C H A P T E R
102  
Medical Management of the Kidney Transplant Recipient:
Cardiovascular Disease and Other Issues
Phuong-Thu T. Pham, Gabriel M. Danovitch, Son V. Pham
Although renal transplantation improves both survival and
quality of life of the patient compared with dialysis, various
medical issues can arise in the transplant recipient. This chapter
provides an approach to the medical management of transplant-
related complications. Infections and malignant neoplasms are
discussed in Chapter 101.
CARDIOVASCULAR DISEASE
Death with a functioning graft is one of the major causes of late
graft loss, with cardiovascular (CV) disease being the most fre-
quent cause. Compared with the general population, CV mortal-
ity in transplant recipients is increased by nearly 10-fold among
patients within the age range of 35 to 44 years and at least
doubled among those between the ages of 55 and 64 years.
Although renal transplantation ameliorates some CV risk by
restoring renal function, it introduces new CV risks, including
impaired glucose tolerance or diabetes mellitus, hypertension,
and dyslipidemia that are derived, in part, from immunosuppres-
sive medications. Renal transplant recipients have both conven-
tional and unconventional CV risk factors (Fig. 102.1).1,2
Conventional Cardiovascular Disease Risk Factors
Post-transplantation Hypertension
Hypertension is a risk factor for both CV disease and kidney
graft failure. The Collaborative Transplant Study (CTS) registry
has documented a graded risk for graft failure with increasing
levels of systolic and diastolic blood pressure.3 Whether aggres-
sive lowering of blood pressure retards the progression of graft
failure similar to the delayed progression of renal disease in the
general population with chronic kidney disease (CKD) remains
to be studied. Hypertension is common after transplantation and
is present in 50% to 90% of renal transplant recipients.4,5 The
wide range in the frequency may reflect the variable definitions
of hypertension, donor source, immunosuppressive medications,
time after transplantation, and level of graft function. Systolic
blood pressure is highest immediately after transplantation and
declines during the first year.4 In the CTS registry, only 8% of
transplant recipients had a systolic blood pressure below
120 mm Hg at 1 year; 33% had a blood pressure in the pre­
hypertension range; 39% had stage 1 hypertension; and 20%
had stage 2 hypertension despite antihypertensive therapy.3 Pre-
existing hypertension, tacrolimus and to a greater degree cyclo-
sporine, corticosteroids, quality of donor organ, delayed graft
function, chronic allograft nephropathy, high body mass
index (BMI) or excess weight gain, acute rejection episodes
independent of creatinine clearance, recurrent or de novo glo-
merulonephritis, and transplant renal artery stenosis have all
been implicated in post-transplantation hypertension. In rare
cases, excess renin output from the native kidneys has also been
suggested to contribute to post-transplantation hypertension.4 In
renal transplant recipients with severe hypertension refractory to
medical therapy, bilateral native nephrectomy has been reported
to improve blood pressure control.6
Management of post-transplantation hypertension should
include attempts to identify and to treat the underlying etiology,
lifestyle modifications (see Chapter 34), and treatment of associ-
ated CV risk factors. The initial target blood pressure goal is
below 130/80 mm Hg, and in those with proteinuria, below
125/75 mm Hg. Although there is a lack of controlled clinical
trials related to selection of antihypertensive agent, we recom-
mend β-blockers in the perioperative setting as they have been
shown to reduce ischemic heart disease events in high-risk can-
didates. In the early post-transplantation period, nondihydro-
pyridine calcium channel blockers (CCBs) and diuretics are
frequently used, the former for their beneficial effect on intra-
glomerular hemodynamics and the latter for their ability to
eliminate salt and water in patients who are volume expanded
postoperatively.
Angiotensin-converting enzyme (ACE) inhibitors and angio-
tensin receptor blockers (ARBs) have been found to block calci-
neurin toxicity in experimental models and are protective in
patients with CKD. Although these effects are desirable, they
can cause acute changes in renal function as well as hyperkalemia
and hence are usually not started until renal function is stable. A
meta-analysis of 21 randomized controlled trials (N = 1549
patients) demonstrated that ACE inhibitors and ARBs reduce
proteinuria in transplant recipients, but they also reduce hema-
tocrit (−3.5%; 95% CI −6.1 to −0.95) and glomerular filtration
rate (GFR; −5.8 ml/min; 95% CI −10.6 to −0.99); there were
insufficient data to determine a benefit on patient or graft sur-
vival.7 Serum potassium and creatinine concentrations must be
closely monitored; a rising serum creatinine concentration of
more than 30% above baseline should also prompt clinicians to
consider transplant renal artery stenosis. Finally, dihydropyri-
dine CCBs were once used extensively because they counter
calcineurin vasoconstriction. However, an unexpected associa-
tion has been reported between the use of dihydropyridine CCBs
and an increased risk for ischemic heart disease.8 Dihydropyri-
dine CCBs are also known to block renal autoregulation in CKD,
in which they can increase proteinuria and may accelerate renal
disease progression, especially in those not taking ACE inhibi-
tors or ARBs.1-2,9,10 Dihydropyridine CCBs should therefore be
1189
1190 SECTION XVII  Transplantation

Cardiovascular Risk Factors in Transplant Recipients

Conventional Unconventional
Modifiable Nonmodifiable Modifiable (+/- potentially modifiable) Nonmodifiable

Hypertension Family history Anemia Prior acute rejection

episodes
Dyslipidemia Diabetes mellitus Proteinuria Preexisting CAC
Obesity Male gender Hyperhomocysteinemia Deceased vs. living donor
Smoking Age Inflammatory cytokines Pretransplantation splenectomy
↑ C-reactive protein
CMV infection*
Hyperuricemia
Impaired allograft function†
Left ventricular hypertrophy‡
CD4 lymphopenia§
Low albumin

Figure 102.1  Cardiovascular risk factors in transplant recipients. *Strict adherence to cytomegalovirus (CMV) prophylaxis protocol/CMV surveil-
lance in high-risk candidates. †Calcineurin inhibitor minimization or withdrawal at the discretion of the clinician (variable results/difficult-to-modify risk
factor). ‡Optimize blood pressure control; use angiotensin-converting enzyme inhibitors, angiotensin receptor AT1 blockers. §Assess risks and benefits
of T cell–depleting antibody treatment. Further studies are needed. CAC, coronary artery calcification.

Potential Advantages and Disadvantages of Different Classes of Antihypertensive Agents1

Classes of drugs Advantages Disadvantages

β-Blockers Perioperative use ↓ ischemic heart disease ↑ Risk of symptomatic bradycardia when used with
events nondihydropyridine CCB
Blunting of hypoglycemic awareness
CCB ↓ CNI-induced renal vasoconstriction2 Monotherapy with dihydropyridine CCB should be used
↑ CNI level (may permit CNI dose reduction with caution4
by up to 40%)3
Diuretics Beneficial in patients who are volume expanded Hyperuricemia, gout
postoperatively
ACE Inhibitor/ARB ↓ Proteinuria Potential worsening of anemia
Potential renal protective and cardioprotective effects
Beneficial in patients with post-transplantation
erythrocytosis
Aldosterone receptor May improve outcomes in heart failure Severe hyperkalemia when used in combination with
Blockers ACEI/ARB or in patients with poor kidney function
α-2-Blockers Benign prostatic hypertrophy
Neurogenic bladder
Direct vasodilators Tachycardia
Central α agonist Depression

Figure 102.2  Potential advantages and disadvantages of different classes of antihypertensive agents. 1In general, there is no absolute con-
traindication to the use of any antihypertensive agent in renal transplant recipients. 2Both dihydropyridine and nondihydropyridine CCB. 3Nondihydro-
pyridine CCB. 4See text. ACE inhibitor, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; CCB, calcium channel blockers;
CNI, calcineurin inhibitors.

used as monotherapy with caution. Potential advantages and
disadvantages of different classes of antihypertensive agents in
renal transplant recipients are shown in Figure 102.2.
Post-transplantation Dyslipidemia
Dyslipidemia is common after transplantation, in part because of
the hyperlipemic effect of corticosteroids, cyclosporine, tacroli-
mus, and sirolimus. Sirolimus and everolimus are associated with
the worst lipid profiles, followed by cyclosporine and then tacro-
limus. Other potential etiologic factors for post-transplantation
dyslipidemia include age, diet, rapid weight gain, hyperinsu-
linemia, preexisting hypercholesterolemia, allograft dysfunction,
proteinuria, and the use of β-blockers and diuretics.
Although hyperlipidemia often improves within the first 6
months after transplantation as the doses of immunosuppressive
agents are reduced, total and low-density lipoprotein cholesterol
goals as defined by the National Cholesterol Education Program
(NCEP) guidelines (http://www.nhlbi.nih.gov/about/ncep/index.
htm) are usually not achieved. Most patients require statins,
which are not only lipid lowering but also protective against CV
 CHAPTER 102  Medical Management of the Kidney Transplant Recipient: Cardiovascular Disease and Other Issues 1191

disease because of their additional effects of reducing circulating sequestrants may increase triglyceride levels. For a more com-
endothelin 1, C-reactive protein levels, systolic and diastolic plete list of drug-drug interaction of statins with other lipid-
blood pressure, and pulse pressure. However, the extent to which lowering agents, readers are referred to reference 14.
statins reduce C-reactive protein and ameliorate hemodynamic The 2004 National Kidney Foundation Work Group sug-
parameters remains to be studied. gested that statin therapy be the first-line treatment of non–
The Assessment of Lescol in Renal Transplantation (ALERT) high-density lipoprotein cholesterol because of its well-established
study demonstrated the efficacy of fluvastatin in reducing low- safety and efficacy in preventing CV disease in randomized trials
density lipoprotein cholesterol during a 5- to 6-year period. The in the general population. Fibrates are used for those intolerant
incidence of major adverse cardiac events was also reduced with of statin despite dose reduction or despite switching to another
treatment, although this was not statistically significant. Addi- statin. Randomized controlled trials evaluating the safety and
tional analysis demonstrated a beneficial effect of early initiation efficacy of statins and fibrates are still needed. For patients with
of fluvastatin on CV outcome; patients who received statin fasting triglyceride levels of 1000 mg/dl (11.29 mmol/l) or
therapy within the first 4 years after transplantation had a risk higher, the Adult Treatment Panel III (ATP III) recommends a
reduction of 64% compared with 19% for those who received very low fat diet (<15% total calories), medium-chain triglycer-
therapy after 10 years. No statin effect on graft loss or doubling ides, and fish oils to replace some long-chain triglycerides. Sug-
of serum creatinine was observed.11,12 In another study, there was gested guidelines for treatment of dyslipidemia are summarized
better graft function at 12 months after transplantation in recipi- in Figure 102.3.
ents who received statins compared with those who did not
receive statin therapy (difference in creatinine clearance of
6 ml/min; P < .001); in addition, less interstitial fibrosis was seen
on protocol biopsies.13
Whereas statins appear beneficial in transplant recipients, Suggested Guidelines for the Treatment of
the use of statins in the presence of calcineurin inhibitors, Post-Transplantation Dyslipidemia
particularly cyclosporine, often results in several-fold increases
in statin blood level and an increased risk for myopathy and LDL1
rhabdomyolysis.14
Other lipid-lowering agents include fibric acid derivatives,
nicotinic acid, bile acid sequestrants, and ezetimibe. Ezetimibe <100 mg/dl 100–129 mg/dl ≥ 130 mg/dl
and statin combination therapy can significantly improve choles- (<2.6 mmol/l) (2.6–3.36 mmol/l) (> 3.36 mmol/l)
terol control because of their complementary mechanisms of
action. Ezetimibe blocks intestinal absorption of dietary choles- No drug therapy TLC
terol and related phytosterols, whereas statin inhibits hepatic Continue to
cholesterol synthesis. Ezetimibe used alone or as adjunctive monitor After 3 months
therapy with statin appears safe and effective in the treatment of
dyslipidemia in renal transplant patients who are refractory to
LDL ≥ 100 mg/dl
statin therapy.15 In a single-center study, the addition of ezeti- >2.6 mmol/l
mibe to statin therapy was shown to prevent the decline in renal
function compared with controls.16 Whether ezetimibe and
statin combination therapy is superior to statin-alone therapy in TLC + suggested drug therapy
CV disease risk factor reduction remains to be elucidated. To
date, no significant drug-drug interaction between ezetimibe and
calcineurin inhibitors or sirolimus has been reported. TG <200 mg/dl TG 200–500 mg/dl TG ≥ 500 mg/dl
(<2.2 mmol/l) (2.2-5.6 mmol/l) (>5.6 mmol/l)
+ Non-HDL ≥130
Drug Therapy for Hypertriglyceridemia and Non–High- *Statins2 mg/dl (3.4 mmol/) Combination
Density Lipoprotein Cholesterol  Severe hypertriglyceridemia Resins3 therapy
(triglyceride level >500 mg/dl) is seen more frequently since the Niacin * Statins2 *Statins2 and
introduction of sirolimus. Management includes sirolimus dose Fibrates (fibrate4, niacin)
reduction, addition of a fibric acid derivative or nicotinic acid,
and, in refractory cases, switching of sirolimus to mycophenolate Figure 102.3  Suggested guidelines for the treatment of post-
mofetil (MMF) or tacrolimus. Of the most used fibric acid transplantation dyslipidemia. All transplant recipients should be
medications—bezafibrate, ciprofibrate, fenofibrate, and regarded as coronary heart disease risk equivalent. Goals: low-density
lipoprotein (LDL) <100 mg/dl (2.6 mmol/l) (optional <70 mg/dl)
gemfibrozil—the first three can increase serum creatinine in (1.8 mmol/l); triglyceride (TG) <200 mg/dl (2.2 mmol/l); high-density lipo-
cyclosporine-treated patients. Although all fibrates in combina- protein (HDL) >40 to 50 mg/dl (1.03-1.29 mmol/l).
tion with statins have been associated with creatine kinase eleva- *If LDL targets are not achieved with statin monotherapy, consider
tions with or without overt rhabdomyolysis and myopathy, combination of statins plus cholesterol absorption inhibitors.5 TLC, thera-
peutic lifestyle change (see text).
gemfibrozil may have a greater risk for causing myopathy com- 1
LDL <70 mg/dl (1.8 mmol/l) has been suggested for very high risk
pared with bezafibrate or fenofibrate.14 Niacin monotherapy has patients (NCEP ATP III guidelines). 2Statins are the most effective drugs
not been reported to cause myopathy, but its combined use with and should be the agents of first choice. Start at low dose in patients
lovastatin, pravastatin, or simvastatin may be associated with receiving cyclosporine and tacrolimus. Monitor for myositis and transa-
rhabdomyolysis. Bile acid sequestrants must be used with caution minitis, particularly in those receiving combination therapy. 3Bile acid
sequestrants should probably not be taken at the same time as cyclo-
because of their potential interference with the absorption of sporine. 4Extreme caution should be used with statin and fibrate combina-
other medications vital to renal transplant recipients. In addition, tion therapy. 5Consider cholesterol absorption inhibitors in patients
studies in the general population suggest that bile acid intolerant of statins.
1192 SECTION XVII  Transplantation
New-Onset Diabetes After Transplantation
New-onset diabetes after transplantation (NODAT) occurs in
4% to 25% of renal transplant recipients. The variation in
reported incidence may be due to differences in definition, dura-
tion of follow-up, and the presence of both modifiable and non-
modifiable risks factors. Major risk factors include African
American and Hispanic ethnicity (compared with Caucasians or
Asians), obesity defined as BMI of 30  kg/m2 or higher, age older
than 40 to 45 years, family history of diabetes among
first-degree relatives, impaired glucose tolerance before trans-
plantation or presence of other components of the metabolic
syndrome, recipients of deceased donor kidneys, and hepatitis
C infection. Risk factors among immunosuppressive therapies
include corticosteroids and the calcineurin inhibitors tacrolimus
and, to a lesser extent, cyclosporine16; neither azathioprine nor
MMF is diabetogenic. MMF may even mitigate the diabeto-
genic effect of tacrolimus, possibly by allowing clinicians to use
lower doses.
Sirolimus is now recognized to be associated with reduced
insulin sensitivity and a defect in the compensatory β-cell
response. Sirolimus may be diabetogenic by impairing insulin-
mediated suppression of hepatic glucose production, causing
ectopic triglyceride deposition leading to insulin resistance, and
by direct β-cell toxicity.17
Other potential risk factors for the development of NODAT
include the presence of certain HLA antigens (such as A30, B27,
and B42), increasing HLA mismatches, acute rejection history,
cytomegalovirus (CMV) infection, and male gender of recipient
and donor.18 Polycystic kidney disease has been suggested to
confer an increased risk for development of diabetes after renal
transplantation in some studies but not in others.18 Risk factors
for NODAT are summarized in Figure 102.4.
Management of NODAT  Management of diabetes is similar
to that of patients in the nontransplant setting, with a recom-
mended target hemoglobin A1c level below 6.5%. Fasting plasma
glucose concentration should be below 100 mg/dl (6 mmol/l),
and a 2-hour postprandial plasma glucose concentration should
be below 140 mg/dl (7.8 mmol/l). Aggressive lowering of hemo-
globin A1c below 6.0% is not recommended because of risks of
hypoglycemia and because in nontransplant patients this has
been associated with increased mortality.19
Non-modifiable
Figure 102.4  Risk factors for new-
onset diabetes after transplantation
(NODAT). 1Consider pretransplantation
treatment of HCV (see text). 2Aggressive • African American, Hispanic
post-transplantation CMV prophylaxis. • Age > 40-45 yrs
3
Counseling on lifestyle modifications. • Recipient male gender
4 • Family history of diabetes
Further studies are needed. HLA, human • HLA A30, B27, B42
leukocyte antigen; HCV, hepatitis C virus; • HLA mismatches
CMV, cytomegalovirus; IGT, impaired • Acute rejection history
glucose tolerance. • Deceased donor
• Male donor
• Polycystic kidneys
Overweight adults with impaired glucose tolerance should
undergo lifestyle modifications including moderation of dietary
sodium (<2400 mg of sodium a day) and saturated fat intake
(<7% of calories from saturated fats, 2% to 3% of calories from
trans-fatty acids), regular aerobic exercise, and weight reduction.
Carbohydrate intake should be limited to 50% to 60% of calorie
intake. The American Heart Association guidelines also sug-
gested more than 25 g/day of dietary fiber and two servings of
fish per week. Defining realistic goals, such as a target weight
loss of 5% to 10% of total body weight, and a patient-centered
approach to education may be invaluable in achieving success.
Modification of immunosuppression should be considered in
high-risk patients. Corticosteroid dose reduction significantly
improves glucose tolerance during the first year after transplan-
tation. However, any dose reduction should be weighed against
the risk of acute rejection. Conversion of tacrolimus to cyclospo-
rine in patients who fail to achieve target glycemic control has
yielded variable results.
Orally administered agents can be used either alone or in
combination with insulin. Although oral agents are often effec-
tive, insulin therapy may be necessary in up to 40% of patients,
particularly in the early post-transplantation period. The choice
of pharmacologic therapy is based on the potential advantages
and disadvantages associated with the different classes of oral
agents. Metformin (a biguanide derivative) is preferred for over-
weight patients but is contraindicated in patients with impaired
graft function (GFR <60 to 70 ml/min) as in this setting it can
cause lactic acidosis. Sulfonylurea derivatives must be prescribed
with care to patients with impaired graft function or to elderly
patients because of the increased risk of hypoglycemia. In these
patients, it is best to start with a low dose and to titrate upward
every 1 to 2 weeks. The “non-sulfonylurea” meglitinides are
insulin secretagogues with a mechanism of action similar to that
of the sulfonylureas. They have a more rapid onset and shorter
duration of action and seemingly lower risks of hypoglycemia.
These agents are best suited for patients whose food intake is
erratic, elderly patients, and patients with impaired graft func-
tion. They are best taken before meals, and the dose may be
omitted if a meal is missed.
The thiazolidinedione derivatives (TZDs) are insulin sensitizers
that may allow a reduction in insulin requirement. Potential
adverse effects of these agents include weight gain, peripheral
Risk Factors for NODAT
Potentially Modifiable Modifiable
Individualization of
immunosuppressive therapy
• HCV infection1 • Tacrolimus
• CMV infection2 • Cyclosporine
• Pre-transplant IGT3 • Corticosteroid
• Proteinuria (see text) • Sirolimus4
Obesity or other component of
the metabolic syndrome
 CHAPTER 102  Medical Management of the Kidney Transplant Recipient: Cardiovascular Disease and Other Issues 1193
edema, anemia, pulmonary edema, and congestive heart failure.
The incidence of peripheral edema is increased when TZDs are
used in combination with insulin. More recently, during the A
Diabetes Outcome Progression Trial (ADOPT) conducted to
compare glycemic control in patients taking rosiglitazone, met-
formin, or glyburide, a higher incidence of fractures on the upper
arm, hand, and foot among female patients treated with rosigli-
tazone was noted.20,21 Subsequently, pioglitazone was also recog-
nized to have similar increased risks of fractures in women but
not in men, although further studies are needed.21 The risk of
fractures associated with the use of TZDs in the transplant
setting is currently not known. Nonetheless, TZDs should be
used with caution, particularly in female transplant recipients
who are also receiving corticosteroids.
The incretin mimetics glucagon-like peptide 1 analogues (GLP-1)
and incretin enhancers dipeptidyl peptidase 4 inhibitors (DPP-4)
belong to a novel class of drugs that have been approved for
use in type 2 diabetes. In contrast to insulin and most other
glucose-lowering agents that cause weight gain and hypoglyce-
mia, GLP-1 inhibitors and DPP-4 inhibitors have either a favor-
able or neutral effect on weight reduction and a lower risk of
hypoglycemia. Exenatide is an incretin mimetic that stimulates
insulin biosynthesis and secretion in a glucose-dependent manner
and has been shown to lower both fasting and postprandial
glucose concentrations. When it is added to sulfonylureas,
thiazolidinediones, or metformin, it results in additional lower-
ing of hemoglobin A1c by approximately 0.5% to 1%. It also
promotes weight loss through its effects on satiety and delayed
gastric emptying. Sitagliptin and vildagliptin are DPP-4 inhibi-
tors that act by enhancing the sensitivity of β cells to glucose,
thereby enhancing glucose-dependent insulin secretion; they
have also been shown to improve markers of β-cell function.
Overall, this class of drugs has been shown to have neutral effects
on weight.
Incretin-based therapy is an attractive treatment option for
patients with NODAT because of its favorable effect on weight
reduction/neutrality. Data on its safety and efficacy in renal
transplant recipients are currently lacking. Caution should be
exercised when these agents are used in the transplant setting,
particularly with regard to drug-drug interactions. Vildagliptin
should be avoided in patients with hepatic impairment, and the
dose of sitagliptin should be adjusted for renal insufficiency.
The routine care of patients with post-transplantation diabe-
tes mellitus should include an evaluation of hemoglobin A1c level
every 3 months and regular screening for diabetic complications,
including microalbuminuria, retinopathy, and polyneuropathy
with associated lower extremity ulcerations and infections.
Fasting lipid profile should be measured annually. In transplant
recipients with multiple CV risk factors, more frequent monitor-
ing of lipid profile should be performed at the discretion of the
clinicians. Figure 102.5 summarizes the suggested guidelines for
the management of NODAT. Of note, hemoglobin A1c cannot
be accurately interpreted within the first 3 months after trans-
plantation as anemia and impaired renal function can directly
interfere with the A1c assay. Recent blood transfusions or the use
of dapsone may also alter hemoglobin A1c levels.
Cigarette Smoking
As in the general population, cigarette smoking is associated with
increased CV morbidity and mortality in renal transplant recipi-
ents.22,23 Stopping smoking 5 years before transplantation reduced
the risk of death by 29% (RR, 0.71; P = .0304).23 Every effort
should be made to encourage patients to stop smoking. A
Management of New-Onset Diabetes
Mellitus After Transplantation
Dietary modification
Dietitian referral
For diabetic dyslipidemia: a diet low in saturated fats and
cholesterol and high in complex carbohydrates and
fiber is recommended.
The AHA1 guidelines suggest limiting cholesterol (<200
mg/day for those with diabetes mellitus); ≤ 7% of
calories from saturated fats, 2% to 3% of calories from
trans-fatty acids, and ≤ 2400 mg sodium/day. More
than 25 g/day of dietary fiber and 2 servings of fish a
week are also recommended.
Lifestyle modifications
Exercise
Weight reduction or avoidance of excessive weight gain
Smoking cessation
Adjustment or modification in immunosuppressive
medications2
Rapid steroid taper, steroid-sparing or steroid avoidance
protocols
Tacrolimus to cyclosporine conversion
Pharmacologic therapy
Acute, marked hyperglycemia (may require inpatient
management)
Intensive insulin therapy (consider insulin drip when
glucose ≥400 mg/dl)
Chronic hyperglycemia: treat to target Hb A1c ≥6.5%
Oral glucose-lowering agent monotherapy or
combination therapy3 and/or insulin therapy
Consider diabetologist referral if Hb A1c remains ≥9.0%
Monitoring of patients with NODAT
Hemoglobin A1c every 3 months
Screening for microalbuminuria
Regular ophthalmologic examination
Regular foot care
Annual fasting lipid profile
Aggressive treatment of dyslipidemia and hypertension
Figure 102.5  Management of new-onset diabetes mellitus after
transplantation. 1American Heart Association. 2Clinicians must be famil-
iar with the patient’s immune history before manipulating immunosup-
pressive therapy. 3The choice of a particular agent should be based on
the characteristics of each individual patient (see text). (Modified from
reference 1.)
multifaceted approach including behavioral and pharmacologic
strategies appears to be most effective.
Obesity
Obesity has a reported prevalence of 9.5% to 29% in transplant
recipients. Studies in renal transplant recipients have shown that
high BMI at transplantation is a significant independent predic-
tor of congestive heart failure and atrial fibrillation.24,25 The
impact of BMI on cardiac-related death follows a U-shaped risk.
In a large registry study, the adjusted risk of cardiac death
increased at both low and high BMI compared with a reference
group with a BMI of 22 to 24 (relative risk of 1.3 for BMI <20
and 1.4 for BMI >36).26
1194 SECTION XVII  Transplantation
Management of post-transplantation obesity includes lifestyle
and dietary modifications. Corticosteroid reduction or with-
drawal must be balanced against the risk of graft rejection and
graft loss. The use of pharmacologic agents for weight reduction
in the post-transplantation period is currently not recommended
because of unknown potential drug-drug interactions. There is
a paucity of data on the safety and efficacy of post-transplantation
gastric bypass surgery in ameliorating comorbid conditions such
as hypertension, diabetes mellitus, and dyslipidemia. In a recent
analysis of the U.S. Renal Data System (USRDS) database, mor-
tality rates in patients undergoing gastric bypass after transplan-
tation were higher compared with those without kidney disease
who had undergone the same surgery. Although the difference
in mortality rates was thought to be within “acceptable range”
and attributed to poor healing associated with the use of immu-
nosuppressive therapy, the routine recommendation of post-
transplantation bariatric surgery awaits further studies.27
Unconventional Cardiovascular Disease
Risk Factors
Proteinuria
Proteinuria has been reported in 9% to 40% of kidney transplant
recipients with a functioning graft.1 Controlled trials evaluating
the beneficial effect of treating proteinuria in reducing CV risk
in renal transplant recipients are lacking. Nonetheless, unless it
is contraindicated, ACE inhibitors or ARBs should be considered
in transplant recipients with microalbuminuria or overt protein-
uria because of their well-established renoprotective, antipro-
teinuric, and cardioprotective effects. Whether the development
of proteinuria associated with sirolimus adversely affects CV
risks is currently unknown.
COMMON LABORATORY ABNORMALITIES
Anemia
Mild anemia is common in the early post-transplantation period
when erythropoietin therapy is typically discontinued, but it
generally improves within several weeks to months. Suggested
etiologic factors for post-transplantation anemia include iron
deficiency, folate deficiency, vitamin B12 deficiency, impaired
graft function, acute rejection episodes, recent infection, and
medications (such as azathioprine, MMF, sirolimus, and ACE
inhibitors and ARBs). Anemia has also been reported to be
more common in African American and female transplant
recipients.
Profound iron deficiency should be treated with intravenous
iron as tolerated. Erythropoietin and darbepoetin alfa are effec-
tive in the treatment of anemic renal transplant recipients.
Refractory or severe anemia mandates a search for postoperative
bleeding, particularly in those with a rapid fall in hematocrit.
Other possibilities include tertiary hyperparathyroidism, under-
lying inflammatory conditions, and parvovirus B19 infection.
Erythropoietin-resistant anemia has been described in patients
receiving sirolimus immunosuppression. In stable kidney trans-
plant recipients, conversion from sirolimus to enteric-coated
MMF may help resolve anemia in these patients.28
Leukopenia and Thrombocytopenia
Leukopenia and thrombocytopenia may be the result of myelo-
suppression due to medications including azathioprine, MMF,
antilymphocyte antibody treatment, sirolimus, and trimethoprim-
sulfamethoxazole. Withholding of the offending agent or dose
reduction generally corrects these hematologic abnormalities.
Severe leukopenia may be safely treated with granulocyte-
stimulating factor. Thrombotic microangiopathy or CMV infec-
tion should be excluded. Parvovirus B19 infection may present
with refractory anemia, pancytopenia, and thrombotic microan-
giopathy. More recently, an increase in the incidence of leuko-
penia was found in kidney and pancreas transplant recipients
receiving alemtuzumab induction therapy.
Erythrocytosis
Post-transplantation erythrocytosis (PTE) occurs in 20% to
25% of transplant recipients within the first 2 years. Risk factors
for PTE include the presence of native kidneys, male gender,
excellent graft function and the absence of rejection episodes,
high baseline hemoglobin concentration before transplantation,
smoking, hypertension, and diabetes mellitus. Transplant renal
artery stenosis is a risk factor for PTE in some but not all studies.
Suggested pathogenic mechanisms include defective feedback
regulation of erythropoietin metabolism, direct stimulation of
erythroid precursors by angiotensin II, and abnormalities in cir-
culating insulin-like growth factor 1 levels. Serum erythropoietin
levels are inconsistently elevated.
Treatment is recommended for hemoglobin levels of 17 to
18 g/dl and higher or hematocrit levels of 52% to 55% and
higher because of the associated risk of thromboembolic com-
plications, hypertension, and headaches. Treatment with ACE
inhibitors or ARBs is often sufficient, although phlebotomy may
occasionally be necessary. A negative association between the use
of sirolimus and PTE has been reported.29 Whether sirolimus
might prove to be beneficial in the prevention and treatment of
PTE remains to be studied.
Hyperkalemia
Mild hyperkalemia is common in renal transplant recipients,
particularly in the early post-transplantation period when rela-
tively high doses of calcineurin inhibitor are given. It is often
associated with mild hyperchloremic acidosis, a clinical presenta-
tion reminiscent of type 4 renal tubular acidosis. Suggested
mechanisms of calcineurin inhibitor–induced hyperkalemia
include hyporeninemic hypoaldosteronism, aldosterone resis-
tance, and inhibition of cortical collecting duct potassium secre-
tory channels. Cyclosporine decreases Na+,K+-ATPase activity in
potassium secretory cells in the cortical and outer medullary
collecting tubules, thereby decreasing intracellular potassium
accumulation required for urinary secretion. In patients receiv-
ing cyclosporine or tacrolimus, a serum potassium level in the
range of 5.2 to 5.5 mmol/l is typically seen and generally does
not require treatment. Higher potassium levels, especially in the
presence of concomitant use of drugs that may exacerbate hyper-
kalemia, such as ACE inhibitors, ARBs, and β-blockers, may
require their discontinuation. Caution is needed when potassium-
containing phosphorus supplements are prescribed. Although
trimethoprim can cause hyperkalemia through an amiloride-like
effect, the routine use of low-dose trimethoprim-sulfamethoxazole
for prophylaxis is rarely the cause of severe or refractory
hyperkalemia in renal transplant recipients. Finally, because
efficient renal potassium secretion requires good urine flow,
urinary obstruction must also be considered in the presence of
hyperkalemia.
 CHAPTER 102  Medical Management of the Kidney Transplant Recipient: Cardiovascular Disease and Other Issues 1195
Treatment of hyperkalemia is discussed in Chapter 9. Sodium
polystyrene sulfonate (Kayexalate) or calcium resonium enemas
should be avoided in the immediate post-transplantation period
to avoid colonic dilation and perforation.
Hypokalemia
Sirolimus may be associated with hypokalemia. Hypokalemia has
been reported in 34% and potassium supplementation was
required in 27% of patients treated with sirolimus.30 Sirolimus-
induced increased tubular secretion of potassium has been sug-
gested as a possible mechanism.31
Hypophosphatemia
Hypophosphatemia is frequently encountered in the first months
after transplantation, and when it is associated with hypercalce-
mia, it suggests post-transplantation hyperparathyroidism. In the
absence of hypercalcemia, renal phosphate wasting syndrome or
malnutrition should be considered.
Early after transplantation, hypophosphatemia may also be
due to massive initial diuresis (particularly after living donor
renal transplantation, when there is immediate graft function),
defective renal phosphate reabsorption due to ischemic injury,
glucosuria (due to hyperglycemia-induced osmotic diuresis),
magnesium depletion, and corticosteroid use—the last by inhib-
iting proximal tubular reabsorption of phosphate. More recently,
persistent increases in fibroblast growth factor 23 (FGF-23, a
phosphatonin) in the post-transplantation period have been sug-
gested to contribute to persistent hypophosphatemia.32 FGF-23
enhances phosphate clearance and is elevated in CKD.
Treatment of hypophosphatemia is discussed in Chapter
10.
Hypercalcemia
Hypercalcemia is common after transplantation and is generally
due to persistent secondary hyperparathyroidism. The concomi-
tant presence of severe hypophosphatemia, particularly in
patients with excellent graft function, may exacerbate hyper­
calcemia through stimulation of renal proximal tubular
1α-hydroxylase. Resolution of soft tissue calcifications, high-
dose corticosteroid therapy, and immobilization are potential
contributing factors. In about two thirds of cases, hypercalcemia
resolves spontaneously within 6 to 12 months. However, spon-
taneous resolution occurs in less than half of those whose
hypercalcemia existed before transplantation. Persistent hyper-
parathyroidism has generally been attributed to continued
autonomous production of parathyroid hormone from nodular
hyperplastic glands, reduced density of calcitriol receptors, and
decreased expression of the membrane calcium sensor receptors
that render cells more resistant to physiologic concentrations of
calcitriol and calcium. The risk for development of persistent
hyperparathyroidism is increased with the duration of dialysis
and the severity of pretransplantation hyperparathyroidism.
Severe hypercalcemia (>11.5 mg/dl [2.9 mmol/l]) or persistent
hypercalcemia (≥12 months) requires further evaluation. Initial
assessment should include an intact parathyroid hormone level.
Imaging studies, including neck ultrasound or parathyroid tech-
netium Tc 99m sestamibi scan, are required to determine if the
clinically observed hyperparathyroidism arises from parathyroid
adenoma, parathyroid gland hyperplasia, or hyperplastic nodular
formation of the parathyroid glands.
Cinacalcet has been shown to reduce serum calcium in renal
transplant recipients with hypercalcemic hyperparathyroidism.
Parathyroidectomy is warranted in patients with tertiary hyper-
parathyroidism or persistent severe hypercalcemia for more than
6 to 12 months, symptomatic or progressive hypercalcemia,
nephrolithiasis, persistent metabolic bone disease, calcium-
related renal allograft dysfunction, or progressive vascular calci-
fication and calciphylaxis.33 Whether the advent of calcimimetics
will reduce the need for parathyroidectomy remains to be studied.
Hypomagnesemia
Cyclosporine, tacrolimus, and sirolimus cause hypomagnesemia
by inducing urinary magnesium wasting. Other factors that may
contribute to post-transplantation hypomagnesemia include
recovery from acute tubular necrosis, postobstructive polyuria,
loop diuretic therapy, and renal tubular acidosis. Hypomagnese-
mia may be more common in diabetics. Serum magnesium con-
centration below 1.5 mg/dl (0.62 mmol/l) is common. Dietary
magnesium intake is usually insufficient, and high-dose oral
magnesium supplementation (e.g., 400 to 800 mg magnesium
oxide three times a day) may be required. The intravenous
administration of magnesium should be considered with severe
hypomagnesemia (<1.0 mg/dl [0.41 mmol/l]), particularly in
patients with coronary artery disease, in those with cardiac
arrhythmias, and in those taking digitalis. Aggressive treatment
of hypomagnesemia reduces cyclosporine-induced neurotoxicity
and aids blood pressure control.
Abnormal Liver Function Test Results
Elevation of hepatic enzymes is common in the early
post-transplantation period and is generally due to drug-related
toxicity. Potential culprits include acyclovir, ganciclovir,
trimethoprim-sulfamethoxazole, cyclosporine, tacrolimus,
statins, and proton pump inhibitors. Cyclosporine and, less
commonly, tacrolimus may cause transient, self-limited,
dose-dependent elevations of transaminases and mild hyperbili-
rubinemia secondary to defective bile secretion. Elevated liver
enzymes due to drug-related adverse effect usually improve or
resolve after drug discontinuation or dose reduction.
Persistent or profound elevation in hepatic liver enzymes
should prompt further evaluation to exclude infectious causes,
including CMV, hepatitis B virus (HBV), and hepatitis C virus
(HCV). In high-risk candidates for primary CMV infections
(recipient seronegative, donor seropositive), it may occasionally
be necessary to initiate CMV therapy pending laboratory results,
particularly when there is a high index of clinical suspicion (fever,
fatigue, malaise, gastroenteritis, leukopenia, or thrombocytope-
nia). Evidence of post-transplantation HBV reactivation (ele-
vated alanine transaminase, histologic hepatitis, and serum DNA
>105 copies/ml) should be treated with lamivudine. Some centers
routinely initiate lamivudine prophylaxis in all HBsAg-positive
candidates at the time of transplantation. Pretransplantation
lamivudine prophylactic therapy is recommended in renal trans-
plant candidates who have HBV DNA above 105 copies/ml
and active liver disease, defined as an alanine transaminase
value more than two times the upper limit of normal or biopsy-
proven hepatic disease. Newer nucleoside analogs including
entecavir and tenofovir have been recently recognized to provide
improved viral suppression with lower emergence of resistance
and toxicity and have become preferred first-line treatment
options for patients with chronic hepatitis B. However, renal
1196 SECTION XVII  Transplantation

Algorithm for the Management of Elevated Hepatic Enzymes in Renal Transplant Recipients

Elevated hepatic enzymes

Drug related?
Common culprits: acyclovir, ganciclovir, valganciclovir,
trimethoprim-sulfamethoxazole, statins, proton pump
inhibitors, isoniazid, cyclosporine, or tacrolimus1

Dose reduction or discontinuation

Yes No
Improvement?

Periodic laboratory reassessment at the Other causes

discretion of the clinicians

Infectious Noninfectious4

CMV: obtain CMV DNA; in
high-risk candidates for
primary infections or in case
of high clinical suspicion,
consider therapy initiation
before obtaining results
(see text)
HBV: obtain PCR DNA; if +
reactivation, initiate
lamivudine therapy2,
consider hepatology
referral
HCV: obtain PCR RNA; if +
reactivation, consider
reduction or manipulation
of immunosuppresion3,
consider hepatology
referral
Nonalcoholic fatty liver
disease (obesity,
dyslipdemia, diabetes
mellitus), alcoholic
hepatitis, etc.

Figure 102.6  Algorithm for the management of elevated hepatic enzymes in renal transplant recipients. 1Cyclosporine and less commonly
tacrolimus may cause transient, self-limited, dose-dependent elevations of aminotransferase levels and mild hyperbilirubinemia secondary to defective
bile secretion. 2Some programs routinely commence lamivudine prophylactic therapy in all HBsAg-positive candidates at the time of transplantation.
3
There is currently no effective treatment of chronic hepatitis C in renal transplant recipients (see text). 4Appropriate evaluation and management similar
to nontransplant settings. CMV, cytomegalovirus; HBV, hepatitis B virus; HCV, hepatitis C virus; PCR, polymerase chain reaction.

dose adjustments and close monitoring of renal function with the
use of tenofovir are advised due to its nephrotoxic potential.
There is currently no effective treatment of chronic hepatitis
C in renal transplant recipients. Although treatment with inter-
feron alfa may result in clearance of HCV RNA in 25% to 50%
of cases, rapid relapse after drug withdrawal is nearly universal.
More important, interferon alfa treatment has been shown to
precipitate acute graft rejection and graft loss and is currently
not recommended for renal transplant recipients with HCV
infection. Management of HCV infection in this population of
patients should probably rely on manipulation of immunosup-
pressive therapy. Experiences gained from liver transplantation
indicate that corticosteroid therapy and antilymphocyte antibody
treatment are associated with enhanced viral replication and
more rapid progression to cirrhosis. On the basis of these obser-
vations, it is advisable to avoid antilymphocyte antibody induc-
tion therapy and to minimize corticosteroid dosage in transplant
recipients with chronic HCV infection. Although early reports
suggested that MMF may reduce HCV replication and delay
recurrence in hepatitis C–positive liver transplant recipients, the
antiviral properties of MMF and its impact on HCV replication
and hepatitis C recurrence have not been consistently demon-
strated in subsequent studies.
In vitro studies show that cyclosporine and mycophenolic acid
(the active metabolite of MMF) are an effective combination for
inhibition of HCV replication in the presence of interferon. In
contrast, tacrolimus and methylprednisolone reduce rather than
enhance the efficacy of interferon.34 HCV-associated chronic
hepatitis occurs in a significantly smaller number of patients
treated with cyclosporine rather than tacrolimus. These studies
suggest that cyclosporine may be superior to tacrolimus as an
immunosuppressive agent in HCV-infected renal transplant
recipients. An algorithm for the management of renal transplant
recipients with elevated hepatic enzymes is shown in Figure
102.6.
BONE AND MINERAL METABOLISM
AFTER TRANSPLANTATION
Post-transplantation Bone Disease
Post-transplantation bone disease is a common complication
after kidney transplantation due to persistent renal osteodys­
trophy, the adverse effects of immunosuppression (mainly
corticosteroids), persistent hyperparathyroidism, abnormalities
in vitamin D metabolism, and reduced GFR. Corticosteroids
 CHAPTER 102  Medical Management of the Kidney Transplant Recipient: Cardiovascular Disease and Other Issues 1197
directly inhibit osteoblastogenesis and induce apoptosis of osteo-
blasts and osteocytes. Corticosteroids also inhibit intestinal
calcium absorption, enhance renal calcium excretion, and directly
suppress gonadal hormone secretion. Low 25-hydroxyvitamin D
levels after renal transplantation may also contribute to bone
disease.
Other factors that have been suggested to contribute to post-
transplantation bone loss include “normal” age-dependent
osteoporosis, persistent metabolic acidosis, phosphate depletion,
diabetes mellitus, hypogonadism, and smoking. Animal models
suggest that cyclosporine and tacrolimus may also contribute to
post-transplantation bone loss by stimulating bone resorption.
The effects of calcineurin inhibitors in humans remains specula-
tive, although increasing alkaline phosphatase and osteocalcin
and increased osteoblastic and osteoclastic activities have
been reported with cyclosporine treatment compared with
azathioprine.
Osteoporosis
Post-transplantation decline in bone mineral density (BMD) is
most pronounced in the first 6 months and correlates with higher
corticosteroid exposure in the early post-transplantation period.
The rate of bone loss varies from 3% to 10% and is most appar-
ent at sites of cancellous bone, particularly the lumbar spine and
axial skeleton. This early rapid decrease in BMD is usually fol-
lowed by a slower rate of bone loss and reflects cumulative
corticosteroid dose. Nonetheless, controversies exist as to
whether bone loss continues to decline, stabilizes, or even
reverses after the first year. A decrease in BMD averaging 1.7%
per year in later post-transplantation years has been reported,
whereas stabilization during the second year followed by an
improvement of 1% to 2% per year thereafter was observed by
others. Nevertheless, osteopenia and osteoporosis prevalence
ranges from 31% to 41% 20 years after renal transplantation.
Evaluation of patients for bone loss or osteoporosis relies on
the measurement of BMD by dual-energy x-ray absorptiometry
(DEXA) scan. However, in the setting of combined osteoporosis
and CKD, DEXA may be completely misleading. For instance,
adynamic bone disease, mild hyperparathyroidism, and genuine
osteoporosis may yield the same BMD, yet therapy is very dif-
ferent. Hence, BMD can only be interpreted in the clinical and
laboratory setting, and bone biopsy should be performed if
uncertainty arises.
Avascular Necrosis
Post-transplantation osteonecrosis (avascular necrosis) occurs
with an incidence of 3% to 16% and most commonly affects the
femoral head and neck. It usually occurs within the first few years
after transplantation and may affect other joints, including the
knees, shoulders, and, less commonly, ankles, elbows, and wrists.
Early avascular necrosis of the femoral head commonly presents
with hip or groin pain or referred knee pain. Symptoms may be
aggravated by weight bearing but may also be paradoxically
worse at night. Use of crutches to avoid weight bearing on the
affected side is advisable. Core decompression, with or without
bone grafting before the femoral head collapse, may relieve pain,
but approximately 60% of cases require total arthroplasty. Oste-
otomy has also been used as a joint-sparing technique to treat
osteonecrosis. Core decompression and osteotomy may have
similar efficacy in early disease, but intertrochanteric osteotomy
may be preferred for patients who have progressed to collapse
of the femoral head by the time of diagnosis. Drastic corticoste-
roid dose reduction or discontinuation has little if any effect on
altering the course of established avascular necrosis and may
jeopardize graft function. Magnetic resonance imaging is the
most sensitive technique for early detection; plain radiographs
are of limited diagnostic value in the early stage. Predisposing
factors for the development of avascular necrosis include greater
exposure to intravenous corticosteroid pulse therapy, low bone
mass, hyperparathyroidism, increasing dialysis duration, exces-
sive weight gain, hyperlipidemia, microvascular thrombosis, and
history of local trauma. Studies in renal transplant recipients
maintained on a corticosteroid-free immunosuppressive regimen
demonstrated low rates of avascular necrosis at 3-year follow-up.35
Prevention and Management of Post-transplantation
Bone Disease
Management of post-transplantation bone disease has largely
been based on studies involving postmenopausal osteoporosis
and corticosteroid-induced osteopenia in nontransplant settings.
Adequate calcium and vitamin D supplementation is generally
recommended after transplantation to prevent rapid bone loss in
the first post-transplantation year. Serum 25-hydroxyvitamin D
levels should be obtained and levels kept above 30 ng/ml. In
patients at increased risk for fracture, consideration should be
given to rapid corticosteroid withdrawal or corticosteroid-free
immunosuppressive protocols after the risks and benefits of acute
rejection are weighed.
Bisphosphonates increase BMD in postmenopausal women
and patients with corticosteroid-induced osteoporosis, particu-
larly at the lumbar spine and trochanter. Although most studies
to date suggest that bisphosphonates have a greater effect on
increasing BMD than vitamin D analogues do, their efficacy in
terms of fracture reduction compared with vitamin D analogues
remains to be determined. In addition, because of the potential
for bisphosphonates to oversuppress bone metabolism, their use
in kidney transplant recipients with known adynamic bone
disease remains unclear. Nonetheless, bisphosphonate therapy
may be justifiable in potential high-risk candidates, including
those with preexisting fractures or severe osteoporosis, patients
with diabetes mellitus, postmenopausal women, and recipients of
simultaneous pancreas-kidney transplants. The Kidney Disease:
Improving Global Outcomes (KDIGO) guidelines suggest that
consideration be given to bone biopsy before bisphosphonate
therapy.
Other treatments are problematic. Calcitonin is considered
relatively ineffective. Many older women and women with CKD
also have deficiency in estrogen, and limited studies have shown
that estrogen replacement therapy improves BMD in postmeno-
pausal liver, lung, and bone marrow transplant recipients. None-
theless, the CV risk associated with estrogen use may outweigh
its benefits, and estrogen should be used with caution. Testos-
terone deficiency has also been implicated in the development
of bone loss and fractures after transplantation. However,
because testosterone may cause dyslipidemia, hepatic enzyme
abnormalities, erythrocytosis, and prostatic hypertrophy, testos-
terone should probably be given only to men with true
hypogonadism.
Gout
Hyperuricemia and gout are common among renal transplant
recipients receiving cyclosporine-based immunosuppression,
with a reported prevalence of 30% to 84% and 2% to 28%,
respectively. Cyclosporine impairs renal excretion of uric acid
secondary to decreases in GFR and increases net uric acid
1198 SECTION XVII  Transplantation
reabsorption by the proximal tubule. Potential contributing risk
factors for the development of post-transplantation hyperurice-
mia and gouty arthritis include pretransplantation hyperurice-
mia, impaired graft function, obesity, and diuretic use.
Management of the acute gouty attack includes topical ice and
rest of the inflamed joint. Pharmacologic treatments include
colchicine, increased corticosteroid dose, and nonsteroidal anti-
inflammatory agents (NSAIDs). The use of NSAIDs, however,
should be avoided in patients with impaired graft function. Other
treatment options have included intra-articular corticosteroids
and parenteral adrenocorticotropic hormone (ACTH); ACTH
is reserved for patients with multiple medical problems, such as
impaired graft function, gastrointestinal bleeding, or gouty
arthritis refractory to conventional therapy.
Management of chronic gout is directed at lowering of uric
acid levels. Allopurinol should be started at a low dose (100 to
200 mg/day), particularly in the presence of impaired allograft
function, because renal insufficiency predisposes to severe allo-
purinol toxicity due to retention of the metabolite oxypurinol.
Allopurinol and azathioprine combination therapy should be
avoided because of inhibition of azathioprine metabolism by
allopurinol. In allopurinol-allergic patients, the new xanthine
oxidase inhibitor febuxostat can be used. It is administered as 40
or 80 mg daily, and the dosing is not modified in renal failure.
Long-term prophylaxis may include reduction or discontinu-
ation of diuretics, chronic low-dose allopurinol therapy, dietary
modification, and consideration of alternative immunosuppres-
sive therapy. Cyclosporine to tacrolimus switch has been reported
to result in resolution of severe polyarticular gout refractory to
conventional therapy. Small doses of colchicine at 0.6 mg daily
may also prevent recurrent gouty attacks. However, colchicine
should be used with caution, particularly in patients on statin
therapy, due to the increased risk of myopathy. NSAIDS should
be avoided in patients with impaired graft function.
OUTPATIENT CARE
We recommend that patients be seen two or three times a week
for the first 2 weeks after transplantation, twice a week for the
next 2 weeks, and weekly for the next month. After the first 2
months, the frequency of outpatient visits depends on the com-
plexity of the patient’s early postoperative course. Patients with
stable graft function and an uneventful postoperative course can
return to work or their regular daily activities 2 to 3 months after
transplantation. Laboratory assessment during the first month
after transplantation should include serum creatinine concentra-
tion and electrolyte values, fasting glucose level, liver enzymes,
calcium and phosphorus levels, immunosuppressive drug levels,
and complete blood count with platelets. Urine dipstick (and, if
clinically indicated, urine culture and urine protein/creatinine
ratio to monitor for disease recurrence, such as focal segmental
glomerulosclerosis) should also be performed. After the first
post-transplantation month, pertinent laboratory evaluation
should be performed at the discretion of the clinician. After the
first post-transplantation year, annual follow-up at a transplanta-
tion center is generally recommended.
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