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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
1.4 Dialysis as Treatment of End-Stage Renal Disease
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
1.6 Dialysis as Treatment of End-Stage Renal Disease
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
2.2 Dialysis as Treatment of End-Stage Renal Disease
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
2.4 Dialysis as Treatment of End-Stage Renal Disease
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
2.5 Dialysate Composition in Hemodialysis and Peritoneal Dialysis
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
2.6 Dialysis as Treatment of End-Stage Renal Disease
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
2.7 Dialysate Composition in Hemodialysis and Peritoneal Dialysis
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
2.8 Dialysis as Treatment of End-Stage Renal Disease
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
3.2 Dialysis as Treatment of End-Stage Renal Disease
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
masstransfer coefficient; Asurfacearea.
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
3.4 Dialysis as Treatment of End-Stage Renal Disease
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
masstransfer coefficient; Asurfacearea.
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
3.5 High-Efficiency and High-Flux Hemodialysis
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
3.6 Dialysis as Treatment of End-Stage Renal Disease
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
masstransfer coefficient; Asurfacearea.
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
3.7 High-Efficiency and High-Flux Hemodialysis
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
3.8 Dialysis as Treatment of End-Stage Renal Disease
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
3.9 High-Efficiency and High-Flux Hemodialysis
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
3.10 Dialysis as Treatment of End-Stage Renal Disease
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
4.2 Dialysis as Treatment of End-Stage Renal Disease
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
4.4 Dialysis as Treatment of End-Stage Renal Disease
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
4.5 Principles of Peritoneal Dialysis
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
4.6 Dialysis as Treatment of End-Stage Renal Disease
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
4.7 Principles of Peritoneal Dialysis
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).
(Continued on next page)
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
4.8 Dialysis as Treatment of End-Stage Renal Disease
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
FIGURE 4-11 (Co n t i n u e d )
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
4.9 Principles of Peritoneal Dialysis
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
4.10 Dialysis as Treatment of End-Stage Renal Disease
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
( (
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
6.6 Dialysis as Treatment of End-Stage Renal Disease
Blood flow rate, m L/ m in
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
6.7 The Dialysis Prescription and Urea Modeling
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
6.8 Dialysis as Treatment of End-Stage Renal Disease
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
7.2 Dialysis as Treatment of End-Stage Renal Disease
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
FIGURE 7-5 (s e e Color Plate)
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
7.4 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 7-9 (s e e Color Plate)
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.)
FIGURE 7-8 (s e e Color Plate)
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
7.5 Complications of Dialysis: Selected Topics
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
FIGURE 7-12 (s e e Color Plate)
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
7.6 Dialysis as Treatment of End-Stage Renal Disease
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
7.7 Complications of Dialysis: Selected Topics
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
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
8.5 Histocompatibility Testing and Organ Sharing
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
8.6 Transplantation as Treatment of End-Stage Renal Disease
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
8.7 Histocompatibility Testing and Organ Sharing
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
8.8 Transplantation as Treatment of End-Stage Renal Disease
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
8.9 Histocompatibility Testing and Organ Sharing
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
8.10 Transplantation as Treatment of End-Stage Renal Disease
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
Years after transplantation
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
8.11 Histocompatibility Testing and Organ Sharing
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
Years after transplantation
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
8.12 Transplantation as Treatment of End-Stage Renal Disease
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
9.2 Transplantation as Treatment of End-Stage Renal Disease
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
9.4 Transplantation as Treatment of End-Stage Renal Disease
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
9.5 Transplant Rejection and its Treatment
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
(Continued on next page)
82
9.6 Transplantation as Treatment of End-Stage Renal Disease
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
FIGURE 9-6 (Co n t i n u e d )
E, Diagnostic and therapeutic approach to chronic rejection.
ATGantithymocyte globulin; ATNacute tubular necrosis; BP
blood pressure; CsAcyclosporine; LDLlow-density lipoprotein.
83
9.7 Transplant Rejection and its Treatment
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
9.8 Transplantation as Treatment of End-Stage Renal Disease
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
(Continued on next page)
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
9.9 Transplant Rejection and its Treatment
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.
FIGURE 9-11 (Co n t i n u e d )
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
9.10 Transplantation as Treatment of End-Stage Renal Disease
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
9.11 Transplant Rejection and its Treatment
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
Physical examination
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].
(Continued on next page)
88
9.12 Transplantation as Treatment of End-Stage Renal Disease
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
FIGURE 9-16 (Co n t i n u e d )
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
9.13 Transplant Rejection and its Treatment
References
1. Terasaki PI, Cecka JM, Gjertson DW, et al.: Risk rate and long-term
kidney transplant survival. Clin Transpl 1996, 443.
2. Chan L, Kam I: Outcome and complications of renal transplantation.
In Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk
CW: 1997.
3. J Clin I mmunol 1995, 15:184.
4. Nephrol Dial Transpl 1997, 12 [editorial comments].
5. Shaikewitz ST, Chan L: Chronic renal transplant rejection. Am J
Kidney Dis 1994, 23:884.
6. Solez K, Axelsen RA, Benediktsson H, et al.: International standardization
of criteria for the histologic diagnosis of renal allograft rejection: the
Banff working classification on renal transplant pathology. Kidney I nt
1993, 44:411.
7. Helderman JH, Hernandez J, Sagalowsky A, et al.: Confirmation of
the utility of fine needle aspiration biopsy of the renal allograft.
Kidney I nt 1988, 34:376.
8. Von Willebrand E, Hughes D: Fine-needle aspiration cytology of the
transplanted kidney. In Kidney Transplantation, edn 4. Edited by
Morris PJ. 1994:301.
9. Suthanthiran M: Clinical application of molecular biology: a study of
allograft rejection with polymerase chain reaction. Am J Med Sci
1997, 313:264.
10. Halloren PF, Lui SL, Miller L: Review of transplantation 1996. Clin
Transpl 1996.
11. Sollinger HW for the US Renal Transplant Mycophenolate Mofetil
Study Group: Mycophenolate mofetil for prevention of acute rejection
in primary cadaveric renal allograft recipients. Transplantation 1995,
60:225.
12. Jordan ML, Shapiro R, Vivas SA, et al.: FK506 rescue for resistant
rejection of renal allografts under primary cyclosporine 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
10.2 Transplantation as Treatment of End-Stage Renal Disease
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.
, 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.
FIGURE 10-9 ( Co n t i n u e d )
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
10.7 Post-transplant Infections
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
Trimethoprimsulfamethoxazole
Trimethoprimsulfamethoxazole
Trimethoprimsulfamethoxazole
Trimethoprimsulfamethoxazole
Trimethoprimsulfamethoxazole
FIGURE 10-13
Prophyl acti c anti bacteri al /
anti protozoal strategi es.
97
10.8 Transplantation as Treatment of End-Stage Renal Disease
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
10.9 Post-transplant Infections
PASSIVE IMMUNIZATION AGENTSIMMUNE GLOBULINS
Immune globulin
HepatitisB(H-BIG*)
Percutaneousinoculation
Perinatal
Sexual exposure
Immuneglobulin (IG)
HepatitisA prophylaxis
HepatitisB
HepatitisC
Measles
Rabies
(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
20.130kg 375units=3vials
30.140kg 500units=4vials
>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.
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
10.10 Transplantation as Treatment of End-Stage Renal Disease
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
10.11 Post-transplant Infections
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
10.12 Transplantation as Treatment of End-Stage Renal Disease
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
10.13 Post-transplant Infections
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.
FIGURE 10-24 (s e e Color Plate)
Histologic lesion in cytomegalovirus infection.
103
10.14 Transplantation as Treatment of End-Stage Renal Disease
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
10.15 Post-transplant Infections
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
10.16 Transplantation as Treatment of End-Stage Renal Disease
SOME ANTITUBERCULOSIS DRUGS
Drug
Primaryantituberculoustherapy
Isoniazid*
(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.
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.
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
Removal of catheter
Lessill, sensitiveorganism, nephrotoxicityowingto amphotericin Band proven microbiologic and clinical response
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
10.22 Transplantation as Treatment of End-Stage Renal Disease
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
10.23 Post-transplant Infections
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
10.24 Transplantation as Treatment of End-Stage Renal Disease
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
10.25 Post-transplant Infections
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
10.26 Transplantation as Treatment of End-Stage Renal Disease
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
10.27 Post-transplant Infections
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
10.28 Transplantation as Treatment of End-Stage Renal Disease
FIGURE 10-53 (s e e Color Plate)
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
FIGURE 10-54 (s e e Color Plate)
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
10.29 Post-transplant Infections
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
L. m on ocy t ogen es
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
L. m on ocy t ogen es
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
Physical examination
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
10.30 Transplantation as Treatment of End-Stage Renal Disease
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
Physical examination
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
10.31 Post-transplant Infections
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
FIGURE 10-61 (s e e Color Plate)
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
Epidemiology
Common in tropical regionsand placeswith poor sanitation
Transmission isthrough fecal-oral route, person-to-person contact, and
water or food
Maycausetravelersdiarrhea
Clinical manifestations
Asymptomatic infection
Self-limited diarrhea, nausea, and abdominal discomfort in healthychildren and adults
Prolonged (subacute) diarrheain someimmunocompetent patients
*Septataintestinalismayinvadethemucosa.
than
with Sandimmune
(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
15.8 Transplantation as Treatment of End-Stage Renal Disease
A
B
C
FIGURE 15-13 (s e e Color Plate)
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
15.9 Kidney-Pancreas Transplantation
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
15.10 Transplantation as Treatment of End-Stage Renal Disease
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
15.11 Kidney-Pancreas Transplantation
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).
(Continued on next page)
188
15.12 Transplantation as Treatment of End-Stage Renal Disease
B
D E
C
FIGURE 15-17 (Co n t i n u e d )
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
15.13 Kidney-Pancreas Transplantation
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
Months posttransplantation
SPK pancreas graft function by era
UScadaveric pancreas transplantations 10/1/19877/31/1997
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
Months posttransplantation
SPK patient survival by era
UScadaveric pancreas transplantations 10/1/19877/31/1997
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
15.14 Transplantation as Treatment of End-Stage Renal Disease
B
%
100
90
80
70
60
50
40
60 54 48 42 36 30 24 18 12 6 0
Months posttransplantation
PAK graft function by era
UScadaveric pancreas transplantations 10/1/877/31/97
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
Months posttransplantation
PAK patient survival by era
UScadaveric pancreas transplantations 10/1/877/31/97
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
Months posttransplantation
PTA patient survival by era
UScadaveric pancreas transplantations 10/1/877/31/97
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
Months posttransplantation
PTA graft function by era
UScadaveric pancreas transplantations 10/1/877/31/97
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
15.15 Kidney-Pancreas Transplantation
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
15.16 Transplantation as Treatment of End-Stage Renal Disease
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
Baseline 5 y Baseline 5 y
Pancreastransplant
recipients A B C
Comparison group
Baseline 5 y Baseline 5 y
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
15.17 Kidney-Pancreas Transplantation
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
,
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
Harmon [4]; with permission.)
*Da t a f rom North American Pediatric Renal Transplant CooperativeStudy.
u
p
p
e
r
9
5
%
C
I
)
1
Timeposttransplantation, m o
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.
(Continued on next page)
202
16.9 Transplantation in Children
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
Timeposttransplantation, m o
6 12 18
B
24 30 36 42 48
01
Recipient age, y Livingrelated donor
25
612
>12
FIGURE 16-19 ( Co n t i n u e d )
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
16.10 Transplantation as Treatment of End-Stage Renal Disease
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
coworkers [20]; with permission.)
204
16.11 Transplantation in Children
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
16.12 Transplantation as Treatment of End-Stage Renal Disease
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
Data from the North American Pediatric
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
16.13 Transplantation in Children
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
coworkers [29]; with permission.)
*P <0.0001compared with control groups.
207
Complications after Transplantation
16.14 Transplantation as Treatment of End-Stage Renal Disease
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
[31]; with permission.)
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
16.15 Transplantation in Children
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
Data from the North American Pediatric
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
[5]; with permission.)
*Four patientshavehad threegraft failures.
209
16.16 Transplantation as Treatment of End-Stage Renal Disease
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
[35]; with permission.)
*P <0.01, test for trend.