Medical Care 1st Year Post Transplant

In-Depth Review
Medical Care of Kidney Transplant Recipients after the First

Posttransplant Year
Arjang Djamali,* Millie Samaniego,* Brenda Muth,* Rebecca Muehrer,*
R. Michael Hofmann,* John Pirsch,* Andrew Howard,
Georges Mourad,
and
Bryan N. Becker*
*Department of Medicine, Nephrology Section, University of Wisconsin, Madison, Madison, Wisconsin;

Metropolitan
Nephrology Associates, Alexandria, Virginia; and

Montpellier Medical School, Montpellier, France
Kidney transplantation is the treatment of choice for patients with ESRD. Despite improvements in short-term patient and
graft outcomes, there has been no major improvement in long-term outcomes. The use of kidney allografts from expanded-
criteria donors, polyoma virus nephropathy, underimmunosuppression, and incomplete functional recovery after rejection
episodes may play a role in the lack of improvement in long-term outcomes. Other factors, including cardiovascular disease,
infections, and malignancies, also shorten patient survival and therefore reduce the functional life of an allograft. There is a
need for interventions that improve long-term outcomes in kidney transplant recipients. These patients are a unique subset
of patients with chronic kidney disease. Therefore, interventions need to address disease progression, comorbid conditions,
and patient mortality through a multifaceted approach. The Kidney Disease Outcomes Quality Initiative from the National
Kidney Foundation, the European Best Practice Guidelines, and the forthcoming Kidney Disease: Improving Global Out-
comes clinical practice guidelines can serve as a cornerstone of this approach. The unique aspects of chronic kidney disease
in the transplant recipient require the integration of specific transplant-oriented problems into this care schema and a concrete
partnership among transplant centers, community nephrologists, and primary care physicians. This article reviews the
contemporary aspects of care for these patients.
Clin J Am Soc Nephrol 1: 623640, 2006. doi: 10.2215/CJN.01371005
W
ith tremendous advances in the fields of transplant
surgery, medicine, and pharmacology during the
past 50 yr, kidney transplantation has become the
treatment of choice for patients with ESRD (13). Currently, one
of every four patients with ESRD in the United States is a
kidney transplant recipient (4). A considerable part of this
success is due to better short-term outcomes that have resulted
from improved management of early postsurgical complica-
tions and prevention of acute rejection episodes (5). However,
new evidence demonstrates that there has been a lack of sig-
nificant improvement in long-term outcomes (2,57). Earlier
studies had reported projected half-lives of 13.8 yr for deceased-
donor transplants that were performed between 1988 and 1996
(8), yet, recent analyses covering the same interval demon-
strated a more modest actual graft half-life of 8 yr (6). These
data on long-term graft survival are even more startling when
one considers that deceased-donor transplants that were per-
formed between 1995 and 2000 manifest a trend toward worse
survival (5), that there is a direct association between chronic
allograft dysfunction and increased cardiovascular mortality
(9), and that graft loss has a detrimental impact on patient
survival (Figure 1) (1,10).
Why have long-term outcomes in kidney transplant recipi-
ents not improved? The use of kidney allografts with varying
quality, e.g., extended-criteria donors, polyoma/BK virus ne-
phropathy, underimmunosuppression, and incomplete recov-
ery of kidney function after rejection episodes in the first post-
transplant year has been invoked (5,6,11). However, other
factors, including cardiovascular disease (CVD), infections, and
malignancies, contribute to reduced patient survival and there-
fore a reduction in the functional life of an allograft (Tables 1
and 2) (9,10,1214). Even when these comorbid complications
lead only to illness, they may take a toll on allograft survival
(9,10,12). As a result, interventions that aim to improving long-
term outcomes in kidney transplant recipients should address
disease progression, comorbid conditions, and patient mortal-
ity. This multifaceted task may be accomplished best through a
partnership among transplant centers, community nephrolo-
gists, and primary care physicians, who already are or inevita-
bly will be involved in the care of kidney transplant recipients.
Kidney transplant recipients are a unique subset of patients
with chronic kidney disease (CKD) (1416). Most of these pa-
tient have stage 2 or 3 CKD, based on the National Kidney
Foundation (NKF) CKD classification schema even immedi-
ately posttransplantation (1518); a large percentage of patients
initiate their transplant function with an estimated GFR (eGFR)
that even may be as low as 30 ml/min (17). Although disease
Published online ahead of print. Publication date available at www.cjasn.org.
Address correspondence to: Dr. Arjang Djamali, University of Wisconsin Madi-
son, School of Medicine, 3034 Fish Hatchery Road, Suite B, Madison, WI 53713.
Phone: 608-270-5681; Fax: 608-270-5677; E-mail: axd@medicine.wisc.edu
Copyright 2006 by the American Society of Nephrology ISSN: 1555-9041/104-0623
progression rates (reported as the mean slope of creatinine
clearance or eGFR) have consistently been reported in the range
of 1.4 to 2.4 ml/min per yr (16,18,19), some patients lose
function more rapidly (5 to 20 ml/min per yr), whereas others
stabilize their GFR (18,19). The rate of loss of function does not
seem to be associated with baseline function of the transplant.
Finally, morbidity and mortality rates increase significantly
from stage 1 to stage 5 CKD in kidney transplant recipients
(15,16). At the same level of kidney function (stage 3), death
rates are higher in kidney transplant recipients compared with
nontransplant patients with CKD (16). Such data suggest that
despite a slower decline in kidney function over time, kidney
transplant recipients have marked differences in comorbidity
and mortality rates compared with their CKD counterparts. As
such, the impact of a 1-ml/min per yr decline in GFR has a
greater impact on long-term outcomes in kidney transplant
recipients.
Kidney transplant recipients return to a higher level of phys-
ical functioning compared with their counterparts on dialysis.
Given this, it is important to recognize that immunosuppres-
sion and graft function are only one component of their health
care. We propose that the objective should be a systematic
integration of transplant, CKD, and general health care. The
NKF Kidney Disease Outcomes Quality Initiative or K/DOQI
(http://www.kidney.org/professionals/kdoqi/guidelines.cfm),
the European Best Practice Guidelines (EBPG; http://www.
ndt-educational.org/guidelines.asp), and the forthcoming In-
ternational Kidney Disease Improving Global Outcomes
(KDIGO; http://www.kdigo.org/welcome.htm) clinical prac-
tice guidelines should be generalized to this unique subset of
individuals who have CKD (17,20). This article reviews the
contemporary aspects of care for these patients.
Kidney Allograft Function
Reduced kidney allograft function is associated directly with
poor graft and patient outcomes (9,10,15,16,21). A close fol-
low-up of kidney allograft function (monthly to every 2 mo in
stable cases) therefore is recommended in all of these patients.
Transplant recipients whose graft is stable after 2 yr may de-
crease the frequency of their actual visits to every 3 to 4 mo but
are encouraged to continue more frequent laboratory testing.
Traditionally, allograft function has been assessed by mea-
surement of serum creatinine values and urinalyses. The
Modification of Diet in Renal Disease (MDRD) estimation
formula for GFR in patients with CKD (22) provides a low
bias and high precision (2.7 and 10.4 ml/min per 1.73 m
2
,
respectively) in predicting GFR in kidney transplant recipi-
ents (23). The MDRD GFR calculator is available online at
http://www.kidney.org/professionals/kdoqi/index.cfm. The ad-
vantage of using GFR or creatinine clearance estimation formu-
las to determine the stage of CKD allows one to implement a
clinical action plan that is consistent with CKD guidelines (17).
Cystatin C is a novel and more sensitive marker of kidney
function in kidney transplant recipients that also may predict
successfully cardiovascular outcomes (2426). Whether one
uses the serum creatinine, cystatin C, or eGFR formula, it still is
crucial to screen for graft dysfunction at regular intervals. At no
time after transplantation can one assume that the allograft is
entirely stable (27). As with native kidney diseases, late allo-
graft dysfunction may be secondary to acute or chronic pro-
cesses.
Acute Kidney Injury or Failure
Acute kidney injury or kidney failure in the late posttrans-
plantation period may be divided into basic categories (Table
Figure 1. Impact of kidney transplant loss on patient survival.
Reprinted with permission from reference (10).
Table 1. Causes of late allograft dysfunction
a
Acute Renal Failure in the Late
Posttransplantation Period
Late Allograft Loss
Prerenal Chronic allograft dysfunction
decreased effective
circulating volume
CAN
CNI nephrotoxicity
volume contraction polyoma (BK) virus
congestive heart failure nephropathy
liver failure recurrent/de novo
renal transplant artery
stenosis
glomerular disease
chronic rejection
drugs (immunologic)
CNI
ACE-I, ARB
acute rejection
Patient death with
NSAID functioning graft
Renal CVD
urinary tract infection
and/or pyelonephritis
infectious complications
malignancies
acute rejection other
acute interstitial nephritis
acute tubular necrosis
recurrent/de novo
glomerular disease
Postrenal
hydronephrosis
a
ACE-I, angiotensin-converting enzyme inhibitor; ARB,
angiotensin receptor blocker; CAN, chronic allograft
nephropathy; CNI, calcineurin inhibitor; CVD, cardiovascular
disease; NSAID, nonsteroidal anti-inflammatory drugs.
624 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 1: 623640, 2006
1). The principal difference is the possibility of acute rejection.
Therefore, the assessment and management of acute injury or
failure in these patients should include the history (including
adherence with immunosuppressive drugs) and physical exam-
ination, serum creatinine, blood urea nitrogen and electrolytes,
blood levels of calcineurin inhibitors (CNI) and/or sirolimus,
urinalysis, urine electrolytes, urine indices, and ultrasono-
graphic assessment of the allograft. Volume depletion, drugs,
and urinary tract infections constitute the largest proportion of
causes of acute injury or failure late after transplantation, and
management is similar to that undertaken in native kidney
disease. It is important to move readily toward treatment,
especially for urinary tract infections, because late infections
(after at least 12 mo of allograft function) are associated with a
reduction in graft survival (28). Acute rejection is a relatively
rare entity in this period. Its diagnosis requires a biopsy, pref-
erably at the transplant center, and should be considered when
the above diagnostics are negative or the creatinine fails to
return to the previous baseline. In general, any change in cre-
atinine 0.3 mg/dl (25 mol/L) needs to be evaluated
promptly.
Acute Rejection
Organ Procurement and Transplantation Network data from
April 2005 demonstrated that acute rejection rates within 1 yr
averaged 14.7% for the 2001 to 2003 period. After the first
posttransplant year, acute rejection rates are less prevalent. Not
all rejection episodes carry the same negative prognostic im-
pact. The available literature shows that recurrent rejection
(5,29), rejection episodes that occur in the setting of potent
immunosuppression (30), episodes that occur beyond month 6
(2932), or episodes with a lack of functional response to ther-
apy (5) have the worst impact on graft survival.
Chronic Allograft Dysfunction
Chronic allograft dysfunction after the first year posttrans-
plantation is secondary to chronic allograft nephropathy
(CAN), drug toxicity, recurrent and/or de novo glomerular
diseases, polyoma (BK) infections, and late acute rejection (Ta-
ble 1) (13,14).
CAN. CAN is a condition of altered kidney allograft func-
tion at least 3 mo posttransplantation, independent from acute
rejection, CNI toxicity, recurrent or de novo disease, or immu-
nologic features that are suggestive of chronic rejection (C4d
staining in the pericapillary tubules, intimal fibrosis with in-

flammatory cells, and duplication of glomerular basement
membrane) (3339). The term CAN is preferred to chronic
rejection because the latter implies an immunologic mechanism
of injury (33,37). However, immune and nonimmune features
(including chronic CNI toxicity) often coexist. Therefore, the
term CAN practically defines a histologic diagnosis that is
characterized by tubular atrophy, interstitial fibrosis, and fi-
brous intimal thickening with variable glomerular lesions (37
39). Accompanying clinical features include a gradual elevation
in serum creatinine, hypertension, and mild to moderate pro-
teinuria (1 to 3 g/24 h) (13,18). These nonspecific pathologic
findings result from a proinflammatory milieu in which the
level of injury from both immune and nonimmune insults
exceeds the capacity of tissue repair (13,38). CAN lesions are
present in up to 94% of grafts at 12 mo posttransplantation
(13,38,40) along with the noted clinical features.
CAN is associated with significant morbidity and mortality
and is the main reason for returning to dialysis after transplan-
tation (38). It is important to appreciate that early and late
posttransplantation events play a role in the progression of
CAN (Table 2).
CNI Nephrotoxicity. Cyclosporine A (CsA) and tacroli-
mus play a significant role in progressive kidney dysfunction
after transplantation (4043). Nearly all kidney allografts dis-
play histopathologic signs of chronic CNI toxicity by 10 yr
posttransplantation (40). CNI manifest nephrotoxicity in sev-
eral ways (41,44). They can mediate acute nephrotoxicity via
reversible afferent arteriolar vasoconstriction, often associated
with subtle volume depletion. This is a common cause for
transient increases in serum creatinine and needs to be fol-
lowed up in a timely manner after improved volume repletion.
CNI are causative agents of thrombotic microangiopathy and
can result independently in progressive and irreversible arte-
riolar hyaline changes and tubulointerstitial fibrosis (38,41,44).
A number of approaches have attempted to stave off nephro-
toxicity through CNI avoidance (4547), withdrawal (4854), or
minimization (51,5557). The rejection risk with any of these
strategies is relatively small (10%), and kidney allograft func-
tion may improve by up to 7 ml/min (5254). This should not
be attempted without previous consultation with the transplant
center.
Antibody-Mediated Rejection. Both cellular and humoral
processes contribute to the pathogenesis of chronic allograft
rejection (39). Antibody-mediated rejection (AMR) includes all
forms of rejection that involve donor-specific antibodies (DSA)
against HLA antigens, ABO isoagglutinins, or non-HLA anti-
gens (i.e., anti-endothelial antibodies) and is defined by the
presence of DSA in the recipients serum and C4d deposition in
the peritubular capillaries as a marker of antibody-mediated
Table 2. Factors involved in the development/
progression of CAN
a
Modifiable Risk
Factors
Nonmodifiable Risk
Factors
Nonimmune Nonimmune
CNI toxicity early delayed graft function
hypertension donor age or poor graft quality
dyslipidemia donor genetic factors
diabetes donor/recipient size mismatch
proteinuria Immune
oxidative stress HLA mismatch
chronic hypoxia previous sensitization (high PRA)
CMV infection previous rejection
Immune
chronic rejection
subclinical rejection
patient noncompliance
suboptimal
immunosuppression
a
CMV, cytomegalovirus; PRA, panel of reactive antigens.
Clin J Am Soc Nephrol 1: 623640, 2006 Medical Care of Kidney Transplant Recipients 625
activation of the complement cascade (58). The chronic form of
AMR occurs after the first year posttransplantation and is more
indolent than its early counterpart (58,59). It has been shown
that one third of patients with CAN develop de novo anti-HLA
antibodies compared with only 4% in kidney transplant recip-
ients with normal allograft function (60). Likewise, the presence
of C4d deposition in the peritubular capillaries has been iden-
tified in one third of patients with chronic allograft dysfunction
(61). Injury to peritubular capillaries can result progressively in
vascular dropout, interstitial fibrosis, and significant scarring of
the kidney allograft (62). Clinically, many of these patients
present with significant proteinuria that results from transplant
glomerulopathy, a specific form of glomerular lesion that is
considered to be the result of immune injury.
A large, multicenter, collaborative study of 2231 kidney
transplant recipients that was undertaken to determine the
frequency of anti-HLA antibodies in renal transplant recipients
with functional transplants (63) showed the presence of anti-
HLA antibodies in 20% of patients (63). In this study, 478
patients who developed anti-HLA antibodies had a signifi-
cantly higher rate of allograft loss at 2 yr than 1753 control
patients without detectable antibodies (15.1 versus 6.8%; P
0.0005) (64). Although these findings suggested a role for anti-
HLA antibodies as predictors of allograft loss, this predictive
value was NS for recipients with serum creatinine levels 2
mg/dl (177 mol/L) (64).
In summary, the current literature supports AMR as a con-
tributor to chronic allograft dysfunction through an indolent
and progressive process. Notwithstanding this evidence,
United Network for Organ Sharing data show that 23% of
HLA-identical kidneys are lost after 10 yr of transplantation,
demonstrating that other factorsincluding non-HLA antibod-
ies and nonimmunologic processesalso play an important
part in the pathogenesis of chronic allograft injury (65). Al-
though there is a role for the monitoring of HLA antibodies in
kidney transplant recipients, routine screening of DSA in kid-
ney transplant recipients is not currently recommended. High-
risk patients (patients with AMR, sensitized patients with PRA
80%, or patients who undergo desensitization protocols) with
increased serum creatinine levels (2 mg/dl) may benefit from
DSA screening and subsequent adjustment of immunosuppres-
sion. Many issues remain unsolved concerning the monitoring
of anti-HLA antibodies, including the choice of diagnostic tech-
niques (i.e., complement-based versus solid-phase assays), the
frequency of testing, and the interpretation of antibody data in
the absence of allograft dysfunction.
Recurrent and/or De Novo Disease. Glomerulonephritis
(GN) is responsible for kidney failure as a primary or contrib-
uting cause in 20 to 40% of patients who receive a transplant
(66). The incidence rate of GN recurrence posttransplantation
ranges between 6 and 19.4% and may result in graft loss in
approximately 8.4% of cases (6668). Because recurrence im-
plies that the patient has biopsy-proven GN in both native and
transplanted kidneys (a condition not always fulfilled), many
studies group de novo and recurrent GN (66). Considering these
limitations, any form of GN may recur at any time posttrans-
plantation (6668). However, focal and segmental glomerulo-
sclerosis, membranoproliferative GN (MPGN), hemolytic ure-
mic syndrome, and membranous glomerulonephritis (MGN)
are more likely to recur within the first posttransplant year,
whereas pauci-immune GN, IgA nephropathy, fibrillary GN,
lupus nephritis, and diabetes recur typically after the first year
(6668). Principal causes of de novo GN in renal allografts
include transplant glomerulopathy, hemolytic uremic syn-
drome, membranous glomerulonephritis, and MPGN (69). The
last two have been associated with hepatitis C virus (HCV)
infection, although MPGN (with or without cryoglobulinemia)
is more commonly described (70,71). HCV infection may be
associated more frequently with glomerular disease in the renal
allograft compared with native kidneys possibly because of
increased HCV RNA titers that result from immunosuppres-
sion (72). Recurrent/de novo GN is associated overall with a
two-fold increased risk for graft loss (6668). It therefore is
important to suspect this condition in individuals with protein-
uria, hematuria, and a slow decline in allograft function after
the first year. The diagnostic approach should include a biopsy
with electron microscopy and immunohistology studies in ad-
dition to appropriate serologic evaluation (6668).
Treatment options for recurrent/de novo GN remain limited
and tend to be supportive, especially after the first posttrans-
plant year. Because these patients are already on immunosup-
pressive agents, management focuses on the removal of the
underlying cause if identified (infection, drugs, or malignancy)
and improved control of BP, proteinuria, and dyslipidemia. The
benefits of angiotensin-converting enzyme inhibitors (ACE-I)
and angiotensin receptor blockers (ARB) in native kidney dis-
easemediated proteinuria have not been demonstrated as ex-
tensively in the transplant population, yet these agents have
important antiproteinuric effects that can improve allograft
survival in individuals with significant proteinuria (73). Cyto-
toxic medications such as cyclophosphamide may have limited
benefits for specific posttransplantation entities, e.g., MPGN
(74), recurrent antiglomerular basement membrane glomeru-
lonephritis (75), and focal and segmental glomerulosclerosis
(76), but their use has to be gauged carefully and other anti-
proliferative immunosuppressive drug dosages may have to be
altered to decrease untoward effects. When graft loss ensues,
retransplantation remains an option. However, the risk for
recurrence typically increases with the number of transplants
(67,77).
Polyoma Virus Infection. Polyoma viruses are ubiquitous
DNA viruses that infect a variety of animals, including hu-
mans. BK virus, a human polyoma virus, was described ini-
tially in a transplant recipient (11,78). It has a remarkable
tropism for the genitourinary tract. BK virusinduced nephrop-
athy is recognized as an important cause of late allograft fail-
ure. The reported incidence of allograft failure has ranged from
15 to 50% in affected individuals (11,7981). Unfortunately,
there are no clinical features that are unique to BK virus infec-
tion. There often is an unexplained rise in serum creatinine,
asymptomatic hematuria, ureteral stenosis, and/or subacute
kidney failure as a result of interstitial nephritis (11,7981).
Diagnosis can be made by biopsy and urine cytology with
identification of characteristic cytopathologic changes. Addi-
tional data suggest that assessment and monitoring of serum
PCR for viral DNA and viral load may be helpful as an adjunct
diagnostic and monitoring test (11,7982). Unfortunately, spe-
cific antiviral therapy for BK nephritis does not currently exist.
Clinical trials have suggested efficacy with low-dose cidofovir
(0.25 to 0.33 mg/kg every 2 to 3 wk intravenously) (81,83) as
well as leflunomide (83,84). Because BK virus infection reflects
the overall state of immunosuppression regardless of the choice
of CNI or adjuvant therapy (82), the basis of treatment is to
decrease immunosuppressive medications (11,7984). This is
another excellent example of the importance of transplant bi-
opsy to investigate an otherwise unexplained, persistent in-
crease in the serum creatinine.
Proteinuria
The evaluation of kidney function in kidney transplant re-
cipients should include routine measurement of urinary protein
excretion. Urine protein to creatinine ratios are a reliable sub-
stitute for 24-h urine collection (85). Proteinuria may be defined
as 200 mg/g creatinine and microalbuminuria 30 mg/g
creatinine on spot urine samples (86). The incidence of protein-
uria in kidney transplant patients ranges between 10 and 25%
(27). Proteinuria from the native kidneys normally resolves
within the first 1 to 10 wk posttransplantation (85). The three
most common causes of persistent proteinuria after kidney
transplantation are CAN, recurrent glomerulonephritis, and
drug-related nephrotoxicity (27,68,8789). Renal vein thrombo-
sis and reflux nephropathy are less common causes of protein-
uria after transplantation (Table 3).
Proteinuria reflects the severity of the underlying glomerular
and tubulointerstitial injury. Presumably, proteinuria also con-
tributes to ongoing transplant dysfunction and fibrosis through
putative mechanisms that involve aberrant proximal tubule
protein uptake and tubular cell toxicity (90,91). It is striking that
despite the evidence that demonstrates the significance of pro-
teinuria in native kidneymediated disease, only recently has
proteinuria been examined in depth in kidney transplantation.
In general, it is an independent risk factor for disease progres-
sion, graft failure, and patient death after kidney transplanta-
tion (27,8690,92). It is interesting that proteinuria may be a
clinical surrogate for predicting outcomes in conjunction with
medication changes. Urinary protein excretion 800 mg/d is
the only independent predictor of negative outcomes in pa-
tients with chronic allograft dysfunction, converted from CNI
to sirolimus (50). Transplant patients therefore should be eval-
uated regularly for proteinuria every 6 to 12 mo after the first
year posttransplantation (27). Because of the cost-effectiveness
of these laboratory tests, we suggest that a spot urine protein/
creatinine be obtained along with a urinalysis at each actual
clinic visit.
Several studies suggest that ACE-I and ARB can have a
beneficial effect in prolonging allograft survival, especially in
transplant recipients with CAN and proteinuria (73,9395). It is
important to strive for BP control (130/80 mmHg and poten-
tially lower if proteinuria is 1 g/24 h) (96) and to look for
possible adverse effects when using these agents. Although up
to a 30% increase in serum creatinine levels after the initiation
of antiproteinuric therapy may be acceptable (97), careful mon-
itoring of kidney function, hematocrit (Hct), and serum potas-
sium levels is warranted as these drugs may result in acute
kidney failure, anemia, and hyperkalemia in kidney transplant
recipients (14).
Cardiovascular and Peripheral Vascular
Disease
It is important to recognize that these entities are intertwined
in terms of pathogenesis and outcomes. CVD is the principal
cause of death in kidney transplant recipients (Figure 2)
(9,10,12,96,98,99). Mortality related to cardiovascular causes ac-
counts for nearly one quarter (23%) of all-cause mortality by 15
yr posttransplantation (100). Of note, even a nonfatal posttrans-
plantation myocardial infarction may predict future graft fail-
ure and death (101). Peripheral vascular disease (cerebral vas-
cular disease and lower extremity vascular disease) afflicts at
least 15% of all kidney transplant recipients in a 10- to 15-yr
period posttransplantation (100).
Both traditional and nontraditional cardiovascular risk fac-
tors, including the concurrent presence of peripheral vascular
disease, contribute to CVD morbidity and mortality in kidney
transplant recipients (Table 4) (96,102). The NKF K/DOQI work
group on CVD concluded that modifiable risk factors should be
targeted for intervention in these patients (Table 4) (96). Tradi-
tional CVD risk factors are shared risk factors for both CKD and
CVD. Therefore, addressing each should have a dual impact.
Table 3. Proteinuria after kidney transplantation
Common causes
CAN
recurrent/de novo disease
native disease (usually resolved by third month
posttransplantation)
urinary tract infections
Less common causes
renal transplant vein thrombosis
renal transplant artery stenosis
drugs
reflux
Figure 2. Cardiovascular mortality in kidney transplant recipi-
ents. Reprinted with permission from reference (98).
Symptomatic patients should undergo prompt functional
and/or invasive testing even if angiography is required. Intra-
venous hydration with bicarbonate (103) or saline, oral N-ace-
tylcysteine (104), and/or ascorbic acid (105) and withholding
CNI, ACE-I, and ARB for 12 h before angiography likely will
reduce the risk for contrast-induced nephropathy in the allo-
graft. Currently, there is insufficient evidence to recommend
for or against routine periodic screening for asymptomatic
CVD in kidney transplant recipients (27). However, we believe
that individuals who are at high-risk, e.g., two or more tradi-
tional cardiac risk factors or a history of a pretransplantation
cardiovascular event or a positive pretransplantation screening
test may benefit from noninvasive stress imaging every 1 to 2 yr
after transplantation.
Hypertension
Both the seventh report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of high BP
and the K/DOQI clinical practice guidelines on hypertension
and antihypertensive agents in CKD defined normal BP as
120/80 mmHg (97,106). With this definition, the incidence of
posttransplantation hypertension ranges up to 80%. The causes
of posttransplantation hypertension are varied and include
CNI use, prednisone, preexisting hypertension, primary kidney
disease, kidney transplant artery stenosis, and graft dysfunc-
tion (100,107). Systolic and diastolic hypertension both are in-
dependent risk factors for graft and patient loss in kidney
transplant recipients (108110). Surprisingly, no large, random-
ized, controlled studies have demonstrated improved long-
term outcomes by decreasing BP in kidney transplantation, yet
a recent analysis of the Collaborative Transplant Study showed
that lower systolic BP (SBP), even after the first posttransplant
year, was associated with improved graft and patient survival
(111). Patients whose SBP was 140 mmHg at 1 yr posttrans-
plantation but controlled to 140 mmHg by 3 yr had signifi-
cantly improved long-term graft outcome compared with pa-
tients with sustained high SBP (relative risk 0.79; 95%
confidence interval 0.73 to 0.86; P 0.001) (111).
As part of best medical practice, it therefore is appropriate to
treat posttransplantation hypertension to target BP values
whenever possible (27,97,106,112). Both the seventh report of
the Joint National Committee and K/DOQI guidelines recom-
mended a target BP of 130/80 mmHg in patients with CKD,
although only K/DOQI specifically addresses BP targets in
renal transplant recipients (97,106). The American Society of
Transplantation (an older guideline) recommends target BP
levels of 140/90 mmHg (27), and the EBPG recommend man-
datory BP control to levels of 130/85 mmHg in kidney trans-
plant patients without proteinuria and 125/75 mmHg in pro-
teinuric patients (112).
Lifestyle modifications are necessary and should include
weight reduction, a DASH (Dietary Approaches to Stop Hyper-
tension) eating plan, dietary sodium reduction, and physical
activity (97). All classes of antihypertensive drugs have been
used in transplant patients, yet no preferred agents are offered
by any of the guidelines. Initial efficacy studies suggested that
calcium channel blockers might have greater benefit in achiev-
ing BP control and limiting graft loss (107,113), but it has not
been shown that calcium channel blockers have a clear benefit
over ACE-I on long-term kidney allograft function and survival
(112). Furthermore, these drugs may be involved in the devel-
opment of edema and CsA-induced gingival hyperplasia (114).
On the basis of the effect of ACE-I and ARB in slowing the rate
of progression in patients with CKD, several groups have used
these agents in CAN, proteinuria, and underlying heart disease
posttransplantation (73,9395,115117). These studies have dis-
sipated initial concerns regarding the safety of ACE-I and ARB
because no significant hyperkalemia or acute changes in kidney
function were observed. However, caution is advised in indi-
viduals with preexisting hyperkalemia, anemia, and suspected
transplant renal artery stenosis (118). The use of diuretics in
hypertensive renal transplant patients may be effective and
often is necessary in combination therapies. These drugs may
result in hypercalcemia, hyponatremia, hyperuricemia, and im-
paired glucose/lipid metabolism in a high-risk group of pa-
tients.
In summary, a target BP of 130/80 mmHg with lower BP
levels (125/75 mmHg if proteinuria 1 g/d) is recommended
in renal transplant recipients (Figure 3). ACE-I and ARB may be
used safely as preferred agents in patients with proteinuria
(urine protein:creatinine ratio 200 mg/g), tolerating up to a
35% rise in baseline serum creatinine levels. Combination ther-
apy frequently is required to control posttransplantation hyper-
tension (96,97,106,110); regardless of the agents selected, a close
follow-up (weekly for 2 wk, then monthly) of BP, serum creat-
inine, electrolytes, and hemoglobin (Hb) levels (in case of
ACE-I and ARB use) is recommended. It is advised to avoid
making changes in BP medications concomitant (within 1 wk)
with changes in immunosuppression. This may complicate the
differential diagnosis in case of a rapid rise in serum creatinine
levels.
Dyslipidemia
Dyslipidemia, alone or as part of the metabolic syndrome, is an
established risk factor for CVD mortality in kidney transplant
recipients (27,119121), as it is in the general population. Post-
Table 4. Traditional and nontraditional risk factors for
CVD in renal transplant recipients
Traditional Risk
Factors
Nontraditional Risk
Factors
Older age Decreased kidney function
Male gender CNI
Family history of CVD Proteinuria
Diabetes Anemia
Hypertension C-reactive protein
Dyslipidemia Oxidative stress
low HDL Advanced glycation end products
high LDL Inflammation
Physical inactivity Homocysteine
Left ventricular
hypertrophy
Uric acid
Hyperparathyroidism
Menopause Obesity
Tobacco use Thrombogenic factors
transplantation hyperlipidemia affects 60 to 80% of patients (122)
and is associated with immunosuppressive treatment, including
sirolimus, corticosteroids, and CsA (121123). Other factors, such
as preexisting familial dyslipidemia, obesity, kidney dysfunction,
proteinuria, and diabetes, also contribute to posttransplantation
hyperlipidemia (121,124). Retrospective studies have reported
posttransplantation dyslipidemia as a risk factor for long-term
graft loss (125). However, the Assessment of Lescol in Renal
Transplant (ALERT) trial, the only randomized, double-blind, pla-
cebo-controlled study to examine the role of a statin on renal end
points, found no significant effect of fluvastatin on kidney trans-
plant outcomes (126). In a post hoc analysis of this trial, fluvastatin
significantly decreased the incidence of myocardial infarction and
cardiac death (127). Other studies have shown similar findings in
that statins can improve patient survival by an average of 24%
among kidney transplant recipients (128).
The evaluation and treatment of posttransplantation dyslip-
idemia should be based on the National Cholesterol Education
Program III and the NKF K/DOQI clinical practice guidelines
(119,121). Dyslipidemia in kidney transplant recipients should
be evaluated at baseline, 2 to 3 mo after a change in treatment,
and at least annually thereafter (121). Recommended goals are
target LDL, non-HDL cholesterol, and triglyceride levels of
100, 130, and 150 mg/dl, respectively (121). Treatment op-
tions include modification of the immunosuppressive regimen
when possible, therapeutic lifestyle changes, statins, fibrates,
nicotinic acid, and bile acid sequestrants (121).
All statins can provide a 30 to 40% reduction in LDL choles-
terol levels. Patients who require maximal LDL cholesterol
lowering may be treated with atorvastatin or simvastatin,
whereas patients with low HDL cholesterol may have a greater
advantage from simvastatin use and those with elevated trig-
lycerides may benefit from high-dose atorvastatin. The final
choice of statins should be left to the judgment of the treating
physician. For the treatment of hypertriglyceridemia, particu-
larly in patients who are treated with sirolimus, gemfibrozil
may be the fibric derivative of choice (121). Although nicotinic
acid derivatives also could be used, fibric acid derivatives are
better tolerated (121). Bile acid sequestrants such as cholestyra-
mine, colestipol, and colesevelam hydrochloride alter the bio-
availability of immunosuppressants and also may increase tri-
glyceride levels (121). Ezetimibe was used recently alone and in
combination with statins to reduce LDL cholesterol in a small-
size study with renal transplant patients (129). However, larger
clinical trials are required to establish the safety and the efficacy
of this drug in kidney transplantation. Antilipemic drugs may
have significant interactions between the classes and with im-
munosuppressant agents. Statins and fibrates interact with CNI
and may result in hepatitis, myositis, and rhabdomyolysis
(121,124). The prevalence of these untoward effects is minimal
in our contemporary era of immunosuppression in the absence
of high-dose fibrate or statin therapy and with close monitoring.
In summary, adult renal transplant recipients with hypertri-
glyceridemia (triglycerides 300 mg/dl, or 5.65 mmol/L) may
be treated with fibrates, and statins can be used for LDL cho-
lesterol levels of 100 mg/dl (2.59 mmol/L; Figure 4). Treat-
ment of proteinuria and other causes of secondary dyslipide-
mia, along with therapeutic lifestyle changes including diet and
physical activity, always should be combined. It monitoring of
treatment efficacy and observing for clinical and biologic signs
of myositis and hepatitis with most current antilipemic agents
are recommended.
Diabetes
New-onset diabetes after transplantation (NODAT) is de-
fined using the definition of diabetes and impaired glucose
tolerance by the World Health Organization and the American
Diabetes Association (www.diabetes.org) (130,131). Fasting
plasma glucose levels 126 mg/dl (7 mmol/L) or 2-h plasma
glucose levels 200 mg/dl (11.1 mmol/L) during an oral glu-
cose tolerance test defines diabetes (130,131). NODAT has a
high incidence in kidney transplant recipients (up to 25%) and
significantly decreases patient and graft survival (132135), and
its prevalence increases continuously with time. Immunosup-
pressive therapy with tacrolimus, older recipient age, deceased-
donor status, hepatitis C, rejection episodes, black race, and
higher body weight all are independent risk factors for NODAT
(Table 5) (132,135,136).
Figure 3. BP management after the first posttransplant year.
Figure 4. Dyslipidemia management after the first posttrans-
plant year.
The International Consensus Guidelines on New-Onset Dia-
betes after Transplantation recommended management strate-
gies to reduce onset and complications are available on the
International Diabetes Federation web site (http://www.
idf.org) (131). Regular evaluation for diabetic retinopathy, ne-
phropathy, and neuropathy should be performed, and appro-
priate measures should be taken. Therapy for all kidney trans-
plant recipients with diabetes should be directed at achievable
targets, including BP 130/80 mmHg, fasting plasma glucose
126 mg/dl, glycosylated Hb 6.5g/dl, urine protein:creati-
nine ratio 200 mg/g, and LDL 100 mg/dl (131,137).
In summary, NODAT has been identified as one of the most
important factors associated with reduced graft function and
patient and graft survival. International Consensus Guidelines
on New-onset Diabetes after Transplantation recommend a
multifaceted approach of weight control, diet and exercise, oral
agent mono- or combination therapy and insulin use for tight
glycemic control (Figure 5) (131). Sulfonylureas, meglitinides,
biguanides, thiazolidinediones, and -glucosidase inhibitors all
may be used depending on the individual characteristics of the
patient and risk for possible side effects (Figure 5) (131,137).
Proteinuria, dyslipidemia, hypertension, and anemia should be
treated accordingly.
Anemia
The American Society of Transplantation defines anemia as
Hb levels of 13 g/dl (Hct of 42%) for male patients and 12
g/dl (Hct of 37%) for female patients (27). The NKF K/DOQI
clinical practice guidelines define anemia as Hb levels 12 g/dl
(Hct of 37%) for male patients and 11 g/dl (Hct of 33%) for
premenopausal women and prepubertal patients (138). Anemia
is a common complication after kidney transplantation, with an
incidence approximating 30 to 40% (139141). It may result
from inadequate erythropoietin production; iron deficiency;
malignancies; oxidative stress/inflammation; hemolytic and
uremic syndrome; and viral infections, including CMV and
Parvovirus B19 infections (Figure 6) (139141). Drugs such as
sirolimus, mycophenolate mofetil, azathioprine, ACE-I, and
ARB are the principal agents that are responsible for late post-
transplantation anemia (118,139142). Although late (1 yr
posttransplantation) anemia has been reported as an indepen-
dent risk factor for cardiovascular morbidity and mortality in
this patient population (143145), there is insufficient evidence
at present as to whether aggressive anemia management can
improve outcomes. Pending the results of prospective, random-
ized trials to determine optimal Hb/Hct levels in kidney trans-
plant recipients, the K/DOQI recommendations for the man-
agement of anemia in patients with CKD may be the best
guideline (138).
In the late posttransplantation period, Hb/Hct levels should
be checked monthly. Anemia workup should be started for Hb
levels 12 g/dl, and treatment with erythropoietic-stimulating
agents (ESA) should be started for Hb 11 g/dl. Target recom-
mended Hb (Hct) should be the same as in patients with CKD
(138), i.e., between 11 (33%) and 12 g/dl (36%), pending the
results of prospective, randomized trials. The current recom-
mended subcutaneous dose of epoetin- in dialysis patients is
80 to 120 IU/kg per wk in two to three divided doses (138). In
renal transplant recipients with anemia, ESA may be dosed
Table 5. Risk factors for NODAT
a
Recipient characteristics
older age (45 yr)
higher body mass index (30)
black race
family history of diabetes
Hispanic ethnicity
education (no college degree)
Donor
deceased donor
male gender
Transplant era (after 1995)
Tacrolimus use
HLA mismatch
Acute rejection
HCV infection
a
HCV, hepatitis C virus; NODAT, new-onset diabetes after
transplantation.
Figure 5. Diabetes management after the first posttransplant
year.
Figure 6. Common causes of posttransplantation anemia. MMF,
mycophenolate mofetil; AZA, azathioprine; CMV, cytomegalo-
virus; TMA, thrombotic microangiopathy.
weekly and their dose changed monthly if needed. If the rise in
Hct after ESA therapy has been 2% during a 2- to 4-wk
period, then the ESA dose should be increased by 50% (138).
Conversely, if Hct levels increase 8% or if the Hb/Hct exceeds
the target Hb/Hct, then the weekly dose should be decreased
by 25%. Abrupt discontinuation of ESA therapy may result in a
collapse of erythropoiesis. Iron supplementation (oral/intrave-
nous) is required for transferrin saturation 20% and/or fer-
ritin levels 100 ng/ml (138).
In summary, posttransplantation anemia is a prevalent com-
plication and an independent risk factor for cardiovascular
morbidity and mortality in kidney transplant recipients. Ane-
mia workup should be initiated for Hb levels 12 g/dl, and
treatment should be targeted to a goal Hb between 11 and 12
g/dl. This goal may be achieved by the removal of causal
agents (Figure 6), oral/intravenous iron supplementation, and
ESA (138,146149).
Bone Metabolism and Disease
Almost all kidney transplant recipients have some degree of
osteodystrophy (disorders of bone remodeling and modeling)
that persists after kidney transplantation (27,150153). The in-
cidence of osteoporosis (bone mineral density 2.5 SD below
the young adult mean value or T score) approximates 60%, and
it results in significant morbidity and mortality, including avas-
cular necrosis and fractures (27,150,151). Maximum bone loss
occurs within the first 3 to 6 mo posttransplantation and con-
tinues during the later stages at a slower rate. Etiologic features
include treatment with corticosteroids and CNI, previous os-
teodystrophy, persistent hyperparathyroidism, hypogonadism,
metabolic acidosis, and smoking (150,151).
Current management recommendations are based on the
available clinical trials and extrapolation from findings in pa-
tients with CKD (151,152,154,155). The cornerstone of these
recommendations is regular follow-up of serum calcium, phos-
phorus, and intact parathyroid hormone levels and annual (at
least during the first 3 yr posttransplantation) assessment of
bone mineral density with dual energy x-ray absorptiometry
scan of the lumbar spine and the dominant hip. Treatment
strategies to reduce bone loss include testosterone/estrogen
replacement when appropriate, elemental calcium and vitamin
D, phosphate binders, correction of metabolic acidosis, weight-
bearing exercise, and oral or intravenous bisphosphonates
(151,152,154,155). Although these strategies result in the pre-
vention of bone loss, a recent meta-analysis of clinical trials that
used bisphosphonates, vitamin D analogues, calcitonin, and
hormone replacement therapy showed no benefit from any
intervention to reduce the incidence of fractures in kidney
transplant recipients (156). Despite recommendations for the
early use of bisphosphonates (152), these antiresorptive agents
present a clear risk for adynamic bone disease (157) and should
be used cautiously in patients with impaired kidney function
after the first year.
The management of tertiary hyperparathyroidism (HPTH)
after transplantation also may be challenging. The EBPG for
renal transplantation recommend that individuals with tertiary
HPTH be observed for 1 year after transplantation whenever
possible to allow for a spontaneous involution (158). After the
first year, persistent HPTH may be treated by surgical parathy-
roidectomy (159), although this procedure may result in de-
creased kidney allograft function through mechanisms that
remain to be defined (160,161). Recently, calcimimetic cinacal-
cet was used to normalize posttransplantation hypercalcemia in
patients with persistent HPTH (162,163). This drug may present
a reasonable alternative to surgical parathyroidectomy. How-
ever, its safety and effectiveness need to be examined in larger
clinical trials.
Infections
Infections remain the second most common cause of death in
kidney transplant recipients (9,10,12,13,27,164). The risk for
infection in these patients is determined primarily by the in-
tensity of exposure to potential pathogens and the net state of
immunosuppression (165). Overall, the most prevalent oppor-
tunistic infections are viral, and CMV is the primary virus
involved. However, a host of community-acquired and oppor-
tunistic bacterial, viral, and fungal infections may occur at
different rates depending on the period after transplantation.
After the first posttransplant year, the majority of patients
benefit from good allograft function and are maintained on
minimal immunosuppression. Community-acquired respira-
tory infections are the principal cause of infectious complica-
tions, as in the general population. Opportunistic infections are
uncommon in this setting except when there is intense expo-
sure to environmental pathogens (165). In a group of patients
with chronic, progressive viral infections (CMV, Epstein-Barr
virus, papillomavirus, HBV, or HCV), signs of progressive
organ damage may be observed (liver or skin cancer or retinitis
with CMV). Finally, a small proportion of individuals may
receive increased immunosuppression for acute rejection epi-
sodes. These patients are at high risk for severe opportunistic
infections, including Pneumocystis carinii, Listeria monocytogenes,
Nocardia asteroides, Cryptococcus neoformans, and aspergillus
(165).
To reduce the burden of infection-related morbidity and
mortality, the American Society of Transplantation has devel-
oped infectious disease guidelines for the prevention and man-
agement of infectious complications of solid-organ transplan-
tation (166). In addition, guidelines on vaccinations, drug
interactions with anti-infective agents, and strategies for safe
living after organ transplantation are available on the American
Society of Transplantation web site (http://www.a-s-t.org/
mobile/index.htm). Briefly, patient vaccination status should
be reviewed at the first clinic visit, and a vaccination strategy
should be developed, keeping in mind that live vaccines are not
given after transplantation and that patients, close contacts, and
family members should receive injectable influenza vaccine
yearly (inhaled influenza vaccine should not be given to trans-
plant recipients or family members). Pneumococcal polysaccha-
ride vaccine should be administered before transplantation and
repeated every 3 to 5 yr after initial vaccination. Vaccination
series should be restarted approximately 6 mo after transplan-
tation, and efficacy should be documented by serologic assays
when available. Finally, adult travelers after kidney transplan-
tation need appropriate counseling and vaccinations before
their trip (167).
In brief, infection and rejection are the two ends of the net
state of immunosuppression in kidney transplant recipients. A
primary goal is the prevention and/or effective treatment of
infection. After the first year posttransplantation, most com-
mon infections are community-acquired respiratory infections.
In subgroups of patients who have chronic viral infections or
are receiving increased immunosuppression for late rejection
episodes, there is greater risk for malignancies and opportunis-
tic infections. Close monitoring of these patients is required for
early diagnosis of complications. Preventive strategies are nec-
essary and encompass counseling and vaccinations.
Malignancies
Posttransplantation malignancies are a major cause of mor-
tality in kidney transplant recipients (10,14,99). These individ-
uals have a significantly increased risk for malignancies com-
pared with age-matched healthy control subjects and even
patients who have ESRD and are on the waiting list for a
transplant (27,168170) (Figure 7). General and more trans-
plant-specific factors contribute to the increased incidence of
malignancies in this patient population. These include age,
smoking, immunosuppression, and chronic viral infections
(169171).
The relative risk for cancer depends on the type of malig-
nancy. It ranges from a two- to three-fold increase for common
malignancies such as lung, prostate, breast, and colon to up to
a 100-fold increase for entities such as Kaposis sarcomas, post-
transplantation lymphoproliferative disease and nonmelano-
matous skin cancers (168170) (Figure 7).
After the first posttransplant year, kidney transplant recipi-
ents should undergo annual or biannual skin examination.
Age-appropriate annual prostate-specific antigen measure-
ments, fecal occult blood testing, digital and rectal examina-
tions, breast examination and mammography, and colonoscopy
are indicated as in the nontransplant patient. Unique screening
may include hepatobiliary ultrasound and serum -fetoprotein
measurements (history of HBV or HCV) as well as cystoscopy
(history of cyclophosphamide use; Table 6) (27,169). In addition
to specific antitumor therapy, treatment strategies for post-
transplantation malignancies include decreasing or modifying
the immunosuppressive regimen (169,172,173). The antiprolif-
erative characteristics of sirolimus may have a salutary impact
on the treatment of some of these malignancies. In a recent
report, regression of cutaneous Kaposis sarcoma was observed
after a switch from a CsA mycophenolate mofetil regimen to
a regimen based on sirolimus in 15 kidney transplant recipients
(173). Sirolimus use has also been associated with decreased
incidence of cancer (including skin cancers) in the first 2 yr
posttransplantation (174).
In summary, with the growing number of kidney transplant
recipients, the prevention, early diagnosis, and treatment of
posttransplantation malignancies remain an important chal-
lenge to both the transplant and the primary care communities
(Figure 7, Table 6). The development of any malignancy should
mandate contact with the transplant center to coordinate the
overall approach to the patient, including tapering of immuno-
suppression.
Obesity and Metabolic Syndrome
Overweight and obesity, defined by a body mass index 25
and 30 kg/m
2
, respectively, present a major quandary after
kidney transplantation (159). Similar to the trend in the general
population, 60% of current kidney transplant recipients are
overweight or obese at the time of transplantation, representing
a 116% increase from 1987 (175). A significant number of pa-
tients gain additional weight after transplantation: The average
weight gain in the first posttransplant year was reported re-
cently to be approximately 3 kg (176). Both posttransplantation
weight gain and obesity are associated with decreased long-
term allograft and patient outcomes (176180). Although it
Figure 7. Posttransplantation malignancies. EBV, Epstein-Barr virus; HPV, human papillomavirus; HBV, hepatitis B virus; HBC,
hepatitis C virus; NHL, non-Hodgkins lymphoma; Skin (NM), skin cancer (nonmelanomas).
remains unknown whether it is the higher incidence of cardio-
vascular comorbid conditions that affects graft outcomes or
obesity-specific issues (hyperfiltration and glomerulopathy),
most studies report a higher likelihood of premature death and
graft loss in obese kidney transplant recipients (176181). Fe-
male, young, black, low-income patients with type 2 diabetes
are at the highest risk for posttransplantation obesity (175,182).
The EBPG considers obesity as a risk factor for increased CVD
after transplantation and recommends lifestyle measures to
address the epidemic (179). However, this complex problem
requires a multifaceted approach and a combination of diet,
exercise, minimization of steroid therapy, and psychologic sup-
port often is needed. Gastric bypass surgery may be a safe and
effective means for achieving significant long-term weight loss
and relief of comorbid conditions after transplantation
(183,184). This approach should be reserved for resistant cases
and requires close collaboration with the transplant center.
The metabolic syndrome (MS) is a condition of impaired
glucose and insulin metabolism, overweight and abdominal fat
distribution, mild dyslipidemia, and hypertension. It is preva-
lent in the US population (age-adjusted prevalence 25%) and is
associated with subsequent development of type 2 diabetes and
CVD (185,186). The working definition of the National Choles-
terol Education Program Expert Panel Adult Treatment Panel
III defines MS as a condition with three or more of the follow-
ing: (1) Waist circumference 102 cm in men and 88 cm in
women, (2) serum triglyceride level 150 mg/dl (1.69 mmol/L),
(3) HDL cholesterol level 40 mg/dl (1.04 mmol/L) in men
and 50 mg/dl (1.29 mmol/L) in women, (4) BP 130/85
mmHg, and (5) serum glucose level 110 mg/dl (6.1 mmol/L)
(187). Data to address the role of MS in kidney transplantation
are scarce (120,188,189). It seems that up to 63% of renal trans-
plant recipients experience MS at a median time of 6 yr post-
transplantation (120). Obesity is a risk factor for developing MS
in kidney transplant patients (188), and waist circumference has
been found to be an independent determinant of inflammation
measured by C-reactive protein levels in these patients (189). A
recent study showed that MS is associated with impaired kid-
ney allograft function after the first posttransplant year, but
only SBP and hypertriglyceridemia seemed to be associated
independently with the decline in kidney function (120).
In summary, weight gain, obesity, and MS are prevalent after
the first posttransplant year. Although there is an association
between these conditions and decreased long-term patient and
allograft outcomes, it remains unknown whether there is un-
derlying causality. A multifaceted approach that includes a
combination of diet, exercise, minimization of steroid therapy,
psychologic support, and gastric bypass surgery may be re-
quired to address this growing epidemic in renal transplant
patients.
Quality of Life and Nonadherence
Kidney transplantation produces greater improvements in
quality of life (QOL) than does dialysis (190,191). A meta-
analysis of prospective studies that evaluated QOL before and
after kidney transplantation found consistent improvement
among the posttransplantation population (192). When specific
domains of QOL were examined, 78% of the studies found
improvement in physical functioning, 85% in mental health,
and 63% in social functioning (192). However, despite such
evidence, many kidney transplant recipients experience ad-
verse effects that affect life satisfaction and QOL (193195).
Sixty-six percent of kidney transplant recipients reported easy
bruising/slow wound healing, 61% noted adverse effects re-
lated to sexuality, and 50% related problems secondary to
changes in physical appearance (193,194).
Transplant recipients are required to take immunosup-
pressive treatment for the rest of their lives, and, unfortu-
nately, adherence to this regimen often is suboptimal. This
may have dramatic effects on graft and patient outcomes
because up to 91% of nonadherent patients may experience
graft loss or death (196). A recent meta-analysis of 325 stud-
ies that were published from 1980 to 2001 and reported the
frequency and impact of nonadherence in adult renal trans-
plant recipients showed that a median (interquartile range)
of 22% (18 to 26%) of recipients were nonadherent and that
the odds for graft failure increased seven-fold (95% confi-
dence interval 4 to 12%) in nonadherent patients compared
with adherent patients (197). Psychosocial and financial bar-
riers often contribute to poor adherence with medications;
however, these are not the only factors: A 1-yr posttrans-
Table 6. Screening for malignancies after the first year posttransplantation
a
Screening Frequency 30 Days 6 Months 12 Months 5 Years
Skin and lip Self-exam Physical
Anogenital Physical, pelvic
PAP smear biopsy
Uterine cervix Pelvic, PAP smear
Sarcomas (including Kaposis) High-risk ethnic
groups
Skin, conjunctiva, oropharyngeal
mucosa biopsy
PTLD Self-exam Physical
Hepatic (HCV and HBV patients) -fetoprotein
Breast Self-exam Physical, mammogram
Colorectal Colonoscopy
Prostate Rectal, PSA
a
HBV, hepatitis B virus; PAP, Papanicolaou; PSA, prostate-specific antigen; PTLD, posttransplantation lymphoproliferative
disease.
plantation compliance rate of only 48% was reported in a free
multidrug immunosuppressive clinic (198).
Conclusions
Kidney transplantation is the optimal treatment for patients
with ESRD; however, despite improvements in short-term pa-
tient and graft outcomes, there has been no major improvement
in long-term outcomes. There is a need for collaboration among
the transplant center, community nephrologists, and primary
care physicians who are involved in the long-term care of these
patients to enhance these outcomes. A number of public re-
sources that provide clinical practice guidelines for the treat-
ment of these patients are available on the Internet (Table 7).
Prevention and early management of disease progression, car-
diovascular complications, infections, and malignancies consti-
tute the cornerstone of this collaborative effort to extend life
span and allograft function.
Acknowledgments
Parts of this work were supported by an American Society of Trans-
plantation/Fujisawa Fellowship Award (A.D.); American Heart Asso-
ciation grant 0235290N (M.S.); and National Institutes of Health grants
KO8-DK067981 (A.D.), RO1-AI49285-05 (B.N.B.), and K24-DK616962-04
(B.N.B.).
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Table 7. Useful Internet resources
American Diabetes Association (ADA) http://www.diabetes.org/homepage.jsp
American Society of Nephrology (ASN) http://ww.asn-online.org
American Society of Transplantation (AST) http://www.a-s-t.org
European Best Practice Guidelines (EBPG) http://www.ndt-educational.org/guidelines.asp
International Diabetes Federation (IDF) http://www.idf.org
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In-Depth Review

Medical Care of Kidney Transplant Recipients after the First

staining in the pericapillary tubules, intimal fibrosis with in-

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