Cardiovascular Complications After Renal

Transplantation and Their Prevention

Akinlolu O. Ojo
By the time of renal transplantation, end-stage renal disease patients have a huge burden of cardiovascular disease
(CVD) andare heavily saturatedwithatherosclerotic risk factors. Worsening of preexisting risk factors or newCVDrisk
factors may develop in the posttransplant period consequent in part to the diabetogenic and atherogenic potential of
immunosuppressive drugs. The annual risk of a fatal or non-fatal CVD event of 3.5 to 5% in kidney transplant
recipients is 50-fold higher than the general population. Renal allograft dysfunction, proteinuria, anemia, moderate
hyperhomocysteinemia and elevated serum C-reactive protein concentrations, each dependently confer greater risk of
CVD morbidity and mortality in the posttransplant period. Long-term care of renal transplant recipients should
programmatically incorporate the recommendations of the National Kidney Foundation Working Groups and Euro-
pean Best Practice Guidelines Expert Group on Renal Transplantations into the management of hypertension, dyslip-
idemia, smoking, and posttransplant diabetes mellitus. Timely utilization of coronary revascularization procedures
should be undertaken as these treatments are equally effective in the kidney transplant population.
(Transplantation 2006;82: 603611)
A
lthough successful renal transplantation is accompanied
by a 10- to 20-year increase in life expectancy (1, 2), the
survival of kidney transplant recipients is significantly short-
ened by atherosclerotic cardiovascular disease (CVD) (3, 4).
The annual risk of a CVD death is 3.5% to 5% in renal trans-
plant recipients, which is 50-fold higher thanthe general pop-
ulation (57). Similarly, the incident cases of congestive heart
failure are three times more likely after kidney transplanta-
tion compared to the general population (8). Stroke accounts
for nearly half of posttransplant CVDdeaths and extracranial
cerebrovascular atherosclerosis occurs four times more fre-
quently in renal transplant recipients compared to controls
(24.5% vs. 6.2%, P0.001) (911). Acute coronary syn-
drome is highly prevalent in the early posttransplant period
and on the average, CVD mortality accounts for 30% and
75% of early and late posttransplant deaths, respectively (6,
12, 13). The durable improvement in allograft survival fol-
lowing the introduction of calcineurin inhibitors has been
accompanied by longer life expectancy, which presents the
opportunity for renal transplant recipients to face a greater
prospect of premature CVD death with a functioning graft
rather than immunologic graft failure and resumption of di-
alysis, which was more prevalent in the early eras (14). Pa-
tients undergoing renal transplantation are already heavily
burdened by a high risk of CVD and they encounter several
factors in the posttransplant period that further accentuate
the prevalence and severity of several CVD risk factors. The
probability of CVD mortality is only modestly reduced in
kidney transplant recipients when compared to dialysis pa-
tients on the kidney transplant waiting list (15, 16). This re-
view focuses on the role of traditional and novel CVD risk
factors and on the primary and secondary preventative strat-
egies available for the management of posttransplant cardio-
vascular disease in the renal transplant population.
Risk Factors for Cardiovascular Disease
Table 1 shows the prevalence of traditional CVDrisk fac-
tors in all dialysis patients, end-stage renal disease (ESRD) pa-
tients eligible for kidney transplantation, and kidney transplant
recipients. Although many of these risk factors may have con-
tributed to the development and progression of the underlying
renal disease, these predisposing factors do not remit following
the successful treatment of the uremic state with kidney trans-
plantation in part because posttransplant immunosuppression,
comorbid conditions, intercurrent illnesses, level of renal allo-
graft function, and patient behavior contribute variously to the
acquisition of new CVD risk factors and/or the aggravation of
existing ones (1723). In addition, novel CVD factors such as
hyperhomocysteinemia, oxidative stress, lupus anticoagulant
antibodies, systemic inflammation, proteinuria, and advanced
glycosylation end products (AGES) have been implicated in the
pathogenesis of CVDin kidney transplant recipients (7, 2429).
The current understanding of the epidemiology, pathophysiol-
ogy, and management of major risk factors for CVD are now
described.
Hypertension
Hypertension, defined as systemic blood pressure (BP)
140/90 (JNC VII) (30), is the most prevalent CVD risk fac-
tor inkidney transplant recipients, affecting 7590%of recip-
ients (20, 3133). Three recent observational studies suggest a
12% increase risk of fatal or nonfatal CVD event for every 1
mm Hg increase in systolic blood pressure (6, 31, 34). Multi-
ple factors contribute to the pathogenesis of posttransplant
hypertension including pretransplant hypertension, high
body mass index, primary kidney disease, quality of donor
organ, delayed graft function, acute rejection, calcineurin in-
hibitor therapy, glucocorticoids, transplant renal artery ste-
nosis and chronic allograft nephropathy (3437). Indirect
evidence suggests that the most potent etiologic factors for
posttransplant hypertension are pretransplant hypertension
and calcineurin inhibitor therapy. Up to half of the patients
had hypertension prior to transplantation either as primary
Department of Medicine, University of Michigan, Ann Arbor, MI.
Address correspondence to: Akinlolu O. Ojo, M.D., Ph.D., University of
Michigan Medical Center, Division of Nephrology, 3914 Taubman Cen-
ter, Box 0364, Ann Arbor, MI 48109-0364.
E-mail: aojo@umich.edu
Received 12 May 2006. Revision requested 26 May 2006.
Accepted 2 June 2006.
Copyright 2006 by Lippincott Williams & Wilkins
ISSN 0041-1337/06/8205-603
DOI: 10.1097/01.tp.0000235527.81917.fe
Transplantation Volume 82, Number 5, September 15, 2006 603
cause of kidney failure or secondary to chronic kidney disease
(5). The prevalence of posttransplant hypertension was sig-
nificantly lower (5060%) prior to the introduction of cal-
cineurin inhibitors in 1983 (33, 38). Calcineurin inhibitors
promote intense afferent arteriolar vasoconstriction via stim-
ulation of the sympathetic nervous system and by upregulat-
ing the local rennin angiotension aldosterone system(39, 40).
Furthermore, calcineurin inhibitors mediates a reduction in
vasodilator prostaglandin, nitric oxide, and increased elabo-
ration of other vasoconstrictor cytokines including adenosine,
thromboxane A2, cysteinyl leukotrienes, platelet-derived growth
factor, and endothelin-1 (4143). Sodium and water reten-
tion mediated by glucocorticoid therapy also contribute to
posttransplant hypertension and may account for 15% of the
risk of posttransplant hypertension in kidney recipients (44).
The etiologic roles of calcineurin inhibitors and glucocorti-
coids present an attractive therapeutic target for the manage-
ment of CVD risk factors as recent clinical trials of transplant
immunosuppression demonstrate significant improvement
in systemic blood pressure control and reduction in the
number of required antihypertensive drugs following the
elimination of calcineurin inhibitor or glucocorticoid from
the maintenance immunosuppressive regimen (4547).
There are no randomized clinical trials of antihyperten-
sive drugs andoptimal bloodpressure goals inkidney transplant
recipients. Basedonlargeclinical trials inthenontransplant pop-
ulation with and without significant renal disease, the National
Kidney Foundation (NKF) KDOQI guidelines include recom-
mended blood pressure goals of 125/75 mmHg for renal trans-
plant recipients with proteinuria and 130/85 mm Hg in the ab-
sence of proteinuria (48).
The management plan for hypertension in the transplant
population should include simultaneous initiation of nonphar-
macologic strategies along with drug therapy. An initial trial of
nonpharmacologic therapy alone may be successful only if the
level of systolic blood pressure is within 10 mm Hg of target BP
and simultaneous initiation of multiple drug therapy should be
considered if the presenting blood pressure readings are 15 mm
Hg higher than target BP (4951). Weight reduction, regular
moderate exercise, dietary sodium, and restriction are essential
(51, 52). The pharmacologic management of hypertension in
renal transplant population presents several unique issues re-
lated to potential drug interactions, drug efficacy, and concur-
rent medical problems. Patients should be stratified by the pres-
enceof proteinuriaanddiabetes mellitus toguidetheselectionof
antihypertensivedrugs (53). Thedihydropyridinecalciumchan-
nel blockers (DHP-CCB) are the most widely utilized class of
drugs, in part because of their putative beneficial effect on cal-
cineurin inhibitor-induced vasoconstriction (5456). DHP-CCB
are potent antihypertensive agents withdocumentedevidence of
CVDprotection in the nontransplant population (57) and have
been demonstrated to be effective in controlling blood pressure
and in preserving graft function in kidney transplant recipients
(55). DHP-CCB are associated with improved renal allograft
functioncomparedtoangiotensinconvertingenzyme inhibitors
(ACEI) in the short and medium terms (56, 58). The use of
DHP-CCB in proteinuric chronic kidney disease patients is as-
sociated with increased risk of renal disease progression and
death except when used in conjunction with angiotensin II
blockade therapy (5961). Long-term cardiovascular protec-
tionappeared to be comparable betweenDHP-CCB, ACEI, and
diuretics in the ALLHAT trial of approximately 40,000 patients
with no significant renal disease or proteinuria (57). The nondi-
hydropyridine calcium channel blockers (non-DHP CCB) are
synergistic withACEI intheir antiproteinuric effect (62, 63). Sig-
nificant dose reductionof the calcineurininhibitors is uniformly
necessary with the non-DHP-CCB. Angiotensin receptors
blockers (ARBs) and ACEI may be particularly attractive in the
kidney transplant population because of their antiproteinuric,
renoprotective, and cardioprotective benefits (6467) but ane-
mia and hyperkalemia may limit the use of optimal dosages of
these drugs ACEI andARB(49). Beta blockers anddiuretics may
be indicated for preexisting CVD and fluid retention respec-
tively, but they both harbor increased potential for metabolic
abnormalities. Bradycardia and blunting of hypoglycemic un-
awareness are serious limiting factor for beta blockers. The larg-
est clinical trial of antihypertensive therapy suggests that thiazide
diuretics should be the preferred initial antihypertensive drug
and this is reinforced by the JNC VII guidelines (51, 57). How-
ever, this recommendation does not apply to renal transplant
recipients, whoareremarkablydifferent fromtheALLHATpop-
ulation (68). In absence of any large clinical trial specifically fo-
cused on kidney transplant recipients, the high prevalence of
proteinuria, diminishedglomerular filtrationrate (GFR), diabe-
tes mellitus, and preexisting CVD should guide the selection of
antihypertensive medication. Specific indications such as pro-
teinuria, graft vasculopathy, or preexisting CVD may warrant
the use of ACEI (or ARB) or beta blockers, respectively, as the
initial agents. Loop diuretics should be added in the presence of
fluid and water retention and poor allograft function. The NKF
working group recommends the use of the JNC VII guidelines
for the management of hypertension in kidney recipients (69).
Cigarette Smoking
Approximately 2530%of kidney transplant recipients
continue to use inhalation tobacco products habitually (17,
70). Smoking increases the risk of CVD death in kidney re-
cipients. The relative risk (RR) of death ranges from 1.56 in
recipients with cumulative smoking history of 1125 pack-
years to a RR of 2.14 for recipients with 25 pack-years (71
74). In the immediate period after allograft implantation,
smoking increased the risk of an acute coronary syndrome by
three- to fourfold (75). In one study, the adverse effects of
smoking dissipated five years after smoking cessation (73).
The immediate postoperative period presents a unique op-
portunity to introduce a smoking cessationprogram. Because
TABLE 1. Prevalence of CVD risk factors in ESRD
patient groups (5, 18, 20, 31, 34, 70, 79, 156158)
Risk factor
Dialysis
patients
(%)
Transplant
candidates
(%)
Transplant
recipients
(%)
Systemic hypertension 80 75 80
Diabetes mellitus 40 35 55
Hypercholesterolemia 25 25 60
Obesity (BMI 30) 14 20 32
Tobacco use 18 24 20
LVH 75 75 52
Anemia (HCT 30%) 32 25 40
604 Transplantation Volume 82, Number 5, September 15, 2006
tobacco use is necessarily terminated during the initial trans-
plant hospitalization, incorporation of smoking cessation
into the early posttransplant care should be essential compo-
nent of the critical pathway preceding discharge. Multifaceted
programs with both behavioral and pharmacologic compo-
nents have been proven to be more effective (76, 77). There
are no documented significant pharmacokinetic interac-
tions between the commonly used immunosuppressants and
tobacco-dissuading drugs.
Dyslipidemia
Hypercholesterolemia is present in 5060% of kidney
transplant recipients (20, 7880). Lipid-lowering therapy de-
crease the risk of cardiovascular events in both primary and
secondary preventions studies in wide range of population
groups (81, 82). The potential benefit of lipid reduction in
renal transplant recipients was demonstrated in the ALERT
study (Assessment of LEscol in Renal Transplantation) in
which 2,102 renal transplant recipients with total cholesterol
4-0-9.0 mmol/L were randomized to fluvastatin 4080
mg/dL versus placebo (83). Fluvastatin lowered low-density
lipoprotein (LDL) cholesterol by 32%. The fluvastatin-
treated patients had a 35% reduction in the incidence of
cardiac death or nonfatal acute myocardial infarction (84).
Figure 1 shows the Kaplan-Meier curves for CVD event rates
between the study groups. In concert with the modified
guidelines of the Adult Treatment Panel III, kidney transplant
recipients should be considered as a high-risk group for ini-
tiation of lipid-lowering treatment and treatment goals. The
recommendation of the NKF Working Group on the man-
agement of dyslipidemia in kidney transplant recipients (Ta-
ble 2) are consistent with the ATP III Panel guidelines and its
recent modifications (85, 86). The NKF working group rec-
ommendations was based on the most comprehensive evalu-
ation of evidence available in the literature and expert opin-
ions and should be considered as main guidelines for clinical
management of dyslipidemia in the kidney transplantation
population. The NKF recommendations cautions against the
use of bile acid sequestrants because of potential interference
with the absorption of immunosuppressive drugs. When bile
acid sequestrants are used as adjunctive therapy, it should be
administered one hour before to four hours after the dose of
calcineurin inhibitors (85). The safety of statins in organ re-
cipients receiving calcinuerin inhibitors and other drugs me-
tabolized in the P450 system is well documented (83, 8791).
Ezetimibe is a newadjunctive agent for lowering LDL choles-
terol that was found to be safe and effective and safe in kidney
transplant recipients in one study of 40 stable kidney trans-
plant recipients (92).
Renal Allograft Dysfunction
DiminishedGFRis anindependent risk for CVDevents
(9395). A 10 ml/min/1.73 m
2
decrease in GFR is associated
with a 610% increase in the risk of a CVD event (93, 95).
This observation is similarly true in renal transplant recipi-
ents (21, 23, 96). Table 3 shows the relationship betweenbase-
line renal allograft function and the risk of CVD event in
kidney transplant recipients in the ALERT study. Strategies
designed to preserve renal allograft functionare likely to ame-
liorate the risk of de novo or recurrent cardiovascular events.
Anemia
It is well established that anemia worsens the severity of
many CVD disorders (congestive heart failure coronary ar-
tery disease and peripheral vascular disease) in the general
population, in patients with chronic kidney disease, and
evidence now showsin kidney transplant recipients (97
99). Anemia is a common problem in kidney transplant
recipients (100102) and it is an independent risk factor
for posttransplant LVH and CVD events (98). Cardiovas-
cular events (myocardial infarction, cardiovascular death,
angina, congestive heart failure) is 35% less likely (RR0.65,
P0.022) in the first six months after transplantation in dia-
betic transplant recipients with hematocrit 30% compared
to those with lower hematocrit levels (103). Single-center and
large multi-institutional studies report anemia prevalence of
3040% at various times after transplantation (101, 104,
105). The Transplant European Survey on Anemia Manage-
ment (TRESAM) survey found a prevalence rate of 38.6% in
4263 kidney transplant recipients from 72 European centers
FIGURE 1. From Andany et al (78). Mean (95% con-
fidence interval) levels of total cholesterol (TC), LDL-
cholesterol, HDL-cholesterol and triglycerides (TG, all
in mmol/L) during the study follow-up period. Placebo
(square) and fluvastatin (circle) groups.
TABLE 2. Management of dyslipidemia in adult kidney transplant recipients (86)
Dyslipidemia Goal Initiate Increase Alternative
TG 500 mg/dL TG 500 mg/dL TLC TLC Fibrate or niacin Fibrate or niacin
LDL 100129 mg/dL LDL 100 mg/dL TLC TLC low dose statin Bile acid seq. or niacin
LDL 130 mg/dL LDL 100 mg/dL TLC low dose statin TLC max. dose statin Bile acid seq. or niacin
TG 200 mg/dL and
non-HDL 130 mg/dL
Non-HDL 130 mg/dL TLC low dose statin TLC max. dose statin Fibrate or niacin
To convert mg/dL to mmol/L, multiply triglycerides by 0.01129 and cholesterol by 0.02586.
TG, triglycerides; LDL, low-density lipoprotein cholesterol; TLC, therapeutic lifestyle changes; seq., sequestrant; max., maximum.
2006 Lippincott Williams & Wilkins 605 Ojo
(100). The high prevalence of posttransplant anemia can-
not be attributed to to uncorrected pretransplant anemia
of CKD as the prevalence five years after kidney transplan-
tation range from 3035% in recipients with functioning
allograft (104).
The etiology of posttransplant anemia is multifactorial:
female gender; calcineurin inhibitors, azathioprine, myco-
phenolate mofetil, sirolimus; poor graft function; older age
group; acute rejection episodes; iron, folate, and vitamin B12
deficiency; recent infection; and angiotensin (II) interrupting
drugs (100, 104, 106, 107). The management of posttransplant
anemia appears to be suboptimal despite the fact that the
major causes of posttransplant anemia are remediable and
the availability of recombinant Human Erythropoietin
(rHuEPO) as an effective drug therapy. According to studies,
only 36% of anemic transplant recipients (Hct 30%) un-
dergo iron studies and less than half of anemic patients are
receiving iron supplementation or rHuEPO (107). Al-
though a significant fraction of posttransplant anemia cases
are due to persistent iron deficiency and immunosuppressive
drug therapy, up to one third of anemia cases in kidney recip-
ients living in developing countries have macrocytic anemia
due to folate and vitamin B12 deficiencies (106). Because of
the link between CVD and posttransplant anemia, effective
management of anemia with supplementation of iron, folate,
vitamin B12, and rHuEPO when indicated is likely to have a
salutary effect on posttransplant CVD. However, caution is
warranted against liberal use of rHuEPO. In kidney trans-
plant recipients with anemia, the use of rHuEPO shortened
the time to achieve target hematocrit but did not have a sig-
nificant impact on the achieved level of hematocrit compared
to non-rHuEPO treated randomized controls (108) and ran-
domized clinical trials in anemic patients with chronic kidney
disease but without kidney transplantation did not demon-
strate improvement in LVH with rHUEPO therapy (109).
Thus, epidemiologic association between LVH and anemia
may not translate into direct benefits inthis conditionfollow-
ing successful treatment of anemia. For these reasons, pro-
spective intervention studies of posttransplant anemia man-
agement would be invaluable to determine the optimal use of
rHuEPO and the potential benefits of anemia treatment on
posttransplant CVD. The role of particularly aggressive pre-
ventative management of posttransplant anemia should also
be tested in high-risk groups such as diabetics and those un-
willing to receive blood transfusions (103, 110).
Hyperhomocysteinemia, Inflammatory Cytokines, and
CD4 Lymphopenia
In parallel with the prevalence of diminished GFR, mod-
erate hyperhomocysteinemia is prevalent in kidney transplant
recipients (25, 28, 111113). Homocysteine is an atherogenic
amino acid that is associated with increased risk of ischemic
heart disease. Several studies have documented that moderate
hyperhomocysteinemia is anindependent riskfactor for CVDin
renal transplant recipients inwhomthe riskof CVDincreasedby
6%for every 1 mol/L increase in total homocysteine level (24,
28, 114). The etiology of hyperhomocysteinemia in renal trans-
plant recipients is not well understood but there is an inverse
relationship between renal allograft function and serumhomo-
cysteine levels (111). Supraphysiologic doses of B-vitamins
can reduce hyperhomocysteinemia in kidney recipients but it is
unclear whether reduction in serum homocysteine concentra-
tionis accompaniedby a reductioninCVDrates (115, 116). The
Folic Acid for Vascular Outcome Reduction in Renal Trans-
plantation study (FAVORIT) is an ongoing clinical trial of
3,000 renal transplant recipients with moderate hyperhomo-
cysteinanemia that should provide a definitive evidence of
potential benefit of CVD reduction with supraphysiologic
doses of vitamin B6 and folic acids in this population. Until
the results of FAVORIT become available in 2008, there is no
basis to treat moderate hyperhomocysteinemia with B-vitamins
as a means to reduce the risk of CVD.
Elevated serum concentrations of C-reactive protein
and sialic acid are independently associated with increased
risk of CVDevents, all-cause mortality, and cardiac mortality
in kidney transplant recipients (26, 117). Bakri et al. found
significantly higher serum concentrations of sialic acid, C-
reactive protein, and fibrinogen in kidney recipients with
CVD compared to those without CVD (117). Single-center
retrospective studies performed by Varagunamet al. revealed
that elevated levels of C-reactive protein was the single most
important predictor of CVD mortality in a series of 115 renal
transplant recipients (26). In this series, CVD death are was
0%, 10%, and22%inkidney recipients withserumC-reactive
protein concentrations of 0 to 5 mg/dL, 5 to 10 mg/dL, and
10 mg/dL, respectively (P0.05). These findings are con-
sistent with recent studies in the general population showing
C-reactive protein and other inflammatory markers as robust
biomarkers andpredictors of ischemic heart disease (27, 118).
Although specific therapies to lower the serum levels of in-
flammatory markers are not yet warranted for preventing
CVD, lowering of serumconcentrations of C-reactive protein
in patients treated with statin for hyperlipidemia is associated
with an independent beneficial effect on the risk of CVD
events (119).
Evidence in HIV patients indicate that intense immu-
nodeficiency states may accelerate atherosclerosis and data
from experimental studies suggest that impairment in T-cell
mediated immunity may contribute to the development and
progression of atherosclerosis (120, 121). Transplant registry
data showed an increased risk of cardiovascular death in renal
transplant recipients treated with T-cell depleting polyclonal
antithymocyte globulins (122). Dulcoux et al. examined
the relationship between peripheral CD4 cell counts and
TABLE 3. Incidences of the endpoints in 1,052 placebo-
treated patients divided into quartiles on the basis of their
baseline creatinine levels (mol/L) (21)
First
(%)
Second
(%)
Third
(%)
Fourth
(%)
Serum creatinine
(mol/L)
111 111134 134167 167
Major adverse
cardiac event
11.5 12.1 11.6 16.0
Cardiac death 4.2 5.1 3.5 8.0
Noncardiovascular
death
5.4 5.1 4.3 10.1
All-cause mortality 11.2 10.9 8.5 22.7
P values have been calculated using univariate Cox regression.
606 Transplantation Volume 82, Number 5, September 15, 2006
atherosclerotic events in 302 renal transplant recipients
and found a linear increase in the risk of CVD events with
decreasing CD4 cell count (123). Multivariate analysis
confirmed that CD4 lymphopenia is an independent risk
factor for cardiovascular complications in renal transplant
recipients. If these findings are confirmed in larger studies,
the use of immunosuppressive drugs with prolonged T-cell
depletion may warrant a reassessment of the risk-benefit
profile of these agents.
Posttransplant Diabetes Mellitus
Diabetes mellitus is a major cause of premature athero-
sclerosis and increased CVD morbidity and mortality. New-
onset insulin resistance and chronic hyperglycemia requiring
treatment with insulin and/or oral hypoglycemic agents is a
common complication affecting 25% of renal transplant re-
cipients (22, 79, 124). A plethora of studies have shown that
kidney transplant recipients who develop posttransplant dia-
betes mellitus (PTDM) are at two- to threefold increased of
fatal and nonfatal CVD events (13, 22, 75, 125127). Risk
factors for development of PTDM include African American
race, posttransplant weight gain, hepatitis C infection, cal-
cineurin inhibitors, glucocorticoid therapy, and hypertension
(22, 79, 128). Tacrolimus is significantly more diabetogenic
compared to cyclosporine with PTDM developing in 20% of
tacrolimus-treated patients compared to 4%in cyclosporine-
treated patients (129). African Americans treated with ta-
crolimus have a 39%risk of PTDMinthe first three years after
transplantation (130, 131).
Because many of the risk factors for PTDM are modifi-
able, excess CVD due to PTDM can be mitigated by: 1) early
diagnosis and treatment with periodic screening of recipients
using fasting serum glucose; 2) behavior management to mini-
mize posttransplant weight gain; 3) use of steroidavoidance reg-
imeninpatients whoare at increasedriskof PTDM; 4) judicious
calcineurin inhibitor minimization and use of calcineurin-free
regimen; 5) aggressive glycemic control including the of multi-
drug hypoglycemic regimen; and 6) periodic surveillance for
CVDin patients with PTDMusing appropriate cardiac imaging
and exercise modalities.
Proteinuria
Proteinuria is prevalent in 2040% of kidney trans-
plant recipients with a functioning allograft (132, 133). It is
nowwell established that abnormal urinary protein excretion
is an independent risk factor for ischemic heart disease in
bothdiabetic andnondiabetic populations (134136). Epide-
miologic studies implicate proteinuria as a more potent pre-
dictor of CVD compared to hypertension, hyperlipidemia,
and male gender (134). Several studies directly implicate pro-
teinuria as an independent predictor of cardiovascular death
in renal transplant recipients (132, 137, 138). Roodnat et al.
found a twofold risk of death in renal transplant recipients
with functioning graft and proteinuria compared to recipi-
ents without proteinuria (137). The 10-year risk of posttrans-
plant CVDis 39.4%vs. 20.9%(P0.001) in proteinuric renal
transplant recipients compared to those without proteinuria
(29). Table 4 shows the prevalence of posttransplant CVD by
proteinuria status (29). Proteinuria appears to be a biomarker
of systemic endothelial dysfunction inherent to the atheroscle-
rotic process (139). Angiotensin converting enzyme inhibitors
and ARBproduce significant reduction in proteinuria in kidney
transplant recipients (67, 140), and the inclusion of these agents
in the antihypertensive regimen of transplant recipients may be
beneficial beyond blood pressure reduction alone.
Other Risk Factors
Left ventricular hypertrophy is present in 5070% of
kidney transplant recipients and is associated with increased
risk of CVD events (141, 142). Obesity is a potent risk factor
for CVD event and death in kidney transplant recipients (16,
71). An increasing fraction of patients on the kidney trans-
plant waiting list have body mass index (BMI) 30. The
average weight gain in the first transplant year posttransplan-
tation range from 2230 pounds with a threefold increase in
the fraction of recipients who attained BMI 30 (from 10%
pretransplant to 30%) (143). Comprehensive weight reduc-
tion program should be undertaken when excessive weight
gain is observed in the posttransplant period as data shows an
independent increased risk of both glucose intolerance and
cardiovascular disease in recipients with high BMI (124, 144).
High pulse pressure is an independent risk factor for CVD
morbidity and mortality (145). Atherothrombotic lesions are
more likely in patients with pretransplant hypercoagulable
states (146). Approximately 28%kidney transplant recipients
have antiphospholipid antibodies (APA) (7). Kidney trans-
plant recipients with APAhave a 33%risk of a CVDevent com-
pared to 9% in kidney recipients without APA (P0.0003, RR
2.82) (7, 147) It is prudent to include screening for APA and
other hypercoagulable states as part of the diagnosis and man-
agement of CVD in the posttransplant period. Ambulatory
blood pressure monitoring may provide insight into the diurnal
variability and efficacy of antihypertensive regimen but
there are no specific indications for its use in the renal
transplant population (148150).
Secondary Prevention
Results of coronary revascularization procedures in
kidney transplant recipients with ischemic heart disease are
comparable to that of the general population, although
long-term results appear to favor surgical revasculariza-
tion (151, 152). In a report on 83 kidney transplant recipi-
ents who underwent percutaneous transluminal coronary
angioplasty (PTCA) or coronary artery bypass grafting (CABG),
Ferguson et al. found actuarial patient survival of 89%, 77%,
and 65% at one, three, and five years with graft loss or wors-
ening of renal function after the procedure (151). In this se-
ries, two patients lost their graft due to chronic rejection 16
TABLE 4. Prevalence of cardiovascular disease
according to the presence of proteinuria in kidney
transplant recipients in recipients without pretransplant
CVD (29)
RTR with
proteinuria
RTR without
proteinuria P value
Posttransplant CVD 35.3.4% 14.6 0.001
Mean time
a
(years) 4.284.3 3.53.23 NS
RTR renal transplant recipients.
a
Mean time SD from transplantation to the development of a cardio-
vascular event.
2006 Lippincott Williams & Wilkins 607 Ojo
and 19 months after PTCA (151). Among 31 kidney recipi-
ents who underwent CABGin Hannover, Germany, early (30
days) postoperative mortality was low(3%, one patient death
due to necrotizing enterocolitis) and there was no perioperative
impairment ingraft functionor graft loss (153). Incontrast, of 13
kidney transplant recipients who underwent cardiac operations
(mostly CABG) in a series from Pittsburgh, seven patients
(54%) developed postoperative acute renal failure and three
patients (23%) did not recover graft function but the overall
early andlate mortality inthis groupwas also low(154). Thus,
coronary revascularization in kidney transplant recipients
appears to confer significant patient survival benefits with
minimal risk to the allograft in most series.
Conclusion
More than 7580% of kidney transplant recipients have
one or more cardiovascular risk factors. Cardiovascular events
develop at annual rate of 3.5% to 5%, putting kidney recipients
at a 50-fold excess compared to the general population. Treat-
ment guidelines for the management of CVDrisk factors should
be incorporated at a programmatic level into the long-termcare
of kidney transplant recipients. Multidimensional strategies
aimed at preserving good allograft function should also been
seen as preventative treatment for cardiovascular disease.
Statins, ezetimibe, calcium channel blockers angiotensin recep-
tor blockade, andthiazolidine are safe andeffective intransplant
recipients and should be used for the same indication as in the
general population. Management of posttransplant anemia is
suboptimal in most series despite a strong link between CVD
and anemia. Additional studies of lipid lowering therapy are
needed to address questions not yet answered by the ALERT
study. Management of novel risk factors such as elevated serum
C-reactive proteinandhyperhomocysteinemia shouldawait ad-
ditional data from ongoing clinical trials, although lifestyle
changes shown to have beneficial effect on these novel risk fac-
tors should be adopted. Coronary revascularization procedures
confer survival benefits in kidney transplant recipients with low
risk of impairment in allograft function.
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