomerulosclerosis [6,7,33]. Four examples are
shown here. In this study, protein excretion decreased by 82% but returned to pretreatment
levels within 2 months in seven of eight patients. More intensive treatment regimens have
led to longer remissions [7]. The nature of the circulating factor responsible for protein
leakage is unknown. There are case reports of children with recurrent focal segmental
glomerulosclerosis responding to high-dose intravenous cyclosporine with remission of
nephrotic syndrome. However, cyclosporine does not prevent recurrence when used as
part of the initial immunosuppressive regimen. (Adapted fromDantal and coworkers [6].)
DIFFERENTIAL DIAGNOSIS OF SEGMENTAL GLOMERULAR
SCARS ON TRANSPLANTATION BIOPSY
Diagnosis
Recurrent FSGS
Rejection
Cyclosporine-related
De n ov o FSGS
Other glomerulonephritides
Features
Recurrent heavyproteinuriawithin 3mo
Original diseasecaused renal failurein <3y
Insidiousonset of proteinuria
Featuresof chronic rejection on biopsy, especiallyvascular sclerosisand glomerulopathy
Previousthrombotic microangiopathyaffectingglomeruli
Original diseasenot FSGS
Chronic rejection excluded
Characteristic immunohistologyand electron microscopy, especiallyin immunoglobulin
A disease
FSGSfocal segmental glomerulosclerosis.
FIGURE 17-23
Segmental glomerular scars in a functioning
graft is a common finding. The interpreta-
tion of the biopsy requires knowledge of
the previous histology in the native kidneys
and the clinical course after transplantation.
Immunohistology and electron microscopy
can be particularly helpful in this setting.
Recurrent focal segmental glomerulosclerosis
is the most common cause of early massive
proteinuria. Both rejection and cyclosporine
therapy, however, can cause segmental scars
indistinguishable from those of focal seg-
mental glomerulosclerosis. Recurrent or de
novo immunoglobulin A disease in an allo-
graft also can cause segmental glomerular
scarring, but with mesangial hypercellularity,
immunoglobulin A detectable by immuno-
staining, and paramesangial deposits on
electron microscopy.
226
RECURRENT IMMUNOGLOBULIN A DISEASE
Features
Histologic recurrence, 25%75%
Clinical recurrence, 1%40%
Timeto recurrence, 2mo to 4y
Clinical presentation: asymptomatic, low-gradeproteinuria, microscopic hematuria
Susceptibility:human leukocyteantigen B35, DR4;immunoglobulin A rheumatoid factors
Graft loss, <10%
FIGURE 17-24
Up to 75% of patients with immunoglobulin A (IgA) disease develop
histologic recurrence within their grafts, which usually presents with
microscopic hematuria and proteinuria [4,14,15]. Many patients,
however, only will have recurrence noted on a routine biopsy after
transplantation. Most studies suggest that the risk of graft loss
resulting from recurrent disease is low (<10%) [4]. However, long-
term follow-up in some studies has suggested an increasing rate of
graft loss with time, approaching 20% at 46 months [14,15].
Conversely, one study has documented 100% graft survival at 2
years in patients with IgA disease who had IgA antihuman leukocyte
antigen (HLA) antibodies [34]. The mechanism is unclear. The
association of IgA disease and the HLA alleles B35 and DR4 may
explain the increased risk of recurrence in grafts from living related
donors because family members are more likely to share HLA genes.
FIGURE 17-25
Histologic slide of a biopsy from a patient with recurrent immuno-
globulin A (IgA) nephropathy. This patient developed proteinuria 9
months after receiving a cadaveric allograft. The biopsy shows features
of recurrent IgA disease with mesangial expansion and a glomerular
tuft adhesion to Bowmans capsule. Immunohistology confirmed
deposition of IgA in the mesangium. At the earliest stages of recur-
rence, mesangial IgA and complement C3 are detectable by 3
months after transplantation, with electron-dense deposits in the
paramesangium but normal appearance on light microscopy. In
patients with progressive renal dysfunction, crescents often are
found in the glomerulus.
RECURRENT HENOCH-SCHONLEIN PURPURA
Features
Risk of recurrence, 30%75%
Clinical recurrence, up to 45%
Timeto recurrence, immediatelyto 20mo
Clinical presentation: often asymptomatic; hematuria, proteinuria, arthralgia,
purpuric rash, melena
Susceptibility: rapid development of renal failurein nativekidneys, age>14y
Graft loss: up to 20%, increased in graftsfromlivingrelated donors
FIGURE 17-26
Most studies have shown that histologic recurrence of Henoch-
Schonlein purpura (HSP) is common but rarely causes graft loss.
Grafts from living related donors have a substantially increased
risk of failure as a result of recurrent HSP. Patients can develop
both renal and extrarenal manifestations of HSP, especially arthral-
gia. Rapid evolution of the original disease and older age at presen-
tation (>14 y) seem to be risk factors for clinical recurrence.
Cyclosporine does not prevent recurrence. It has been arbitrarily
suggested that transplantation should be avoided for 12 months
after resolution of the purpura; however, individual cases of recur-
rent disease have been reported despite delays of over 3 years
between resolution of purpura and grafting.
227
MESANGIOCAPILLARY GLOMERULONEPHRITIS
Type II
50%100%
10%20%
1mo to 7y(usually<1y)
Frequentlyasymptomatic
nonnephrotic proteinuria,
microscopic hematuria
Male, rapidlyprogressive
courseof initial disease,
nephrotic syndromeafter
transplantation
Type I
9%70%
30%40%
2wk to 7y(median, 1.5y)
Rarelyasymptomatic;
proteinuria, nephrotic
syndrome, microscopic
hematuria
Graftsfromlivingrelated donor
Feature
Histologic recurrence
Clinical recurrence
Timeto recurrence
Clinical presentation
Risk factors
FIGURE 17-27
Both mesangiocapillary glomerulonephritis (MCGN) type I (mesan-
gial and subendothelial deposits) and type II (dense deposit disease)
commonly recur after transplantation. Silent recurrence is found
more often in type II disease, whereas recurrence of type I MCGN
frequently causes nephrotic syndrome and graft failure [35]. An
increased risk of recurrence of type I MCGN occurs in grafts from
living related donors. Type II disease recurs more often in male
patients who progressed rapidly to end-stage renal failure before
transplantation. The onset of nephrotic syndrome in type II disease
usually heralds graft failure. No established treatment for recurrent
disease exists, although anecdotally aspirin plus dipyridamole and
cyclophosphamide have been used with some success in recurrent
type I MCGN. Plasma exchange has been reported to improve the
histologic changes and induce a clinical remission in one patient
with recurrence of type II MCGN [36].
Subendothelial
deposits
Basement
membrane
Mononuclear
cell nucleus
Capillary
lumen
Interpositioned
mesangial
cell
Podocytes
Endothelial
cell A
Continuous band of
electron-densematerial
in basement membrane
Capillary
lumen
Cell nucleus
Endothelial cell Basement membrane
Podocyte
foot
processes
B
FIGURE 17-28
Electron micrographs of mesangiocapillary glomerulonephritis (MCGN) type I (A) and
type II (B). The histologic features of recurrence are the same as for the primary disease.
In type II MCGN the ribbonlike band of electron-dense material within the glomerular
basement membrane has been observed as early as 3 weeks after transplantation. Initially,
the recurrence is focal but subsequently progresses to involve most of the capillary walls.
Failing grafts frequently have segmental glomerular necrosis and extracapillary crescents.
Making the diagnosis is not difficult when electron microscopy has been performed on
the transplantation biopsy. In MCGN type I, electron-dense deposits first appear in the
mesangium and subsequently in a subendothelial position. Mesangial cell interposition
frequently is visible on electron microscopy, and on light microscopy the capillary walls
appear thickened and show a double contour. The differential diagnosis is MCGN caused
by acute or chronic transplantation glomerulopathy. Global changes, immune deposits,
and increased mesangial cells, however, are rare in chronic transplantation glomerulopathy.
Endocapillary proliferation and macrophages within capillary loops are important features
of acute transplantation glomerulopathy, which usually are absent in recurrent MCGN [13].
228
FEATURES OF RECURRENT AND DE NOVOMEMBRANOUS NEPHROPATHY AFTER TRANSPLANTATION
Features
Incidence
Clinical presentation
Timeof onset
Histology
Risk factorsfor graft failure
Incidenceof graft failure
Denovomembranous
2%5%
Often asymptomatic; proteinuria, nephrotic syndromedevelopsslowly
4mo to 6y(mean 22mo)
Identical to nativemembranousnephropathy, often showsfeaturesof
chronic rejection
Nonespecific
Increased over controls; maybeashigh as50%but most patientsalso
havechronic rejection
Recurrent membranous
3%57%
Proteinuria, nephrotic syndromedevelopsrapidly
1wk to 2y(mean 10mo)
Identical to nativemembranousnephropathy, often showsfeaturesof
chronic rejection
Malegender, aggressiveclinical course
50%60%, but somestudieshaveshown no increased graft failurerate
compared with other nephritides
FIGURE 17-29
Recurrence of membranous nephropathy in transplantations is variable,
with studies reporting incidences from 3% to 57% [4,37]. The major
differential diagnosis is de novo membranous nephropathy in patients
with a different underlying renal pathology. De novo allograft mem-
branous glomerulonephritis reported in 2% to 5% of transplantations
is often asymptomatic and usually associated with chronic rejection
FIGURE 17-30
Histologic slide of a biopsy showing extensive spike formation
along the glomerular basement membrane. This woman had recurrent
membranous disease 8 months after transplantation. She developed
nephrotic range proteinuria and subsequent renal dysfunction.
Both recurrent and de novo membranous glomerulonephritis are
indistinguishable from idiopathic membranous nephropathy. The
initial lesions are generally stage I or II, although the deposits
subsequently become diffuse and intramembranous.
Histologic slide showing deposition of antiglomerular basement
membrane (GBM) antibody along the GBM, which is seen in over
half of patients with Goodpastures syndrome who receive an allograft
while circulating antibodies are still detectable [39]. In most of these
cases no histologic abnormalities are seen within the glomerulus, how-
ever, and patients remain asymptomatic with normal renal function.
Approximately 25% of patients with antibody deposition will develop
features of crescentic and rapidly progressive glomerulonephritis and
subsequently suffer graft loss. Delaying transplantation for at least 6
months after antibodies have become undetectable reduces the
recurrence rate to only 5% to 15%.
[38]. In contrast, recurrent disease frequently causes nephrotic syn-
drome, developing within the first 2 years after transplantation. Data
on the incidence of graft failure attributable to membranous disease
are confusing. Cyclosporine therapy has made no difference in the
incidence of the two entities, and hepatitis C virus infection may be
associated with membranous disease after transplantation.
229
0
0
100
50
15 12 9 6 3
No treatment
Immunosuppression
alone
With plasma
exchange
+
immunosuppression
A
n
t
i
b
o
d
y

t
i
t
e
r
,

%
Time, m o
FIGURE 17-32
Without treatment, circulating antiglomerular basement mem-
brane autoantibodies become undetectable within 6 to 18 months
of disease onset [40,41]. Treatment of the primary disease with
plasma exchange, cyclophosphamide, and steroids leads to rapid
loss of circulating antibodies. Patients who need transplantation
while circulating antibodies are still detectable should be treated
with plasma exchange before and after transplantation to minimize
circulating antibody levels and with cyclophosphamide therapy for
2 months. A similar approach should be used in patients with clini-
cal recurrence. Patients who have linear immunoglobulin deposi-
tion in the absence of focal necrosis, crescents, or renal dysfunction
do not require treatment.
DIFFERENTIAL DIAGNOSIS OF LINEAR DEPOSITION
OF IMMUNOGLOBULIN ALONG THE GLOMERULAR
BASEMENT MEMBRANE IN TRANSPLANTATION BIOPSY
Recurrent antiglomerular basement membranedisease
Antiglomerular basement membranediseasein patientswith Alportssyndrome
Chronic transplant glomerulopathy
Diabetesmellitus
Myeloma
Recurrent mesangiocapillaryglomerulonephritistypeI
(rarelyfibrillarynephritis, and normal cadaveric graftsafter initial perfusion)
FIGURE 17-33
Linear immunoglobulin G (IgG) is found in 1% to 4% of routine
renal allograft biopsies from patients with neither antiglomerular
basement membrane (GBM) disease nor Alports syndrome. Linear
antibody deposition in anti-GBM disease is diffuse and global and, in
practice, is rarely confused with the nonspecific antibody deposition
seen in other conditions. In chronic transplantation glomerulopathy
the antibody deposition is focal and segmental, and focal necrosis and
cellular crescents are extremely rare. The finding of linear antibody
deposits on a transplantation biopsy should lead to testing for
circulating anti-GBM antibodies. Early graft loss or dysfunction,
along with linear IgG staining, may be the first indication that a
patient with an unidentified cause for end-stage renal disease has
Alports syndrome.
MUTATIONS IN GLOMERULAR BASEMENT
MEMBRANE COLLAGEN GENES
Chromosome
13
2
X
X
Collagen
1and 2chainsof typeIV
3and 4chainsof typeIV
5chain of typeIV
6chain of typeIV
Diseases caused by mutations
Autosomal recessiveor dominant
Alportssyndrome
Classic X-linked Alportssyndrome
Diffuseleiomyomatosis
FIGURE 17-34
Mutations have been identified in about half of patients with Alports
syndrome and are found in the genes for the 3, 4, or 5 chains of
type IV collagen, which are the major constituents of the glomerular
basement membrane. After transplantation, approximately 15% of
patients develop linear deposition of immunoglobulin G (IgG)
along the glomerular basement membrane (GBM), and circulating
anti-GBM antibodies specific for the 3 or 5 chains of type IV
collagen [4244]. It is unclear why only some patients develop
antibodies. Clinical disease, however, is rare. Only 20% of patients
with antibody deposition develop urinary abnormalities from 1
month to 2 years after grafting. Those patients who do develop
proteinuria or hematuria usually lose their grafts. In some cases,
treatment with cyclophosphamide did not prevent graft loss.
230
FIGURE 17-35
The microangiopathic hemolysis of recurrent hemolytic uremic
syndrome (HUS) is identical to the original disease, with extensive
erythrocyte fragmentation and thrombocytopenia. The incidence
of HUS recurrence is difficult to assess. At one extreme, five of 11
children suffered graft loss because of recurrent disease. However,
most series have reported substantially lower recurrence rates: no
recurrences in 16 adults and children, one of 34 grafts in 28 children,
and two probable recurrences of 24 grafts in 20 children [4,45,46].
Graft loss occurs in 10% to 50% of patients with recurrence. HUS
has been diagnosed 1 day to 15 months after transplantation (usually
in less than 2 months), and the incidence of recurrence is increased in
patients receiving grafts less than 3 months after their initial disease.
Treatment of recurrent disease is plasma exchange for plasma or
cryosupernatant, or plasma infusions, and dose reduction of cyclo-
sporine. Recurrence may be prevented by aspirin and dipyridamole.
DIFFERENTIAL DIAGNOSIS OF RECURRENT
HEMOLYTIC UREMIC SYNDROME
Thrombotic microangiopathyassociated with cyclosporine
Acutevascular rejection
Accelerated phasehypertension
Tacrolimus- (FK-506) associated thrombotic microangiopathy
OTHER CONDITIONS THAT RECUR IN RENAL ALLOGRAFTS
Disease
Systemic sclerosis
Fabrysdisease
Immunotactoid glomerulopathy
Mixed essential cryoglobulinemia
Cystinosis
Recurrence rate
20%
Rarerecurrenceof
ceramidein thegraft
50%
50%
0%
Outcome
Usuallygraft failure
Poor
Nephrotic syndrome
Poor
Good
Comments
Differentiation fromacuteand chronic vascular rejection can bedifficult
Renal transplantation doesnot halt theprogressof Fabrysdiseasebecausethenew kidneyis
not an adequatesourceof -galactosidase; patientshavefrequent systemic complications
Nephrosisreported between 21and 60mo
Recurrenceassociated with extrarenal featuresincludingarthralgiasand purpura
Cystinosisdoesnot recur; however, theallograft can becomeinfiltrated bymacrophages
containingcysteine, with no pathologic or clinical effect
FIGURE 17-36
Blood film abnormalities, microangiopathic hemolytic anemia,
thrombocytopenia, and acute renal failure occur in accelerated
hypertension and acute vascular rejection. A renal biopsy usually
distinguishes acute vascular rejection, and malignant hypertension
should be obvious clinically. The microangiopathy of cyclosporine
can be difficult to differentiate from hemolytic uremic syndrome;
however, glomerular pathology usually is less marked and vascular
changes more obvious with cyclosporine toxicity. De novo
hemolytic uremic syndrome also has been reported in patients
treated with tacrolimus (FK-506) [27].
FIGURE 17-37
A number of other conditions have been reported to recur in allo-
grafts. Very few patients with systemic sclerosis have received
transplantation, and the incidence of acute renal failure caused by
systemic sclerosis has declined with the widespread use of angiotensin-
converting enzyme (ACE) inhibitors. About 20% of patients with a
malignant course of scleroderma receiving a transplantation develop
recurrence, which usually causes graft loss. The value of ACE
inhibitors after transplantation is unknown. Two of four patients
with immunotactoid glomerulopathy developed recurrent disease
heralded by massive proteinuria. Transplantation in Fabrys disease
rarely leads to graft-related problems; however, patients die from
systemic complications of ceramide deposition.
231
MANAGEMENT OF RECURRENT DISEASE AFTER KIDNEY TRANSPLANTATION
Treatment of recurrence
Plasmaexchange, immunoadsorption, steroids,
angiotensin-convertingenzymeinhibitors,
nonsteroidal anti-inflammatorydrugs
With crescents: plasmaexchange, cytotoxics
?Steroids
Aspirin, dipyridamole
?Plasmaexchange
?Cytotoxicsand steroids
Plasmaexchange, cyclophosphamide
Plasmaexchange, plasmainfusion
Cyclophosphamideand steroids
Glycemic control
Aggressiveperioperativedialysis, hydration, low oxalate
diet, low ascorbic acid diet, phosphatesupplements,
magnesiumglycerophosphate, pyridoxine
Disease
MesangiocapillaryglomerulonephritistypeII
Antineutrophil cytoplasmantibodyassociated vasculitis
Diabetes
Oxalosis
FIGURE 17-38
No controlled data exist on the management
of recurrent disease after transplantation.
For patients with primary hyperoxaluria,
measures to prevent further deposition of
oxalate have proved successful in controlling
recurrent renal oxalosis [9]. In diabetes
mellitus, the pathophysiology of recurrent
nephropathy undoubtedly reflects the same
insults as those causing the initial renal failure,
and good evidence exists that glycemic control
can slow the development of end-organ
damage. Plasma exchange and immuno-
adsorption are promising therapies for
patients with nephrosis who have recurrent
focal segmental glomerulosclerosis; however,
these therapies do not provide sustained
remission [6,7]. In all these cases, establishing
a diagnosis of recurrent disease is critical in
identifying a possible treatment modality.
WHEN TO AVOID USING LIVING RELATED DONORS
IN KIDNEY TRANSPLANTATION
Focal segmental glomerulosclerosiswith risk factorsfor earlyrecurrence
MesangiocapillaryglomerulonephritistypeII with risk factors
(familial immunoglobulin A nephropathyand hemolytic uremic syndrome)
FIGURE 17-39
In these diseases, rapid recurrence leading to graft failure is frequent
enough to warrant extreme caution in using living related donors.
Even excluding these conditions, the overall rate of recurrence of
glomerulonephritis is substantially increased in living related donors,
and patients should be made aware of this risk [4]. For familial
diseases, the risk of recurrence is even higher (eg, some families
with immunoglobulin A disease and hemolytic uremic syndrome).
Finally, recurrent glomerulonephritis has been reported in up to
30% of renal isografts, with disease onset between 2 weeks and
16 years after grafting.
References
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233

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1

If theperitoneal capillary blood flow is infinite,

2000 3000 4000

Theincidenceand severity of theseinfectionsand, to alesser extent, theother

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