Posttransplantation

Monitoring and Outcomes

62

Jagbir S. Gill

The management of kidney transplant recipients is complex

and spans a wide range of clinical scenarios. Posttransplant
care begins in the immediate postsurgical period and continues through the various phases that make up the natural
history of kidney transplantation. Whereas the early phases of
care focus primarily on postsurgical management, monitoring
of allograft function, and optimization of immunosuppression,
later phases of care extend this focus to include ongoing assessment and management of factors that contribute to chronic
allograft dysfunction, allograft loss, and death with a functioning graft. The nuances of posttransplant care have changed
significantly over time as our understanding of the natural history of transplantation has evolved, the case-mix of transplant
recipients has become more complex, and new technologies
to monitor transplant recipients have emerged. In this chapter, we will review the major aspects of posttransplant care
through this continuum in the current era of transplantation.

RECIPIENT AND DONOR CHARACTERISTICS

With changes in the demographics of the population with
end-stage renal disease (ESRD) and improvements in technologies and immunosuppression, the benefits of kidney
transplantation are now offered to patients who previously
would not have been eligible. With these successes come
increased challenges and complexities in posttransplant
care, along with a greater need to individualize care for various subgroups of kidney transplant recipients. For instance,
older adult patients are the fastest-growing segment of kidney transplant recipients, with patients 65 years of age and
older accounting for more than 16% of all recipients in the
United States in 2009. The complexities of pre- and posttransplant care are unique in older adult recipients because
they are more likely to have a greater burden of comorbid disease and a higher risk for death with a functioning
allograft. However, the risk for acute allograft rejection is
lower in older transplant recipients as a result of immunosenescence, which may allow for decreased use of immunosuppression. Therefore posttransplant care must be tailored
to risks and outcomes within individual populations. Also,
with the increased success of desensitization strategies, both
HLA- and ABO-incompatible transplantation are realities
in our current era, but these cases require more intense
follow-up given their higher risk for rejection and allograft
loss. Other high-risk recipient groups include human immunodeficiency virus (HIV)-positive recipients, repeat transplant
recipients, and multiorgan transplant recipients, each of
which bring unique challenges to posttransplant care.

Similarly, the characteristics of deceased donors have

changed over time, further complicating early posttransplant
care. In the face of increasing demand for transplantation,
organs from higher-risk deceased donors are routinely
transplanted in selected recipients. Expanded criteria
donors (ECDs) include donors 60 years of age or older and
those aged 50 to 59 years with two or more high-risk characteristics, including long-standing hypertension, a terminal
serum creatinine above 1.5mg/dL, or death due to a cerebral vascular accident. Recipients who receive ECD kidneys
have an increased risk for delayed graft function (DGF) and
a 70% increased risk for allograft loss from any cause, compared with recipients who receive kidneys from deceased
donors aged 18 to 39 years with no comorbidities. Organs
from ECDs are allocated only to recipient populations that
continue to derive a significant survival benefit from transplantation, such as older adult and diabetic transplant candidates. In addition, kidneys are increasingly transplanted
from donors after cardiac death (DCDs), as opposed to
donors after brain death. In fact, DCDs now contribute
nearly 12% of all organs in the United States. Not surprisingly, kidneys from DCDs are subject to a greater degree
of ischemic injury at the time of donation, often resulting
in DGF. However, long-term allograft and patient survival
remain similar in recipients of kidneys from DCDs or from
donors after brain death.

THE FIRST WEEK

Most kidney transplant recipients have a hospital duration
ranging from 4 to 7 days following surgery. In the acute postoperative phase, care of the transplant recipient involves
assessment for immediate graft function, management of
potential surgical complications, and treatment of postoperative fluid and electrolyte shifts.
The details of kidney transplantation surgery vary
depending on whether the donor kidney is from a living
donor or a deceased donor, as well as the specific anatomy
of a given recipient. In general, the surgery involves engraftment in the iliac fossa with vascular anastomoses between
the donor renal artery to the recipient external iliac artery
and the donor vein to the external iliac vein. Perioperative
complications that may require surgical exploration and
management include bleeding and thrombosis of the renal
artery or vein.
Assessment of graft function involves quantifying urine
output (keeping the baseline urine output of the recipient
in mind) and following serum chemistries every 12 to 24

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hours. Immediate graft function is denoted by a rapid drop

in serum creatinine levels and urine output in excess of 100
mL/hour, and is expected in all living donor kidney transplant recipients and in most recipients of deceased donor
kidneys. Immediate graft function is less likely in recipients
of kidneys from ECDs and DCDs, and in cases with prolonged
cold ischemic times (>24 hours).
DGF is typically denoted as the requirement for dialysis
within the first week posttransplant and occurs in less than
5% of living donor transplant recipients, 22% of standard
criteria deceased donor recipients, 32% of ECD recipients,
and over 37% of DCD recipients. In addition to donor factors, the duration of cold ischemic time and warm ischemic
time are important predictors of DGF. Dialysis is initiated
based on volume status and metabolic parameters. Either
hemodialysis or peritoneal dialysis may be performed
depending on the patients baseline dialysis modality. In the
case of peritoneal dialysis, it is important to confirm that
the peritoneum was not breached during the surgery before
resumption of dialysis.
Although the cause of DGF is usually acute ischemic tubular
injury, alternate causes (including vascular thrombosis and
early acute rejection) need to be considered. Therefore a
Doppler kidney ultrasound to assess for blood flow in the
allograft is recommended within hours of a clinical change
in allograft function. Elevated resistive indices may suggest
either tubular injury or rejection; thus, the baseline risk for
rejection and duration of DGF should be considered in
assessing the cause of early graft dysfunction. If rejection is
suspected or DGF persists beyond 1 week, an allograft biopsy
should be performed.
Reduced exposure to calcineurin inhibitors (CNIs) in
the setting of DGF is recommended to avoid further tubular injury associated with CNI nephrotoxicity, but this must
be balanced with the risk for rejection. The use of induction
immunosuppressive agents is recommended if CNIs are to be
reduced or avoided in the setting of DGF. There are few data
to support a uniform approach to immunosuppression in the
setting of DGF, but some centers prefer to use T lymphocyte
depleting antibodies (thymoglobulin) for induction, along
with immediate initiation of an antimetabolite (mycophenolate) and corticosteroids, with delayed introduction of CNI
only once there is evidence of graft function. The majority of
DGF cases recover within 1 to 3 months, but numerous studies have demonstrated inferior allograft survival in patients
who have developed DGF.
Fluid and electrolyte management is a key component
of early postoperative care. Hemodynamic extremes of
hypotension and volume overload should be avoided in
older adult patients and in those with compromised cardiac
function. Electrolyte shifts, including hypercalcemia and
hypophosphatemia associated with secondary hyperparathyroidism and hypomagnesemia associated with diuretic
use, may be seen early posttransplantation and should be
managed accordingly.

OUTPATIENT CARE
Following discharge from the hospital, transplant recipients
are closely followed by the transplant center. The frequency
of monitoring is greatest during the first 3 months, as the

risk for rejection is highest during this period. Patients are

followed twice weekly during the first month posttransplant
and then weekly for the remainder of the first 3 months,
with the frequency of visits gradually reduced to every 4 to 8
weeks by the end of the first year.
Routine posttransplant monitoring includes a follow-up
history and physical examination along with measurement
of serum chemistries, a complete blood count, liver enzymes,
whole blood CNI levels, and urinalysis. Spot albumin-tocreatinine ratios are also periodically monitored. Preemptive
viral screening and monitoring are indicated for the first 3 to
6 months at variable frequencies depending on the patients
risk for infection.

IMMUNOSUPPRESSION
Immunosuppression after transplant consists of induction
therapy, followed by lifelong maintenance immunotherapy.
Chapter 63 provides greater details on specific induction
and maintenance agents, including their side effect profiles. Induction therapy is administered at the time of transplantation and includes intravenous methylprednisolone,
along with either an anti-CD25 antibody (basiliximab) or a
T lymphocytedepleting antibody (the polyclonal antibody
thymoglobulin). Alemtuzumab is a monoclonal antibody
used in the management of chronic lymphocytic leukemia that results in potent lymphocyte depletion, and has
been increasingly used as an induction agent in kidney
transplantation.
Maintenance immunosuppression typically consists of
triple immunosuppressive therapy with a CNI, an antimetabolite, and low-dose corticosteroids. Until the early
2000s, azathioprine was the preferred posttransplantation
antimetabolite; however, mycophenolic acid (MPA) agents
more selectively target lymphocytes, resulting in superior
efficacy in preventing acute rejection and increased patient
tolerability. Rapamycin has been studied as an alternative
to CNIs or for use in combination with CNIs. Although
concerns regarding wound healing and nephrotoxicity
have minimized the use of rapamycin as a primary de novo
immunosuppressant agent after transplantation, data suggesting a reduced risk for malignancies with the use of
rapamycin have renewed interest in this agent, particularly
for patients with recurrent skin cancers posttransplant.
Belatacept is a recently approved intravenously administered costimulatory blocker that binds CD80 and CD86
on the surface of antigen presenting cells to inhibit T cell
activation and promote anergy and apoptosis. The optimal
indication for this agent remains unclear and will likely be
refined in the coming years.

IMMUNOSUPPRESSIVE PROTOCOLS
The majority of transplant recipients are maintained on triple immunosuppressive therapy including CNI, MPA, and
corticosteroids. Low rates of acute rejection and growing
concern with the adverse effects of these agents, including chronic CNI nephrotoxicity, have led to strategies to
minimize immunosuppressive exposure. Minimization
of CNI and corticosteroid exposure has been most frequently studied, but ongoing debate continues, countering

CHAPTER 62 POSTTRANSPLANTATION MONITORING AND OUTCOMES

the merits of immunosuppression minimization with the

increasingly recognized importance of chronic immunemediated injury.
Posttransplant corticosteroid exposure has been reduced
significantly, with prednisone doses rapidly tapered to 5
to 10 mg daily within the first 4 to 6 weeks after surgery.
Late withdrawal of corticosteroids has been largely abandoned in the face of numerous studies demonstrating an
increased risk for rejection when corticosteroids are withdrawn beyond 3 to 6 months posttransplant. Early corticosteroid withdrawal or avoidance strategies, however, have
demonstrated largely favorable outcomes. A metaanalysis
of 34 studies, including 5637 patients receiving steroid
withdrawal or avoidance regimens, found that steroid
avoidance reduced the risk for hyperlipidemia, hypertension, and new-onset diabetes after transplantation. Woodle and colleagues conducted a multicenter randomized
controlled trial of early corticosteroid withdrawal (within
7 days) compared with low-dose maintenance corticosteroids in a CNI- and MPA-based regimen. The early steroid
withdrawal group had an increased rate of biopsy-proven
acute rejection and chronic allograft nephropathy, but no
difference was found in the composite primary endpoint of
death, graft loss, or severe acute rejection through 5 years.
When examined separately, graft and patient survival were
also not different. Although steroid exposure should be
minimized whenever possible, corticosteroid avoidance or
early withdrawal should be reserved for patients at low risk
for rejection and only with careful and frequent posttransplant monitoring.

LONG-TERM DRUG DOSING AND MONITORING

Because of inter- and intrapatient variability in the bioavailability and absorption of CNI, routine whole blood drug
level monitoring is essential. Trough levels of CNI correlate
well with drug exposure and clinical events, particularly for
tacrolimus. However, evidence exists that peak drug levels
(2 hours after dose) of cyclosporine correlate better with
drug exposure and clinical events, including acute rejection. As a result, certain centers have adopted peak level,
or C2 monitoring, for cyclosporine. Although specific
therapeutic targets may vary depending on concomitant
immunosuppression, levels are typically kept highest in
the first month after transplant, with a gradual reduction
over the next 6 months. In interpreting drug levels, it is
important to remember that different labs may use different assays, resulting in different results.
Routine therapeutic drug level monitoring is not recommended for MPA, because trough levels do not correlate
well with clinical efficacy and the repeat measurements
required to appropriately calculate the area under the curve
are labor intensive and not feasible for routine measurement. Target doses (2 g daily for mycophenolate mofetil
and 1440 mg daily for mycophenolate sodium) are based
on clinical trials demonstrating efficacy at these doses. Transient dose reduction or temporary discontinuation of MPA
is recommended in cases of significant diarrheal symptoms
or profound leukopenia. However, full doses should be
resumed after resolution of symptoms, if tolerated, because
prolonged dose reductions or discontinuations are associated with inferior allograft survival.

555

ADVERSE EFFECTS AND DRUG INTERACTIONS

Adverse effects of immunosuppressant medications should
be assessed during each follow-up visit. Significant effects of
corticosteroids include cataracts, bone loss and fractures,
avascular necrosis, hypertension, weight gain, dyslipidemia,
glucose intolerance, mood lability, and acne. MPAs may
confer bone marrow toxicity (leukopenia, anemia), gastric
reflux, diarrhea, and pancreatitis. CNIs may cause acute
and chronic nephrotoxicity, although the impact of CNIs
on chronic graft function is being increasingly questioned.
Other significant effects of CNIs include hypomagnesemia,
hyperkalemia, hyperuricemia, neurotoxicity (e.g., tremor),
and rarely, thrombotic microangiopathy. Tacrolimus is more
strongly associated with new-onset diabetes after transplantation than cyclosporine, whereas cyclosporine is more
commonly associated with cosmetic changes, including gingival hyperplasia and hirsutism.
The narrow therapeutic and toxic window for CNIs in
addition to the high potential for altered metabolism from
interference of the cytochrome 450 (CYP450) mechanism
mandate careful examination and recognition of potential
drug interactions. Common CYP450 drug inhibitors (which
will increase CNI levels) and inducers (which will lower
CNI levels) are outlined in Table 62.1. New drugs should
be introduced with care, and drug levels should be carefully
monitored, when indicated. MPA is not metabolized via the

Table 62.1Selected Common Drug Interactions

With Calcineurin Inhibitors
Increases CNI Level
(Inhibits Enzyme)*

Decreases CNI Level

(Stimulates Enzyme)*

Calcium channel blockers

Diltiazem
Verapamil

Antibiotics
Rifabutin
Rifampin

Antiarrhythmics
Amiodarone

Antiepileptics
Phenobarbital
Phenytoin
Carbamazepine

HIV protease inhibitors

Ritonavir
Saquinavir
Indinavir

Herbal substances
St. Johns wort

Azole antifungal agents

Ketoconazole
Clotrimazole
Itraconazole
Voriconazole
Antibiotics
Erythromycin base
Synercid (quinupristin and
dalfopristin)
Antidepressants
Fluvoxamine
Other agents
Grapefruit juice

HIV, Human immunodeficiency virus.

*Listed drugs interact with the calcineurin inhibitors (CNI) cyclosporine
and tacrolimus because they are metabolized by the cytochrome
P450 CYP3A4 isoenzyme.

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CYP450 enzyme pathway, and there are fewer drug interactions compared with CNI; however, any drugs that may
potentiate leukopenia should not be used in conjunction
with these agents.

ALLOGRAFT DYSFUNCTION
The immune response to an allograft involves (1) recognition of foreign antigens, (2) activation of recipient lymphocytes, and (3) effector mechanisms leading to rejection of
the allograft. The human major histocompatibility complex
(MHC) is a cluster of genes on chromosome 6 that encodes
human leukocyte antigens (HLA) in addition to other
agents critical in controlling the immune response; MHC
is the key factor in the initiation of the immune response
to an allograft. The HLA antigens are the major barriers
to transplantation, and allogeneic donor HLA antigens are
the main targets of the immune system in rejection of the
graft. However, the role of non-HLA antigens in inciting an
immune response and subsequent rejection is increasingly
being realized.

ACUTE ALLOGRAFT DYSFUNCTION

A 15% to 20% increase in serum creatinine from baseline
suggests graft dysfunction and warrants a thorough evaluation, including an assessment of risk factors for acute kidney
injury, an ultrasound of the allograft, and often an allograft
biopsy. Nonimmune causes of allograft dysfunction should
be ruled out, including CNI nephrotoxicity, acute interstitial
nephritis, pyelonephritis, ischemic injury, recurrent native
kidney disease, and BK nephropathy. Supratherapeutic CNI
levels and the presence of isometric tubular vacuolization or
arteriolar hyalinosis on biopsy (Fig. 62.1) strongly suggest
acute CNI nephrotoxicity, although an allograft biopsy is not
usually required for diagnosis since a reduction in CNI dose
will quickly improve kidney function. Recurrent native kidney
disease rates vary depending on the original cause of ESRD
and require allograft biopsy for diagnosis. BK polyomavirus
nephropathy may cause graft injury with a high risk for subsequent graft loss, but a histologic diagnosis is often difficult.
The Banff classification has standardized criteria for
allograft pathology, including those for acute rejection
(Box 62.1). The glomeruli, tubules, interstitium, and vessels should be examined for the presence of inflammation
and lymphocyte infiltration. Interstitial inflammation with
lymphocytes is scored from 0 (absent) to 3 (severe). Tubulitis is the definitive aspect of acute cellular rejection and is
quantified from mild (t1) to severe (t3). Vessel wall infiltration, or arteritis, represents a greater severity of rejection
(grade II) and ranges from mild/moderate (v1) to severe
(v2). Although lymphocyte infiltration in the glomeruli
may accompany acute rejection, it is not a criterion of
rejection.
Treatment of acute cellular rejection includes intravenous
pulse corticosteroids, intensification of maintenance immunosuppression, and polyclonal antilymphocyte antibodies
(thymoglobulin) in more severe cases. Although recovery
from acute rejection has improved dramatically over time,
an episode of acute rejection (even if successfully treated)
significantly increases the risk for early graft loss.

Figure 62.1 Pathology of acute CNI nephrotoxicity showing

isometric tubular vacuolization (arrows).

Antibody-mediated rejection (AMR) involves the production of antidonor antibodies by plasma cells, either from
memory or naive B cells or from those that existed before
transplantation. These donor-specific antibodies (DSAs)
interact with allograft vascular endothelium, resulting in
complement activation, cell death, loss of vascular integrity,
and subsequent ischemic injury. In addition to the presence
of circulating DSA, the diagnosis of AMR requires the presence of immunopathologic staining for the complement
component C4d in peritubular capillaries and histologic
evidence of acute or chronic tissue injury. These histologic
findings may include acute tubular injury, vasculitis, and
peritubular capillary inflammation.
The importance of DSA appears to extend beyond the
acute rejection episode; chronic exposure to low levels of
DSA (even in the absence of a clinical episode of AMR)
may lead to chronic AMR. As a result, the treatment of
AMR primarily targets DSA and the subsequent complement activation that it ultimately induces. Plasmapheresis
and high-dose intravenous immune globulin (IVIG) aim to
lower DSA levels through removal or inactivation, respectively. Anti-CD20 agents (rituximab) aim to reduce antibody
levels by depleting B lymphocytes and preventing the maturation of new DSA-producing plasma cells. The proteasome
inhibitor bortezomib causes apoptosis of normal plasma
cells and has had favorable results in the treatment of AMR
in small single-center uncontrolled studies. Although its
benefit is largely unproven, bortezomib may be considered
in refractory cases of AMR.

CHRONIC ALLOGRAFT DYSFUNCTION

A gradual decline in kidney function manifested by a
slowly rising creatinine, increasing levels of proteinuria,

CHAPTER 62 POSTTRANSPLANTATION MONITORING AND OUTCOMES

557

Box 62.1Banff 2007 Criteria for Allograft Pathology

1. Normal
2. Antibody-mediated changes (may coincide with categories
3, 4, and 5)
C4d deposition without morphologic evidence of active
rejection
C4d+, presence of circulating antidonor antibody, no signs of
acute or chronic TCMR or ACMR
Acute antibody-mediated rejection
C4d+, presence of circulating antidonor antibodies, morphologic evidence of acute tissue injury such as (type/grade):

I. ATN-like minimal inflammation

II. Capillary and glomerular inflammation (ptc/g>0) and/or
thromboses

III. Arterial -v3*
Chronic active antibody-mediated rejection
C4d+, presence of circulating antidonor antibodies, morphologic evidence of chronic tissue injury such as glomerular
double contours and/or peritubular capillary basement
membrane multilayering and/or interstitial fibrosis/tubular
atrophy and/or fibrosis.
3. Borderline changes
Suspicious for acute T-cellmediated rejection. No intimal
arteritis, but foci of tubulitis (t1, t2, or t3) with minor interstitial inflammation (i0 or i1) or interstitial infiltration (i2, i3) with
mild (t1) tubulitis (t1, i1 or greater)

4. T-cellmediated rejection (TCMR; may coincide with 2, 5,

and 6)
Acute T cell mediated rejection (type/grade)
IA. Significant interstitial infiltration (i2; >25% of parenchyma
affected) and foci of moderate tubulitis (t2; >4 mononuclear cells/tubular cross section or group of 10 tubular
cells)
IB. 
Significant interstitial infiltration (i2; >25% of parenchyma affected) and foci of severe tubulitis (t3; >10
mononuclear cells/tubular cross-section or group of 10
tubular cells)
IIA. Mild-to-moderate intimal arteritis (v1)
IIB. Severe intimal arteritis comprising >25% of the luminal
area (v2)
III. Transmural arteritis and/or arterial fibrinoid change and
necrosis of medial smooth muscle
Chronic active T-cellmediated rejection
Chronic allograft arteriopathy (arterial intimal fibrosis with
mononuclear cell infiltration)
5. Interstitial fibrosis and tubular atrophy, no evidence of
any specific etiology (grade)
I. 
Mild interstitial fibrosis (ci1) and tubular atrophy (ct1);
<25% of cortical area affected
II. Moderate interstitial fibrosis (ci2) and tubular atrophy (ct2);
26%-50% of cortical area affected
III. Severe interstitial fibrosis (ci3) and tubular atrophy (ct3);
>50% of cortical area affected
6. Other: changes not considered to be due to rejectionacute
and/or chronic (may coincide with categories 2, 3, 4, and 5)

ATN, Acute tubular necrosis; C4d+, activated complement component C4d; cg, glomerulopathy; ci, interstitial fibrosis; ct, tubular atrophy; g, glomerulitis;
i, interstitial infiltration; ptc, peritubular capillaritis; t, tubulitis; v, vessel wall infiltration or arteritis.
*Degrees of lymphocyte infiltration are scored 0 (absent) to 3 (severe).

and worsening hypertension denotes chronic allograft

dysfunction and typically precedes chronic allograft loss.
Chronic allograft loss is defined as allograft failure that
occurs after 1 year posttransplant. For years, the term
chronic allograft nephropathy was cited as the most common
cause of chronic allograft loss, without a clear understanding of its underlying etiology. In the 2005 Banff reclassification, this term was abandoned and replaced with the
term interstitial fibrosis and tubular atrophy (IF/TA) to more
accurately represent the histologic findings associated with
chronic allograft loss, without ascribing any specific cause
to the histologic changes. A number of histologic changes
may be seen in chronic failing allografts, including vascular
changes (endothelial inflammation and intimal thickening), glomerular changes (glomerular capillary wall thickening, often with a double contour appearancetermed
transplant glomerulopathy), and interstitial fibrosis with
tubular atrophy. Many of these histologic changes are
associated with inferior allograft survival. For instance,
transplant glomerulopathy carries one of the worse prognoses with 5-year graft survival rates of less than 50% from
the time of diagnosis. The Banff classification grades the
degree of IF/TA (I, II, III) according to the severity of
interstitial fibrosis (mild, moderate, severe) and tubular
atrophy (mild to severe), but these grades have not been
precisely correlated with allograft outcomes.

It is clear from long-term protocol biopsy studies that

the underlying causes of these histologic changes are
multifactorial and include both immune-mediated and
non-immunemediated processes, such as chronic CNI
nephrotoxicity, recurrent disease, and subclinical and overt
chronic antibody-mediated rejection.
Chronic CNI nephrotoxicity was first described in the
1970s and is attributed to the renal vasoconstrictive effects
of CNI and direct tubular toxicity. The histologic hallmarks
of chronic CNI nephrotoxicity are largely nonspecific and
include stripped interstitial fibrosis, glomerular sclerosis,
and arteriolar hyalinosis (the only specific finding of CNI
nephrotoxicity). CNI nephrotoxicity has been touted as a
key contributor to chronic allograft dysfunction, but recent
studies have suggested a more prominent role for immunemediated injury in chronic allograft dysfunction, bringing
into question the safety of CNI minimization posttransplantation. Therefore the relative importance of CNI nephrotoxicity and chronic rejection remains an active source of
debate.
Chronic active antibody-mediated rejection is a subset
of AMR and is characterized by the presence of circulating DSA and histologic evidence of chronic allograft injury,
including transplant glomerulopathy, peritubular capillary
basement membrane multilayering, and interstitial fibrosis
and tubular atrophy. The mechanism and treatment of

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chronic antibody-mediated damage is not precisely defined,

but it is recognized as a key therapeutic target in reducing
the risk for chronic allograft loss.

ASSESSMENT OF ALLOGRAFT DYSFUNCTION

Current strategies to monitor allograft function are limited
to serum creatinine, proteinuria, and surveillance allograft
biopsies in some programs. Unfortunately, aside from the
invasive procedure of an allograft biopsy, these are late markers of allograft dysfunction and are inadequate to detect early
immune injury, subclinical rejection, and chronic allograft
inflammation, all of which are increasingly recognized as
important contributors of chronic allograft function.
Allograft biopsy remains the gold standard for early detection of allograft changes since histologic rejection can be
seen before changes in serum creatinine. However, the
impact of interventions that are guided solely by biopsy
findings remains unclear, with a recent randomized study
demonstrating no effect with treatment. Ultimately, the
invasive nature of a biopsy and patient reluctance limit
the widespread use of surveillance biopsies. Therefore
novel noninvasive markers of immune-mediated injury and
chronic inflammation are needed.
DSAs are routinely monitored before transplantation
because they correlate with increased rates of subclinical
and clinical AMR in the early posttransplant period. In the
setting of AMR, DSA levels may also be a useful therapeutic
target and can be monitored during these treatment regimens, although the precise therapeutic targets are unknown.
De novo DSAs posttransplant have also been associated with
higher transplant failure rates and may occur before proteinuria or changes in serum creatinine. Therefore some have
advocated for routine monitoring of DSAs posttransplant.
However, the cost-effectiveness of routine DSA monitoring,
particularly in stable low-risk and intermediate-risk patients,
remains unclear.
A number of unique biomarkers have been studied to
detect acute rejection and early allograft injury, including
urinary markers related to cytotoxic T lymphocytes (granzyme A/B, perforin, Fas ligand, serpin B9), regulatory
T cells (FOXP3), CD4 T cells (chemokines, TIM-3), and
markers of renal tubular injury (NGAL, A1M, cleaved B2M).
Although a number of promising observations have been
made, most of these markers still require further validation
to document their clinical applicability and usefulness.

INFECTIOUS COMPLICATIONS
PROPHYLAXIS AND MONITORING
The risk for infection is related to the overall level of immunosuppression, recipient factors, donor factors, and community
exposures. Strategies to minimize infection after transplant
include pretransplant vaccination and a combination of universal posttransplant prophylaxis (e.g., perioperative antibiotic
prophylaxis) and preemptive therapy (e.g., monitoring and
treating for viremic states).
Universal prophylaxis is given to all patients for a defined
time period, and includes the administration of perioperative antibiotics and low-dose trimethoprim-sulfamethoxazole

(TMP-SMZ) for 6 months to lifetime after transplant to prevent Pneumocystis jirovecii pneumonia (formerly known as
PCP), Toxoplasma gondii, many Nocardia and Listeria species,
and common urinary and respiratory pathogens. Patients
intolerant to TMP-SMZ may receive either atovaquone or
dapsone instead.
Preemptive therapy utilizes quantitative assays at predetermined intervals to detect early infection, with initiation
of therapy when there is a positive assay. Preemptive therapy
is often used in monitoring for cytomegalovirus (CMV),
Epstein-Barr virus (EBV), BK polyomavirus, and viral hepatitis, depending on donor and recipient factors.

APPROACH TO POSTTRANSPLANT INFECTIONS

Clinical presentations of infectious disease may be variable
and atypical in immunosuppressed patients. Therefore,
workup for a suspected infection should be broad and may
include blood and urine cultures, a chest radiograph, and
bronchoscopic evaluation when investigating pulmonary
infiltrates. In cases where the source of infection is unclear,
the threshold for initiation of broad-spectrum antibiotics
should be low. Consideration of donor-derived infections,
latent viral infections, and new opportunistic infections, factoring in the timing posttransplant, is important in developing
a differential diagnosis.
A detailed approach to and management of infectious complications posttransplant are outlined in Chapter 64 and will
not be discussed in this chapter, with the exception of human
BK polyomaviruses. The human polyomavirus BK (BKV)
causes BK nephropathy in up 10% of kidney transplant recipients. BKV may be harbored within the recipient or in the
uroepithelium of the donor, with reactivation and replication
upon immunosuppression. Renal tubular epithelial invasion
produces an inflammatory response similar to acute rejection, with resultant atrophy and fibrosis. A creeping increase
of serum creatinine, along with BKV viruria and viremia, is
often the only clinical sign of BK nephropathy. Therefore
preemptive screening is essential. BKV PCR should be performed once every 3 months for the first 2 years posttransplant, and then annually until the fifth year. Viremic patients
should have immunosuppressive doses reduced and undergo
an allograft biopsy if there is evidence of kidney dysfunction.
In patients with sustained viremia despite a reduction in
immunosuppression, adjunctive therapy with cidofovir, leflunomide, IVIG, and fluoroquinolones may be considered,
although these treatments remains largely unproven.

HEMATOLOGIC COMPLICATIONS
Common causes of hematologic complications after transplant are outlined in Table 62.2. Nearly half of kidney transplant recipients will be anemic within the first 6 months
posttransplant, with 10% to 40% remaining anemic at 1 year,
irrespective of graft function. Within days of kidney transplantation, erythropoietin levels increase as a result of the
functioning allograft, with an early surge to supraphysiologic
levels in the first 2 to 3 weeks. Despite this, anemia may persist
because of a number of factors, including baseline anemia,
surgical blood loss, iron deficiency, allograft dysfunction,
and viral illness. In addition, a number of drugs introduced

CHAPTER 62 POSTTRANSPLANTATION MONITORING AND OUTCOMES

Table 62.2Hematologic Complications Post

Kidney Transplantation
Hematologic
Complication
Anemia

Leukopenia

Thrombocytopenia

Cause(s)
Allograft dysfunction (early or late
posttransplant)
Iron deficiency
Blood loss
EPO resistance
Immunosuppressive medications
(mycophenolic acid agents, azathioprine, rapamycin)
Other medications (trimethoprimsulfamethoxazole, valganciclovir,
ganciclovir, ACE inhibitors)
Infections (parvovirus B19, CMV, BK
polyomavirus, tuberculosis, varicella
zoster virus)
Comorbid conditions (e.g., cardiovascular
disease, peripheral vascular disease)
Hemolytic anemia (minor ABO incompatibility, rhesus D unmatching,
autoimmune anemia)
Immunosuppressive medications
(mycophenolic acid agents, azathioprine, rapamycin, thymoglobulin,
alemtuzumab)
Other medications (valganciclovir, ganciclovir, trimethoprim-sulfamethoxazole)
Infections (cytomegalovirus, tuberculosis,
and overwhelming bacterial infections)
Immunosuppressive medications (thymoglobulin, alemtuzumab, azathioprine,
rapamycin)
Other medications (antibiotics, antiviral
agents, heparin)
Infection
HUS/TTP (CNI use)
Autoimmune thrombocytopenia

posttransplant may cause anemia, including antimetabolites

(mycophenolic acid, azathioprine), antiviral agents, antibiotics (e.g., TMP-SMX), and ACE inhibitors. Although some
agents, such as ACE inhibitors, may result in isolated anemia,
most of these drugs typically impact other cell lines as well.
Workup of posttransplant anemia should include iron
studies, a reticulocyte count, and an assessment of other
cell lines. If the etiology remains unclear or involves more
than one cell line, a hematologist should be consulted. Parvovirus B19 should also be considered with unexplained
isolated anemia.
Leukopenia, with or without anemia, is most often
associated with immunosuppressive or antiviral medications. Dose reductions or discontinuation usually improve
medication-related cytopenias within a matter of days to
weeks. If cytopenias persist, alternate etiologies should be
explored. Anemia and thrombocytopenia, with or without
allograft dysfunction, may indicate hemolytic uremic syndrome. This may be secondary to CNI or recurrent HUSTTP, and generally portends a poor prognosis warranting
therapy with plasmapheresis.

559

METABOLIC COMPLICATIONS
Many of the metabolic abnormalities that contribute to
renal osteodystrophy in ESRD patients, such as phosphate
retention, secondary hyperparathyroidism, decreased calcitriol synthesis, and 2-microglobulin (2M) accumulation,
are reversed with transplantation; however, a degree of
hyperparathyroidism may persist. Persistent uncontrolled
hyperparathyroidism-associated hypercalcemia increases
the risk for posttransplant bone disease and contributes to
vascular calcifications. In cases of severe symptomatic or
persistent hypercalcemia, parathyroidectomy may be indicated. The use of calcimimetics posttransplant is not well
established, with trials ongoing to examine their use in this
setting. To date, cinacalcet therapy has been shown to effectively normalize serum calcium levels, but the impact on
PTH and serum phosphorous levels has been variable.
Hypophosphatemia after transplantation is induced by
phosphate wasting in the urine as a result of hyperparathyroidism and PTH-independent pathways, such as persistent elevations of FGF-23. Plasma phosphate levels below 1.0 mg/dL
can cause muscle weakness and possibly osteomalacia, and
should be reversed with supplementation. Osteopenia and
osteonecrosis posttransplant are caused by multiple factors,
including persistent uremia-induced abnormalities in calcium
homeostasis and acquired defects in mineral metabolism
induced by immunosuppressive medications. Measures to
prevent and treat posttransplant bone disease include
minimizing corticosteroid exposure, providing supplemental calcium, treating vitamin D deficiency, and encouraging
weight-bearing exercise. Antiresorptive agents may be considered, but data on their benefits in kidney transplant
recipients are lacking.

POSTTRANSPLANT MALIGNANCY
Incidence rates of malignancies at 1 and 3 years posttransplant
compared with the general population are outlined in Table
62.3. Kidney transplant recipients have a higher incidence
of most cancers posttransplant, but the risks are particularly
high for certain viral-mediated malignancies, including EBVrelated posttransplant lymphoproliferative disease (PTLD),
skin and lip cancers, and HHV-8-associated Kaposi sarcoma.
In addition, certain malignancies are more common in
patients with kidney disease, such as kidney and urinary tract
malignancies. Risk factors for cancer after transplant include
advanced recipient age, white race, male sex, and prior history
of cancer. Recipients with prior cancers must be disease-free
for an established time before transplantation, and should be
monitored more intensively after transplantation.
Successful treatment of malignancy relies on regular
screening and early detection. Typically, malignancy-
screening guidelines from the general population are
applicable in the posttransplant setting and should be
coordinated annually after transplant. Cancers of the skin
are the most common malignancies in adult kidney transplant recipients and include squamous and basal cell carcinomas, malignant melanomas, and Merkel cell tumors.
Kidney transplant recipients have a 250-fold and 10-fold
increased incidence of squamous cell carcinoma and basal

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SECTION 11 KIDNEY REPLACEMENT THERAPIES: DIALYSIS AND TRANSPLANTATION

Table 62.3Age-Adjusted Cancer Rates* in Male and Female Transplant Recipients Compared With
the U.S. Population
Cancer Rates in Men
Type of Cancer

Cancer Rates in Women

U.S. Population

1 Year
Posttransplant

3 Years
Posttransplant

19.0
24.0

60.4
2017.1

131.3
2160.2

12.1
14.3

99.9
851.6

63.5
1320.5

3.2

37.9

98.6

2.5

11.5

93.5

U.S. Population

1 Year
Posttransplant

3 Years
Posttransplant

Skin Cancers
Melanoma
Nonmelanoma
skin
Lymphomas
Hodgkins
lymphoma
NHL

22

882

150.7

15.7

667.5

456.7

66.4
8.8
9.4
12.3
2.0
11.0

137.2
17.4
33.5
19.8
3.8
38.9

107.7
21.3
39.2
12.4
4.1
4.1

48.5
2.2
5.4
9.6
1.4
5.1

91.1
3.6
83.2
25.1
25.1
23.7

137.0
6.2
24.3
44.1
0
21.4

38.3
16.0
162.0
5.5

148.9
671.0
477.4
21.3

60.9
226.1
265.8
20.4

10.0
8.4

9.4
16.2
0.7
3.0

69.0
767.7

9.4
29.5
51.7
14.6

36.3
122.9

53.7
42.4
21.5
26.5

1.5
89.1
7.9
1.5

6.8
149.4
15.1
55.0

6.0
202.8
36.3
26.1

134.1
53.4
1.7
0.1

343.4
141.8
8.9
56.0

144.3
194.1
21.0
6.2

Gastrointestinal
Colon
Esophagus
Hepatobiliary
Pancreas
Small intestine
Stomach
Genitourinary
Bladder
Kidney
Prostate
Testes
Cervix
Ovary
Uterus
Vulvovaginal
Other
Breast
Lung
CNS
Kaposi sarcoma

Modified from Table 3 in Kasiske BL, Snyder J, Gilbertson DT, et al: Cancer after kidney transplantation in the United States, Am J
Transplant 4:905-913, 2004.
CNS, Central nervous system; NHL, non-Hodgkin's lymphoma.
*Rates per 100,000 for U.S. population. Rates per 100,000 person-years for transplant recipients. All rates standardized to the 2000 U.S.
census population.

cell carcinoma, respectively, compared with the general

population. Patients should be counseled to minimize sun
exposure, use protective clothing and sunscreen regularly,
and perform annual self-examinations for skin lesions. Suspicious lesions should be biopsied, and patients with recurrent lesions should be routinely followed by a dermatologist.
EBV-associated PTLD is characterized by lymphoproliferation, and includes clinical syndromes ranging from
infectious mononucleosis to life-threatening malignancies.
Of note, PTLD remains relatively uncommon in kidney
transplant recipients (1%-2%), typically occurring in the
context of primary EBV infection within the first year posttransplant. Additional risk factors for PTLD include young
recipient age, CMV mismatch or disease, and the use of

T lymphocytedepleting antibody. Universal prophylaxis

for EBV is not recommended. However, antiviral prophylaxis (acyclovir or ganciclovir) may be considered for EBVnegative recipients with EBV-positive donors because it may
result in a reduced rate of PTLD. Prophylaxis with IVIG
has been shown to reduce the incidence of non-Hodgkins
lymphoma posttransplant in retrospective studies, but prospective randomized controlled trials in pediatric patients
have been inconclusive. High viral loads often predate the
clinical presentation of PTLD; therefore, frequent EBV viral
load monitoring is recommended in high-risk populations.
If viremia occurs in the absence of other clinical signs of
PTLD, reduction of immunosuppression and initiation of
antiviral therapy may be indicated. Most PTLD cases are

CHAPTER 62 POSTTRANSPLANTATION MONITORING AND OUTCOMES

non-Hodgkin's lymphomas of B cell origin and are CD20positive. Mortality rates with PTLD are greater than 50%,
with increased age, elevated lactate dehydrogenase levels,
multiorgan involvement, and the presence of constitutional
symptoms predicting a higher risk for death. The importance of clonality in PTLD is often debated, with monoclonal B cell lymphomas considered more malignant and
resistant to treatment compared with polyclonal lymphomas.
Treatment involves reduction of immunosuppression and
typically includes administration of an anti-CD20 agent
(rituximab), with or without additional cytotoxic therapies.
Immunosuppressive reduction should be considered in
all patients with malignancy posttransplant, but it should be
reviewed in each case to balance the risks for rejection and
recurrent malignancy. The role of mTOR in malignancies
has been the subject of increased study in the last decade.
Indeed, rapamycin has been shown to suppress the growth
and proliferation of certain tumors in various animal models. Small studies in humans have suggested that rapamycin
may confer a reduced risk for malignancy compared with
CNIs, particularly in skin and renal cancers. However, in an
analysis of Medicare claims data for transplant recipients in
the United States, de novo use of rapamycin was associated
with an increased risk for PTLD. Although further studies
are clearly needed to delineate the benefits of rapamycin
in reducing the risk for posttransplant malignancy, many
centers currently consider converting patients with recurrent malignancies to a rapamycin-based immunosuppressive
regimen.

Table 62.4Cardiovascular Risk Factors Post

Kidney Transplantation
Cardiovascular
Risk Factor
Hypertension

Obesity

Dyslipidemia

Diabetes

CARDIOVASCULAR RISK FACTORS

Cardiovascular death is the leading cause of allograft loss
and accounts for nearly 60% of deaths posttransplant. Risk
factors for coronary disease after transplantation include
the traditional risk factors of increased age, diabetes mellitus, hypertension, cigarette smoking, and hyperlipidemia,
as well as proteinuria, reduced kidney function, elevated
lipoprotein(a) levels, elevated CRP and IL6 levels, and obesity, particularly in the context of the metabolic syndrome
(Table 62.4).

561

Reduced kidney
function
Elevated
homocysteine

Contributing Factors Posttransplant

Volume overload
Calcineurin inhibitors
Corticosteroids
Allograft dysfunction
Renal artery stenosis
Liberalization of dietary restrictions
Persistent physical inactivity
Chronic corticosteroid use
Corticosteroids may cause elevations
in LDL and total cholesterol, but are
associated most strongly with hypertriglyceridemia posttransplant
Calcineurin inhibitors are associated with
elevated total cholesterol and LDL
levels and reductions in HDL levels
independent of corticosteroid use
Rapamycin is mostly associated with
hypertriglyceridemia
Calcineurin inhibitors (especially tacrolimus) are associated with hyperglycemia
and NODAT
Corticosteroids are associated with
hyperglycemia and NODAT
Rapamycin is associated with hyperglycemia and NODAT
Chronic hepatitis C infection is associated with pre- and posttransplant
diabetes possibly due to HCV-induced
islet cell dysfunction and liver dysfunction associated with insulin resistance
Immune- and non-immunemediated
allograft injury with resultant chronic
kidney disease
Homocysteine levels continue to rise
post kidney transplantation and may
be associated with cyclosporine use

NODAT, New-onset diabetes after transplantation.

METABOLIC SYNDROME

OBESITY

The constellation of central obesity, dyslipidemia, hypertension, and fasting hyperglycemia is called metabolic syndrome and is associated with an increased risk for diabetes
mellitus, proteinuria, reduced kidney function, and cardiovascular disease in the general population. Numerous studies have reported a high prevalence of metabolic syndrome
both before and after transplantation. In one U.S. study, the
pretransplant prevalence of metabolic syndrome was 57.2%
in nondiabetic recipients, and metabolic syndrome pretransplant was an independent risk factor for new-onset diabetes
after transplantation (NODAT) in 31.4% of recipients. After
transplantation, metabolic syndrome has been reported in up
to 63% of recipients and is associated with worse kidney function and allograft survival. Among the various components of
metabolic syndrome, systolic hypertension and hypertriglyceridemia have been reported to have the greatest negative
impact on long-term allograft function.

Pretransplant obesity (BMI >30) increases the risk for surgical

wound infections, allograft loss, and cardiovascular disease
posttransplant. Weight gain is common posttransplant, particularly in women, African-Americans, low-income patients,
and recipients with pretransplant obesity. All transplant recipients should receive counseling on the importance on diet
and exercise. Pharmacologic agents and surgical options for
weight loss may be considered in morbidly obesity patients
both before and after transplantation.

HYPERTENSION
Hypertension is seen in 60% to 80% of all transplant recipients and is associated with worse allograft survival. In the
early posttransplant period, volume management, allograft
function, and changes to baseline antihypertensive therapy
may contribute to hypertension. Immunosuppressive agents,

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SECTION 11 KIDNEY REPLACEMENT THERAPIES: DIALYSIS AND TRANSPLANTATION

including CNIs and corticosteroids, may further exacerbate

hypertensive states. For instance, cyclosporine increases both
systemic and renal vascular resistance and induces renal vasoconstriction via increased release of vasoconstrictors, such as
endothelin.
The presence of atherosclerotic disease and complications during organ procurement and transplantation
increase the risk for transplant renal artery stenosis (RAS).
In addition, CMV infection and DGF have been found to be
associated with RAS. Therefore in cases of refractory hypertension posttransplant, particularly when associated with
unexplained allograft dysfunction, RAS should be considered. As in the nontransplant setting, ACE inhibitorinduced
reversible decline in kidney function may be suggestive of
RAS. Blood pressure targets are variable and depend on
comorbid disease, including diabetic status and presence of
proteinuria. The KDIGO guideline for care of the kidney
transplant recipient suggests maintaining blood pressure at
less than 130/80 mm Hg.
Calcium channel blockers, ACE inhibitors, and beta
blockers may all be considered first-line antihypertensive
agents posttransplant, with selection of a specific agent
dependent on other patient-specific factors. A recent
Cochrane Group metaanalysis of randomized trials found
that only calcium channel blockers reduced graft loss and
improved GFR compared with placebo, whereas ACE inhibitors more effectively reduced proteinuria. Notably, the
renoprotective benefits of ACE inhibitors posttransplant
have not been confirmed.

DYSLIPIDEMIA
The Assessment of Lescol in Renal Transplantation (ALERT)
trial was a large multicenter study of stable transplant recipients who received either fluvastatin (Lescol) or placebo
with the outcome of lowering LDL cholesterol and reducing the risk for cardiac events. After 5 years of follow-up,
the fluvastatin group had lower total and LDL cholesterol
and fewer cardiac deaths and nonfatal MIs, but there was no
difference in major adverse cardiac events. It is important
to note that despite concerns regarding increased risks for
statin-induced rhabdomyolysis due to CNI coadministration,
no increased risk for rhabdomyolysis was noted in the statin
arm of the trial. Therefore, although the mortality benefit of
statins posttransplant remains unproven, statins remain the
drug of choice for the treatment of dyslipidemia in transplant recipients.

NEW-ONSET DIABETES AFTER TRANSPLANTATION

The incidence of NODAT has been variably reported, but
recent studies note a prevalence of 16% at 1 year posttransplant. The development of NODAT confers a 46%
increased risk for graft loss and an 87% increased risk for
death posttransplant, with a tripling of the risk for cardiovascular death. The reason for an increased risk for graft
loss remains unclear, but it may be due to a combination
of diabetic nephropathy and the implications of reduced
immunosuppression to avoid NODAT.
In addition to traditional risk factors for diabetes (older
age, obesity, preexisting glucose intolerance, and a family
history of diabetes mellitus), risk factors for NODAT

include the type and degree of immunosuppression, AfricanAmerican race, level of HLA matching, chronic hepatitis C
infection, and the cause of ESRD, with some reports suggesting a higher risk associated with polycystic kidney disease.
Calcineurin inhibitors, particularly tacrolimus, may cause
pancreatic beta cell dysfunction and contribute to insulin
resistance. Cyclosporine is less diabetogenic than tacrolimus,
and some centers have advocated the use of cyclosporine in
patients at high risk for developing NODAT. Alternatively,
reduced doses of CNI are recommended to minimize the
risk for NODAT. However, no comparative studies have
been conducted to demonstrate the benefit and safety of
cyclosporine-based immunosuppression or low-dose CNI in
patients at high risk for NODAT. Rapamycin is also diabetogenic, and has been shown to worsen glycemic control
after conversion from a CNI.
Corticosteroids cause hyperglycemia through a number
of mechanisms in a dose-dependent manner. Therefore,
rapid reduction of prednisone to maintenance doses (510 mg/day) significantly improves hyperglycemia. However,
the relative benefit of complete steroid withdrawal versus
maintenance with low-dose prednisone has not been consistently demonstrated.
All transplant recipients should have fasting blood glucose levels checked weekly for the first month, and then at
3, 6, and 12 months thereafter. Impaired fasting blood glucose results should be further evaluated with an oral glucose
tolerance test. HbA1C assessment should be used to direct
therapy in patients with NODAT. Hyperglycemic patients
should receive counseling on diet and lifestyle modification, and be initiated on therapy if hyperglycemia persists.
All oral hypoglycemic agents have been found to be safe
and effective posttransplant; however, the metabolism and
adverse effects of each drug should be considered in relation to immunosuppressant medications and the level of
allograft function.
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