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Review Article

Cardiovascular disease: Prevention and treatmentin renal transplant recipients

Santosh Varughese

Professor, Department of Nephrology, Christian Medical College, Vellore 632004, India

a r t i c l e i n f o

Article history:

Received 18 October 2013

Accepted 25 November 2013

Available online 11 December 2013

Keywords:

Cardiovascular disease

Renal replacement therapy

Allograft rejection

E-mail address: santosh@cmcvellore.ac.in2211-9477/$ e see front matter Copyright ªhttp://dx.doi.org/10.1016/j.cqn.2013.11.007

a b s t r a c t

Despite improved survival, renal transplant recipients remain at a high risk of increased

mortality and mortality from cardiovascular disease. Both traditional cardiovascular dis-

ease (CVD) risk factors and those unique to this population add to the burden of disease,

making their CVD risk 50 times that of the general population. This article discusses our

present understanding of cardiovascular disease, the risk factors, including dyslipidemia,

hypertension, allograft rejection and dysfunction, anemia, proteinuria and new onset

diabetes after transplantation (NODAT), as well as prevention and management of these

risk factors. Cardiovascular interventions as well as future considerations are also briefly

discussed.

Copyright ª 2013, Reed Elsevier India Pvt. Ltd. All rights reserved.

1. Introduction

For patients with end stage renal disease (ESRD), renal trans-

plantation is considered to be the best form of renal replace-

ment therapy (RRT). When compared to patients on dialysis,

transplantation is expected to provide a better quality of life as

well as improved survival by about 10e20 years.1,2 However,

the long-term survival of renal transplant recipients does not

approach that of their otherwise healthy compatriots, owing

mainly to increased cardiovascular morbidity and mortality3

with about half dying with a functioning allograft,4 and car-

diovascular disease (CVD) and cerebrovascular accidents

(CVA) accounting for half these deaths.5,6 The annual CVD

related risk is about 3.5e5%.7e9 The risk of developing pre-

mature CVD in an ESRD patient is ten to 20 times that of the

general population and a successful transplantation sub-

stantially reduces the risk to three to five times and is more

pronounced in younger patients.10e12 (Also see Fig. 1).

The mortality risk in the renal transplant recipient con-

tinues throughout the post-transplant period and persists up

.2013, Reed Elsevier India

to allograft failure. Data from the United States Renal Data

System (USRDS) estimates that about 40% of recipients expe-

rience a cardiovascular event in the first three years post renal

transplant.13 The burden of CVD in renal transplant recipients

is a combination of multiple traditional and non-traditional

risk factors, the latter includes pre-transplant disease and

undesired results of immunosuppressive therapy. This article

attempts to highlight the importance of some of these risk

factors as well as prevention and management of CVD in

these patients.

2. Etiology of CVD in renal transplantrecipients

It is unfortunate that CVD is often presumed to imply coro-

nary artery disease (CAD) unlike the general populationwhere

the two may be more synonymous. Although myocardial

infarction is common in renal transplant recipients, two other

common presentations are those of congestive heart failure

Pvt. Ltd. All rights reserved.

Fig. 1 e Mortality from CVD in transplant recipients, ESRD

patients and general population.11,12

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6 185

(CHF) and sudden cardiac death, presumably due to

arrhythmias.14e16 CHF is the second most common cause of

hospitalization in renal transplant recipients17 more so in the

elderly and the diabetics.14 Though CAD is indeed common,

CVD is quite often the result of altered ventricular function

and geometry. This condition has been termed “cardiomyop-

athy of overload”18 or uremic cardiomyopathy, a term

describing the structural and functional cardiac abnormalities

resulting from the pre-transplant uremic milleu19 (Fig. 2).

3. Traditional risk factors

The Third Report of the Expert Panel on Detection, Evaluation

and Treatment of High Blood Cholesterol in Adults (Adult

Treatment Panel III, or ATP III) from the National Cholesterol

Education Program (NCEP)20 described major risk factors for

the development of CAD. These are listed below (see Table 1)

and are probably as important in transplant recipients as in

the general population. The importance of other traditional

risk factors predisposing to CVD like obesity, (especially

abdominal obesity), family history of premature CAD, seden-

tary lifestyle, ethnicity and psychosocial factors have not been

rigorously studied in transplant recipients but are probably

important.22 CVD risk is probably a continuum and increases

akin to dose response, i.e. more the number of risk factors,

duration of exposure and severity of risk, higher the CVD risk.

While true of the general population, this awaits confirmation

in renal transplant recipients.

4. Additional risk factors of CVD in renaltransplant recipients

Renal transplant recipients have additional risk factors not

shared with the general population as a result of the

underlying or past kidney disease and specifically related to

kidney transplantation. The contributions of some of these

non-traditional risk factors are discussed below.

4.1. Post-transplant dyslipidemia

An elevated level of plasma lipids is a frequently encountered

post-transplant complication. About 40% of recipients develop

hypercholesterolemia while about 6% have hyper-

triglyceridemia.23 These changes begin early in trans-

plantation with elevation in total cholesterol, LDL cholesterol,

by 1e1.5 mmol/L (about 38e58 mg/dL) and smaller increase in

HDL cholesterol and triglyceridemia by sixth post-transplant

week.24 The concentration of intermediate lipoprotein that

are specially atherogenic also increase.25 Dyslipidemia con-

tributions to CAD and CVD risk and has also have association

with reduced graft survival.26 Immunosuppressive medica-

tions decrease the risk of allograft rejection but this comes

with the price of increased CVD risk.5

Long-term corticosteroids, even at low doses, cause dysli-

pidemia.27 Calcineurin inhibitors, especially cyclosporine

contribute to post-transplant dyslipidemia28 as do prolifera-

tion signal inhibitors or mammalian target-of-rapamycin in-

hibitors (PSI/mTOR) in a dose-dependent manner.29,30 It may

be possible that despite the elevated plasma lipids associated

with mTOR inhibitors, the CVD risk may not be elevated

because of their antiproliferative effect on vascular endothe-

lium.31 Mycophenolate mofetil and azathioprine have not

been implicated in the etiology of post-transplant

dyslipidemia.

4.2. Hypertension

Presence of systolic blood pressure (SBP) > 140 mmHg or

diastolic blood pressure (DBP) > 90 mmHg qualifies the

diagnosis of hypertension in the renal transplant recipient as

per the Seventh Report of the Joint National Committee on

Prevention, Detection, and Evaluation of High Blood Pressure

(JNC VII).32 The prevalence of hypertension is between 75 and

90% of renal transplant recipients,5,33,34 a figure that has not

changed remarkably with time.35,36 In the large Collaborative

Transplant Study, about 55% of the total cohort of 29,751

patients had blood pressures that were uncontrolled.37 The

hypertensive renal transplant recipients were observed to

have poor long-term allograft survival.38 In another retro-

spective cohort of 1666 renal transplant recipients, elevation

of SBP of only 1 mmHg was associated with an 18% increase

in death and 17% increase in death-censored graft failure.39

Similar observations were made in two other reports.8,35

The etiology of hypertension in renal allograft recipients is

multi-factorial.40,41 The possible contributors include

obesity,42 presence of delayed graft function, rejection epi-

sodes, corticosteroids, preexisting hypertension, calcineurin

inhibitors (CNI), presence of delayed graft function (DGF),

quality of donor kidney, renal artery stenosis in the trans-

planted kidney,43 chronic graft dysfunction and native kidney

disease i.e. etiology of CKD pre-transplant. Of these, the most

important contributors possibly are CNI based immunosup-

pression and preexisting hypertension,36 the latter being

present in nearly half the renal transplant recipients.7 CNIs,

Disordered myocardial perfusion Cardiomyopathy

Atherosclerotic Non-atherosclerotic

Coronary Artery Disease

Concentric Left Ventricular Hypertrophy

Left Ventricular Dilatation

Diastolic Dysfunction

Systolic Dysfunction

Arrhythmias Myocardial Infarction Pump Failure

Death

Fig. 2 e Causes of cardiovascular death in renal transplant recipients (modified).18

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6186

especially cyclosporine, upregulate the renin angiotensin

aldosterone system (RAAS) and activate the sympathetic

nervous system (SNS) causing afferent arteriolar vasocon-

striction and salt retention leading to hypertension in renal

transplant recipients.44e46 Experimental data suggests that

CNIs additionally cause reduction in vasodilator prostaglan-

dins and nitric oxide (NO) and increases vasoconstrictors like

adenosine, thromboxane A2, cysteinyl leukotrienes, platelet-

derived growth factor, and endothelin-1.47e49 Weight gain,

salt retention and the mineralocorticoid effect of corticoste-

roids is another significant contributor to post-transplant

hypertension and may contribute 15% of the post-transplant

hypertension risk.50

4.3. Allograft rejection and dysfunction

The post-transplant CVD risk increases with the number of

rejection episodes51,52 possibly a consequence of intravenous

anti-rejection therapy with corticosteroids. Similar to the

general population where decreased renal function is associ-

ated with increased risk of CVD53,54 and decrease in glomer-

ular filtration rate (GFR) of as small as 10 ml/min/1.73 m2 is

associated with a 6e10% increased risk55,56 allograft

dysfunction is associated with increased CVD risk57,58 as well

as all-cause and cardiovascular mortality.14,59 Graft failure

and ESRD increases the mortality risk further.60

4.4. Anemia

Anemia is seen in about a third of renal transplant recipients

and is more than expected from allograft dysfunction61,62 and

is possibly multifactorial. Pre-transplant anemia, rejection

episodes, CNI use, low iron stores, ongoing occult blood loss,

drugs (anti-proliferative agents, angiotensin- converting

enzyme inhibitors, angiotensin receptor blockers), folate and

vitamin B12 deficiencies, older age group, infections and

inflammation are important contributors.63e67 Anemia is an

important risk factor for left ventricular hypertrophy (LVH)

and CVD69 and is associated with increased mortality.68,69

4.5. Proteinuria

In the general population,microalbuminuria is a risk factor for

CAD in both diabetic and non-diabetic patients,70e72 perhaps a

more important risk factor than male sex, hypertension and

dyslipidemia.70 Proteinuria is present in 20e40% of renal

transplant recipients73,74 and is an independent predictor of

mortality due to CVD,74e76 with the risk more than twice

compared to those without proteinuria.75 The 10-year risk of

CVD in proteinuric recipients is 39.4% compared to 20.9% in

non-proteinuric recipients.73 Proteinuria is perhaps a sentinel

signaling systemic endothelial dysfunction heralding the

process of atherosclerosis.77

4.6. New onset diabetes after transplantation (NODAT)

Diabetesmellitus is the leading cause of ESRDworldwide with

20% of renal transplant recipients having pre-transplant dia-

betes mellitus.78 Added to this is the observed increasing rate

of new onset diabetes after transplantation (NODAT) with

time. The United States Renal Data System (USRDS) data

showed that the prevalence of NODAT increased from less

than 10% of renal transplant recipients at three months to

nearly a quarter by 36 months.79 Hepatitis C virus infection,

older age, AfricaneAmerican and Hispanic race, obesity,79

metabolic syndrome,80,81 CNI and corticosteroid based

immunosuppression and hypertension82,83 are important risk

factors for development of NODAT. Twenty per cent of

Table 1 e Cardiovascular risk factors in renal allograftrecipients.21

Major risk factors for coronary heart disease in

ATP III guidelines

1. High low density lipoprotein (LDL) cholesterol

(>159 mg/dL or 4.11 mmol/L)

2. Cigarette smoking

3. Hypertension (blood pressure >140/90 mm Hg or

on antihypertensive medication)

4. Low high density lipoprotein (HDL) cholesterol

(<40 mg/dL or 1.03 mmol/L)

5. Family history of premature CAD (male first-degree

relatives <55 years or female first-degree

relative <65 years)

6. Age (men �45 years, women �55 years)

7. Diabetes mellitus

Other predisposing risk factors

1. Obesity, i.e. body mass index >30 kg/m2

2. Abdominal obesity (i.e. waist circumference

>102 cm (40 inches) for men and >88 cm

(35 inches)) for women

3. Physical inactivity

4. Family history of premature coronary artery disease

5. Ethnic characteristics

6. Psychosocial factors

Nontraditional biomarkers

1. Elevated serum triglycerides

2. Small LDL particles

3. Elevated serum homocysteine

4. Elevated serum lipoprotein (a)

5. Prothrombotic factors (e.g. fibrinogen)

6. Inflammatory markers (e.g. C-reactive

protein, IL-6, CMV)

7. B-type natriuretic peptide/N-terminal pro-atrial

natriuretic peptide,

8. Aldosterone

Risk factors associated with kidney disease or transplant

1. Immunosuppressive agents

2. Graft failure

3. Graft dysfunction (elevated homocysteinemia,

proteinuria, predisposition to vascular calcification)

4. Anemia

Fig. 3 e Survival (with functioning graft) e rejection,

NODAT or both.12,91

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6 187

recipients receiving tacrolimus develop NODAT compared to

4% in those receiving cyclosporine.84 The risks appear to be

additive as 39% AfricaneAmerican recipients on tacrolimus

develop NODAT.85,86 It has been proven incontrovertibly that

renal transplant recipients who develop NODAT have a two to

three-fold CVD risk compared to those without

NODAT6,8,79,87e90 with two-fold increase in mortality,79,82,91

similar to pre-transplant diabetes mellitus. Beyond the first

year post-transplant, NODAT influences patient survivalmore

than rejection episodes (see Fig. 3).91

Both impaired insulin secretion and development of insu-

lin resistance have been implicated in the pathogenesis of

NODAT. The underlying mechanism possibly involves FK

binding protein and it’s binding to CNI and mTOR inhibitors

resulting in diminished insulin secretion. Tacrolimus causes a

75% decrease in insulin secretion while cyclosporine causes a

50% decrease.92 Recipients with NODAT also show a 40%

decrease in insulin sensitivity compared to unaffected

recipients.92

5. Prevention and management of CVD inrenal transplant recipients

Despite the clinician’s best attempts, it may be impossible to

prevent emergence of many of the CVD risk factors in the

renal transplant recipient. However, several of these may be

amenable to intervention and every effort must be taken to

reduce the CVD risks in these patients.

5.1. Lifestyle modification

The initial step in CVDprevention andmanagement is lifestyle

modification. Dietary restriction of saturated fat to <7%, plant

sterols 2 g per day, cholesterol <200 mg per day and intake of

10e25 g per day of soluble fiber as advised by the National

Cholesterol Education Project plan III20 has been shown to be

beneficial by itself in some patients.93,94 Since obesity is

emerging as an important risk factor for CVD andmortality in

renal transplant recipients,42,95 maintenance of appropriate

weight and adequate physical activity20 are vital to reduce

CVD risk. Lifestyle modification alone is insufficient in most

patients who require drug therapy to control their dyslipide-

mia. JNC VII suggests the Dietary Approaches to Stop Hyper-

tension [DASH] diet consisting of 1600 mg/day of sodium and

high intake of fruits and vegetables.32 This has not been

studied in renal transplant recipients but has the potential to

lower SBP by 11.4 mm Hg and DBP by 5.5 mmHg.96 Such strict

compliance is likely to be poor with only 22% in one report.97

5.2. Lipid lowering agents

The lipid lowering benefit of 3ehydroxy 3-

MethylglutaryleCoenzyme A (HMG-CoA) reductase in-

hibitors or statins as they are commonly known to have un-

equivocally been proven to lower the CVD risk in the general

population.98 The ALERT trial (Assessment of Lescol in Renal

Transplantation)14 was a randomized controlled trial

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6188

conducted to evaluate the efficacy of statin therapy on

lowering CVD risk in renal transplant recipients. 2102 re-

cipients were randomized to receive either fluvastatin [40 mg

or 80 mg] or a placebo. In the fluvastatin group, there was 35%

less CVD mortality or non-fatal myocardial infarction (MI).

Open label administration of fluvastatin 80 mg in the exten-

sion phase of the ALERT trial showed decrease in cardiac

events in the stain treated group.15 Starting statins early

appeared to confer the greatest CVD risk reduction

advantage.99

The pleotropic benefits of statins in reducing proteinuria100

and inflammation as evidenced by reduced C-reactive protein

(CRP)101 has been demonstrated in the general population and

awaits confirmation among renal transplant recipients. Some

exciting preliminary reports in renal transplant recipients are

decline in degree of interstitial fibrosis in protocol transplant

kidney biopsies,102 lowering of blood pressures103 and in those

with post-transplant glomerulonephritis, improvement in

graft survival when combined with RAAS blockade.104

The recently published Kidney Disease Improving Global

Outcomes (KDIGO) Clinical Practice Guideline for Lipid Man-

agement in Chronic Kidney Disease suggests treatment of all

adult renal transplant recipients with statins.105 The most

commonly used HMG-CoA reductase inhibitor, Atorvastatin is

metabolized by the cytochrome P450 system (CYP3A4). Co-

administration of the CNI cyclosporine with atorvastatin

leads to the latter’s accumulation and side effects, most

notably rhabdomyolsis.106 Tacrolimus has overtaken cyclo-

sporine as the preferred CNI in renal transplant recipients and

unlike the former, does not interact significantly with ator-

vastatin.107 Along with atorvastatin, fluvastatin and pravas-

tatin are the preferred agents in both CKD patients and renal

transplant recipients as theydonot require dosage adjustment

for renal function. The latter two do not rely on cytochrome

P450 for their metabolism and are perhaps safer23,108 though

head to head comparison in renal transplant recipients has

never been done. Side effects, especially rhabdomyolysis are

also commonwithmore lipophilic status like simvastatin and

lovastatin and these are more likely to cause toxicity by extra

hepatic deposition.109 Ezetimibe is a relatively new adjunctive

lipid-lowering compound that acts by selectively inhibiting

gastro-intestinal tract absorption of cholesterol and related

phytosterols by targeting the jejunal enterocyte brush border

cholesterol transport protein Nieman Pick C1 like 1 protein.110

Itsusefulness in theCKDpopulationwasproven in theStudyof

Heart and Renal Protection (SHARP), where it was combined

with simvastatin.111 Its safety and efficacy was shown in 40

stable kidney transplant recipients.112

5.3. Anti-hypertensive therapy

Dihydropyridine calcium channel blockers (DHP-CCB) have

been shown to decrease CVD risk in the general population113

and are popular as the first line antihypertensive agents in

renal transplant recipients.39 They are also expected to

counteract CNI induced vasoconstrictive effects114e116 and

elevation in plasma uric acid.117 Although, initial reports

seemed to suggest that DHP-CCB improved graft function

compared with ACEi,115,118,126 these were likely the result of a

decrease in ACEi induced efferent arteriolar vasodilatation

rather than any true benefit. In fact, it is possible that DHP-

CCBs may be associated with an independent relative rise of

2.26 for CVD.42 Additionally, they frequently cause edema in

renal transplant recipients. Non DHP-CCB interfere with the

metabolism of CNI leading to elevated plasma levels of

cyclosporine and tacrolimus.39 This interaction has been

shown to be economically advantageous119 and may be

exploited in resource poor settings, similar to ketoconazole,120

to achieve adequate trough CNI levels using lower doses.

The cardioprotective and renoprotective effects of RAAS

blockade with ACEi or ARBs in renal transplant recipi-

ents121e124 has been clearly seen in reduction of proteinuria125

and improved 10 year actual patient survival [74% vs 53%,

P ¼ 0.002] and graft survival [59% vs 41%, P < 0.001] compared

to those who were not receiving ACEi/ARB.126 However the

much larger Collaborative Transplant Study involving 17,209

renal transplant recipients did not show a similar benefit in

those receiving RAAS blockade.37 Early use of ACEi/ARBs in the

renal transplant recipient have been documented to be safe

without any major effect on GFR.127,128

Nevertheless in the event of volume depletion or poor oral

intake, a combination of CNI induced afferent arteriolar

vasoconstriction and ACEi/ARB induced efferent arteriolar

vasodilatation are likely to render renal transplant recipient

vulnerable to acute kidney injury129 and early discontinuation

of the letter may be prudent in such a clinical setting. Also,

development of hyperkalemia and anemia may limit use of

these drugs.130

Neither ACEi nor ARB has been proven superior to CCB in

cardio protection. Both lisinopril and nifedipine have been

shown to decrease the left ventricular mass index equally.131

Beta blockers may be prescribed in renal transplant re-

cipients with preexisting CAD but by virtue of adrenergic

blockade, may render diabetics susceptible to hypoglycemic

unawareness.36 Patients need to bemonitored for bradycardia

and beta blocker dosage adjusted. Diuretics are indicated in

recipients with fluid retention.36

The KDIGO guideline for kidney transplant recipients sug-

gests maintaining SBP <130 mmHg and DBP <80 mmHg in

these aged 18 years or greater and in those less than 18 years of

age, < 90th percentile for age, sex and height.132 No single

agent or class has been recommended specifically except if

there is significant proteinuria i.e. 24 h urine protein �1 g for

�18 years old and�600mg/m2 for<18 years old. In this group,

an angiotensin converting enzyme inhibitor [ACEi] or an

angiotensin receptor blocker [ARB] is the preferred agent.132

The previous National Kidney Foundation - Kidney Disease

Outcomes Quality Initiative (NKF-KDOQI) guidelines133 had

recommended blood pressure goal of 125/75 mmHg in protei-

nuric renal transplant recipients. This was derived from

studies in the non-transplant CKD patients. Stratifying pa-

tients based on presence of microalbuminuria or diabetes

mellitus134 to initiate therapy with ACEi/ARB has not been

formally studied in renal transplant recipients.

5.4. Cessation of smoking

It is estimated that in the developed world, more than a

quarter of renal transplant recipients continue to smoke.135,136

The prevalencemay be lesser in countries like India but robust

Table 2 e Diagnostic thresholds for diabetes and lesserdegrees of impaired glucose regulation.149

Category Test

Fasting plasmaglucose

2 h Post-prandialplasma glucose

Normal <100 mg/dl <140 mg/dl

(<5.6 mmol/l) (<7.8 mmol/l)

Impaired Fasting

Glucose (IFG)

100e125 mg/dl

(5.6e6.9 mmol/l) e

Impaired Glucose

Tolerance (IGT)

e 140e199 mg/dl

(7.8e11.0 mmol/l)

Diabetes mellitus �126 mg/dl �200 mg/dl

(�7.0 mmol/l) (�11.1 mmol/l)

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6 189

data is lacking. Smoking substantially increases the risk of

CVD mortality death in renal transplant recipients with the

relative risk (RR) of mortality increasing from 1.56 in those

with cumulative smoking history of 11e25 pack-years to 2.14

for recipients with more than 25 pack-years history.95,137e139

The KDIGO recommends that all renal transplant recipient

be screened and counseled against tobacco use.132 After the

counseling at the time of initial evaluation, an annual

screening is also required.132 Smokers have a three- to four-

fold increased risk of an acute coronary event syndrome in the

immediate post-transplant period.87 KDIGO recommends of-

fering treatment to all who use tobacco in any form.132 The

peri-operative period is an opportune moment to advocate for

smoking cessation.36 The sooner the cessation of smoking, the

greater the benefit. For example, cessation of smoking in CKD

and five years prior to transplantation shows 34% reduction in

CVD risk in renal transplant recipients.138

5.5. Blood sugar control

The CVD risk from NODAT may be reduced by effective

modification of risk factors for development of NODAT in

Table 3 e Drugs used to treat diabetes in renal transplant recip

Class Drugs Dos

Second-generation

sulfonylureas

Glipizide Prefe

Glyburide Not

Glimepiride Begin

Thiazolidinediones Pioglitazone Non

Meglitinide Repaglinide Prefe

Nateglinide Rena

Biguanides Metformin Not

with

a-Glucosidase inhibitors Acarbose, Voglibose Not

crea

Glucagon-like peptide-1

(GLP-1) (incretin mimetic)

Exenatide Non

DPP-IV inhibitors (gliptins) Sitagliptin, Vildagliptin,

Saxagliptin, Linagliptin

(Sita

Redu

By 5

By 7

Insulin Rapid acting: regular,

lispro, aspart

Non

Intermediate acting: NPH

Long acting: glargine, detemir

renal transplant recipients. Some of the important measures

that can be adopted are periodic screening of recipients for

early diagnosis and treatment, life-style modification to

reduce weight gain, institute changes in immunosuppressive

regimes (e.g. steroid avoidance in recipients at increased risk

of NODAT, CNI minimization or CNI-free regimen) and in re-

cipients with NODAT, regular surveillance for CVD and strict

control of blood sugars36 (OJO). The latter frequently needs

Insulin, soon after onset, albeit transiently.140 One can ima-

gine that the prevalence of NODAT would be on the rise

because of increased Tacrolimus use but the converse is true

with adoption of steroids-free protocols and lower doses of

tacrolimus in current practice.141e146

The International Consensus Guidelines released in 2003

suggested that diagnosis for NODAT be based on the American

Diabetes Association (ADA) criteria for diagnosing dia-

betes.147,148 The 2003 revised ADA targets149 are listed in

Table 2. The KDIGO guideline for kidney transplant recipients

recommends screening all recipients with a minimum fre-

quency of weekly for 4 weeks, three-monthly for a year and

annually thereafter using fasting blood glucose, oral glucose

tolerance testing (OGTT) and/or glycated hemoglobin

(HbA1C).132 Screening for NODAT is also to be done at start of

or increase in dose of corticosteroids, CNI or mTOR in-

hibitors.132 Abnormal glucose values should be confirmed by

repeating the test on another day. Screening with OGTT is

more sensitive and has been recommended in certain at-risk

patients.142,150 HbA1C is not tested in the first three post-

transplant months.147,148

The expected benefit of weight loss and exercise in pre-

venting onset of diabetes in overweight patients,151,152 while

yet unproven in renal transplant recipients, are likely to

benefit them as well. Once diagnosed, treatment of NODAT is

similar to control of type 2 diabetes mellitus in the general

population.12 Lifestyle modifications are the first step in blood

sugar control after which oral hypoglycemic agents are

ients (modified).147

ing recommendations Adverse effects/drug interactions

rred agent Hypoglycemia

recommended

with low dosage

e Edema, CHF

rred agent Levels may be increased with

statin/fibrate use

lly cleared Begin with low dosage

recommended, especially

reduced GFR

Lactic acidosis

recommended with

tinine � 2.0 mg/dl

Gastrointestinal distress

e No published data on interactions

gliptin)

ce dosage:

0% if GFR 30e50 ml/min

5% if GFR <30 ml/min

No published data on interactions

e Hypoglycemia

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6190

initiated in a stepwise manner. A common schedule is to

begin with a single drug, add another to achieve glycemic

status and thereafter insulin. Early use of insulin is often

required as the onset is frequently very sudden.148 It is esti-

mated that nearly 40% of renal transplant recipients require

insulin for blood sugar control.153 The commonly used drugs

are listed in Table 3. The rationale for blood sugar control

stems from its effect in the general population where a 1%

decrease in HbA1c decreases CVD mortality by up to 20%.154

KDIGO recommends keeping the HbA1C between 7 and 7.5%

and avoiding targeting HbA1C of six or less.132 A meta-

analysis showed the benefit of RAAS blockade in prevention

of type 2 diabetes.155 Whether the same is true in renal

transplant recipients is unknown. A retrospective study from

Toronto reported that use of statins resulted in a 70% reduc-

tion in incidence of NODAT.156 With the new KDIGO guideline

suggesting widespread use of statin in renal transplant re-

ceipts,105 wemaywitness a decline in the incidence of NODAT

worldwide in the coming years.

5.6. Antiplatelet agents

In the general population, antiplatelet agents have been

incontrovertibly been shown to be useful for secondary pre-

vention of CVD in patientswith known atherosclerotic disease

(CAD, ischemic CVA and peripheral vascular disease) and for

primary prevention in patients with diabetes.157e159 In a large

observational study, use of acetyl salicylic acid (ASA) in 860

CKD patients with myocardial infarction was associated with

improved survival.160 ASA use was beneficial even in ESRD

patients despite the risk of platelet dysfunction due to ure-

mia.160 Improved survival and graft function has been re-

ported in a retrospective study of 830 renal transplant

recipients treatedwith low dose ASA (100mg/day).161 Reduced

risk of allograft renal vein thrombosis has also been re-

ported.162 The risk of gastro-intestinal bleeds is ten times

higher in renal transplant recipients163 compared to the gen-

eral population making universal ASA therapy unadvisable.

KDIGO recommends CVD prophylaxis with ASA (65e100 mg/

day) in all renal transplant recipients with known

Fig. 4 e Overview of CVD management in re

atherosclerotic disease, unless contraindicated and in di-

abetics based on patient preference and balance of ischemic

risk with risk of bleeding.132

6. Revascularization

The current world-wide practice of pre-transplant evaluation

of CVD risk and revascularization of all significant coronary

artery lesions164 stems from a small randomized trial of 26

type I diabetic patients with silent CAD done two decades ago

which showed reduction in future CVD risk.165 Coronary ar-

tery revascularization appears to have similar beneficial ef-

fects in renal transplant recipients with CAD as in the general

population. The long-term resultswith coronary artery bypass

grafting (CABG) are slightly better166,167 in some series while

one center reported acute kidney injury post CABG in seven of

their 13 recipients (54%) with non-recovery of allograft func-

tion in three (23%).168 Mortality did not appear to be affected

though.

7. The future

Apart from those discussed above, there are several potential

risk factors that may prove significant in the future. Cyto-

megalovirus (CMV) infection has been implicated in CVD risk

in renal transplant recipients.169,170 KDIGO recommends

chemoprophylaxis against CMV infection for a minimum of

three months132 which should mitigate the CVD risk as well.

Presence of an inherent pro-thrombotic tendency increases

risk of atherothrombotic lesions and CVD.171 It is estimated

that antiphospholipid antibodies (APLA) are present in about

28% renal transplant recipients9 and they consequently have

an increased risk of CVD compared to recipients without

APLA, (33% vs 9%, P¼ 0.0003, RR 2.82).172 Some authors suggest

routine pre-transplant screening for a prothrombotic state

including APLA.36 Use of Ambulatory blood pressure moni-

toring (ABPM) in renal transplant recipients may provide

valuable information regarding diurnal variability and

nal transplant recipients (modified).12,91

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6 191

antihypertensive efficacy.173e175 Inflammatory markers like

CRP,176 sialic acid,177 fibrinogen and other such biomarkers are

associated with increased CVD risk events as well as cardiac

and all-cause mortality in renal transplant recipients. The

reduction of CRP by statins101 as discussed above is a potential

intervention for reduction of inflammation. A linear increase

in the risk of CVD events with decreasing CD4 cell count has

been seen in renal transplant recipients178 suggesting that

impaired T-cell mediated immunity may contribute to

atherosclerosis and CVD.179,180 This awaits confirmation in

larger prospective studies.

Post-transplant cardiovascular events are currently being

studied prospectively181 using established cardiovascular

scoring systems e Framingham risk factor score,182,183 Euro-

pean Systematic Coronary Risk Evaluation (SCORE) equa-

tion,184 the REGICOR (Registre Gironı del COR (Gerona Heart

Registry)185 and DORICA (Dyslipidemia, Obesity, and Cardio-

vascular Risk) functions,186 the latter two have been devel-

oped specifically addressing the Spanish population. It is

hoped that the findings of this study will throw further light

on our understanding of the relationship between cardiovas-

cular risk factors and post-transplant CVD. If the data does

generate a risk-prediction score, it will need validation in

other populations.

8. Conclusion

CVD is common in renal transplant recipients and is multi-

factorial in etiology. Early addressing of risk factors is likely

to prevent or delay progression of CVD. Prevention of CVD risk

factors must begin prior to transplant itself. Except for statin

therapy for dyslipidemia, now a KDIGO recommendation,

robust data from the transplant recipient pool is lacking for

most treatment recommendations. Future trials may throw

light on possible newer interventions. The ongoing cardio-

vascular scores trial may help us understand the problem of

CVD better. Fig. 4 depicts an overview of CVD management in

renal transplant recipients.

Conflicts of interest

The author has none to declare.

r e f e r e n c e s

1. Wolfe RA, Ashby VB, Milford EL, et al. Comparison ofmortality in all patients on dialysis, patients on dialysisawaiting transplantation, and recipients of a first cadaverictransplant. N Engl J Med. 1999;341(23):1725e1730.

2. Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K.Comparison of survival probabilities for dialysis patients vscadaveric renal transplant recipients. JAMA.1993;270(11):1339e1343.

3. Arend SM, Mallat MJ, Westendorp RJ, van der Woude FJ, vanEs LA. Patient survival after renal transplantation; more than25 years follow-up. Nephrol Dial Transplant.1997;12:1672e1679.

4. Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY,Port FK. Long-term survival in renal transplant recipientswith graft function. Kidney Int. 2000;57:307e313.

5. Fellstrom B. Risk factors for and management of post-transplantation cardiovascular disease. BioDrugs.2001;15:261e278.

6. Lindholm A, Albrechtsen D, Frodin L, Tufveson G,Persson NH, Lundgren G. Ischemic heart diseasedmajorcause of death and graft loss after renal transplantation inScandinavia. Transplantation. 1995;60:451e457.

7. Foley RN, Parfrey PS, Sarnak MJ. Epidemiology ofcardiovascular disease in chronic renal disease. J Am SocNephrol. 1998;9(12 suppl l):S16eS23.

8. Aakhus S, Dahl K, Wideroe TE. Cardiovascular disease instable renal transplant patients in Norway: morbidity andmortality during a 5-yr follow-up. Clin Transplant.2004;18(5):596e604.

9. Ducloux D, Bourrinet E, Motte G, Chalopin JM.Antiphospholipid antibodies as a risk factor foratherosclerotic events in renal transplant recipients. KidneyInt. 2003;64(3):1065e1070.

10. Baigent C, Burbury K, Wheeler D. Premature cardiovasculardisease in chronic renal failure. Lancet. 2000;356:147e152.

11. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology ofcardiovascular disease in chronic renal disease. Am J KidneyDis. 1998;32(5 suppl 3):S112eS119.

12. Jardine AG, Gaston RS, Fellstrom BC, Holdaas H. Preventionof cardiovascular disease in adult recipients of kidneytransplants. Lancet. 2011;378(9800):1419e1427.

13. U.S. Renal Data System. USRDS 2007 Annual Data Report: Atlasof Chronic Kidney Disease and End-Stage Renal Disease in theUnited States. Bethesda: National Institutes of Health,National Institute of Diabetes and Digestive and KidneyDisease; 2007.

14. Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatinon cardiac outcomes in renal transplant recipients: amulticentre, randomised, placebo-controlled trial. Lancet.2003;361:2024e2031.

15. Holdaas H, Fellstrom B, Cole E, et al, for the Assessment ofLEscol in Renal Transplantation (ALERT) Study Investigators.Long-term cardiac outcomes in renal transplant recipientsreceiving fluvastatin: the ALERT extension study. Am JTransplant. 2005;5:2929e2936.

16. Israni AK, Snyder JJ, Skeans MA, et al, for the PORTInvestigators. Predicting coronary heart disease after kidneytransplantation: patient outcomes in renal transplantation(PORT) study. Am J Transplant. 2010;10:338e353.

17. Larsen CP, Grinyo J, Medina-Pestana J, et al. Belatacept-basedregimens versus a cyclosporine A-based regimen in kidneytransplant recipients: 2-year results from the BENEFIT andBENEFIT-EXT studies. Transplantation. 2010;90:1528e1535.

18. Rigatto C. Management of cardiovascular disease in therenal transplant recipient. Cardiol Clin. 2005;23(3):331e342.

19. Mark PB, Johnston N, Groenning BA, et al. Redefinition ofuremic cardiomyopathy by contrast-enhanced cardiacmagnetic resonance imaging. Kidney Int.2006;69:1839e1845.

20. National Cholesterol Education Program (NCEP) Expert Panelon Detection, Evaluation, and Treatment of High BloodCholesterol in Adults (Adult Treatment Panel III). Thirdreport of the National cholesterol Education Program (NCEP)expert panel on detection, evaluation, and treatment of highblood cholesterol in adults (adult treatment panel III) finalreport. Circulation. 2002;106(25):3143e3421.

21. Kiberd BA. Cardiovascular disease in kidney transplantrecipients. Adv Stud Med. 2007;7(6):169e178.

22. Mancia G. Total cardiovascular risk: a new treatmentconcept. J Hypertens. 2005;24(suppl 2):S17eS24.

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6192

23. Kasiske B, Cosio FG, Beto J, et al. Clinical practice guidelinesfor managing dyslipidemias in kidney transplant patients: areport from the Managing Dyslipidemias in Chronic KidneyDisease Work Group of the National Kidney FoundationKidney Disease Outcomes Quality Initiative. Am J Transplant.2004;4(suppl 7):13e53.

24. Holdaas H, Jardine AG, Wheeler DC, et al. The effect offluvastatin on acute renal allograft rejection: a randomisedmulticentre trial. Kidney Int. 2001;60:1990e1997.

25. Holdaas H, Kobashigawa JA, Fellstrom B, Jardine AG. Specialtransplant populations: transplant recipients. In:Ballantyne CM, ed. Clinical Lipidology. Philadelphia: Elsevier;2009:486e499.

26. Wissing KM, Abramowicz D, Broeders N, Vereerstraeten P.Hypercholesterolemia is associated with increased kidneygraft loss caused by chronic rejection in male patients withprevious acute rejection. Transplantation. 2000 Aug15;70(3):464e472.

27. Miller LW. Cardiovascular toxicities of immunosuppressiveagents. Am J Transplant. 2002;2:807e818.

28. Vincenti F, Jensik SC, Filo RS, Miller J, Pirsch J. A long-term comparison of tacrolimus (FK506) and cyclosporinein kidney transplantation: evidence for improvedallograft survival at five years. Transplantation.2002;73:775e782.

29. van Hooff JP, Squifflet JP, Wlodarczyk Z, Vanrenterghem Y,Paczek L. A prospective randomized multicenter study oftacrolimus in combination with sirolimus in renal-transplant recipients. Transplantation. 2003;75:1934e1939.

30. Chueh SC, Kahan BD. Dyslipidemia in renal transplantrecipients treated with a sirolimus and cyclosporine-basedimmunosuppressive regimen: incidence, risk factors,progression, and prognosis. Transplantation.2003;76:375e382.

31. Blum CB. Effects of sirolimus on lipids in renal allograftrecipients: an analysis using the Framingham risk model.Am J Transplant. 2002;2:551e559.

32. Chobanian AV, Bakris GL, Black HR, et al, Joint NationalCommittee on Prevention, Detection, Evaluation, andTreatment of High Blood Pressure. National Heart, Lung, andBlood Institute; National High Blood Pressure EducationProgram Coordinating Committee. Seventh report of theJoint National Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pressure.Hypertension. 2003;42(6):1206e1252.

33. First MR, Neylan JF, Rocher LL, Tejani A. Hypertension afterrenal transplantation. J Am Soc Nephrol. 1994;4(suppl1):S30eS36.

34. Diaz JM, Sainz Z, Guirado LL, et al. Risk factors forcardiovascular disease after renal transplantation.Transplant Proc. 2003;35(5):1722e1724.

35. Campistol JM, Romero R, Paul J, Gutierrez-Dalmau A.Epidemiology of arterial hypertension in renal transplantpatients: changes over the last decade. Nephrol DialTransplant. 2004;19(suppl 3):62e66.

36. Ojo AO. Cardiovascular complications after renaltransplantation and their prevention. Transplantation.2006;82:603e611.

37. Opelz G, Zeier M, Laux G, Morath C, Dohler B. Noimprovement of patient or graft survival in transplantrecipients treated with angiotensin-converting enzymeinhibitors or angiotensin II type 1 receptor blockers: acollaborative transplant study report. J Am Soc Nephrol.2006;17:3257e3262.

38. Opelz G, Wujciak T, Ritz E. Association of chronic kidneygraft failure with recipient blood pressure. CollaborativeTransplant Study. Kidney Int. 1998;53:217e222.

39. Kasiske BL, Anjum S, Shah R, et al. Hypertension afterkidney transplantation. Am J Kidney Dis. 2004;43:1071e1081.

40. Midtvedt K, Hartmann A. Hypertension after kidneytransplantation: are treatment guidelines emerging? NephrolDial Transplant. 2002;17(7):1166e1169.

41. Cosio FG, Dillion JJ, Falkenhain ME, et al. Racial differences inrenal allograft survival: the role of systemic hypertension.Kidney Int. 1995;47:36e41.

42. Kasiske BL, Chakkera HA, Roel J. Explained and unexplainedischemic heart disease risk after renal transplantation. J AmSoc Nephrol. 2000;11(9):1735e1743.

43. Bolad IA, Breen J, Rogers P, et al. Prevalence and significanceof renal artery stenosis and abdominal aortic atherosclerosisearly after heart transplantation. Transplant Proc.2002;34(8):3236e3238.

44. Boots JM, Christiaans MH, van Hooff JP. Effect ofimmunosuppressive agents on long-term survival of renaltransplant recipients: focus on the cardiovascular risk.Drugs. 2004;64:2047e2073.

45. Bantle JP, Nath KA, Sutherland DE, Najarian JS, Ferris TF.Effects of cyclosporine on the renin-angiotensin-aldosteronesystem and potassium excretion in renal transplantrecipients. Arch Intern Med. 1985;145(3):505e508.

46. Bennett WM. Insights into chronic cyclosporinenephrotoxicity. Int J Clin Pharmacol Ther.1996;34(11):515e519.

47. Endoh M, Odamaki M, Ikegaya N, Kumagai H. Factorsinvolved in the development of hypertension induced by alow-protein diet in rats with renal injury. Kidney Blood PressRes. 2004;27(1):1e9.

48. Lanese DM, Coger JD. Effects of endothelin receptorantagonism on cyclosporine-induced vasoconstriction inisolated rat renal arterioles. J Clin Invest. 1993;91:2144e2149.

49. Zhang R, Leslie B, Boudreaux JP, Frey D, Reisin E.Hypertension after kidney transplantation: impact,pathogenesis and therapy. Am J Med Sci. 2003;325(4):202e208.

50. Veenstra D, Best J, Hornberger J, Sullivan S, Hricik D.Incidence and long-term cost of steroid-related side effectsafter renal transplantation. Am J Kidney Dis.1999;33(5):829e839.

51. Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ.Cardiovascular disease after renal transplantation. J Am SocNephrol. 1996;7:158e165.

52. Kasiske BL. Risk factors for accelerated atherosclerosis inrenal transplant recipients. Am J Med. 1988;84:985e992.

53. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney diseaseas a risk factor for development of cardiovascular disease: astatement from the American Heart Association Councils onKidney in Cardiovascular Disease, High Blood PressureResearch, Clinical Cardiology, and Epidemiology andPrevention. Circulation. 2003;108:2154e2169.

54. Manjunath G, Tighiouart H, Coresh J, et al. Level of kidneyfunction as a risk factor for cardiovascular outcomes in theelderly. Kidney Int. 2003;63(3):1121e1129.

55. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronickidney disease and the risks of death, cardiovascular events,and hospitalization. N Engl J Med. 2004;351(13):1296e1305.

56. Rahman M, Brown CD, Coresh J, et al. The prevalence ofreduced glomerular filtration rate in older hypertensivepatients and its association with cardiovascular disease: areport from the Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial. Arch Intern Med.2004;164(9):969e976.

57. Fellstrom B, Jardine AG, Soveri I, et al. Renal dysfunction as arisk factor for mortality and cardiovascular disease in renaltransplantation: experience from the Assessment of Lescolin Renal Transplantation Trial. Transplantation.2005;79(9):1160e1163.

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6 193

58. Forsythe JL. Graft function and other risk factors aspredictors of cardiovascular disease outcome.Transplantation. 2001;72:S16eS19.

59. Meier-Kriesche HU, Baliga R, Kaplan B. Decreased renalfunction is a strong risk factor for cardiovascular death afterrenal transplantation. Transplantation. 2003;75(8):1291e1295.

60. Gill JS, Rose C, Pereira BJ, Tonelli M. The importance oftransitions between dialysis and transplantation in the careof end-stage renal disease patients. Kidney Int.2007;71:442e447.

61. Chadban SJ, Baines L, Polkinghorne K, et al. Anemia afterkidney transplantation is not completely explained byreduced kidney function. Am J Kidney Dis. 2007;49:301e309.

62. Zadrazil J, Horak P, Horcicka V, Zahalkova J, Strebl P,Hruby M. Endogenous erythropoietin levels and anemia inlong-term renal transplant recipients. Kidney Blood Press Res.2007;30:108e116.

63. Rigatto C. Anemia, renal transplantation, and the anemiaparadox. Semin Nephrol. 2006;26:307e312.

64. Vanrenterghem Y. Anaemia after renal transplantation.Nephrol Dial Transplant. 2004;19:v54ev58.

65. Winkelmayer WC, Kewalramani R, Rutstein M, Gabardi S,Vonvisger T, Chandraker A. Pharmacoepidemiology ofanemia in kidney transplant recipients. J Am Soc Nephrol.2004;15(5):1347e1352.

66. Karakus‚ S, Kanbay M, Koseo�glu HK, Colak T, Haberal M.Causes of anemia in renal transplant recipients. TransplantProc. 2004;36(1):164e165.

67. Mix TC, Kazmi W, Khan S, et al. Anemia: a continuingproblem following kidney transplantation. Am J Transplant.2003;3(11):1426e1433.

68. Rigatto C, Foley R, Jeffery J, Negrijn C, Tribula C, Parfrey P.Electrocardiographic left ventricular hypertrophy in renaltransplant recipients: prognostic value and impact of bloodpressure and anemia. J Am Soc Nephrol. 2003;14:462e468.

69. Imoagene-Oyedeji AE, Rosas SE, Doyle AM, Goral S,Bloom RD. Posttransplantation anemia at 12 months inkidney recipients treated with mycophenolate mofetil: riskfactors and implications for mortality. J Am Soc Nephrol.2006;17:3240e3247.

70. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S,Schroll M, Jensen JS. Urinary albumin excretion. Anindependent predictor of ischemic heart disease. ArteriosclerThromb Vasc Biol. 1999;19(8):1992e1997.

71. Bonora E, Targher G, Formentini G, et al. The metabolicsyndrome is an independent predictor of cardiovasculardisease in type 2 diabetic subjects. Prospective data from theVerona Diabetes Complications Study. Diabet Med.2004;21(1):52e58.

72. Anavekar NS, Gans DJ, Berl T, et al. Predictors ofcardiovascular events in patients with type 2 diabeticnephropathy and hypertension: a case for albuminuria.Kidney Int. 2004;92:S50eS55.

73. Fernandez-Fresnedo G, Escallada R, Rodrigo E, et al. The riskof cardiovascular disease associated with proteinuria inrenal transplant patients. Transplantation.2002;73:1345e1348.

74. Fernandez-Fresnedo G, Plaza JJ, Sanchez-Plumed J, Sanz-Guajardo A, Palomar-Fontanet R, Arias M. Proteinuria: a newmarker of long-term graft and patient survival in kidneytransplantation, 19 suppl 3 Nephrol Dial Transplant.2004:iii47eiii51.

75. Roodnat JI, Mulder PG, Rischen-Vos J, et al. Proteinuria afterrenal transplantation affects not only graft survival but alsopatient survival. Transplantation. 2001;72(3):438e444.

76. Alonso A, Oliver J. Causes of death and mortality risk factors.Nephrol Dial Transplant. 2004;19:iii8e19.

77. Lim HS, Blann AD, Chong AY, Freestone B, Lip GY. Plasmavascular endothelial growth factor, angiopoietin-1, andangiopoietin-2 in diabetes: implications for cardiovascularrisk and effects of multifactorial intervention. Diabetes Care.2004;27(12):2918e2924.

78. 2006 Annual Report of the U.S. Organ Procurement andTransplantation Network and the Scientific Registry of TransplantRecipients: Transplant Data 1996e2005. Richmond, VA: UnitedNetwork of Organ Sharing; 2006.

79. Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetesmellitus after kidney transplantation in the united states.Am J Transplant. 2003;3:178e185.

80. Porrini E, Delgado P, Bigo C, et al. Impact of metabolicsyndrome on graft function and survival after cadavericrenal transplantation. Am J Kidney Dis. 2006;48:134e142.

81. Ducloux D, Kazory A, Chalopin JM. Posttransplant diabetesmellitus and atherosclerotic events in renal transplantrecipients: a prospective study. Transplantation.2005;79:438e443.

82. Hjelmesaeth J, Hartmann A, Midtvedt K, et al. Metaboliccardiovascular syndrome after renal transplantation.Nephrol Dial Transplant. 2001;16(5):1047e1052.

83. Dimeny EM. Cardiovascular disease after renaltransplantation. Kidney Int. 2002;80:S78eS84.

84. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. Acomparison of tacrolimus (FK506) and cyclosporine forimmunosuppression after cadaveric renal transplantation.FK506 Study Group. Transplantation. 1997;63(7):977e983.

85. Hricik DE, Anton HA, Knauss TC, et al. Outcomes of AfricanAmerican kidney transplant recipients treated withsirolimus, tacrolimus, and corticosteroids. Transplantation.2002;74(2):189e193.

86. Onwubalili JK, Obineche EN. High incidence of post-transplant diabetes mellitus in a single-centre study. NephrolDial Transplant. 1992;7(4):346e349.

87. Chuang P, Gibney EM, Chan L, Ho PM, Parikh CR. Predictorsof cardiovascular events and associated mortality withintwo years of kidney transplantation. Transplant Proc.2004;36(5):1387e1391.

88. Fernandez-Fresnedo G, Escallada R, de Francisco AL, et al.Posttransplant diabetes is a cardiovascular risk factor inrenal transplant patients. Transplant Proc. 2003;35(2):700.

89. Jacobs U, Ferber J, Heimbach D, Klehr HU. Manifestation ofmetabolic risk factors after renal transplantation: III. Impacton cerebrocardiovascular complications. Transplant Proc.1995;27(3):2052e2053.

90. Revanur VK, Jardine AG, Kingsmore DB, Jaques BC,Hamilton DH, Jindal RM. Influence of diabetes mellitus onpatient and graft survival in recipients of renaltransplantation. Clin Transplant. 2001;15:89e94.

91. Cole EH, Johnston O, Rose CL, Gill JS. Impact of acuterejection and new-onset diabetes on long-term transplantgraft and patient survival. Clin J Am Soc Nephrol.2008;3:814e821.

92. Vincenti F, Friman S, Scheuermann E, et al, for the DIRECT(Diabetes Incidence after Renal Transplantation: Neoral CMonitoring Versus Tacrolimus) Investigators. Results of aninternational, randomized trial comparing glucosemetabolism disorders and outcome with cyclosporineversus tacrolimus. Am J Transplant. 2007;7:1506e1514.

93. Lopes IM, Martin M, Errasti P, Martinez JA. Benefits of adietary intervention on weight loss, body composition, andlipid profile after renal transplantation. Nutrition.1999;15:7e10.

94. Cupisti A, D’Alessandro C, Ghiadoni L, Morelli E, Panichi V,Barsotti G. Effect of a soy protein diet on serum lipids ofrenal transplant patients. J Ren Nutr. 2004;14:31e35.

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6194

95. Kasiske BL. Epidemiology of cardiovascular disease afterrenal transplantation. Transplantation. 2001;72:S5eS8.

96. Appel L, Moore T, Obarzanek E, et al. The DASHCollaborative Research Group: a clinical trial of the effects ofdietary patterns on blood pressure. N Engl J Med.1997;336:1117e1124.

97. Mitka M. DASH dietary plan could benefit many, but fewhypertensive patients follow it. JAMA. 2007;298:164e165.

98. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacyand safety of cholesterol-lowering treatment: prospectivemeta-analysis of data from 90,056 participants in 14randomised trials of statins. Lancet. 2005;366:1267e1278.

99. Holdaas H, Fellstrom B, Jardine AG, et al, ALERT Study Group.Beneficial effect of early initiation of lipid lowering therapyfollowing renal transplantation. Nephrol Dial Transplant.2005;20:974e980.

100. Sandhu S, Wiebe N, Fried L, Tonelli M. Statins for improvingrenal outcomes: a meta-analysis. J Am Soc Nephrol.2006;17:2006e2016.

101. Ridker P, Cannon C, Morrow D, et al, Pravastatin orAtorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22)Investigators. C reactive protein levels and outcomes afterstatin therapy. N Engl J Med. 2005;352:20e28.

102. Masterson R, Hewitson T, Leikis M, Walker R, Cohney S,Becker G. Impact of statin treatment on 1-year functionaland histologic renal allograft outcome. Transplantation.2005;80:332e338.

103. Prasad GV, Ahmed A, Nash MM, Zaltzman JS. Blood pressurereduction with HMG-CoA reductase inhibitors in renaltransplant recipients. Kidney Int. 2003;63(1):360e364.

104. Pazik J, Ostrowska J, Lewandowski Z, et al. Renin-Angiotensin-Aldosterone system inhibitors and statinsprolong graft survival in post-transplant glomerulonephritis.Ann Transplant. 2008;13(4):41e45.

105. KDIGO clinical practice guideline for lipid management inchronic kidney disease. Chapter 2: pharmacologicalcholesterol-lowering treatment in adults. Kidney Int Suppl.2013;3:271e279.

106. Maltz H, Balog D, Cheigh J. Rhabdomyolysis associated withconcomitant use of atorvastatin and cyclosporine. AnnPharmacother. 1999;33:1176e1179.

107. Lemahieu WP, Hermann M, Asberg A, et al. Combinedtherapy with atorvastatin and calcineurin inhibitors: nointeractions with tacrolimus. Am J Transplant.2005;5:2236e2243.

108. Nogueira J, Weir M. The unique character of cardiovasculardisease in chronic kidney disease and its implications fortreatment with lipid-lowering drugs. Clin J Am Soc Nephrol.2007;2:766e785.

109. Neuvonen PJ, Niemi M, Backman JT. Drug interactions withlipid-lowering drugs: mechanisms and clinical relevance.Clin Pharmacol Ther. 2006;80:565e581.

110. Phan BA, Dayspring TD, Toth PP. Ezetimibe therapy:mechanism of action and clinical update. Vasc Health RiskManag. 2012;8:415e427.

111. Baigent C, Landray MJ, Reith C, et al, for the SHARPInvestigators. The effects of lowering LDL cholesterol withsimvastatin plus ezetimibe in patients with chronic kidneydisease (Study of Heart and Renal Protection):a randomised placebo-controlled trial. Lancet.2011;377:2181e2192.

112. Puthenparumpil JJ, Keough-Ryan T, Kiberd M, et al.Treatment of hypercholesterolemia with ezetimibe in thekidney transplant population. Transplant Proc.2005;37(2):1033e1035.

113. ALLHAT Officers and Coordinators for the ALLHATCollaborative Research Group, The Antihypertensive and

Lipid-Lowering Treatment to Prevent Heart Attack Trial.Major outcomes in high-risk hypertensive patientsrandomized to angiotensin-converting enzyme inhibitor orcalcium channel blocker vs diuretic: the Antihypertensiveand Lipid-Lowering Treatment to Prevent Heart AttackTrial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981e2997.

114. Midtvedt K, Hartmann A, Foss A, et al. Sustainedimprovement of renal graft function for two years inhypertensive renal transplant recipients treated withnifedipine as compared to lisinopril. Transplantation.2001;72(11):1787e1792.

115. Midtvedt K, Hartmann A, Holdaas H, Fauchald P. Efficacy ofnifedipine or lisinopril in the treatment of hypertensionafter renal transplantation: a double-blind randomisedcomparative trial. Clin Transplant. 2001;15(6):426e431.

116. Harper SJ, Moorhouse J, Veitch PS, et al. Nifedipine improvesimmediate, and 6- and 12-month graft function incyclosporin A (CyA) treated renal allograft recipients, 5 suppl1 Transpl Int. 1992:S69eS72.

117. Chanard J, Toupance O, Lavaud S, HuraultdeLigny B,Bernaud C, Moulin B. Amlodipine reduces cyclosporineinduced hyperuricaemia in hypertensive renal transplantrecipients. Nephrol Dial Transplant. 2003;18:2147e2153.

118. Kuypers DR, Neumayer HH, Fritsche L, et al, LacidipineStudy Group. Calcium channel blockade and preservation ofrenal graft function in cyclosporine-treated recipients: aprospective randomized placebo-controlled 2-year study.Transplantation. 2004;78:1204e1211.

119. Kumana CR, Tong MK, Li CS, et al. Diltiazem co-treatment inrenal transplant patients receiving microemulsioncyclosporin. Br J Clin Pharmacol. 2003;56(6):670e678.

120. Abraham MA, Thomas PP, John GT, et al. Efficacy and safetyof low-dose ketoconazole (50 mg) to reduce the cost ofcyclosporine in renal allograft recipients. Transplant Proc.2003;35(1):215e216.

121. Omoto K, Tanabe K, Tokumoto T, Shimmura H, Ishida H,Toma H. Use of candesartan cilexetil decreases proteinuriain renal transplant patients with chronic allograftdysfunction. Transplantation. 2003;76(8):1170e1174.

122. Inigo P, Campistol JM, Saracho R, et al. Renoprotectiveeffects of losartan in renal transplant recipients. Results ofa retrospective study. Nephron Clin Pract.2003;95(3):c84ec90.

123. del Castillo D, Campistol JM, Guirado L, et al. Efficacy andsafety of losartan in the treatment of hypertension in renaltransplant recipients. Kidney Int. 1998;68:S135eS139.

124. Campistol JM, Inigo P, Jimenez W, et al. Losartan decreasesplasma levels of TGF-beta1 in transplant patients withchronic allograft nephropathy. Kidney Int.1999;56(2):714e719.

125. Hiremath S, Fergusson D, Doucette S, Mulay AV, Knoll GA.Renin angiotensin system blockade in kidneytransplantation: a systematic review of the evidence. Am JTransplant. 2007;7:2350e2360.

126. Heinze G, Mitterbauer C, Regele H, et al. Angiotensin-converting enzyme inhibitor or angiotensin II type 1receptor antagonist therapy is associated with prolongedpatient and graft survival after renal transplantation. J AmSoc Nephrol. 2006;17:889e899.

127. Formica Jr RN, Friedman AL, Lorber MI, Bia MJ. Angiotensin-converting enzyme inhibitors and angiotensin II receptorblockers used for the treatment of hypertension appear to besafe in the early posttransplant period. Transplant Proc.2004;36:2675e2678.

128. Lorenz M, Billensteiner E, Bodingbauer M, Oberbauer R,Horl WH, Haas M. The effect of ACE inhibitor andangiotensin II blocker therapy on early posttransplantkidney graft function. Am J Kidney Dis. 2004;43:1065e1070.

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6 195

129. Shirali AC, Bia MJ. Management of cardiovascular disease inrenal transplant recipients. Clin J Am Soc Nephrol.2008;3:491e504.

130. Weir MR. Blood pressure management in the kidneytransplant recipient. Adv Chronic Kidney Dis.2004;11(2):172e183.

131. Midtvedt K, Ihlen H, Hartmann A, et al. Reduction of leftventricular mass by lisinopril and nifedipine inhypertensive renal transplant recipients: a prospectiverandomized double blind study. Transplantation.2001;72:107e111.

132. Kasiske BL, Zeier MG, Chapman JR, et al, Kidney Disease:Improving Global Outcomes. KDIGO clinical practiceguideline for the care of kidney transplant recipients: asummary. Kidney Int. 2010;77(4):299e311.

133. Bakris GL, Williams M, Dworkin L, et al. Preserving renalfunction in adults with hypertension and diabetes: aconsensus approach. National Kidney FoundationHypertension and Diabetes Executive Committees WorkingGroup. Am J Kidney Dis. 2000;36(3):646e661.

134. Bakris G. Inclusion of albuminuria in hypertension and heartguidelines. Kidney Int Suppl. 2004;92:S124eS125.

135. Aker S, Ivens K, Guo Z, Grabensee B, Heering P.Cardiovascular complications after renal transplantation.Transplant Proc. 1998;30:2039e2042.

136. Yavuz A, Tuncer M, Gurkan A, et al. Cigarette smoking inrenal transplant recipients. Transplant Proc.2004;36(1):108e110.

137. Cosio FG, Falkenhain ME, Pesavento TE, et al. Patientsurvival after renal transplantation: II. The impact ofsmoking. Clin Transplant. 1999;13(4):336e341.

138. Kasiske BL, Klinger D. Cigarette smoking in renal transplantrecipients. J Am Soc Nephrol. 2000;11(4):753e759.

139. Sung RS, Althoen M, Howell TA, Ojo AO, Merion RM. Excessrisk of renal allograft loss associated with cigarette smoking.Transplantation. 2001;71(12):1752e1757.

140. Luan FL, Stuckey LJ, Ojo AO. Abnormal glucose metabolismand metabolic syndrome in non-diabetic kidney transplantrecipients early after transplantation. Transplantation.2010;89:1034e1039.

141. Haririan A, Sillix DH, Morawski K, et al. Short-termexperience with early steroid withdrawal inAfricaneAmerican renal transplant recipients. Am JTransplant. 2006;6:2396e2402.

142. Crutchlow MF, Bloom RD. Transplant-associatedhyperglycemia: a new look at an old problem. Clin J Am SocNephrol. 2007;2:343e355.

143. Rostaing L, Cantarovich D, Mourad G, et al, CARMEN StudyGroup. Corticosteroid-free immunosuppression withtacrolimus, mycophenolate mofetil, and daclizumabinduction in renal transplantation. Transplantation.2005;79:807e814.

144. Meier-Kriesche H, Li S, Gruessner RW, et al.Immunosuppression: evolution in practice and trends,1994e2004. Am J Transplant. 2006;6:1111e1131.

145. Gallon L, Winoto J, Leventhal J, Parker M, Kaufman D.Effect of prednisone versus no prednisone as part ofmaintenance immunosuppression on long-term renaltransplant function. Clin J Am Soc Nephrol.2006;1:1029e1038.

146. van Hooff JP, Christiaans MH, van Duijnhoven EM.Tacrolimus and posttransplant diabetes mellitus in renaltransplantation. Transplantation. 2005;79:1465e1469.

147. Davidson J, Wilkinson A, Dantal J, et al. International ExpertPanel: new-onset diabetes after transplantation: 2003International consensus guidelines. Proceedings of aninternational expert panel meeting. Barcelona, Spain, 19February 2003. Transplantation. 2003;75(10 suppl l):SS3e24.

148. Wilkinson A, Davidson J, Dotta F, et al. Guidelines for thetreatment and management of new-onset diabetes aftertransplantation. Clin Transplant. 2005;19:291e298.

149. Genuth S, Alberti KG, Bennett P, et al, Expert Committee onthe Diagnosis and Classification of Diabetes Mellitus.Follow-up report on the diagnosis of diabetes mellitus.Diabetes Care. 2003;26(11):3160e3167.

150. Armstrong KA, Prins JB, Beller EM, et al. Should an oralglucose tolerance test be performed routinely in all renaltransplant recipients? Clin J Am Soc Nephrol.2006;1:100e108.

151. Tuomilehto J, Lindstrom J, Eriksson J, et al, The FinnishDiabetes Prevention Study Group. Prevention of type 2diabetes mellitus by changes in lifestyle among subjectswith impaired glucose tolerance. N Engl J Med.2001;344:1343e1350.

152. Lindstrom J, Ilanne-Parikka P, Peltonen M, et al. Sustainedreduction in the incidence of type 2 diabetes by lifestyleintervention: follow-up of the Finnish diabetes preventionstudy. Lancet. 2006;368:1673e1679.

153. Jindal RM, Hjelmesaeth J. Impact and management ofposttransplant diabetes mellitus. Transplantation.2000;70:SS58eSS63.

154. Selvin E, Marinopoulos S, Berkenblit G, et al. Glycosylatedhemoglobin and cardiovascular disease in diabetes mellitus.Ann Intern Med. 2004;141:421e431.

155. Scheen AJ. Renin-angiotensin system inhibition preventstype 2 diabetes mellitus. Part 1. A meta-analysis ofrandomized clinical trials. Diabete Metab. 2004;30:487e496.

156. Prasad GV, Kim SJ, Huang M, et al. Reduced incidence ofnew-onset diabetes mellitus after renal transplantation with3-hydroxy-3-methylglutaryl-coenzyme A reductaseinhibitors (statins). Am J Transplant. 2004;4:1897e1903.

157. Antiplatelet Trialists Collaboration. Collaborative overviewof randomised trials of antiplatelet therapy-I: prevention ofdeath, myocardial infarction, and stroke by prolongedantiplatelet therapy in various categories of patients. BMJ.1994;308:81e106.

158. Antiplatelet Trialists’ Collaboration. Secondary preventionof vascular disease by prolonged antiplatelet treatment. BrMed J (Clin Res Ed). 1988;296:320e331.

159. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy forprevention of death, myocardial infarction, and stroke inhigh risk patients. BMJ. 2002;324(7329):71e86.

160. Wright R, Reeder G, Herzog C, et al. Acute myocardialinfarction and renal dysfunction: a high risk combination.Ann Intern Med. 2002;137:563e570.

161. Grotz W, Siebig S, Olschewski M, et al. Low-dose aspirintherapy is associated with improved allograft function andprolonged allograft survival after kidney transplantation.Transplantation. 2004;77:1848e1853.

162. Robertson AJ, Nargund V, Gray DW, Morris PJ. Low doseaspirin as prophylaxis against renal-vein thrombosis inrenal-transplant recipients. Nephrol Dial Transplant.2000;15(11):1865e1868.

163. Matsumoto C, Swanson SJ, Agodoa LY, Holtzmuller KC,Abbott KC. Hospitalized gastrointestinal bleeding andprocedures after renal transplantation in the United States. JNephrol. 2003;16(1):49e56.

164. de Lemos JA, Hillis LD. Diagnosis and management ofcoronary artery disease in patients with end-stage renaldisease on hemodialysis. J Am Soc Nephrol.1996;7(10):2044e2054.

165. Manske CL, Wang Y, Rector T, Wilson RF, White CW.Coronary revascularisation in insulin-dependent diabeticpatients with chronic renal failure. Lancet. 1992 Oct24;340(8826):998e1002.

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 8 4e1 9 6196

166. Ferguson ER, Hudson SL, Diethelm AG, Pacifico AD, Dean LS,Holman WL. Outcome after myocardial revascularizationand renal transplantation: a 25-year single institutionexperience. Ann Surg. 1999;230(2):232e241.

167. Herzog CA, Ma JZ, Collins AJ. Long-term outcome of renaltransplant recipients in the United States after coronaryrevascularization procedures. Circulation.2004;109(23):2866e2871.

168. Mitruka SN, Griffith BP, Kormos RL, et al. Cardiac operationsin solid organ transplant recipients. Ann Thorac Surg.1997;64(5):1270e1278.

169. Humar A, Gillingham K, Payne WD, Sutherland DE, Matas AJ.Increased incidence of cardiac complications in kidneytransplant recipients with cytomegalovirus disease.Transplantation. 2000;70:310e313.

170. Ismail A, Khosravi H, Olson H. The role of infection inatherosclerosis and coronary artery disease: a newtherapeutic target. Heart Dis. 1999;1:233e240.

171. Boughey JC, Bowen 2nd PA, Gifford RR. Renaltransplantation in patients with hypercoagulable states. J S CMed Assoc. 2003;99(12):372e374.

172. Ducloux D, Pellet E, Fournier V, et al. Prevalence and clinicalsignificance of antiphospholipid antibodies in renaltransplant recipients. Transplantation. 1999;67(1):90e93.

173. Haydar AA, Covic A, Jayawardene S, et al. Insights fromambulatory blood pressure monitoring: diagnosis ofhypertension and diurnal blood pressure in renal transplantrecipients. Transplantation. 2004;77(6):849e853.

174. Oliveras A, Vazquez S, Hurtado S, Vila J, Puig JM, Lloveras J.Ambulatory blood pressure monitoring in renal transplantpatients:modifiable parameters after active antihypertensivetreatment. Transplant Proc. 2004;36(5):1352e1354.

175. Marcondes AM, De Lima JJ, Giorgi DM, et al. Twenty-fourhour blood pressure profile and left ventricular hypertrophyearly after renal transplantation. Ren Fail.2002;24(2):207e213.

176. Varagunam M, Finney H, Trevitt R, et al.Pretransplantation levels of C-reactive protein predict all-

cause and cardiovascular mortality, but not graft outcome,in kidney transplant recipients. Am J Kidney Dis.2004;43(3):502e507.

177. Bakri RS, Afzali B, Covic A, et al. Cardiovascular disease inrenal allograft recipients is associated with elevated sialicacid or markers of inflammation. Clin Transplant.2004;18(2):201e204.

178. Ducloux D, Challier B, Saas P, Tiberghien P, Chalopin JM. CD4cell lymphopenia and atherosclerosis in renal transplantrecipients. J Am Soc Nephrol. 2003;14(3):767e772.

179. Constans J, Marchand JM, Conri C, et al. Asymptomaticatherosclerosis in HIV-positive patients: a case-controlultrasound study. Ann Med. 1995;27:683e685.

180. Krishnaswamy G, Chi DS, Kelley JL, Sarubbi F, Smith JK,Peiris A. The cardiovascular and metabolic complications ofHIV infection. Cardiol Rev. 2000;8:260e268.

181. Pita-Fernandez S, Pertega-Dıaz S, Valdes-Canedo F, et al.Incidence of cardiovascular events after kidneytransplantation and cardiovascular risk scores: studyprotocol. BMC Cardiovasc Disord. 2011;11:2.

182. Anderson KM, Wilson PW, Odell PM, Kannel WB. An updatedcoronary risk profile. A statement for health professionals.Circulation. 1991;83(1):356e362.

183. Wilson PW, D’Agostino RB, Levy D, Belanger AM,Silbershatz H, Kannel WB. Prediction of coronary heartdisease using risk factor categories. Circulation. 1998 May12;97(18):1837e1847.

184. Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: theSCORE project. Eur Heart J. 2003;24(11):987e1003.

185. Aranceta J, Perez Rodrigo C, Foz Sala M, et al. [Tables ofcoronary risk evaluation adapted to the Spanish population:the DORICA study]. Med Clin (Barc). 2004 Nov20;123(18):686e691.

186. Marrugat J, Solanas P, D’Agostino R, et al. [Coronary riskestimation in Spain using a calibrated Framinghamfunction]. Rev Esp Cardiol. 2003 Mar;56(3):253e261.